Background: This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin. Methods: In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135). Results: At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (–0.47%; 95% confidence interval, –0.61 to –0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%). Conclusion Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.

Background: To analyze the effects of socioeconomic status (type of insurance and income level) and cancer stage on the survival of patients with liver cancer in Korea. Methods: A retrospective cohort study was constructed using data from the Healthcare Big Data Platform project in Korea between January 1, 2007, and December 31, 2017. A total of 143,511 patients in Korea diagnosed with liver cancer (International Classification of Diseases, 10th Revision [ICD-10] codes C22, C220, and C221) were followed for an average of 11 years. Of these, 110,443 died. The patient’s insurance type and income level were used as indicators of socioeconomic status. Unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a Cox proportional hazards regression model to analyze the relationship between the effects of sex, age, and cancer stage at first diagnosis (Surveillance, Epidemiology, and the End Results; SEER), type of insurance, and income level on the survival of patients with liver cancer. The interactive effects of the type of insurance, income level, and cancer stage on liver cancer death were also analyzed. Results: The lowest income group (medical aid) showed a higher risk for mortality (HR (95% CI); 1.37 (1.27–1.47) for all patients, 1.44 (1.32–1.57) for men, and 1.16 (1.01–1.34) for women) compared to the highest income group (1–6) among liver cancer (ICD-10 code C22) patients. The risk of liver cancer death was also higher in the lowest income group with a distant cancer stage (SEER = 7) diagnosis than for any other group. Conclusion Liver cancer patients with lower socioeconomic status and more severe cancer stages were at greater risk of death. Reducing social inequalities is needed to improve mortality rates among patients in lower social class groups who present with advanced cancer.

Background: Worldwide, sepsis is the leading cause of death in hospitals. If mortality rates in patients with sepsis can be predicted early, medical resources can be allocated efficiently. We constructed machine learning (ML) models to predict the mortality of patients with sepsis in a hospital emergency department. Methods: This study prospectively collected nationwide data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Patients were enrolled from 19 hospitals between September 2019 and December 2020. For acquired data from 3,657 survivors and 1,455 deaths, six ML models (logistic regression, support vector machine, random forest, extreme gradient boosting [XGBoost], light gradient boosting machine, and categorical boosting [CatBoost]) were constructed using fivefold cross-validation to predict mortality. Through these models, 44 clinical variables measured on the day of admission were compared with six sequential organ failure assessment (SOFA) components (PaO 2 /FIO 2 [PF], platelets (PLT), bilirubin, cardiovascular, Glasgow Coma Scale score, and creatinine).The confidence interval (CI) was obtained by performing 10,000 repeated measurements via random sampling of the test dataset. All results were explained and interpreted using Shapley’s additive explanations (SHAP). Results: Of the 5,112 participants, CatBoost exhibited the highest area under the curve (AUC) of 0.800 (95% CI, 0.756–0.840) using clinical variables. Using the SOFA components for the same patient, XGBoost exhibited the highest AUC of 0.678 (95% CI, 0.626–0.730). As interpreted by SHAP, albumin, lactate, blood urea nitrogen, and international normalization ratio were determined to significantly affect the results. Additionally, PF and PLTs in the SOFA component significantly influenced the prediction results. Conclusion Newly established ML-based models achieved good prediction of mortality in patients with sepsis. Using several clinical variables acquired at the baseline can provide more accurate results for early predictions than using SOFA components. Additionally, the impact of each variable was identified.

BACKGROUND: Breast cancer patients suffer from lowered quality of life (QoL) after surgery. Breast conservancy surgery (BCS) such as partial mastectomy is being practiced and studied as an alternative to solve this problem. This study confirmed breast tissue reconstruction in a pig model by fabricating a 3-dimensional (3D) printed Polycaprolactone spherical scaffold (PCL ball) to fit the tissue resected after partial mastectomy. METHODS: A 3D printed Polycaprolactone spherical scaffold with a structure that can help adipose tissue regeneration was produced using computer-aided design (CAD). A physical property test was conducted for optimization. In order to enhance biocompatibility, collagen coating was applied and a comparative study was conducted for 3 months in a partial mastectomy pig model. RESULTS: In order to identify adipose tissue and fibroglandular tissue, which mainly constitute breast tissue, the degree of adipose tissue and collagen regeneration was confirmed in a pig model after 3 months. As a result, it was confirmed that a lot of adipose tissue was regenerated in the PCL ball, whereas more collagen was regenerated in the collagen-coated Polycaprolactone spherical scaffold (PCL–COL ball). In addition, as a result of confirming the expression levels of TNF-a and IL-6, it was confirmed that PCL ball showed higher levels than PCL–COL ball. CONCLUSION Through this study, we were able to confirm the regeneration of adipose tissue through a 3-dimensional structure in a pig model. Studies were conducted on medium and large-sized animal models for the final purpose of clinical use and reconstruction of human breast tissue, and the possibility was confirmed.

Background: The purpose of this study was to identify the characteristics of dry mouth and gastrointestinal (GI) disorders in antidepressant patients. Methods: The study included 103 antidepressant-taking patients. Antidepressants were classified according to their mode of action. The GI disorders were investigated using the medical records of the patients. The Patient Health Questionnaire-15 and a questionnaire for assessing dry mouth symptoms were used in this study. Results: The score for “overall discomfort due to dry mouth in daily life” (31.72±33.82), “dry mouth at night or in the morning” (47.86±35.87), and “dry mouth during the day” (39.83±31.67) were slightly higher than “discomfort in chewing or swallowing foods”. According to somatization severity, the mean values were 116.36±113.34 in the mild, 213.18±136.98 in the moderate, and 277.59±201.44 in the severe, the between-group difference was significant (F=10.294, p<0.001). According to the class of antidepressants, the mean score was 180.00±147.5 for vortioxetine, 194.25±169.33 for selective serotonin reuptake inhibitors (SSRIs), 223.61±156.70 for serotonin and norepinephrine reuptake inhibitors (SNRIs), 75.00±57.00 for norepinephrine dopamine reuptake inhibitors (NDRIs), 201.67±174.66 for Nassau, and 116.67±132.03 for agomelatine. A total of 67 (65.0%) patients had at least one GI disorder. Conclusion The study findings are expected to help increase medication compliance in antidepressant patients by better controlling the side effects experienced by the patients.

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Background: The impact of reflux esophagitis on the decline of lung function has been rarely reported. This study was performed to evaluate the association between erosive reflux esophagitis and lung function changes. Methods: We included patients with normal lung function who underwent esophagogastroduodenoscopy for health screening from a health screening center. Patients with persistent erosive reflux esophagitis on two discrete endoscopic examinations were designated as the erosive reflux esophagitis group. We also selected patients without erosive reflux esophagitis and matched them 1:4 with patients from the erosive reflux esophagitis group. We estimated annual forced expiratory volume in 1 second (FEV1 ) and forced vital capacity (FVC) changes from baseline and compared these estimates by the linear mixed regression model. We also estimated the biannual incidence of chronic obstructive pulmonary disease (COPD). Results: In total, 1,050 patients (210 patients with erosive reflux esophagitis, and 840 matched controls) were included. The median follow-up duration for spirometry was six years. In patients with erosive reflux esophagitis, mild reflux esophagitis (A grade) was most common (165 patients, 78.6%). The adjusted annual FEV1 change in patients with erosive reflux esophagitis was −51.8 mL/yr, while it decreased by 46.8 mL/yr in controls (P = 0.270).The adjusted annual FVC decline was similar between the two groups (−55.8 vs. −50.5 mL/ yr, P = 0.215). The estimated COPD incidence during the follow-up period was not different between the erosive reflux esophagitis and control groups. Conclusion In patients with normal lung function, the presence of erosive reflux esophagitis did not affect the annual declines in FEV1 or FVC.

Background: Remdesivir is widely used for the treatment of coronavirus disease 2019 (COVID-19), but controversies regarding its efficacy still remain. Methods: A retrospective cohort study was conducted to evaluate the effect of remdesivir on clinical and virologic outcomes of severe COVID-19 patients from June to July 2020. Primary clinical endpoints included clinical recovery, additional mechanical ventilator (MV) support, and duration of oxygen or MV support. Viral load reduction by hospital day (HD) 15 was evaluated by calculating changes in cycle threshold (Ct) values. Results: A total of 86 severe COVID-19 patients were evaluated including 48 remdesivirtreated patients. Baseline characteristics were not significantly different between the two groups. Remdesivir was administered an average of 7.42 days from symptom onset. The proportions of clinical recovery of the remdesivir and supportive care group at HD 14 (56.3% and 39.5%) and HD 28 (87.5% and 78.9%) were not statistically different. The proportion of patients requiring MV support by HD 28 was significantly lower in the remdesivir group than in the supportive care group (22.9% vs. 44.7%, P = 0.032), and MV duration was significantly shorter in the remdesivir group (average, 1.97 vs. 5.37 days; P = 0.017). Analysis of upper respiratory tract specimens demonstrated that increases of Ct value from HD 1–5 to 11–15 were significantly greater in the remdesivir group than the supportive care group (average, 10.19 vs. 5.36; P = 0.007), and the slope of the Ct value increase was also significantly steeper in the remdesivir group (average, 5.10 vs. 2.68; P = 0.007). Conclusion The remdesivir group showed clinical and virologic benefit in terms of MV requirement and viral load reduction, supporting remdesivir treatment for severe COVID-19.

Background/Aims: Steatohepatitis related to metabolic syndrome is a chronic liver disease prevalent in patients not only with non-alcoholic steatohepatitis but also with alcoholic liver disease and chronic viral hepatitis. On the other hand, there is limited data on the effects of hepatotonic agents in these patients. Therefore, this study evaluated the efficacy of a combined hepatotonic agent in this population. Methods: Thirty-three adults with chronic hepatitis and one or more components of metabolic syndrome were assigned randomly to receive biphenyl dimethyl dicarboxylate/ursodeoxycholic acid or a placebo for 24 weeks. The primary outcome was the normalization of ALT (≤40 U/L). The secondary outcomes were the change in controlled attenuation parameter, transient elastography, and Chronic Liver Disease Questionnaire score. Results: The 33 patients were assigned randomly to two groups. Eight (50%) of 16 patients who received the intervention drug showed the normalization of ALT, whereas only one (6%) of 17 patients in the placebo group did so. In contrast, the change in controlled attenuation, transient elastography, and Chronic Liver Disease Questionnaire were similar in the two groups. ALT was changed significantly during the four assessment periods, and this change was affected by the group. The interaction between the group and time was also significant. AST was changed significantly during the same period. This change was not affected by the group. Conclusions Biphenyl dimethyl dicarboxylate/ursodeoxycholic acid combination reduced ALT in chronic liver disease related to metabolic syndrome. On the other hand, there is no evidence that this leads to improved hepatic steatosis and fibrosis within 6 months.