Auricular vagus nerve stimulation (aVNS) is one of the promising neuromodulation techniques due to its non-invasiveness, convenience, and effectiveness. aVNS has been suggested as a potential treatment for neurodegenerative diseases showing impaired cerebrospinal fluid (CSF) dynamics. Improving CSF flow has been proposed as a key mechanism of the therapeutic effect on neurodegenerative diseases. However, aVNS parameters have been set empirically and the effective parameter that maximize the effect remains elusive. Here we show that 30 minutes of low-frequency aVNS increased arterial vasomotion events and enhanced cortical CSF influx along the branches of middle cerebral arteries. By using in vivo two photon imaging or widefield fluorescence microscopy with plasma and CSF tracers for visualizing blood vessels and perivascular spaces, arterial vasomotion and cortical CSF influx dynamics were acquired. The low-frequency (2 Hz) aVNS, but not middleand high-frequency (40 and 100 Hz) aVNS, significantly increased the number of vasomotion events compared to the sham group. Accordingly, in the CSF imaging, 2 Hz of aVNS markedly enhanced the CSF influx. Our findings demonstrate that lowfrequency aVNS is the effective parameter in respect to modulating vasomotion and CSF influx, resulting in brain clearance effect.

Background: Respiratory infections play a major role in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This study assessed the prevalence of bacterial and viral pathogens and their clinical impact on patients with AECOPD. Methods: This retrospective study included 1,186 patients diagnosed with AECOPD at 28 hospitals in South Korea between 2015 and 2018. We evaluated the identification rates of pathogens, basic patient characteristics, clinical features, and the factors associated with infections by potentially drug-resistant (PDR) pathogens using various microbiological tests. Results: Bacteria, viruses, and both were detected in 262 (22.1%), 265 (22.5%), and 129 (10.9%) of patients, respectively. The most common pathogens included Pseudomonas aeruginosa (17.8%), Mycoplasma pneumoniae (11.2%), Streptococcus pneumoniae (9.0%), influenza A virus (19.0%), rhinovirus (15.8%), and respiratory syncytial virus (6.4%). Notably, a history of pulmonary tuberculosis (odds ratio [OR], 1.66; p=0.046), bronchiectasis (OR, 1.99; p=0.032), and the use of a triple inhaler regimen within the past 6 months (OR, 2.04; p=0.005) were identified as significant factors associated with infection by PDR pathogens. Moreover, patients infected with PDR pathogens exhibited extended hospital stays (15.9 days vs. 12.4 days, p=0.018) and higher intensive care unit admission rates (15.9% vs. 9.5%, p=0.030). Conclusion This study demonstrates that a variety of pathogens are involved in episodes of AECOPD. Nevertheless, additional research is required to confirm their role in the onset and progression of AECOPD.

Background: Computed tomography (CT) scans are utilized to assess emphysema, a prominent phenotype of chronic obstructive pulmonary disease (COPD). Variability in CT protocols and equipment across hospitals can impact accuracy. This study aims to implement kernel conversion across different CT settings and evaluate changes in the correlation between the emphysema index pre- and post-kernel conversion, along with clinical measures in COPD patients. Methods: Data were extracted from the Korea COPD Subgroup Study database, which included CT scan images from 484 COPD patients. These images underwent kernel conversion. Emphysema extent was quantified using the percentage of low-attenuation areas (%LAA-950) determined by a deep learning-based program. The correlation between %LAA-950 and clinical parameters, including lung function tests, the modified Medical Research Council (mMRC), 6-minute walking distance (6MWD), COPD assessment test (CAT), and the St. George’s Respiratory Questionnaire for COPD (SGRQ-c), was analyzed. Subsequently, these values were compared across various CT settings. Results: A total of 484 participants were included. Kernel conversion significantly reduced the variance in %LAA-950 values (before vs. after: 12.6±11.0 vs. 8.8±11.9). Post-kernel conversion, %LAA-950 demonstrated moderate correlations with forced expiratory volume in 1 second (r=–0.41), residual volume/total lung capacity (r=0.42), mMRC (r=0.25), CAT score (r=0.12), SGRQ-c (r=0.21), and 6MWD (r=0.15), all of which were improved compared to the unconverted dataset (all p<0.01). Conclusion CT images processed through kernel conversion enhance the correlation between the extent of emphysema and clinical parameters in COPD.

Background/Aims: Although the association between the use of proton pump inhibitors (PPIs) and the risk of gastric cancer has been postulated in casecontrol and cohort studies, it remains still controversial. We aim to evaluate association of PPI use with gastric cancer in regions with high prevalence of gastric cancer, particularly in patients who underwent eradication of Helicobacter pylori, by systemic review and meta-analysis. Methods: Comprehensive literature search through the PubMed, Embase, and Cochrane database was performed in October 2023. We used random effects model to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs) between PPI use and gastric cancer.The Cochran Q-statistic and the I² test were employed for evaluating potential heterogeneity between studies. Results: Two case-control and 6 cohort studies were identified. PPI use was significantly associated with the development of gastric cancer (OR, 2.02; 95% CI, 1.35-3.01). In subgroup analysis carried out according to the study design, sample size, and adjustment of confounding factors (age, sex, and H. pylori), such association was significant. A meta-analysis of 4 studies performed in patients with H. pylori eradication history showed that the use of PPIs was significantly associated with an elevated incidence of gastric cancer (OR, 2.10; 95% CI, 1.48-2.97). Conclusions Long-term use of PPIs is associated with an increased risk of gastric cancer in Asian regions with high prevalence of gastric cancer, particularly in subjects who have eradication history of H. pylori. Optimization of long-term PPI use seems to be necessary in regions where gastric cancer is prevalent.

Background/Aims: Serum gastrin levels may be elevated following proton pump inhibitor (PPI) therapy. We aim to elucidate the predictors for the development of hypergastrinemia in maintenance treatment for mild gastroesophageal reflux disease (GERD) using a half-dose PPI. Methods: This study analyzed data from a prospective randomized trial to compare continuous versus on-demand maintenance treatment modalities in patients with mild GERD. Age, sex, body mass index, Helicobacter pylori infection, serum gastrin levels, pepsinogen (PG) I/II ratios, total days of PPI intake, and weight-based PPI dosage (mg/kg) were evaluated. Results: Data from 293 patients who completed a randomized trial were analyzed (continuous group, n = 147 vs on-demand group, n = 146). In univariate analysis, age (P < 0.001), H. pylori infection (P = 0.012), baseline gastrin levels (P < 0.001), and baseline PG ratios (P = 0.016) significantly correlated with post-treatment gastrin levels. In multivariate analysis, age, baseline gastrin levels, and baseline PG ratios were independently associated with final serum gastrin levels. In univariate analysis, age (P = 0.018), H. pylori infection (P = 0.028), baseline gastrin levels (P = 0.011), and baseline PG ratios (P = 0.031) significantly correlated with the development of hypergastrinemia. In multivariate analysis, age, baseline gastrin levels, and baseline PG ratios were independently associated with the development of hypergastrinemia. Conclusion Old age, high baseline serum gastrin levels, and low baseline PG ratios are significant predictors of the development of hypergastrinemia in maintenance treatment for mild GERD using a half-dose PPI.

Although histone deacetylase 6 (HDAC6) is considered a therapeutic target for Alzheimer’s disease (AD), its role in cholinergic dysfunction in AD patients remains unclear. This study investigated the effects of (E)-3-(2-(4-fluorostyryl)thiazol-4-yl)-N-hydroxypropanamide (4-FHA), a new synthetic HDAC6 inhibitor, on cognitive and memory impairments in a scopolamine-induced-AD mouse model. Behaviorally, 4-FHA improved scopolamine-induced memory impairments in the Y-maze, passive avoidance, and Morris water maze tests. In addition, 4-FHA ameliorated scopolamine-induced cognitive impairments in the novel object recognition and place recognition tests. Furthermore, 4-FHA increased acetylation of α-tubulin (a major HDAC6 substrate); the expression of BDNF; and the phosphorylation of ERK 1/2, CREB, and ChAT in the hippocampus of scopolamine-treated mice. In summary, according to our data 4-FHA, an HDAC6 inhibitor, improved the cognitive and memory deficits of the AD mouse model by normalizing BDNF signaling and synaptic transmission, suggesting that 4-FHA might be a potential therapeutic candidate for AD.

The common data model (CDM) has found widespread application in healthcare studies, but its utilization in cancer research has been limited. This article describes the development and implementation strategy for Cancer Clinical Library Databases (CCLDs), which are standardized cancer-specific databases established under the Korea-Clinical Data Utilization Network for Research Excellence (K-CURE) project by the Korean Ministry of Health and Welfare. Fifteen leading hospitals and fourteen academic associations in Korea are engaged in constructing CCLDs for 10 primary cancer types. For each cancer type-specific CCLD, cancer data experts determine key clinical data items essential for cancer research, standardize these items across cancer types, and create a standardized schema. Comprehensive clinical records covering diagnosis, treatment, and outcomes, with annual updates, are collected for each cancer patient in the target population, and quality control is based on six-sigma standards. To protect patient privacy, CCLDs follow stringent data security guidelines by pseudonymizing personal identification information and operating within a closed analysis environment. Researchers can apply for access to CCLD data through the K-CURE portal, which is subject to Institutional Review Board and Data Review Board approval. The CCLD is considered a pioneering standardized cancer-specific database, significantly representing Korea’s cancer data. It is expected to overcome limitations of previous CDMs and provide a valuable resource for multicenter cancer research in Korea.

Purpose: This study investigated the recurrence patterns and timing in patients with pathologic N2 (pN2) non-small cell lung cancer (NSCLC) according to the residual tumor (R) descriptor proposed by the International Association for the Study of Lung Cancer (IASLC). Materials and Methods: From 2004 to 2021, patients with pN2 NSCLC who underwent anatomical resection were analyzed according to the IASLC R criteria using medical records from a single center. Survival analysis was performed using Cox proportional hazards models. Recurrence patterns between complete (R0) and uncertain resections (R[un]) were compared. Results: In total, 1,373 patients were enrolled in this study: 576 (42.0%) in R0, 286 (20.8%) in R(un), and 511 (37.2%) in R1/R2 according to the IASLC R criteria. The most common reason for R(un) classification was positivity for the highest lymph node (88.8%). In multivariable analysis, the hazard ratios for recurrence in R(un) and R1/R2 compared to R0 were 1.18 (95% confidence interval [CI], 0.96–1.46) and 1.58 (1.31–1.90), respectively. The hazard rate curves displayed similar patterns among groups, peaking at approximately 12 months after surgery. There was a significant difference in distant recurrence patterns between R0 and R(un). Further analysis after stratification with the IASLC N2 descriptor showed significant differences in distant recurrence patterns between R0 and R(un) in patients pN2a1 and pN2a2 disease, but not in those with pN2b disease. Conclusion The IASLC R criteria has prognostic relevance in patients with pN2 NSCLC. R(un) is a highly heterogeneous group, and the involvement of the highest mediastinal lymph node can affect distant recurrence patterns.

Purpose: The International Association for the Study of Lung Cancer suggests further subdivision of pathologic N (pN) category in non–small-cell lung cancer (NSCLC) by incorporating the location and number of involved lymph node (LN) stations. We reclassified patients with the station-based N2b disease into single-zone and multi-zone N2b groups and compared survival outcomes between the groups. Materials and Methods: This retrospective study included patients with pN2 NSCLC who underwent lobectomy from 2006 to 2019. The N2 disease was subdivided into four categories: single-station N2 without N1 (N2a1), single-station N2 with N1 (N2a2), multiple-station N2 with single zone involvement (single-zone N2b), and multiple-station N2 with multiple zone involvement (multi-zone N2b). LN zones included in the subdivision of N2 disease were upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal. Results: Among 996 eligible patients, 211 (21.2%), 394 (39.6%), and 391 (39.3%) were confirmed to have pN2a1, pN2a2, and pN2b disease, respectively. In multivariable analysis after adjustment for sex, age, pT category, and adjuvant chemotherapy, overall survival was significantly better with single-zone N2b disease (n=125, 12.6%) than with multi-zone N2b disease (n=266, 26.7%) (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49 to 0.90; p=0.009) and was comparable to that of N2a2 disease (HR, 1.12; 95% CI, 0.83 to 1.49; p=0.46). Conclusion Prognosis of single-zone LN metastasis was better than that of multiple-zone LN metastasis in patients with N2b NSCLC. Along with the station-based N descriptors, zone-based descriptors might ensure optimal staging, enabling the most appropriate decision-making on adjuvant therapy for patients with pN2 NSCLC.

Purpose: This study aimed to assess prognostic factors associated with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and to predict 5-year survival based on these factors. Materials and Methods: Patients who underwent definitive hepatectomy from 2006 to 2022 at a single institution was retrospectively analyzed. Inclusion criteria involved a pathologically confirmed diagnosis of cHCC-CCA. Results: A total of 80 patients with diagnosed cHCC-CCA were included in the analysis. The median progression-free survival was 15.6 months, while distant metastasis-free survival (DMFS), hepatic progression-free survival, and overall survival (OS) were 50.8, 21.5, and 85.1 months, respectively. In 52 cases of recurrence, intrahepatic recurrence was the most common initial recurrence (34/52), with distant metastasis in 17 cases. Factors associated with poor DMFS included tumor necrosis, lymphovascular invasion (LVI), perineural invasion, and histologic compact type. Postoperative carbohydrate antigen 19-9, tumor necrosis, LVI, and close/positive margin were associated with poor OS. LVI emerged as a key factor affecting both DMFS and OS, with a 5-year OS of 93.3% for patients without LVI compared to 35.8% with LVI. Based on these factors, a nomogram predicting 3-year and 5-year DMFS and OS was developed, demonstrating high concordance with actual survival in the cohort (Harrell C-index 0.809 for OS, 0.801 for DMFS, respectively). Conclusion The prognosis of cHCC-CCA is notably poor when combined with LVI. Given the significant impact of adverse features, accurate outcome prediction is crucial. Moreover, consideration of adjuvant therapy may be warranted for patients exhibiting poor survival and increased risk of local recurrence or distant metastasis.