Mitochondrial DNA mosaicism in normal human somatic cells.

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.

Effect of Bromfenac on Reducing Neuroinflammation in an Ischemia-Reperfusion Glaucoma Model.

In the context of glaucoma, intraocular pressure (IOP) and age are recognized as the primary factors contributing to its onset and progression. However, significant reductions in IOP fail to completely halt its advancement. An emerging body of literature highlights the role of neuroinflammation in glaucoma. This study aimed to explore Bromfenac's anti-inflammatory properties in mitigating neuroinflammation associated with glaucoma using an ischemia-reperfusion (IR) glaucoma model. Bromfenac's impact on microglia and astrocytes under pressure was assessed via Western blotting and an enzyme-linked immunosorbent assay. Immunohistochemical staining was used to evaluate glial activation and changes in inflammatory marker expression in the IR model. Bromfenac led to the downregulation of inflammatory markers, which were elevated in the conditions of elevated pressure, and necroptosis markers were downregulated in astrocytes. In the IR model, elevated levels of GFAP and Iba-1 indicated glial activation. Following Bromfenac administration, levels of iNOS, COX-2, and PGE2-R were reduced, suggesting a decrease in neuroinflammation. Furthermore, Bromfenac administration in the IR model resulted in the improved survival of retinal ganglion cells (RGCs) and preservation of retinal function, as demonstrated by immunohistochemical staining and electroretinography. In summary, Bromfenac proved effective in diminishing neuroinflammation and resulted in enhanced RGC survival.

Exploring Neuroprotective Effects of Topical Brimonidine in Experimental Diabetic Retinopathy.

BACKGROUND/AIM: Diabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a selective adrenoceptor agonist, on diabetic retinal neurodegeneration, recognizing the critical role of neurodegeneration in diabetic retinopathy. MATERIALS AND METHODS: Streptozotocin-induced diabetes was established in adult male Sprague-Dawley rats to mimic diabetic retinopathy. Rats, except non-diabetic control rats, received topical applications of 0.15% brimonidine tartrate (treatment group) or balanced salt solution (diabetic control group) twice daily following diabetes induction. Each group comprised six randomly assigned animals. Retinal samples were analyzed using immunofluorescence staining, apoptosis assay, and western blot. RESULTS: Topical brimonidine treatment reduced apoptosis of retinal ganglion cells at 8 weeks after induction of diabetes (p<0.05). Glial activation induced by diabetes was reduced by brimonidine treatment. Immunoblot and immunofluorescence assay revealed that the decrease in phospho- protein kinase B (AKT) level resulting from diabetes was also attenuated by brimonidine (p<0.05). Furthermore, brimonidine alleviated the decrease in anti-apoptotic proteins [BCL2 apoptosis regulator (BCL2) and BCL-xl] induced by diabetes (p<0.05). Elevation of phospho-p38 mitogen-activated protein kinase (p38MAPK) and p53 in diabetic rats were reduced by brimonidine (p<0.05). Additionally, brimonidine treatment attenuated the upregulation of the pro-apoptotic molecule BCL-2 associated X in retinas of diabetic rats (p<0.05). CONCLUSION: These findings suggest that topical brimonidine treatment may protect retinal ganglion cells in experimental diabetes by modulating the AKT pathway and reducing pro-apoptotic p38MAPK levels. This presents a potential neuroprotective approach in diabetes, offering the advantage of localized treatment without the added burden of oral medication.

Motion-Accommodating Dual-Layer Hydrogel Dressing to Deliver Adipose-Derived Stem Cells to Wounds.

BACKGROUND: Current dressing materials cannot secure a cell survival-promoting wound environment for stem cell delivery due to insufficient assimilation to skin motion. The authors developed a novel motion-accommodating dual-layer hydrogel dressing for stem cell delivery into such wounds. METHODS: Dorsal hand skin movement was evaluated to determine the potential range of deformation for a dressing. The outer hydrogel (OH) was fabricated with an alginate-acrylamide double-network hydrogel with a covalently cross-linked elastomer coat. The tough adhesive consisted of a chitosan-based bridging polymer and coupling reagents. OH material properties and adhesiveness on porcine skin were measured. An oxidized alginate-based inner hydrogel (IH) containing human adipose-derived stem cells (ASCs) was evaluated for cell-supporting and cell-releasing properties. The OH's function as a secondary dressing, and dual-layer hydrogel cell delivery potential in wounds were assessed in a rodent model. RESULTS: The dual-layer hydrogel consisted of OH and IH. The OH target range of deformation was up to 25% strain. The OH adhered to porcine skin, and showed significantly higher adhesion energy than common secondary dressings and endured 900 flexion-extension cycles without detachment. OH showed a similar moisture vapor transmission rate as moisture-retentive dressings. IH maintained embedded cell survival for three days with significant cell release on the contacting surface. OH showed less fibrotic wound healing than other secondary dressings in vivo. The dual-layer hydrogel successfully delivered ASCs into open wounds of nude mice (13 ± 3 cells/HPF). CONCLUSIONS: The novel dual-layer hydrogel can accommodate patient movement and deliver ASCs into the wound bed by securing the wound microenvironment.

A Modified eCura System to Stratify the Risk of Lymph Node Metastasis in Undifferentiated-Type Early Gastric Cancer After Endoscopic Resection.

PURPOSE: The original eCura system was designed to stratify the risk of lymph node metastasis (LNM) after endoscopic resection (ER) in patients with early gastric cancer (EGC). We assessed the effectiveness of a modified eCura system for reflecting the characteristics of undifferentiated-type (UD)-EGC. MATERIALS AND METHODS: Six hundred thirty-four patients who underwent non-curative ER for UD-EGC and received either additional surgery (radical surgery group; n=270) or no further treatment (no additional treatment group; n=364) from 18 institutions between 2005 and 2015 were retrospectively included in this study. The eCuraU system assigned 1 point each for tumors >20 mm in size, ulceration, positive vertical margin, and submucosal invasion <500 µm; 2 points for submucosal invasion ≥500 µm; and 3 points for lymphovascular invasion. RESULTS: LNM rates in the radical surgery group were 1.1%, 5.4%, and 13.3% for the low- (0-1 point), intermediate- (2-3 points), and high-risk (4-8 points), respectively (P-for-trend<0.001). The eCuraU system showed a significantly higher probability of identifying patients with LNM as high-risk than the eCura system (66.7% vs. 22.2%; McNemar P<0.001). In the no additional treatment group, overall survival (93.4%, 87.2%, and 67.6% at 5 years) and cancer-specific survival (99.6%, 98.9%, and 92.9% at 5 years) differed significantly among the low-, intermediate-, and high-risk categories, respectively (both P<0.001). In the high-risk category, surgery outperformed no treatment in terms of overall mortality (hazard ratio, 3.26; P=0.015). CONCLUSIONS: The eCuraU system stratified the risk of LNM in patients with UD-EGC after ER. It is strongly recommended that high-risk patients undergo additional surgery.

Expression of Immunoglobulin G4 in Eosinophilic Esophagitis.

Background: Eosinophilic esophagitis (EoE) is a disease that has been subcategorized into two endoscopic phenotypes: inflammatory and fibrostenotic. Moreover, studies have shown a link between EoE and immunoglobulin G4 (IgG4), a subclass of the immunoglobulin G (IgG) antibody. In this study, we aimed to evaluate the relationship between histologic IgG4 expression and endoscopic phenotypes in patients with EoE. Methods: This case-control study included patients diagnosed with EoE (n = 19) and patients with non-obstructive dysphagia without abnormal findings as controls (NOD; n = 12). The EoE group was further divided into three subgroups based on endoscopic phenotype: inflammatory, fibrostenotic, or combined. Retrospective examination of endoscopic findings and pathological slides was performed to analyze IgG4 staining. Results: Histological analysis revealed a significant difference in IgG4 cell count (15.00 vs. 0.58, p = 0.003) and eosinophil cell count (84.67 vs. 0.08, p < 0.001) between the EoE and NOD groups. Symptom manifestation and blood test results were similar across all three endoscopic EoE phenotypes. However, histological analysis revealed a significant difference in IgG4 cell count between the inflammatory, fibrostenotic, and combined phenotypes (4.13 vs. 17.6 vs. 59.7, p = 0.030). Conclusions: IgG4 expression was higher in EoE patients than in those with NOD, the highest being in the combined phenotype subgroup. These findings emphasize the important role of endoscopic and histological examination in diagnosing EoE and the need for further research in this area.

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).

Wnt/ß-catenin pathway is a key signaling pathway to trastuzumab resistance in gastric cancer cells.

BACKGROUND: Trastuzumab is the only approved target agent for the first-line treatment of human epidermal growth factor receptor-2 (HER-2) positive gastric cancer; however, trastuzumab resistance is a major problem in clinical practice. To comprehend the mechanism of trastuzumab resistance, we focused on the Wnt/ß-catenin signaling pathway and its influence on the phenotypes and behavior of trastuzumab-resistant gastric cancer cells. METHODS: Trastuzumab-resistant NCI-N87R cells were established in vitro from the human gastric cancer cell line NCI-N87 by dose-escalating repeated trastuzumab treatment. We investigated the phenotypes of NCI-N87R cells, including Wnt signaling pathway activity. Gastric cancer organoid cells were incubated with complete medium and Wnt3a-depletion medium, and their resistance to trastuzumab was compared. RESULTS: NCI-N87R exhibited stemness and epithelial-mesenchymal transition (EMT)-like phenotypes, along with decreased levels of the epithelial marker E-cadherin and increased levels of the mesenchymal markers Vimentin and Snail along with an increased Wnt signaling pathway activity. When gastric cancer cells were incubated in Wnt3a-conditioned medium. Wnt signaling pathway activity and resistance to trastuzumab increased. Gastric cancer patient-derived organoids incubated in Wnt3a-depletion medium were more susceptible to dose-dependent inhibition of cell viability by trastuzumab than those incubated in complete medium. CONCLUSIONS: Trastuzumab-resistant gastric cancer cells exhibited EMT-like phenotype, and trastuzumab resistance was promoted by the Wnt/ß-catenin signaling pathway. The Wnt/ß-catenin pathway is a key signaling pathway for trastuzumab resistance in gastric cancer cells.

Risk of all-cause and cause-specific mortality associated with immune-mediated inflammatory diseases in Korea.

Objective: Immune-mediated inflammatory disease (IMID) is associated with an increased risk of mortality. It is unclear whether the higher mortality is attributable to the IMIDs themselves or to the higher prevalence of comorbidities in IMIDs. We aimed to investigate whether IMIDs per se confer a higher risk of mortality. Methods: From the Korean National Health Insurance Service-National Sample Cohort database, this population-based cohort study included 25,736 patients newly diagnosed with IMIDs between January 2007 and December 2017, and 128,680 individuals without IMIDs who were matched for age, sex, income, hypertension, type 2 diabetes, dyslipidemia, and the Charlson comorbidity index. All individuals were retrospectively observed through December 31, 2019. The outcomes included all-cause and cause-specific mortalities. Adjustments for age, sex, and comorbidities were performed using multivariable Cox proportional hazard regression analyses, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the outcomes were estimated. Results: The adjusted risk of all-cause mortality was significantly lower in patients with IMIDs than that in those without (aHR, 0.890; 95% CI, 0.841-0.942). Regarding cause-specific mortality, cancer-specific (aHR, 0.788; 95% CI, 0.712-0.872) and cardiovascular disease-specific (aHR, 0.798; 95% CI, 0.701-0.908) mortalities were the two causes of death that showed significantly lower risks in patients with IMIDs. A similar trend was observed when organ based IMIDs were analyzed separately (i.e., gut, joint, and skin IMIDs). Conclusion: After adjusting for comorbidities, IMIDs were associated with a lower risk of all-cause mortality compared to those without IMIDs. This was attributable to the lower risks of cancer-and cardiovascular disease-specific mortalities.

Association of immune-mediated inflammatory diseases with depression and anxiety in patients with type 2 diabetes: A nationwide population-based study.

Objective: Patients with type 2 diabetes (T2DM) are at a high risk of developing depression and anxiety. To better stratify the risk, we aimed to assess whether the presence of immune-mediated inflammatory diseases (IMIDs) confers a higher risk of depression and anxiety in these patients. Methods: Patients with T2DM without prior depression or anxiety who underwent national health examination between 2009 and 2012 (n = 1,612,705) were enrolled from the nationwide health check-up data from Korean National Health Insurance Service. The outcome events were incident depression and anxiety, defined as International Classification of Diseases, 10th Revision codes F32-F33 and F40-F41, respectively. Multivariable Cox proportional hazard regression analyses were conducted to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) according to the existence of IMIDs. Results: Over an average follow-up time of 6.4 years, existence of gut IMIDs was associated with a higher risk of depression (aHR: 1.28 [95% CI: 1.08-1.53]) and anxiety (1.22 [1.06-1.42]). Existence of joint IMIDs was associated with a higher risk of depression (1.34 [1.31-1.37]) and anxiety (1.31 [1.29-1.34]). Existence of skin IMID was associated with a higher risk of depression (1.18 [1.14-1.23]) and anxiety (1.13 [1.09-1.16]). The effect sizes of IMIDs on depression and anxiety were larger in those with ≥ 2 IMIDs (1.42 [1.19-1.69] and 1.49 [1.29-1.72], respectively) than in those with one IMID (1.30 [1.27-1.32] and 1.26 [1.24-1.28], respectively). Conclusion: In patients with T2DM, presence of IMIDs was associated with a higher risk of depression and anxiety. More stringent attention and screening for anxiety and depression should be encouraged in patients with T2DM and comorbid IMIDs due to clinical implications of psychological distress on patient-reported outcomes and prognosis.

External Validation of the eCura System for Undifferentiated-Type Early Gastric Cancer with Noncurative Endoscopic Resection.

Background/Aims: The eCura system, a scoring model for stratifying the lymph node metastasis risk after noncurative endoscopic resection for early gastric cancer (EGC), has been internally validated, primarily for differentiated-type EGC. We aimed to externally validate this model for undifferentiated-type EGC. Methods: This multicenter, retrospective cohort study included 634 patients who underwent additional surgery (radical surgery group, n=270) or were followed up without additional treatment (no additional treatment group, n=364) after noncurative endoscopic resection for undifferentiated-type EGC between 2005 and 2015. The lymph node metastasis and survival rates were compared according to the risk categories. Results: For the radical surgery group, the lymph node metastasis rates were 2.6%, 10.9%, and 14.8% for the low-, intermediate-, and high-risk eCura categories, respectively (p for trend=0.003). For the low-, intermediate-, and high-risk categories in the no additional treatment group, the overall survival (92.7%, 68.9%, and 80.0% at 5 years, respectively, p<0.001) and cancer-specific survival rates (99.7%, 94.7%, and 80.0% at 5 years, respectively, p<0.001) differed significantly. In the multivariate analysis, the hazard ratios (95% confidence interval) in the no additional treatment group relative to the radical surgery group were 3.18 (1.41 to 7.17; p=0.005) for overall mortality and 2.60 (0.46 to 14.66; p=0.280) for cancer-specific mortality in the intermediate-to-high risk category. No such differences were noted in the low-risk category. Conclusions: The eCura system can be applied to undifferentiated-type EGC. Close follow-up without additional treatment might be considered for low-risk patients, while additional surgery is recommended for intermediate- and high-risk patients.

Angiotensin II-Related Activation of Scleral Fibroblasts and Their Role on Retinal Ganglion Cell Death in Glaucoma.

We identify the angiotensin II (AngII)-associated changes in the extracellular matrix (ECM) and the biomechanical properties of the sclera after systemic hypotension. Systemic hypotension was induced by administering oral hydrochlorothiazide. AngII receptor levels and ECM components in the sclera and biomechanical properties were evaluated based on the stress-strain relationship after systemic hypotension. The effect of inhibiting the AngII receptor with losartan was determined in the systemic hypotensive animal model and the cultured scleral fibroblasts from this model. The effect of losartan on retinal ganglion cell (RGC) death was evaluated in the retina. Both AngII receptor type I (AT-1R) and type II (AT-2R) increased in the sclera after systemic hypotension. Proteins related to the activation of fibroblasts (transforming growth factor [TGF]-ß1 and TGF-ß2) indicated that transformation to myofibroblasts (α smooth muscle actin [SMA]), and the major ECM protein (collagen type I) increased in the sclera after systemic hypotension. These changes were associated with stiffening of the sclera in the biomechanical analysis. Administering losartan in the sub-Tenon tissue significantly decreased the expression of AT-1R, αSMA, TGF-ß, and collagen type I in the cultured scleral fibroblasts and the sclera of systemic hypotensive rats. The sclera became less stiff after the losartan treatment. A significant increase in the number of RGCs and decrease in glial cell activation was found in the retina after the losartan treatment. These findings suggest that AngII plays a role in scleral fibrosis after systemic hypotension and that inhibiting AngII could modulate the tissue properties of the sclera, resulting in the protection of RGCs.

Risk of Metabolic Syndrome and Fatty Liver Diseases in Gastric Cancer Survivors: A Propensity Score-Matched Analysis.

Background/Aims: To investigate the risk of metabolic syndrome and fatty liver diseases in gastric cancer survivors compared to non-cancer subjects. Methods: The data from the health screening registry of the Gangnam Severance Hospital from 2014-2019 was used. Ninety-one gastric cancer survivors and a propensity-score-matching 445 non-cancer subjects were analyzed. Gastric cancer survivors were divided into those with surgical treatment (OpGC, n=66) and non-surgical treatment (non-OpGC, n=25). Metabolic syndrome, fatty liver by ultrasonography, and metabolic dysfunction-associated fatty liver disease (MAFLD) were assessed. Results: Metabolic syndrome was in 15.4% of gastric cancer survivors (OpGC; 13.6%, non-OpGC; 20.0%). Fatty liver by ultrasonography was in 35.2% in gastric cancer survivors (OpGC; 30.3%, non-OpGC: 48.0%). MAFLD was in 27.5% of gastric cancer survivor (OpGC; 21.2%, non-OpGC; 44.0%). After adjusting for age, sex, smoking, and alcohol, the risk of metabolic syndrome was lower in OpGC than in non-cancer subjects (OR, 0.372; 95% CI, 0.176-0.786, p=0.010). After adjusting, OpGC showed lower risks of fatty liver by ultrasonography (OR, 0.545; 95% CI, 0.306-0.970, p=0.039) and MAFLD (OR, 0.375; 95% CI, 0.197-0.711, p=0.003) than did non-cancer subjects. There were no significant differences in the risks of metabolic syndrome and fatty liver diseases between non-OpGC and non-cancer subjects. Conclusions: OpGC showed lower risks of metabolic syndrome, fatty liver by ultrasonography, and MAFLD than non-cancer subjects, but there were no significant differences in the risks between non-OpGC and non-cancer subjects. Further studies on metabolic syndrome and fatty liver diseases in gastric cancer survivors are warranted.

Nomogram for pre-procedural prediction of non-curative endoscopic resection in patients with early gastric cancer.

BACKGROUND: Non-curative resection (non-CR) after endoscopic submucosal dissection (ESD) requires additional surgery due to the possibility of lymph node metastasis (LNM). Therefore, it is important to accurately predict the risk of non-CR to avoid unnecessary preoperative procedures. Thus, we aimed to develop and verify a nomogram to predict the risk of non-CR prior to ESD. METHODS: Patients who underwent ESD for early gastric cancer (EGC) were divided into CR and non-CR groups based on the present ESD criteria. The pre-procedural factors, such as endoscopic features, radiologic findings, and pathology of the lesion, were compared between the groups to identify the risk factors associated with non-CR. A nomogram was developed using multivariate analysis, and its predictive value was assessed using an external validation group. RESULTS: Among 824 patients, 682 were curative (82.7%) and 142 were non-curative (17.3%). By comparing two groups, endoscopic features including redness, whitish mucosal change, fold convergence, and large lesion size; histologic features such as moderately or poorly differentiated or signet ring cell carcinoma; and abnormal CT findings including non-specific lymph node enlargement and fold thickening were identified as significant predictors of non-CR. The nomogram was developed based on these predictors and showed good predictive performance in the external validation, with an area under the curve of 0.87. CONCLUSIONS: We developed a nomogram to predict the risk of non-CR prior to ESD. These predictive factors in addition to the existing ESD criteria can help provide the best treatment option for patients with EGC.

Relieving Anxiety Through Virtual Reality Prior to Endoscopic Procedures.

PURPOSE: Endoscopic procedures can cause anxiety, which can lead to more uncomfortable, difficult, and incomplete procedures, in addition to greater use of sedative medication. Here, we investigate whether exposing patients to virtual reality (VR) prior to endoscopic procedures can reduce their anxiety levels. MATERIALS AND METHODS: Forty patients at Gangnam Severance Hospital were enrolled and divided into the VR group and the control group. Patients in the VR group were exposed to VR prior to their procedure to alleviate anxiety. The primary data outcomes were State-Trait Anxiety Inventory (STAI), pain score, satisfaction with sedation, and satisfaction with the procedure. RESULTS: The mean STAI-state and STAI-trait did not differ significantly between the control group and the VR group. While defining a high anxiety STAI score as ≥45 in an STAI-state, the proportion of patients with high anxiety at baseline was 35% and increased to 50% prior to the procedure in the control group. However, in the VR group, the proportion of patients with high anxiety at baseline was 60% and decreased to 50% prior to the procedure. The proportion changes of patients with high anxiety in the STAI-state exhibited a significant difference between the control and VR groups (p=0.007). Furthermore, patients' satisfaction with sedation was significantly greater in the VR group compared to the control group (p=0.017). CONCLUSION: VR exposure may relieve patients' anxiety levels prior to endoscopic procedures, but further well-designed placebo-controlled studies are needed. VR, an inexpensive, easily available, and non-invasive method, also improved the satisfaction with sedation of endoscopic procedures.

Association of Waist Circumference with the Risk of Inflammatory Bowel Disease: a Nationwide Cohort Study of 10 Million Individuals in Korea.

BACKGROUND AND AIMS: Metabolic syndrome may share the pathophysiology of adipose tissue dysregulation and inadequate immune response with inflammatory bowel disease [IBD]. We determined the association of abdominal obesity [AO] with the risk of developing IBD. METHODS: We conducted a nationwide population-based cohort study using the Korean National Health Insurance Services database. A total of 10 082 568 participants of the 2009 national health screening programme were enrolled. Newly diagnosed Crohn's disease [CD] and ulcerative colitis [UC] were identified using the International Classification of Diseases 10th Revision and specialized national codes for rare intractable diseases. Waist circumference [WC] was classified into six groups and compared with the reference values of 85.0-89.9 cm for men and 80.0-84.9 cm for women. AO was defined as a WC of ≥90 cm for men and ≥85 cm for women. RESULTS: During a median follow-up of 9.3 years, the incidence rates of CD and UC were 2.11 and 8.40 per 100 000 person-years, respectively. After adjustment for age, sex, lifestyle behaviours, income and body mass index [BMI], the increase in baseline WC was significantly associated with the risk of developing CD, but not UC, compared to the references. The risk of developing CD in subjects with AO increased significantly compared to those without AO [adjusted hazard ratio, 1.40; 95% confidence interval, 1.21-1.61], regardless of obesity based on BMI. CONCLUSIONS: Individuals with AO bore an increased risk of developing CD proportional to WC, but not UC, suggesting that visceral adiposity is related to the pathophysiology of CD.

A Randomized, Double-Blind, Active-Control, Noninferiority, Multicenter, Phase 4 Study to Evaluate the Efficacy and Safety of Esomeprazole/Sodium Bicarbonate 20/800 mg in Patients with Nonerosive Gastroesophageal Reflux Disease.

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Ⓡ (esomeprazole 20 mg with sodium bicarbonate 800 mg) or NexiumⓇ (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Ⓡ group and 175 in the NexiumⓇ 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Ⓡ group and 35% in the NexiumⓇ 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Ⓡ is as effective and safe as NexiumⓇ for managing typical symptoms in patients with NERD (ClinicalTrial.gov identifier: NCT03928470).

Triglyceride-glucose index is associated with gastroesophageal reflux disease and erosive reflux disease: a health checkup cohort study.

The triglyceride-glucose (TyG) index was proposed as a useful marker of metabolic syndrome. Insulin resistance, the main mechanism underlying metabolic syndrome, is related to gastroesophageal reflux disease (GERD). This study aimed to elucidate the association between the TyG index and GERD/erosive reflux disease (ERD). We retrospectively reviewed the electronic medical records of patients who underwent gastroduodenoscopy at a checkup center. The calculation of TyG index used following formula: ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). We divided the patients into four groups according to the TyG index quartile (Q). We evaluated the relationship between the alteration of the TyG index and GERD in patients who received health checkups two times. Among the 52,605 enrolled patients, 3073 (5.8%) and 434 (0.8%) were diagnosed with GERD and ERD, respectively. The odds ratios (ORs) for GERD in the TyG index progressively increased across quartiles (P < 0.001): Q2 (OR = 2.477), Q3 (OR = 3.013), and Q4 (OR = 4.027) compared with Q1, which was used as a reference, respectively. Those for ERD also progressively increased across quartiles (P < 0.001): Q2 (OR = 4.264), Q3 (OR = 4.841), and Q4 (OR = 7.390) compared with Q1, respectively. Moreover, the degree of TyG index increase during the first and second tests in the GERD group was more prominent than in the control group (P = 0.001). In conclusion, the higher TyG index was significantly associated with GERD. The TyG index may be a novel predictive biomarker of GERD and ERD.

Randomized controlled trial to evaluate the efficacy and safety of fexuprazan compared with esomeprazole in erosive esophagitis.

BACKGROUND: Fexuprazan, a novel potassium-competitive acid blocker, reversibly suppresses the K+/H+-ATPase enzyme in proton pumps within gastric parietal cells. Fexuprazan's suppression of gastric acid was maintained in healthy individuals for 24 h in a dose-dependent manner. AIM: To compare fexuprazan to esomeprazole and establish its efficacy and safety in patients with erosive esophagitis (EE). METHODS: Korean adult patients with endoscopically confirmed EE were randomized 1:1 to receive fexuprazan 40 mg or esomeprazole 40 mg once daily for eight weeks. The primary endpoint was the proportion of patients with healed EE confirmed by endoscopy at week 8. The secondary endpoints included the healing rate of EE at week 4, symptom response, and quality of life assessment. Safety profiles and serum gastrin levels were compared between the groups. RESULTS: Of the 263 randomized, 218 completed the study per protocol (fexuprazan 40 mg, n = 107; esomeprazole 40 mg, n = 111). Fexuprazan was non-inferior to esomeprazole regarding the healing rate at week 8 [99.1% (106/107) vs 99.1% (110/111)]. There were no between-group differences in the EE healing rate at week 4 [90.3% (93/103) vs 88.5% (92/104)], symptom responses, and quality of life assessments. Additionally, serum gastrin levels at weeks 4 and 8 and drug-related side effects did not significantly differ between the groups. CONCLUSION: Fexuprazan 40 mg is non-inferior to esomeprazole 40 mg in EE healing at week 8. We suggest that fexuprazan is an alternative promising treatment option to PPIs for patients with EE.