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Background/Objectives : Breast cancer is the most common cancer in women worldwide, requiring strategic efforts to reduce its mortality. This study aimed to develop a predictive classification model for breast cancer mortality using real-world data, including various clinical features. Methods : A total of 11,286 patients with breast cancer from the National Cancer Center were included in this study. The mortality rate of the total sample was approximately 6.2%. Propensity score matching was used to reduce bias. Several machine learning models, including extreme gradient boosting, were applied to 31 clinical features. To enhance model interpretability, we used the SHapley Additive exPlanations method. ML analyses were also performed on the samples, excluding patients who developed other cancers after breast cancer. Results : Among the ML models, the XGB model exhibited the highest discriminatory power, with an area under the curve of 0.8722 and a specificity of 0.9472. Key predictors of the mortality classification model included occurrence in other organs, age at diagnosis, N stage, T stage, curative radiation treatment, and Ki-67(%). Even after excluding patients who developed other cancers after breast cancer, the XGB model remained the best-performing, with an AUC of 0.8518 and a specificity of 0.9766. Additionally, the top predictors from SHAP were similar to the results for the overall sample. Conclusions : Our models provided excellent predictions of breast cancer mortality using real-world data from South Korea. Explainable artificial intelligence, such as SHAP, validated the clinical applicability and interpretability of these models.

Background/aims: Colonic stenting plays a vital role in the management of acute malignant colonic obstruction. The increasing use of self-expandable metal stents (SEMS) and the diverse challenges posed by colonic obstruction at various locations underscore the importance of effective training for colonic stent placement., Methods: All the components of the simulator were manufactured using silicone molding techniques in conjunction with three-dimensional (3D) printing. 3D images sourced from computed tomography scans and colonoscopy images were converted into a stereolithography format. Acrylonitrile butadiene styrene copolymers have been used in fused deposition modeling to produce moldings., Results: The simulator replicated the large intestine from the rectum to the cecum, mimicking the texture and shape of the human colon. It enables training for colonoscopy insertion, cecum intubation, loop reduction, and stenting within stenotic areas. Interchangeable stenotic modules for four sites (rectum, sigmoid colon, descending colon, and ascending colon) were easily assembled for training. These modules integrate tumor contours and blood vessel structures with a translucent center, allowing real-time visualization during stenting. Successful and repeatable demonstrations of stent insertion and expansion using the reusable SEMS were consistently achieved., Conclusions: This innovative simulator offers a secure colonic stenting practice across various locations, potentially enhancing clinical outcomes by improving operator proficiency during actual procedures.

This paper provides a comprehensive overview of the Cancer Public Library Database (CPLD), established under the Korean Clinical Data Utilization for Research Excellence project (K-CURE). The CPLD links data from four major population-based public sources: the Korea National Cancer Incidence Database in the Korea Central Cancer Registry, cause-of-death data in Statistics Korea, the National Health Information Database in the National Health Insurance Service, and the National Health Insurance Research Database in the Health Insurance Review & Assessment Service. These databases are linked using an encrypted resident registration number. The CPLD, established in 2022 and updated annually, comprises 1,983,499 men and women newly diagnosed with cancer between 2012 and 2019. It contains data on cancer registration and death, demographics, medical claims, general health checkups, and national cancer screening. The most common cancers among men in the CPLD were stomach (16.1%), lung (14.0%), colorectal (13.3%), prostate (9.6%), and liver (9.3%) cancers. The most common cancers among women were thyroid (20.4%), breast (16.6%), colorectal (9.0%), stomach (7.8%), and lung (6.2%) cancers. Among them, 571,285 died between 2012 and 2020 owing to cancer (89.2%) or other causes (10.8%). Upon approval, the CPLD is accessible to researchers through the K-CURE portal. The CPLD is a unique resource for diverse cancer research to investigate medical use before a cancer diagnosis, during initial diagnosis and treatment, and long-term follow-up. This offers expanded insight into healthcare delivery across the cancer continuum, from screening to end-of-life care.

Purpose: This study aims to prospectively analyze the effects of anticholinergic therapy using imidafenacin on detrusor overactivity occurring after robot-assisted radical prostatectomy (RARP)., Materials and Methods: Patients were followed-up at outpatient visits 2-4 weeks post-surgery (visit 2) to confirm the presence of urinary incontinence. Those confirmed with urinary incontinence were randomly assigned in a 1:1 ratio to the anticholinergic medication group (imidafenacin 0.1 mg twice daily) or the control group. Patients were followed-up at 1, 3, and 6 months post-surgery for observational assessments, including the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS)., Results: A total of 49 patients (25 in the treatment group and 24 in the control group) were randomized for the study. There were no differences observed between the groups in terms of age, comorbidities, prostate size, or pathological staging. According to the IPSS questionnaire results, there was no statistically significant difference between the medication and control groups (p=0.161). However, when comparing storage and voiding symptoms separately, there was a statistically significant improvement in storage symptom scores (p=0.012). OABSS also revealed statistically significant improvement in symptoms from 3 months post-surgery (p=0.005), which persisted until 6 months post-surgery (IPSS storage: p=0.023, OABSS: p=0.013)., Conclusions: In the case of urinary incontinence that occurs after RARP, even if the function of the intrinsic sphincter is sufficiently preserved, if urinary incontinence persists due to changes in the bladder, pharmacological therapy using imidafenacin can be beneficial in managing urinary incontinence., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

The ring finger protein 113A (RNF113A) serves as an E3 ubiquitin ligase and a subunit of the spliceosome. Mutations in the RNF113A gene are associated with X-linked trichothiodystrophy (TTD). However, the cellular roles of RNF113A remain largely unknown. In this study, we performed transcriptome profiling of RNF113A knockout (KO) HeLa cells using RNA sequencing and revealed the upregulation of NRF2 pathway-associated genes. Further analysis confirmed that the KO of RNF113A promotes nuclear localization of the NRF2 protein and elevates the mRNA levels of NRF2 target genes. RNF113A KO cells showed high levels of intracellular reactive oxygen species (ROS) and decreased resistance to cell death following H 2 O 2 treatment. Additionally, RNF113A KO cells more sensitively formed stress granules (SGs) under arsenite-induced oxidative stress. Moreover, RNF113A KO cells exhibited a decrease in glutathione levels, which could be attributed to a reduction in GLUT1 expression levels, leading to decreased glucose uptake reactions and lower intracellular glucose levels. These alterations potentially caused a reduction in ROS scavenging activity. Taken together, our findings suggest that the loss of RNF113A promotes oxidative stress-mediated activation of the NRF2 pathway, providing novel insights into RNF113A-associated human diseases., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging., Methods: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations., Results: scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELL hi regulatory T cells (Tregs) and activated TIGIT hi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs., Conclusion: We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis., (© 2024. The Author(s).)

Background: Changes in the local population are intricately linked to healthcare infrastructure, which subsequently impacts the healthcare sector. A decreasing local population can result in lagging health infrastructure, potentially leading to adverse health outcomes as patients may be at risk of not receiving optimal care and treatment. While some studies have explored the relationship between chronic diseases and local population decline, evidence regarding cancer is insufficient. In this study, we focused on how deteriorating management of chronic diseases such as dyslipidemia could influence the risk of cancer. We investigated the relationship between changes in the local population and cancer incidence among patients with dyslipidemia., Methods: This cohort study was conducted using claims data. Data from adult patients with dyslipidemia from the National Health Insurance Service-National Sample Cohort conducted between 2002 and 2015 were included. Population changes in each region were obtained from the Korean Statistical Information Service and were used to link each individual's regional code. Cancer risk was the dependent variable, and Cox proportional hazards regression was used to estimate the target associations., Results: Data from 336,883 patients with dyslipidemia were analyzed. Individuals who resided in areas with a decreasing population had a higher risk of cancer than those living in areas with an increasing population (decrease: hazard ratio (HR) = 1.06, 95% CI = 1.03-1.10; normal: HR = 1.05, 95% CI = 1.02-1.09). Participants living in regions with a low number of hospitals had a higher risk of cancer than those in regions with a higher number of hospitals (HR = 1.20, 95% CI = 1.12-1.29)., Conclusion: Patients in regions where the population has declined are at a higher risk of cancer, highlighting the importance of managing medical problems caused by regional extinction. This could provide evidence for and useful insights into official policies on population decline and cancer risk., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Fragmented cancer care, defined as receipt of care from multiple hospitals, has been shown to be associated with poor patient outcomes and high expense. However, evidence regarding the effects of hospital choice by patients with cancer on overall survival are lacking. Thus, we investigated the relationship between patterns of fragmented care and five-year mortality in patients with gastric cancer., Materials and Methods: Using the Korean National Health Insurance senior cohort of adults aged ≥60 years, we identified patients with gastric cancer who underwent gastrectomy during 2007-2014. We examined the distribution of the study population by five-year mortality, and used Kaplan-Meier survival curves/log-rank test and Cox proportional hazard model to compare five-year mortality with fragmented cancer care., Results: Among the participants, 19.5% died within five years. There were more deaths among patients who received fragmented care, especially those who transferred to smaller hospitals (46.6%) than to larger ones (40.0%). The likelihood of five-year mortality was higher in patients who received fragmented cancer care upon moving from large to small hospitals than those who did not transfer hospitals (hazard ratio, 1.28; 95% confidence interval, 1.10-1.48, P = .001). Moreover, mortality was higher among patients treated in large hospitals or in the capital area for initial treatment, and this association was greater for patients from rural areas., Discussion: Fragmentation of cancer care was associated with reduced survival, and the risk of mortality was higher among patients who moved from large to small hospitals., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study investigates the synergistic effects of incorporating graphene oxide (GO) and polyvinyl alcohol (PVA) fibers into cement paste mixtures, aiming to modify their rheological properties and flexural behaviors with resistance to crack formation. The relationship between static yield stress and critical shear strain was examined in ten cement paste mixtures with varying concentrations of 6 mm and 12 mm PVA fibers and 0.05% GO. Additionally, viscosity analyses were performed. For the specimens fabricated from these mixtures, flexural strength tests were conducted using the Digital Image Correlation (DIC) technique for precise strain analysis under load history. The results indicated a significant increase in static yield stress, viscosity, and critical shear strain due to the combined addition of GO and PVA fibers, more so than when added individually. Notably, in PVA fiber-reinforced cement mixtures, the integration of GO increased the crack initiation load by up to 23% and enhanced pre-crack strain by 30 to 50%, demonstrating a notable delay in crack initiation and a reduction in crack propagation. Microstructural analyses using Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray Spectroscopy (EDS) revealed a concentrated presence of GO around and on the PVA fibers. This promotes increased C-S-H gel formation, resulting in a denser microstructure. Additionally, GO effectively interacts with PVA fibers, enhancing the adherence of hydration products at their interface.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target., (© 2024. The Author(s).)

Background: Poor glycemic control has been linked to psychiatric symptoms. However, studies investigating the relationship between glycemic variability (GV) and depression and anxiety disorders are limited. We investigated the association of GV with depression and anxiety disorders. In addition, the relationship between trends in fasting plasma glucose (FPG) levels and these disorders were explored., Methods: We analyzed the National Health Insurance Service-National Sample Cohort database (2002-2013) with 151,814 participants who had at least three health screenings between 2002 and 2010. Visit-to-visit FPG variability was measured as variability independent of the mean (VIM). Depression and anxiety disorders were diagnosed using ICD-10 codes (F41 for anxiety and F32 or F33 for depression) after index date. We analyzed the association between GV and incidences of these disorders using Kaplan-Meier and Cox proportional hazards methods. Trajectory analysis was conducted to explore the relationship between FPG trends and these disorders., Results: During follow-up, 7166 and 14,149 patients were newly diagnosed with depression and anxiety disorders, respectively. The highest quartile group of FPG-VIM had a greater incidence of depression and anxiety than the lowest quartile group, with adjusted hazard ratios of 1.09 (95 % confidence interval [CI]: 1.02-1.17) and 1.08 (95 % CI: 1.03-1.14). Group with persistent hyperglycemia, identified through trajectory clustering of FPG levels, had a 1.43-fold increased risk of depression compared to those with consistently low FPG levels., Limitations: Potential selection bias by including participants with at least three health screenings., Conclusions: High GV and persistent hyperglycemia are associated with increased incidence of depression and anxiety disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Synthetic data generation (SDG) based on generative adversarial networks (GANs) is used in health care, but research on preserving data with logical relationships with synthetic tabular data (STD) remains challenging. Filtering methods for SDG can lead to the loss of important information., Objective: This study proposed a divide-and-conquer (DC) method to generate STD based on the GAN algorithm, while preserving data with logical relationships., Methods: The proposed method was evaluated on data from the Korea Association for Lung Cancer Registry (KALC-R) and 2 benchmark data sets (breast cancer and diabetes). The DC-based SDG strategy comprises 3 steps: (1) We used 2 different partitioning methods (the class-specific criterion distinguished between survival and death groups, while the Cramer V criterion identified the highest correlation between columns in the original data); (2) the entire data set was divided into a number of subsets, which were then used as input for the conditional tabular generative adversarial network and the copula generative adversarial network to generate synthetic data; and (3) the generated synthetic data were consolidated into a single entity. For validation, we compared DC-based SDG and conditional sampling (CS)-based SDG through the performances of machine learning models. In addition, we generated imbalanced and balanced synthetic data for each of the 3 data sets and compared their performance using 4 classifiers: decision tree (DT), random forest (RF), Extreme Gradient Boosting (XGBoost), and light gradient-boosting machine (LGBM) models., Results: The synthetic data of the 3 diseases (non-small cell lung cancer [NSCLC], breast cancer, and diabetes) generated by our proposed model outperformed the 4 classifiers (DT, RF, XGBoost, and LGBM). The CS- versus DC-based model performances were compared using the mean area under the curve (SD) values: 74.87 (SD 0.77) versus 63.87 (SD 2.02) for NSCLC, 73.31 (SD 1.11) versus 67.96 (SD 2.15) for breast cancer, and 61.57 (SD 0.09) versus 60.08 (SD 0.17) for diabetes (DT); 85.61 (SD 0.29) versus 79.01 (SD 1.20) for NSCLC, 78.05 (SD 1.59) versus 73.48 (SD 4.73) for breast cancer, and 59.98 (SD 0.24) versus 58.55 (SD 0.17) for diabetes (RF); 85.20 (SD 0.82) versus 76.42 (SD 0.93) for NSCLC, 77.86 (SD 2.27) versus 68.32 (SD 2.37) for breast cancer, and 60.18 (SD 0.20) versus 58.98 (SD 0.29) for diabetes (XGBoost); and 85.14 (SD 0.77) versus 77.62 (SD 1.85) for NSCLC, 78.16 (SD 1.52) versus 70.02 (SD 2.17) for breast cancer, and 61.75 (SD 0.13) versus 61.12 (SD 0.23) for diabetes (LGBM). In addition, we found that balanced synthetic data performed better., Conclusions: This study is the first attempt to generate and validate STD based on a DC approach and shows improved performance using STD. The necessity for balanced SDG was also demonstrated., (©Ha Ye Jin Kang, Erdenebileg Batbaatar, Dong-Woo Choi, Kui Son Choi, Minsam Ko, Kwang Sun Ryu. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 24.11.2023.)

Aims: Using rosuvastatin, the RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial showed the beneficial effects of combining moderate-intensity statin with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease. This study investigated whether the beneficial effects of combination lipid-lowering therapy extend to patients treated with atorvastatin, not rosuvastatin, in daily clinical practice., Methods and Results: Using stabilized inverse probability of treatment weighting, a total of 31 993 patients who were prescribed atorvastatin after drug-eluting stent (DES) implantation were identified from a nationwide cohort database: 6 215 patients with atorvastatin 20 mg plus ezetimibe 10 mg (combination lipid-lowering therapy) and 25 778 patients with atorvastatin 40-80 mg monotherapy. The primary endpoint was the 3-year composite of cardiovascular death, myocardial infarction, coronary artery revascularization, hospitalization for heart failure treatment, or non-fatal stroke in accordance with the RACING trial design. Combination lipid-lowering therapy was associated with a lower incidence of the primary endpoint (12.9% vs. 15.1% in high-intensity atorvastatin monotherapy; hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.74-0.88, p < 0.001). Compared with high-intensity atorvastatin monotherapy, combination lipid-lowering therapy was also significantly associated with lower rates of statin discontinuation (10.0% vs. 8.4%, HR 0.81, 95% CI 0.73-0.90, p < 0.001) and new-onset diabetes requiring medication (8.8% vs. 7.0%, HR 0.80, 95% CI 0.70-0.92, p = 0.002)., Conclusions: In clinical practice, a combined lipid-lowering approach utilizing ezetimibe and moderate-intensity atorvastatin was correlated with favorable clinical outcomes, drug compliance, and a reduced incidence of new-onset diabetes requiring medications in patients treated with DES implantation. Trial registration: ClinicalTrial.gov (NCT04715594)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Small heat shock proteins (sHSPs) play a crucial role under abiotic stress and are present in all organisms, from eukaryotes to prokaryotes. However, studies on the sHSP gene family in red alga are limited. In this study, we aimed to identify and characterize NysHSP genes from the genome of N. yezoensis, a marine red alga adapted to the stressful intertidal zone. We identified seven NysHSP genes distributed on all three chromosomes. Expression analysis revealed that all NysHSP genes responded to H 2 O 2 and heat stress in the gametophytic thalli, but these genes responded only to heat stress in the sporophytic conchocelis. NysHSP20.3, which has an acidic isoelectric point (pI) and short N-terminal region, was localized as granules in the cytosol. Fluorescence imaging of the NysHSP25.8-GFP and NysHSP28.4-GFP fusion proteins revealed that these proteins were located in the chloroplast. Based on their characteristics and cellular localization, the NysHSPs are divided into two subfamilies. Subfamily I includes four sHSP genes that strongly respond to heat stress and encode a protein localized in the cytosol. The NysHSP gene of subfamily II encodes a polypeptide with a long N-terminal region located in the chloroplast. This study provides insights into the evolution and function of the sHSP gene family of the marine red alga N. yezoensis and how it adapts to the stressful intertidal zone., (© 2023. The Author(s), under exclusive licence to Cell Stress Society International.)

Aplastic anemia (AA) is a lethal hematological disorder; however, its pathogenesis is not fully understood. Although immunosuppressive therapy (IST) is a major treatment option for AA, one-third of patients do not respond to IST and its resistance mechanism remains elusive. To understand AA pathogenesis and IST resistance, we performed single-cell RNA sequencing (scRNA-seq) of bone marrow (BM) from healthy controls and patients with AA at diagnosis. We found that CD34 + early-stage erythroid precursor cells and PROM1 + hematopoietic stem cells were significantly depleted in AA, which suggests that the depletion of CD34 + early-stage erythroid precursor cells and PROM1 + hematopoietic stem cells might be one of the major mechanisms for AA pathogenesis related with BM-cell hypoplasia. More importantly, we observed the significant enrichment of CD8 + T cells and T cell-activating intercellular interactions in IST responders, indicating the association between the expansion and activation of T cells and the positive response of IST in AA. Taken together, our findings represent a valuable resource offering novel insights into the cellular heterogeneity in the BM of AA and reveal potential biomarkers for IST, building the foundation for future precision therapies in AA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Brown adipose tissue (BAT) plays a crucial role in regulating metabolic homeostasis through a unique energy expenditure process known as non-shivering thermogenesis. To achieve this, BAT utilizes a diverse menu of circulating nutrients to support its high metabolic demand. Additionally, BAT secretes metabolite-derived bioactive factors that can serve as either metabolic fuels or signaling molecules, facilitating BAT-mediated intratissue and/or intertissue communication. This suggests that BAT actively participates in systemic metabolite exchange, an interesting feature that is beginning to be explored. Here, we introduce a protocol for in vivo mouse-level optimized BAT arteriovenous metabolomics. The protocol focuses on relevant methods for thermogenic stimulations and an arteriovenous blood sampling technique using Sulzer's vein, which selectively drains interscapular BAT-derived venous blood and systemic arterial blood. Next, a gas chromatography-based metabolomics protocol using those blood samples is demonstrated. The use of this technique should expand the understanding of BAT-regulated metabolite exchange at the inter-organ level by measuring the net uptake and release of metabolites by BAT.

Background: The risk of inappropriate drug exposure in elderly colorectal cancer (CRC) survivors after the initial cancer treatment has not been well studied. This study investigated the association of polypharmacy (PP) with overall survival, hospitalization, and emergency room (ER) visits among older CRC survivors., Methods: A retrospective cohort study was conducted using the Korean National Health Insurance claims data follow-up from 2002 to 2017. Participants comprised those aged ≥65 years who were hospitalized with a diagnosis of CRC received cancer treatment and survived at least 2 years from the initial CRC diagnosis between 2003 and 2012. PP was defined based on the number of individual drugs during the third year, after 2 years of survival since the initial cancer treatment. PP was categorized as follows: non-PP (zero to four prescribed drugs); PP (five to nine drugs), and excessive PP (≥10 drugs). Main outcomes are all-cause mortality, hospitalization, and ER visits., Results: Of the 55,228 participants, 44.5% died, 83.1% were hospitalized, and 46.1% visited the ER. The PP and excess PP groups showed increased risk of all-cause mortality, hospitalization, and ER visit compared with the low PP group, and was highly associated among groups including patients aged 65 to 74 years and those in low-level frailty groups., Conclusions: These risks can be minimized by increasing awareness and enhancing behaviors among health care professionals, especially clinician and pharmacists, to be aware of potential drug interactions, review, and ongoing monitoring., Plain Language Summary: The risk of inappropriate drug exposure in older colorectal cancer (CRC) survivors after the initial cancer treatment has not been well studied. Polypharmacy was associated with adverse outcomes, including all-cause mortality, hospitalization, and emergency room visits among older CRC survivors and it was particularly associated with those who were 65 to 75 years and those with low risk of frailty. When prescribing drugs, physicians should be mindful of finding a balance between adequate treatment of diseases and avoiding adverse drug effects in survivors of CRC., (© 2023 American Cancer Society.)

Purpose: It is necessary to estimate the hospice usage and hospice-related cost for entire cancer patients using nationwide cohort data to establish a suitable ethical and cultural infrastructure. This study aims to show the effects of hospital hospice care on healthcare expenditure among South Korean cancer patients., Methods: This study is a retrospective cohort study using customized health information data provided by the National Health Insurance Service. Individuals who were diagnosed with stomach, colorectal, or lung cancer between 2003 and 2012 were defined as new cancer patients, which included 7,176 subjects. Patients who died under hospital-based hospice care during the follow-up period from January 2016 to December 2018 comprised the treatment group. Healthcare expenditure was the dependent variable. Generalized estimating equations was used., Results: Among the subjects, 2,219 (30.9%) had used hospice care at an average total cost of 948,771 (± 3,417,384) won. Individuals who had used hospice care had a lower odds ratio (EXP(β)) of healthcare expenditure than those who did not (Total cost: EXP(β) = 0.27, 95% confidence intervals (CI) = 0.25-0.30; Hospitalization cost: EXP(β) = 0.32, 95% CI = 0.29-0.35; Outpatient cost: EXP(β) = 0.02, 95% CI = 0.02-0.02)., Conclusion: Healthcare expenditure was reduced among those cancer patients in South Korea who used hospice care compared with among those who did not. This emphasizes the importance of using hospice care and encourages those hesitant to use hospice care. The results provide useful insights into both official policy and the existing practices of healthcare systems., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial examined the effects of combination therapy with moderate-intensity statin and ezetimibe in patients with atherosclerotic cardiovascular disease compared with high-intensity statin monotherapy., Objectives: This observational study was conducted to evaluate the impact of 2 treatment strategies used in the RACING trial in clinical practice., Methods: After stabilized inverse probability of treatment weighting, a total of 72,050 patients who were prescribed rosuvastatin after drug-eluting stent implantation were identified from a nationwide cohort database: 10,794 patients with rosuvastatin 10 mg plus ezetimibe 10 mg (combination lipid-lowering therapy) and 61,256 patients with rosuvastatin 20 mg monotherapy. The primary endpoint was the 3-year composite event of cardiovascular death, myocardial infarction, coronary artery revascularization, hospitalization for heart failure treatment, or nonfatal stroke in accordance with the RACING trial., Results: Combination lipid-lowering therapy was associated with a lower occurrence of the primary endpoint (11.6% vs 15.2% for those with high-intensity statin monotherapy; HR: 0.75; 95% CI: 0.70-0.79; P < 0.001). Compared with high-intensity statin monotherapy, combination lipid-lowering therapy was associated with fewer discontinuations of statin (6.5% vs 7.6%; HR: 0.85; 95% CI: 0.78-0.94: P < 0.001) and a lower occurrence of new-onset diabetes requiring medication (7.7% vs 9.6%; HR: 0.80; 95% CI: 0.72-0.88; P < 0.001)., Conclusions: In clinical practice, combination lipid-lowering therapy with ezetimibe and moderate-intensity statin was associated with favorable clinical outcomes and drug compliance in patients treated with drug-eluting stent implantation. (CONNECT DES Registry; NCT04715594)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Cardiovascular Research Center, Seoul, Korea. The funder had no role in the design and conduct of the study; data collection, management, statistical analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Gastrointestinal (GI) cancer occurs in digestive organs such as the stomach, colon, liver, esophagus, and pancreas. About 83,034 cases occurred in Korea alone in 2020. Dietary factors, alcohol consumption, Helicobacter pylori ( H. pylori ), and lifestyle factors increase the incidence of diseases such as gastritis, peptic ulcer, pancreatitis, and gastroesophageal reflux disease (GERD), which can develop into GI cancer. However, in 2019, the US Food and Drug Administration announced that the drugs ranitidine and nizatidine, which are used for digestive disorders, contain carcinogens. In this study, we investigated the effects of ranitidine and nizatidine on the development of GI cancer., Materials and Methods: In this study, using National Health Insurance Service-National Sample Cohort (NHIS-NSC) version 2.5 (updated from 2002 to 2019), subjects who developed GI cancer were enrolled in the case group, and those who were at risk of, but did not develop, cancer were enrolled in the control group. Thereafter, risk-set matching was performed (1:3 ratio) by sex and age at the time of diagnosis of cancer in the case group. Through this procedure, 22,931 cases and 68,793 controls were identified. The associations of ranitidine and/or nizatidine with GI cancer were confirmed by adjusted odds ratios (aORs) and 95% confidence intervals (CIs) calculated through conditional logistic regression analysis., Results: The aORs of ranitidine and/or nizatidine users were lower than those of nonusers in all average prescription days groups (< 30 days/year: aOR [95% CI] = 0.79 [0.75-0.82]; 30-59 days/year: aOR [95% CI] = 0.66 [0.59-0.73]; 60-89 days/year: aOR [95% CI] = 0.69 [0.59-0.81]; ≥ 90 days/year: aOR [95% CI] = 0.69 [0.59-0.79]). Sensitivity analyses were conducted with different lag periods for the onset of GI cancer after drug administration, and these analyses yielded consistent results. Additional analyses were also performed by dividing subjects into groups based on cancer types and CCI scores, and these analyses produced the same results., Conclusion: Our study, using nationwide retrospective cohort data, did not find evidence suggesting that ranitidine and nizatidine increase the risk of GI cancer. In fact, we observed that the incidence of GI cancer was lower in individuals who used the drugs compared to nonusers. These findings suggest a potential beneficial effect of these drugs on cancer risk, likely attributed to their ability to improve digestive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Nam, Choi and Park.)

Background: Although strengthening coverage has improved cancer care, there are concerns related to medical distortion. Previous studies have only examined whether patients visit a specific hospital, and not the continuum of patients with cancer, resulting in a lack of evidence in South Korea. This study aimed to investigate the patterns in hospital type for cancer care and analyze their association with outcomes., Methods: The data for this study were obtained from the National Health Insurance Services Sampled Cohort database. This study included patients with four types of cancer (top four cancer incidence in 2020): gastric (3353), colorectal (2915), lung (1351), and thyroid (5158) cancer. The latent class mixed model was used to investigate cancer care patterns, and multiple regression or survival analysis was performed to examine medical cost, length of stay (LOS), and mortality., Results: The patterns in each cancer type were classified into two to four classes, namely, mainly visited clinics or hospitals, mainly visited general hospitals, mainly visited tertiary hospitals (MT), and tertiary to general hospitals through trajectory modeling based on the utilization of cancer care. Compared to the MT pattern, other patterns were generally associated with higher cost, LOS, and mortality., Conclusion: The patterns found in this study may be a more realistic way of defining patients with cancer in South Korea compared to previous studies, and its association-related outcomes may be used as a basis to address problems in the healthcare system and prepare alternatives for patients with cancer. Future studies should review cancer care patterns related to other factors such as regional distribution., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background and Objectives: Previous studies have reported the protective effect of pioglitazone on dementia in patients with type 2 diabetes mellitus (DM). Recent studies have shown that pioglitazone also lowers the risk of primary and recurrent stroke. Understanding the characteristics of patients particularly associated with the benefits of pioglitazone would facilitate its personalized use by specifying subpopulations during routine clinical care. The aim of this study was to examine the effects of pioglitazone use on dementia in consideration of stroke occurrence., Methods: Using nationwide longitudinal data of patients with DM from the Korean National Health Insurance Service DM cohort (2002-2017), we investigated the association of pioglitazone use with incident dementia in patients with new-onset type 2 DM. The heterogeneity of the treatment effect was examined using exploratory analyses. Using a multistate model, we assessed the extent to which incident stroke affects the association between pioglitazone use and dementia., Results: Pioglitazone use was associated with a reduced risk of dementia, compared with nonuse (adjusted hazard ratio [aHR] = 0.84, 95% CI 0.75-0.95); the risk reduction in dementia was greater among patients with a history of ischemic heart disease or stroke before DM onset (aHR = 0.46, 95% CI 0.24-0.90; aHR = 0.57, 95% CI 0.38-0.86, respectively). The incidence of stroke was also reduced by pioglitazone use (aHR = 0.81, 95% CI 0.66-1.00). However, when the stroke developed during the observation period of pioglitazone use, such lowered risk of dementia was not observed (aHR = 1.27, 95% CI 0.80-2.04)., Discussion: Pioglitazone use is associated with a lower risk of dementia in patients with DM, particularly in those with a history of stroke or ischemic heart disease, suggesting the possibility of applying a personalized approach when choosing pioglitazone to suppress dementia in patients with DM., (© 2023 American Academy of Neurology.)

Recent studies reported bisphenol A (BPA) and propyl paraben (PrP) are found in human urine, blood, and breast milk samples as well as in food, packaging, socks, and clothes. This means that the two chemicals co-exist in consumer products, and humans are exposed simultaneously to the mixture chemicals. However, the studies on the mixture effects of the two chemicals on human health are not enough. This study was designed to elucidate the effects of orally administered PrP, BPA, and their mixture effects on the uterotrophic response using ovariectomized rats. In addition, the correlation between the uterotrophic response and tissue concentrations of the two chemicals was studied to investigate whether one chemical has any effect on the absorption, distribution, or excretion of the other chemical. Histopathology, hematology, and plasma biochemistry analysis were also performed to evaluate the chemicals' toxicological effects in the treated rats. Although a significant increase in uterus weight (absolute and relative) was observed in the positive chemical (17β-estradiol) treated group, there were no statistical differences in the uterus weight between the vehicle control and the chemical-treated groups. However, a slight increase in the endometrial glands and a change in the cuboidal to columnar epithelium of the endometrial epithelium were observed in the mixture-treated group. There was no significant toxicity in all treated groups by the hematology and plasma biochemistry analysis results. The results of tissue distribution showed that BPA was mostly detected in the liver while PrP was not detected in most tissues, and the BPA level was higher when the rats were treated with PrP than without PrP, suggesting that PrP may increase the absorption of BPA after oral administration.

Purpose: As older patients with gastric cancer increase in Korea, no consensus indicative of anti-cancer treatment exists for the oldest old (age 85+). We investigated potential disparities in the proportion of surgery-including active treatment and the degree of survival improvement over time by age groups, and whether heterogeneity exists in the protective effect of time period on overall survival (OS) by age at diagnosis clusters., Materials and Methods: A nationwide cohort ( N = 63,975) of older patients with gastric cancer (age at diagnosis 70+) in 2005-2012 were followed until the end of 2018. Patients were categorized into four time period groups by their year of diagnosis. Cancer treatment patterns and 5-year OS were analyzed accordingly, and a random coefficients Cox model with random intercepts and random slopes of time period by age at diagnosis clusters was employed., Results: The mean age of patients was 76.4, and 60.4% were males. Most patients had 0-1 comorbidities (73.3%) and low-risk frailty scores (74.2%). Roughly two-thirds of patients received some form of anti-cancer treatment (62.4%), and while the number of comorbidities and the proportion of high-risk frailty scores trended toward an increase, the proportion of patients receiving anti-cancer treatment increased from 58% in 2005-2006 to 69.6% in 2011-2012. The proportion of surgery-including active treatment increased to over 70% in the 70-74 years old group, while stagnating at 10% in the 90+ years old group. Differences in the slope of 5-year OS improvement resulted in a widening survival gap between the old (age 70-84) and the oldest old. The protective effect of time period on OS hazard in the oldest old was not monotonically reduced with increasing "chronological" age but varied quite randomly, especially among female patients., Conclusion: Our study showed no upper age limit in terms of benefiting from the advances in the detection and treatment of gastric cancer over time. Thus, "functional" age rather than "chronological" age should be the criterion for anti-cancer screening and treatment, and actual implementation of proven treatments in the oldest old patients to reduce their non-compliance with treatment in clinical practice is needed to improve gastric cancer survival for all., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Choi, Kim, Kang, Jhang, Jeong, Nam and Park.)

Background and Purpose: Nelonemdaz (Neu2000) has both selective antagonism against 2B subunit of N-methyl-D-aspartate receptor and antioxidant activity. This drug provides sufficient evidence of neuroprotection in acute cerebral ischemia/reperfusion models. This phase III trial aims to determine this effect in patients., Design: The Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz is a multicenter, double-blinded clinical trial. A total of 496 patients will be randomly assigned into the nelonemdaz (a total of 5,250 mg divided by 10 times for 5 days) and placebo groups. Patients will be included if they have an acute ischemic stroke (National Institutes of Health Stroke Scale score ≥8) caused by intracranial large vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score ≥4), and if they are expected to undergo endovascular thrombectomy within 12 hours after stroke onset., Endpoints: The primary endpoint is a favorable shift in the modified Rankin Scale (mRS) score at 90 days after the first dose of drug. The data will be analyzed by the Cochran-Mantel-Haenszel shift test. The secondary endpoints include functional independence (mRS 0-2) at 35 and 90 days, the favorable shift of mRS at 35 days, the proportion of mRS 0 at 35 and 90 days, and the occurrence rates of symptomatic intracranial hemorrhage within 7 days., Conclusion: This trial will clarify the efficacy and safety of nelonemdaz in patients with acute ischemic stroke and endovascular thrombectomy. This study has been registered at ClinicalTrials. gov (NCT05041010).

Background: Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms., Methods: We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients., Results: Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255)., Conclusions: A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: We aimed to investigate the association between fragmented cancer care in the early phase after cancer diagnosis and patient outcomes using national insurance claim data., Methods: From a nationwide sampled cohort database, we identified National Health Insurance beneficiaries diagnosed with gastric cancer (ICD-10: C16) in South Korea during 2005-2013. We analyzed the results of a multiple logistic regression analysis using the generalized estimated equation model to investigate which patient and institution characteristics affected fragmented cancer care during the first year after diagnosis. Then, survival analysis using the Cox proportional hazard model was conducted to investigate the association between fragmented cancer care and five-year mortality., Results: Of 2879 gastric cancer patients, 11.9% received fragmented cancer care by changing their most visited medical institution during the first year after diagnosis. We found that patients with fragmented cancer care had a higher risk of five-year mortality (HR: 1.310, 95% CI: 1.023-1.677). This association was evident among patients who only received chemotherapy or radiotherapy (HR: 1.633, 95% CI: 1.005-2.654)., Conclusions: Fragmented cancer care was associated with increased risk of five-year mortality. Additionally, changes in the most visited medical institution occurred more frequently in either patients with severe conditions or patients who mainly visited smaller medical institutions. Further study is warranted to confirm these findings and examine a causal relationship between fragmented cancer care and survival., (© 2022. The Author(s).)

Backgruound: An excess of thyroid hormones in Graves' disease (GD) has profound effects on systemic energy metabolism that are currently partially understood. In this study, we aimed to provide a comprehensive understanding of the metabolite changes that occur when patients with GD transition from hyperthyroidism to euthyroidism with methimazole treatment., Methods: Eighteen patients (mean age, 38.6±14.7 years; 66.7% female) with newly diagnosed or relapsed GD attending the endocrinology outpatient clinics in a single institution were recruited between January 2019 and July 2020. All subjects were treated with methimazole to achieve euthyroidism. We explored metabolomics by performing liquid chromatography-mass spectrometry analysis of plasma samples of these patients and then performed multivariate statistical analysis of the metabolomics data., Results: Two hundred metabolites were measured before and after 12 weeks of methimazole treatment in patients with GD. The levels of 61 metabolites, including palmitic acid (C16:0) and oleic acid (C18:1), were elevated in methimazole-naïve patients with GD, and these levels were decreased by methimazole treatment. The levels of another 15 metabolites, including glycine and creatinine, were increased after recovery of euthyroidism upon methimazole treatment in patients with GD. Pathway analysis of metabolomics data showed that hyperthyroidism was closely related to aminoacyl-transfer ribonucleic acid biosynthesis and branched-chain amino acid biosynthesis pathways., Conclusion: In this study, significant variations of plasma metabolomic patterns that occur during the transition from hyperthyroidism to euthyroidism were detected in patients with GD via untargeted metabolomics analysis.

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.

Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy., Methods: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks., Results: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P =0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported., Conclusions: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088.

Although continuous treatment leads to better patient outcomes, evidence regarding the effect of the continuity of care (COC) on preventable hospitalisation and medical expenses in Korea for patients with dyslipidaemia is insufficient. We evaluated the effect of COC on preventable hospitalisation and medical expenses for patients with dyslipidaemia. This study used National Health Insurance Sampling cohort data (2008-2015). We measured COC with the Bice-Boxerman index based on the outpatient visits of patients diagnosed with dyslipidaemia for the first time. Preventable hospitalisation included admission for cardiovascular disease (CVD) and all costs for outpatient visits. We evaluated the association of COC with preventable hospitalisation and medical expenses using a generalised estimating equation model. Patients (N = 53,372) with newly diagnosed dyslipidaemia participated. Compared to non-hospitalised patients, hospitalised patients had higher fragmentation scores for CVD, met more healthcare providers, had higher total outpatient visits and had a lower proportion of primary healthcare providers served. A higher fragmentation score was associated with an increased risk of hospitalisation (rate ratio [RR]: 1.873, 95% confidence interval [CI]: 1.520-2.309) and healthcare expenditure (RR: 1.381, 95% CI: 1.322-1.442). The magnitude of the effect of COC on hospitalisation differed according to patients' drug intake and residence location. Fragmentation of care was associated with preventable hospitalisation and increased healthcare costs, especially for patients taking medications/living in rural areas. It is necessary to promote a more effective COC., (© 2022 John Wiley & Sons Ltd.)

Malignant pleural effusion (MPE) is a complication of lung cancer that can be used as an alternative method for tissue sampling because it is generally simple and minimally invasive. Our study evaluated the diagnostic potential of non-small-cell lung carcinoma (NSCLC)-associated MPE in terms of understanding tumor heterogeneity and identifying response factors for EGFR tyrosine kinase inhibitor (TKI) therapy. We performed a single-cell RNA sequencing analysis of 31,743 cells isolated from the MPEs of 9 patients with NSCLC (5 resistant and 4 sensitive to EGFR TKI) with EGFR mutations. Interestingly, lung epithelial precursor-like cells with upregulated GNB2L1 and CAV1 expression were enriched in the EGFR TKI-resistant group. Moreover, GZMK upregulated transitional effector T cells, and plasmacytoid dendritic cells were significantly enriched in the EGFR TKI-resistant patients. Our results suggest that cellular plasticity and immunosuppressive microenvironment in MPEs are potentially associated with the TKI response of patients with EGFR-mutated NSCLC., Competing Interests: JS Ahn reports personal fees from Amgen, Pfizer, AstraZeneca, Menarini, Roche, Eisai, Boehringer Ingelheim, BMSOno, MSD, Janssen, Samsung Bioepis, outside the submitted work. S.H.L. reports grants and personal fees from MSD, personal fees from Novartis, AstraZeneca, BMS, Roche, outside the submitted work. K Park reports personal fees from Astellas, Astra Zeneca, AMGEN, BluePrint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Merck KGaA, MSD, Novartis, ONO, Puma Biotechnology, Roche, outside the submitted work., (© 2022 The Authors.)

MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Bacteriobilia, the colonization of bacteria in bile, can be caused by obstructive cholangitis or preoperative biliary drainage (PBD), and is not uncommon condition in patients undergoing pancreatoduodenectomy (PD). This study aims to investigate the effect of intraoperatively detected bacteriobilia on surgical outcomes after PD., Methods: For patients who underwent PD in Samsung Medical Center between 2018 and 2020, an intraoperative bile culture was performed prospectively, and their clinicopathological data were retrospectively reviewed. Surgical outcomes were compared between the patients, classified according to PBD and bacteriobilia. Logistic regression analysis was performed to identify factors increasing postoperative complications., Results: A total of 382 patients were included, and 202 (52.9%) patients had PBD (PBD group). Bacteriobilia was significantly more common in PBD group comparing to non-PBD group (31.1% vs 75.2%, P < 0.001), but there was no difference in postoperative complications. Among PBD group, there were more patients with major complications and CR-POPF in endoscopic drainage group comparing to percutaneous drainage group (37.9% vs 14.6%, P = 0.002; 17.0% vs 4.2%, P = 0.025, respectively). In multivariable analysis, bacteriobilia increased the risk of wound complications (P = 0.041), but not the risks of other short-term adverse outcomes., Conclusion: Bacteriobilia itself does not exacerbate short-term postoperative outcomes after PD except for wound complication. Therefore, surgery could be performed as planned regardless of bacteriobilia, without the need to wait for negative cultures., (© 2022. The Society for Surgery of the Alimentary Tract.)

Purpose: Fragmented cancer care (FC) means that patients visit multiple providers for treatment, which is common in cancer care. While FC is associated with poor health outcomes in patients with colorectal cancer (CRC) worldwide, there is still a lack of evidence in South Korea. We investigated the association between FC and 5-year morality in patients with CRC using population-based claims data., Methods: The study population was followed up from 2002 to 2015. Data were collected from Korea National Health Insurance claims. Participants comprised patients with CRC diagnosed with International Classification of Diseases (ICD)-10 (C18.x-C20.x) and a special claim code for cancer (V193). Data were analyzed using the Kaplan-Meier curve with a log-rank test and Cox proportional hazard model. The effect of FC on patients' 5-year survival was examined., Results: Of 3467 patients with CRC, 20.0% had experienced FC. FC was significantly associated with an increased risk of 5-year mortality (hazard ratio 1.516, 95% confidence interval 1.274-1.804). FC was prevalent in those who had a low income level, underwent chemotherapy, did not undergo radiation therapy, and did not visit a tertiary hospital for their first treatment., Conclusion: Efforts to decrease FC and integrate complex cancer care within appropriate healthcare delivery systems may improve survivorship among patients with CRC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The nodal stage of pancreatic ductal adenocarcinoma (PDAC) is revised in the AJCC 8th edition. Studies on the prognosis of PDAC according to lymph node metastasis (LNM) are still ongoing. We attempted to find the patterns of nodal involvement and to reveal its clinical significance to overall survival (OS)., Methods: We analyzed 585 patients who received pancreatic head cancer surgery diagnosed as PDAC from January 2007 to December 2016. Patients were classified into three groups: Group 1 (G1, patients without LNM), Group 2 (G2, those with LNM only in the peripancreatic area), and Group 3 (G3 those with LNM in the other area and/or peripancreatic LNM). Risk factors were analyzed by Cox-regression test and overall survival was compared by Kaplan-Meier analysis., Results: LNM in peripancreatic area was the most common (88.7%). In the multivariate analysis, T stage, nuclear differentiation, adjuvant treatment, and the G2 and G3 were independent risk factors for OS (G2 over G1, HR 1.384, 95% CI 1.046-1.802; P = .036 and G3 over G1, HR 2.383, 95% CI 1.378-4.103; P = .001). G3 showed worse OS than G2 (P = .006). In the N1 status, LNM to the pericholedochal (PC) and superior mesenteric artery (SMA) areas resulted in worse OS than the G2 (P = .011 and P = .019)., Conclusions: We found that LNM beyond the peripancreatic area significantly affects OS in pancreatic head cancer patients. Depending on the station of the LNM, different risk-stratification and treatment strategies will need to be considered., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Highly pathogenic avian influenza (HPAI) is a fatal zoonotic disease that damages the poultry industry and endangers human lives via exposure to the pathogen. A risk assessment model that precisely predicts high-risk groups and occurrence of HPAI infection is essential for effective biosecurity measures that minimize the socio-economic losses of massive outbreaks. However, the conventional risk prediction approaches have difficulty incorporating the broad range of factors associated with HPAI infections at poultry holdings. Therefore, it is difficult to accommodate the complexity of the dynamic transmission mechanisms and generate risk estimation on a real-time basis. We proposed a continuous risk prediction framework for HPAI occurrences that used machine learning algorithms (MLAs). This integrated environmental, on-farm biosecurity, meteorological, vehicle movement tracking, and HPAI wild bird surveillance data to improve accuracy and timeliness. This framework consisted of (i) the generation of 1788 predictors from six types of data and reconstructed them with an outcome variable into a data mart based on a temporal assumption (i.e. infected period and day-ahead forecasting); (ii) training of the predictors with the temporally rearranged outcome variable that corresponded to HPAI H5N6 infected state at each individual farm on daily basis during the 2016-2017 HPAI epidemic using three different MLAs [Random Forest, Gradient Boosting Machine (GBM), and eXtreme Gradient Boosting]; (iii) predicting the daily risk of HPAI infection during the 2017-2018 HPAI epidemic using the pre-trained MLA models for each farm across the country. The models predicted the high risk to 8-10 out of 19 infected premises during the infected period in advance. The GBM MLAs outperformed the 7-day forecasting of HPAI prediction at individual poultry holdings, with an area under the curve (AUC) of receiver operating characteristic of 0.88. Therefore, this approach enhances the flexibility and timing of interventions against HPAI outbreaks at poultry farms., (© 2021 Wiley-VCH GmbH.)

Background: Optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) who have undergone drug-eluting stent (DES) implantation is not clearly established. This study sought to impact of DAPT duration on real-world clinical outcome in patients with or without DM., Methods: Using a nationwide cohort database, we investigate the association between DAPT duration and clinical outcome between 1 and 3 years after percutaneous coronary intervention (PCI). Primary outcome was all-cause death. Secondary outcomes were cardiovascular death, myocardial infarction, and composite bleeding events. After weighting, 90,100 DES-treated patients were included; 29,544 patients with DM and 60,556 without DM; 31,233 patients with standard DAPT (6-12 months) and 58,867 with prolonged DAPT (12-24 months)., Results: The incidence of all-cause death was significantly lower in patients with prolonged DAPT [8.3% vs. 10.5% in those with standard DAPT, hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.72-0.84] in diabetic patients and non-diabetic patients (4.5% vs. 5.0% in those with standard DAPT, HR 0.89, 95% CI 0.83-0.96). The incidence of composite bleeding events was 5.7% vs. 5.4%, respectively, (HR 1.07, 95% CI 0.96-1.18) in diabetic patients and 5.6% vs. 5.0%, respectively, in non-diabetic patients (HR 1.13, 95% CI 1.05-1.21). There was a significant interaction between the presence of DM and DAPT duration for all-cause death (p for interaction, p int = 0.01) that further favored prolonged DAPT in diabetic patients. However, there was no significant interaction between the presence of DM and DAPT duration for composite bleeding events (p int = 0.38)., Conclusions: This study showed that prolonged rather than standard DAPT might be clinically beneficial in diabetic patients with DES implantation., Trial Registration: ClinicalTrial.gov (NCT04715594)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Choi, Kim, Suh, Hong, Ahn, Kim, Kim, Ko, Choi, Park, Jang, Nam and Hong.)

Continuity of care and area deprivation have been implicated as possible risk factors of suicide in psychiatric patients. This nested case-control study aimed to examine the association between continuity of care and area deprivation and suicide death in patients with psychiatric disorders. Data were collected from the Korean National Health Insurance Service National Sample Cohort, 2003-2013. The subjects were 974 patients with psychiatric disorders who completed suicides. Each case was compared to three control cases with propensity score matching by gender, age, and follow-up period with incidence density sampling, comprising the final control group of 2,922 living patients. Hazard ratios (HR) for suicide risk considering continuity of care and area deprivation were analysed using a multiple conditional logistic regression. The average follow-up periods between the case and control groups were not statistically different (case: 277.6 weeks, control: 271.4 weeks, p = .245). Both poor continuity of care and higher area deprivation proved to be associated with increased risk of suicide (poor continuity of care; adjusted HR [AHR]: 3.38, 95% confidence intervals [CI]: 2.58-4.43, highest area deprivation; AHR: 1.93, 95% CI: 1.53-2.44). Poor continuity of care combined with highest area deprivation showed a negative synergistic effect on a highly increased risk of suicide (AHR: 2.88, 95% CI: 1.45-5.74). Age was effect modified between suicide risk and poor continuity of care as well as suicide risk and higher area deprivation. A strong patient-provider relationship with good continuity of care may lead to a lower possibility of suicide in psychiatric patients. Moreover, improving community capacity for suicide prevention as well as appropriate postvention should be addressed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Aims: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stent in patients with chronic kidney disease (CKD) is not clearly established. This study purposed to compare clinical outcomes of patients with 6-12 (standard) versus 12-24 months (prolonged) DAPT according to CKD., Methods: Using a nationwide, claim-based database, we retrospectively evaluated association between DAPT duration and clinical outcomes including death, composite ischemic event, and composite bleeding event between 1 and 3 years after PCI. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2 . Of 73,941 eligible patients, 13,425 (18.2%) had CKD and 49,019 (66%) were prescribed prolonged DAPT. Prolonged DAPT had no significant impact on the risk of clinical outcomes in patients with normal renal function., Results: In patients with CKD, prolonged DAPT was associated with a lower risk of all-cause death (HR 0.85, 95% CI 0.76-0.95) and composite ischemic events (HR 0.87, 95% CI 0.78-0.96) and a higher risk of composite bleeding events (HR 1.18, 95% CI 1.02-1.37). Benefit of prolonged DAPT on reducing composite ischemic event increased significantly in patients with worsened renal dysfunction (p interaction  = 0.02) while there was no significant interaction between its bleeding risk and renal dysfunction (p interaction  = 0.22)., Conclusions: While standard DAPT would be recommended in patients with normal renal function, tailored decision for DAPT duration would be considered in those with CKD to balance between ischemic and bleeding risks., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: It is unclear whether beta-blocker treatment is advantageous in patients with stable coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI). We evaluated the clinical impact of long-term beta-blocker maintenance in patients with stable CAD after PCI with drug-eluting stent (DES)., Methods: From a nationwide cohort database, we identified the stable CAD patients without current or prior history of myocardial infarction or heart failure who underwent DES implantation. An intention-to-treat principle was used to analyze the impact of beta-blocker treatment on long-term outcomes of major adverse cardiovascular events (MACE) composed of cardiovascular death, myocardial infarction, and hospitalization with heart failure., Results: After stabilized inverse probability of treatment weighting, a total of 78,380 patients with stable CAD was enrolled; 45,746 patients with and 32,634 without beta-blocker treatment. At 5 years after PCI with a 6-month quarantine period, the adjusted incidence of MACE was significantly higher in patients treated with beta-blockers [10.0 vs. 9.1%; hazard ratio (HR) 1.11, 95% CI 1.06-1.16, p < 0.001] in an intention-to-treat analysis. There was no significant difference in all-cause death between patients treated with and without beta-blockers (8.1 vs. 8.2%; HR 0.99, 95% CI 0.94-1.04, p = 0.62). Statistical analysis with a time-varying Cox regression and rank-preserving structure failure time model revealed similar results to the intention-to-treat analysis., Conclusions: Among patients with stable CAD undergoing DES implantation, long-term maintenance with beta-blocker treatment might not be associated with clinical outcome improvement., Trial Registration: ClinicalTrial.gov (NCT04715594)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Choi, Kim, Suh, Hong, Ahn, Kim, Kim, Ko, Choi, Park, Jang, Nam and Hong.)

Background: Despite the theoretical benefits of biodegradable polymer drug-eluting stents (BP-DES), clinical benefits of BP-DES over durable polymer DES (DP-DES) have not been clearly demonstrated. Using data from a large-volume nationwide cohort, we compared long-term clinical outcomes between BP-DES- and DP-DES-treated patients., Methods: A retrospective cohort study that enrolled all patients who underwent percutaneous coronary intervention (PCI) with new-generation DES between 2010 and 2016 in Korea was conducted by using the National Health Insurance Service database. The outcomes of interest were all-cause death, cardiovascular death, and myocardial infarction (MI)., Results: A total of 127,731 patients treated with new-generation DES with thin struts (<90 μm) were enrolled for this analysis. After stabilized inverse probability of treatment weighting, the incidence of all-cause death was significantly lower in patients treated with BP-DES ( n = 19,521) at 5 years after PCI (11.3 vs. 13.0% in those treated with DP-DES [ n = 108,067], hazard ratio [HR] 0.92, 95% confidence interval [CI], 0.88-0.96, p < 0.001), while showing no statistically significant difference at 2 years after PCI (5.7 vs. 6.0%, respectively, HR 0.95, 95% CI, 0.89-1.01, p = 0.238). Similarly, use of BP-DES was associated with a lower incidence of cardiovascular death (7.4 vs. 9.6% in those treated with DP-DES, HR 0.82, 95% CI, 0.77-0.87, p < 0.001), and MI (7.4 vs. 8.7%, respectively, HR 0.90, 95% CI, 0.86-0.94, p = 0.006) at 5 years after PCI. There was no statistically significant difference of cardiovascular death (4.6 vs. 4.9%, respectively, HR 0.93, 95% CI, 0.85-1.01, p = 0.120) and MI (5.0 vs. 5.1%, respectively, HR 0.98, 95% CI, 0.92-1.05, p = 0.461) at 2 years after PCI., Conclusions: Implantation of BP-DES was associated with a lower risk of all-cause death, cardiovascular death, and MI compared with DP-DES implantation. This difference was clearly apparent at 5 years after DES implantation., Clinical Trial Registration: ClinicalTrial.gov, NCT04715594., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Choi, Suh, Hong, Ahn, Kim, Kim, Ko, Choi, Park, Jang, Nam and Hong.)

Background: Although survival based outcomes of lung cancer patients have been well developed, institutional transition of cancer care, that is, when patients transfer from primary visiting hospitals to other hospitals, and mortality have not yet been explored using a large-scale representative population-based sample., Methods: Data from the Korean National Elderly Sampled Cohort survey were used to identify patients with lung cancer who were diagnosed during 2005-2013 and followed up with for at least 1 year after diagnosis (3738 patients with lung cancer aged over 60 years). First, the authors examined the distribution of the study population by mortality, and Kaplan-Meier survival curves/log-rank test were used to compare mortality based on institutional transition of cancer care. Survival analysis using the Cox proportional hazard model was conducted after controlling for all other variables., Results: Results showed that 1-year mortality was higher in patients who underwent institutional transition of cancer care during 30 days after diagnosis (44.2% vs. 39.7%, p = .027); however, this was not associated with 5-year mortality. The Cox proportional hazard model showed that patients who underwent institutional transition of cancer care during 30 days after diagnosis exhibited statistically significant associations with high mortality for 1 year and 5 years (1-year mortality, Hazard ratio [HR]: 1.279, p = .001; 5-year mortality, HR: 1.158, p = .002)., Conclusion: This study found that institutional transition of cancer care was associated with higher mortality among elderly patients with lung cancer. Future consideration should also be given to the limitation of patients' choice when opting for institutional transition of care since there are currently no control mechanisms in this regard. Results of this study merit health policymakers' attention., (© 2022. The Author(s).)

Diabetes is an ambulatory care sensitive condition that quality of care can prevent complications development and hospitalization needs. However, diabetes patients with disability face greater challenges with receiving quality diabetes care than those without disabilities. This study examined diabetes-related avoidable hospitalizations (DRAH) focusing on the association with disability. We used nationally representative health insurance cohort data from 2002 to 2013. The study population is people who were newly diagnosed with type 2 diabetes. We measured the cumulated number of DRAH using the Prevention Quality Indicators (PQIs). The variables of interest were disability severity and type. We performed a recurrent events analysis using Cox proportional hazard regression model. Among 49,410 type 2 diabetes patients, 12,231 (24.8%) experienced DRAHs at least once during the follow-up period. Among the total population, 5924 (12.0%) diabetes patients were registered as disabled. The findings report that disability severity was significantly associated with higher risks for DRAH, where severely disabled diabetes patients showed the highest hazard ratio of 2.24 (95% CI 1.80-2.79). Among three DRAH indicators, severely disabled diabetes patients showed increased risks for long-term (AHR 2.21, 95% CI 1.89-2.60) and uncontrolled (AHR 2.28, 95% CI 1.80-2.88) DRAH. In addition, intellectual (AHR 5.52, 95% CI 3.78-8.05) and mental (AHR 3.97, 95% CI 2.29-6.89) disability showed higher risks than other types of disability. In conclusion, diabetes patients with disability are at higher risk for DRAH compared to those without disabilities, and those with intellectual and mental disabilities were more likely to experience DRAH compared to those with physical or other types of disability. These findings call for action to find the more appropriate interventions to improve targeted diabetes primary care for patients with disability. Further research is needed to better understand determinants of increasing risks of DRAH., (© 2022. The Author(s).)