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Background and Aims: HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX 3 CR1 + macrophages to protumorigenic properties in the peritumoral area., Approach and Results: In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14 + CD11b + HLA-DR - macrophages with CX 3 CR1 in the HCC adjacent region where α-smooth muscle actin-expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX 3 CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX 3 CR1 + Ly6C + macrophages was mostly observed with decreased CD8 + T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX 3 CR1 + Ly6C + macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX 3 CR1 + Ly6C + macrophages and human blood CD14 + cells, leading to the suppression of CD8 + T-cell proliferation. Moreover, genetic deficiency of CX 3 CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development., Conclusions: We showed that CX 3 CR1 + Ly6C + macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX 3 CR1 + Ly6C + macrophages, subsequently depriving CD8 + T cells of arginine and promoting HCC., (Copyright © The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Advancements in neonatal care have increased preterm infant survival but paradoxically raised intraventricular hemorrhage (IVH) rates. This study explores IVH prevalence and long-term outcomes of very low birth weight (VLBW) infants in Korea over a decade., Methods: Using Korean National Health Insurance data (NHIS, 2010-2019), we identified 3372 VLBW infants with IVH among 4,129,808 live births. Health-related claims data, encompassing diagnostic codes, diagnostic test costs, and administered procedures were sourced from the NHIS database. The results of the developmental assessments  are categorized into four groups based on standard deviation (SD) scores. Neonatal characteristics and complications were compared among the groups. Logistic regression models were employed to identify significant changes in the incidence of complications and to calculate odds ratios with corresponding 95% confidence intervals for each risk factor associated with mortality and morbidity in IVH. Long-term growth and development were compared between the two groups (years 2010-2013 and 2014-2017)., Results: IVH prevalence was 12% in VLBW and 16% in extremely low birth weight (ELBW) infants. Over the past decade, IVH rates increased significantly in ELBW infants (P = 0.0113), while mortality decreased (P = 0.0225). Major improvements in certain neurodevelopmental outcomes and reductions in early morbidities have been observed among VLBW infants with IVH. Ten percent of the population received surgical treatments such as external ventricular drainage (EVD) or a ventriculoperitoneal (VP) shunt, with the choice of treatment methods remaining consistent over time. The IVH with surgical intervention group exhibited higher incidences of delayed development, cerebral palsy, seizure disorder, and growth failure (height, weight, and head circumference) up to 72 months of age (P < 0.0001). Surgical treatments were also significantly associated with abnormal developmental screening test results., Conclusions: The neurodevelopmental outcomes of infants with IVH, especially those subjected to surgical treatments, continue to be a matter of concern. It is imperative to prioritize specialized care for patients receiving surgical treatments and closely monitor their growth and development after discharge to improve developmental prognosis. Supplementary file2 (MP4 77987 kb)., (© 2024. The Author(s).)

Background: The relationship between early life factors and childhood pulmonary function and structure in preterm infants remains unclear., Purpose: This study investigated the impact of bronchopulmonary dysplasia (BPD) and perinatal factors on childhood pulmonary function and structure., Methods: This longitudinal cohort study included preterm participants aged ≥5 years born between 2005 and 2015. The children were grouped by BPD severity according to National Institutes of Health criteria. Pulmonary function tests (PFTs) were performed using spirometry. Chest computed tomography (CT) scans were obtained and scored for hyperaeration or parenchymal lesions. PFT results and chest CT scores were analyzed with perinatal factors., Results: A total 150 children (66 females) aged 7.7 years (6.4-9.9 years) were categorized into non/mild BPD (n=68), moderate BPD (n=39), and severe BPD (n=43) groups. The median z score for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced midexpiratory flow (FEF25%-75%) were significantly lower in the severe versus non/mild BPD group (-1.24 vs. -0.18, -0.22 vs. 0.41, -1.80 vs. -1.12, and -1.88 vs. -1.00, respectively; all P<0.05). The median z scores of FEV1, FEV1/ FVC, and FEF25%-75% among asymptomatic patients were also significantly lower in the severe versus non/mild BPD group (-0.82 vs. 0.09, -1.68 vs. -0.87, -1.59 vs. -0.61, respectively; all P<0.05). The severe BPD group had a higher median (range) CT score than the non/mild BPD group (6 [0-12] vs. 1 [0-10], P<0.001). Prenatal oligohydramnios was strongly associated with both low pulmonary function (FEV1/FVC

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

Background/aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice., Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events., Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort., Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Introduction: A narrow safety margin (NSM) after endoscopic submucosal dissection (ESD) is a well-recognized risk factor for local recurrence in early gastric cancer (EGC). However, only a few studies have investigated the risk factors for the development of NSM., Methods: The medical records and pathologic specimens of patients with EGC who underwent ESD from January 2020 to December 2020 at a single tertiary hospital (Daejeon, South Korea) were reviewed., Results: A total of 218 patients were enrolled and 29 had NSM (&lt;3 mm). When comparing the NSM and the control groups, the size of the lesion, the depth of invasion, and the operating endoscopist were found to be risk factors for the development of NSM. The increased length of the subepithelial spread of the lesion was associated with a narrower safety margin. Logistic regression analysis revealed that lesion size was a risk factor for NSM, and a marginally significant difference between endoscopists was found., Conclusions: Multiple factors may need to be considered during ESD, including lesion size, invasion depth, operating endoscopist, and subepithelial spread., (© 2024 S. Karger AG, Basel.)

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed., (© 2024. The Author(s).)

Background: Dexamethasone is widely used as a systemic corticosteroid to treat and prevent bronchopulmonary dysplasia (BPD) in preterm infants. We evaluated the current epidemiology of dexamethasone use to prevent BPD and analyse the factors associated with the response to dexamethasone in very low birthweight infants using a nationwide database., Methods: We included very low birthweight infants born between January 2013 and December 2020 with a gestational age of 23-31 weeks using data from the Korean Neonatal Network registry. Patients were grouped based on their dexamethasone use into 'Dex' or 'No Dex' groups. Clinical variables and data were collected, and the annual trends of dexamethasone use and the proportion of patients who received dexamethasone according to gestational age were analysed. Respiratory outcomes were compared between the groups. Univariate and multivariate analyses were performed to analyse factors associated with the response to dexamethasone in BPD., Results: Of 11 261 eligible infants, 2313 (20.5%) received dexamethasone, and 1714 (74.1%) of them were diagnosed with moderate-to-severe BPD. The 8-year annual prevalence of dexamethasone use was 17.7-22.3%. The 'Dex' group had more moderate-to-severe BPD, more frequent invasive ventilation use at a postmenstrual age of 36 weeks and longer ventilator duration. Birth weight, 5-minute APGAR score, pulmonary hypertension within the first 28 days, surgical treatment of patent ductus arteriosus, medical treatment of patent ductus arteriosus, pathological chorioamnionitis, hydrocortisone or budesonide use, surgical management of necrotising enterocolitis and fungal sepsis were associated with BPD after dexamethasone use., Conclusions: Approximately 20.5% of preterm infants received dexamethasone, and the frequency increased as gestational age decreased. Poor response to dexamethasone was associated with antenatal and postnatal inflammation, low birth weight and early pulmonary hypertension., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Accurate prediction of postnatal growth failure (PGF) can be beneficial for early intervention and prevention. We aimed to develop a machine learning model to predict PGF at discharge among very low birth weight (VLBW) infants using extreme gradient boosting. A total of 729 VLBW infants, born between 2013 and 2017 in four hospitals, were included. PGF was defined as a decrease in z-score between birth and discharge that was greater than 1.28. Feature selection and addition were performed to improve the accuracy of prediction at four different time points, including 0, 7, 14, and 28 days after birth. A total of 12 features with high contribution at all time points by feature importance were decided upon, and good performance was shown as an area under the receiver operating characteristic curve (AUROC) of 0.78 at 7 days. After adding weight change to the 12 features-which included sex, gestational age, birth weight, small for gestational age, maternal hypertension, respiratory distress syndrome, duration of invasive ventilation, duration of non-invasive ventilation, patent ductus arteriosus, sepsis, use of parenteral nutrition, and reach at full enteral nutrition-the AUROC at 7 days after birth was shown as 0.84. Our prediction model for PGF performed well at early detection. Its potential clinical application as a supplemental tool could be helpful for reducing PGF and improving child health.

Background: Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC., Methods: Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias., Results: There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival., Conclusions: Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4 + NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719; p = 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338; p = 0.002) and NRG4 (HR, 431.763; p = 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC.

Background/aims: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Ultrasound, the most used tool for diagnosing NAFLD, is operator-dependent and shows suboptimal performance in patients with mild steatosis. However, few studies have been conducted on whether alternative noninvasive methods are useful for diagnosing mild hepatic steatosis. Also, little is known about whether noninvasive tests are useful for grading the severity of hepatic steatosis or the degree of intrahepatic inflammation. Therefore, we aimed to evaluate whether the HSI, the FLI and HU values in CT could be used to discriminate mild hepatic steatosis and to evaluate the severity of hepatic steatosis or the degree of intrahepatic inflammation in patients with low-grade fatty liver disease using liver biopsy as a reference standard., Methods: Demographic, laboratory, CT imaging, and histological data of patients who underwent liver resection or biopsy were analyzed. The performance of the HSI, HU values and the FLI for diagnosing mild hepatic steatosis was evaluated by calculating the area under the receiver operating characteristic curve. Whether the degree of hepatic steatosis and intrahepatic inflammation could be predicted using the HSI, HU values or the FLI was also analyzed. Moreover, we validate the results using magnetic resonance imaging proton density fat fraction as an another reference standard., Results: The AUROC for diagnosing mild hepatic steatosis was 0.810 (p < 0.001) for the HSI, 0.732 (p < 0.001) for liver HU value, 0.802 (p < 0.001) for the difference between liver and spleen HU value (L-S HU value) and 0.813 (p < 0.001) for the FLI. Liver HU and L-S HU values were negatively correlated with the percentage of hepatic steatosis and NAFLD activity score (NAS) and significantly different between steatosis grades and between NAS grades. The L-S HU value was demonstrated the good performance for grading the severity of hepatic steatosis and the degree of intrahepatic inflammation., Conclusions: The HU values on CT are feasible for stratifying hepatic fat content and evaluating the degree of intrahepatic inflammation, and the HSI and the FLI demonstrated good performance with high sensitivity and specificity in diagnosing mild hepatic steatosis., (© 2023. The Author(s).)

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges., (© 2023. The Author(s).)

As the use of carbon-fiber-reinforced plastic (CFRP) and glass-fiber-reinforced plastic is frequent in the field of construction, a method for measuring FRP resin content is needed. Herein, thermal gravimetric analysis (TGA) was employed to optimize the heat treatment conditions (temperature and time) for determining the resin content in which only the resin was removed without fiber heat loss. Accordingly, the measurement was performed in 100 °C increments at a resin pyrolysis temperature up to 800 °C with a heat treatment time of 4 h to continuously observe the degree of thermal decomposition of the resin. The thermal decomposition of unsaturated polyester was confirmed at the melting point (350 ℃) regardless of the type of fibers used as reinforcement. In the case of CFRP, most of the resin decomposition occurred at 300 °C. Notably, the resin was removed at a pyrolysis temperature of 400 ℃ and almost no change in weight was observed. However, at a pyrolysis temperature of 500 °C or higher, the thermal decomposition of the fibers occurred partially. The results show that the composite resin was removed within 10 min at a pyrolysis temperature of 400 °C in an air atmosphere when using TGA.

Background: Sudden infant death syndrome (SIDS) still remains one of the leading causes of infant death worldwide, especially in high-income countries. To date, however, there is no detailed information on the global health burden of SIDS., Aims: To characterize the global disease burden of SIDS and its trends from 1990 to 2019 and to compare the burden of SIDS according to the socio-demographic index (SDI)., Design: Systematic analysis based on the Global Burden of Disease (GBD) 2019 data., Methods: Epidemiological data of 204 countries from 1990 to 2019 were collected via various methods including civil registration and vital statistics in the original GBD study. Estimates for mortality and disease burden of SIDS were modeled. Crude mortality and mortality rates per 100 000 population were analyzed. Disability-adjusted life years (DALYs) and DALY rates were also assessed., Results: In 2019, mortality rate of SIDS accounted for 20.98 [95% Uncertainty Interval, 9.15-46.16] globally, which was a 51% decrease from 1990. SIDS was most prevalent in Western sub-Saharan Africa, High-income North America and Oceania in 2019. The burden of SIDS was higher in males than females consistently from 1990 to 2019. Higher SDI and income level was associated with lower burden of SIDS; furthermore, countries with higher SDI and income had greater decreases in SIDS burden from 1990 to 2019., Conclusions: The burden of SIDS has decreased drastically from 1990 to 2019. However, the improvements have occurred disproportionately between regions and SDI levels. Focused preventive efforts in under-resourced populations are needed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The aims of the study were to develop and evaluate a machine learning model with which to predict postnatal growth failure (PGF) among very low birth weight (VLBW) infants., Materials and Methods: Of 10425 VLBW infants registered in the Korean Neonatal Network between 2013 and 2017, 7954 infants were included. PGF was defined as a decrease in Z score >1.28 at discharge, compared to that at birth. Six metrics [area under the receiver operating characteristic curve (AUROC), accuracy, precision, sensitivity, specificity, and F1 score] were obtained at five time points (at birth, 7 days, 14 days, 28 days after birth, and at discharge). Machine learning models were built using four different techniques [extreme gradient boosting (XGB), random forest, support vector machine, and convolutional neural network] to compare against the conventional multiple logistic regression (MLR) model., Results: The XGB algorithm showed the best performance with all six metrics across the board. When compared with MLR, XGB showed a significantly higher AUROC ( p =0.03) for Day 7, which was the primary performance metric. Using optimal cut-off points, for Day 7, XGB still showed better performances in terms of AUROC (0.74), accuracy (0.68), and F1 score (0.67). AUROC values seemed to increase slightly from birth to 7 days after birth with significance, almost reaching a plateau after 7 days after birth., Conclusion: We have shown the possibility of predicting PGF through machine learning algorithms, especially XGB. Such models may help neonatologists in the early diagnosis of high-risk infants for PGF for early intervention., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

Background: Long-term growth data of very low birth weight (VLBW) infants are currently collected in the Korean Neonatal Network (KNN) and National Health Insurance Service (NHIS) database. However, variance in the number of infants, check-up time, and check-up parameters led to decreased credibility of cumulated data. We aimed to compare the data on serial growth outcomes by major morbidities from birth to 5 years in VLBW infants between the KNN and NHIS databases., Methods: We combined the NHIS and KNN data of VLBW infants born between 2013 and 2015. The check-up times in the NHIS database were at 4-6, 9-12, 18-24, 30-36, 42-48, and 54-60 months of age, whereas in the KNN were at 18-24 months of corrected age and at 36 months of age., Result: Among 8,864 VLBW infants enrolled based on the birth certificates from the Statistics Korea, 6,086 infants (69%) were enrolled in the KNN, and 5,086 infants (57%) participated in the NHIS health check-up. Among 6,068 infants, 3,428 infants (56%) were enrolled at a corrected age of 18-24 months and 2,572 infants (42%) were enrolled at a chronological age of 33-36 months according to the KNN follow-up registry. However, based on the national birth statistics data, the overall follow-up rate of the KNN at 36 months of age was as low as 29%. The NHIS screening rate was lower at first (23%); however, it increased over time to exceed the KNN follow-up rate. Growth failure (weight under 10th percentile) at corrected ages of 18-24 months and 36 months were more common in the NHIS than KNN (42% vs. 20%, 37% vs. 34.5%). Infants with bronchopulmonary dysplasia and periventricular leukomalacia showed similar rates of growth failure at 2 years but varying rates at 3 years between the KNN and NHIS., Conclusion: By integrating the KNN and NHIS data indirectly at continuous time points according to morbidities, we found that there are discontinuities and discrepancies between the two databases among VLBW infants. Establishing an integrated system by patient level linking the KNN and NHIS databases can lead to better understanding and improved neonatal outcomes in VLBW infants in Korea., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Introduction: Although signet ring cell carcinoma (SRC) is a subtype of poorly cohesive carcinoma (PC), the differences in the biological behavior between the 2 morphologically similar carcinomas have not been fully studied. Therefore, we performed transcriptome analysis to evaluate the differences of genetic expressions between SRC and PC., Methods: The study group consisted of patients with SRC or PC pathology from patients with early gastric cancer (EGC) whose depth of invasion was localized in the mucosal layer. A total of 18 patients were enrolled. The patients were divided into 3 groups based on their histologic type and lymph node (LN) status. Group 1 consisted of patients with PC and positive LN metastasis, Group 2 consisted of patients with PC without LN metastasis, and Group 3 consisted of patients with SRC without LN metastasis. Transcriptome analysis was performed using the nCounter PanCancer Progression Panel Kit., Results: The expression of 77 genes in Group 1 was altered compared to that in normal tissues. The expression of 49 and 13 genes in Groups 2 and 3, respectively, was altered when compared to that in normal tissues. Groups 1 and 2 showed similar genetic expressions. However, Group 3 showed numerous differences in gene expression including Roundabout4 (Robo4) compared to the other groups, especially Group 1., Conclusion: Our data suggest that gene expression patterns were different between SRC and PC and expression of ROBO4 may play an important role in the prognosis of SRC and PC type of EGC., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Bronchopulmonary dysplasia (BPD) can cause respiratory morbidity beyond the neonatal period. We aimed to analyze the association of BPD on childhood lower respiratory illness (LRI) and asthma among patients diagnosed with respiratory distress syndrome (RDS). This case-control study analyzed data between 2002 and 2015 from a nationwide database. We included 55,066 children with RDS. Two-year LRI and asthma at ages 3 and 5 were assessed. Readmission for LRIs within 2 years of birth occurred in 53.9% and 37.9% of the BPD (n = 9470) and non-BPD (n = 45,596) cases, respectively. In the BPD group, the median number of hospitalizations, mechanical ventilation and oxygen use rates were significantly higher, while the hospitalization duration was significantly longer (P < 0.001 for all). The relative risk of BPD was 1.42 (1.39-1.45) on total readmission and 6.53 (5.96-7.15) on intensive care unit readmission. Asthma prevalence was significantly higher in BPD group (57.6% vs. 48.9% at age 3 and 44.3% vs. 38.2% at age 5, P < 0.001). In children with RDS, BPD could affect repetitive and worse LRI as an independent risk factor for respiratory morbidity during the first 2 years of life. BPD may also be a crucial risk factor for asthma in preschoolers., (© 2022. The Author(s).)

Background: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer., Methods: We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively., Results: Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U- 13 C 6 ]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production., Conclusions: Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Enteric fever is a systemic disease caused by Salmonella enterica serovar Typhi or Salmonella enterica serovar Paratyphi, characterized by high fever and abdominal pain. Most patients with enteric fever improve within a few days after antibiotic treatment. However, some patients do not recover as easily and develop fatal life-threatening complications, including intestinal hemorrhage. Lower gastrointestinal bleeding has been reported in 10% of cases. However, upper gastrointestinal bleeding has rarely been reported in patients with enteric fever. We present a case of gastric ulcer hemorrhage caused by enteric fever., Case Presentation: A 32-year-old woman, complaining of fever lasting four days and right upper quadrant pain and melena that started one day before admission, consulted our hospital. Abdominal computed tomography revealed mild hepatomegaly and gastroscopy revealed multiple active gastric ulcers with flat black hemorrhagic spots. The melena of the patient stopped on the third day. On the fifth admission day, she developed hematochezia. At that time, Salmonella enterica serovar Typhi was isolated from the blood culture. The antibiotic regimen was switched to ceftriaxone. Her hematochezia spontaneously resolved the following day. Finally, the patient was discharged on the 12th admission day without clinical symptoms. However, her fever recurred one month after discharge, and she was readmitted and Salmonella enterica serovar Typhi was confirmed again via blood culture. She was treated with ceftriaxone for one month, and was discharged without complications., Conclusion: Our case showed that although rare, active gastric ulcers can develop in patients with enteric fever. Therefore, upper and lower gastrointestinal bleeding should be suspected in patients with enteric fever, especially showing relapsing bacteremia., (© 2022. The Author(s).)

The risk of neurodevelopmental disorders in low birth weight (LBW) infants has gained recognition but remains debatable. We investigated the risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in school-aged children according to their birth weight. We conducted a retrospective cohort study using the Korean National Health Insurance claims data of 2,143,652 children who were born between 2008 and 2012. Gestational age of infants was not available; thus, outcomes were not adjusted with it. Not only infants with birth weights of < 1.5 kg, but also 2.0-2.4 kg and 1.5-1.9 kg were associated with having ADHD; odds ratio (OR), 1.41 (95% confidence interval [CI] 1.33-1.50), and 1.49 (95% CI 1.33-1.66), respectively. The OR in infants with birth weights of 2.0-2.4 kg and 1.5-1.9 kg was 1.91 (95% CI 1.79-2.05) and 3.25 (95% CI 2.95-3.59), respectively, indicating increased odds of having ASD. Subgroup analysis for children without perinatal diseases showed similar results. In this national cohort, infants with birth weights of < 2.5 kg were associated with ADHD and ASD, regardless of perinatal history. Children born with LBW need detailed clinical follow-up., (© 2022. The Author(s).)

In the present study, fiber-reinforced plastics (FRP) grid-reinforced concrete with very rapid hardening polymer (VRHP) mortar composites were fabricated using three types of design methods for the FRP grid (hand lay-up method, resin infusion method, and prepreg oven vacuum bagging method), along with two types of fibers (carbon fiber and glass fiber) and two types of sheets (fabric and prepreg). The FRP grid was prepared by cutting the FRP laminates into a 10 mm thick, 50 mm × 50 mm grid. The tensile behavior of the FRP grid embedded in composites was systematically analyzed in terms of the load extension, fracture mode, partial tensile strain, and load-bearing rate. The CFRP grid manufactured by the prepreg OVB method showed the best tensile behavior compared to the CFRP grid manufactured by the hand lay-up and resin infusion methods. The load-bearing of each grid point was proportional to the height from the load-bearing part when reaching the maximum tensile load. In addition, finite element analysis was conducted to compare the experimental and analysis results.

Growth in preterm infants has long-term implications for neurodevelopmental outcomes. We aimed to estimate the nationwide growth outcomes from birth to 5 years in infants born under 1500 g and to analyze the effects of major morbidities in preterm infants on growth. In total, 2961 children born in 2013 with a birth weight under 1500 g who underwent an infant health checkup between 2013 and 2018 according to the National Health Insurance Service database were included. Checkups were conducted at 4-6, 9-12, 18-24, 30-36, 42-48, and 54-60 months of age. Information was obtained from the International Classification of Diseases-10 codes or a questionnaire administered during the check-up. At 60 months of age, the mean percentiles of weight, height, and head circumference fell within only the 30-40th percentile of normal growth values. About 30% of infants had growth parameters below the 10th percentile and showed worse neurodevelopmental outcomes. Using multiple logistic regression, infants with bronchopulmonary dysplasia showed a significantly higher incidence of growth restriction in all three categories of weight (odds ratio [OR] 1.50), height (OR 1.33), and head circumference (OR 1.36) at 60 months. Sepsis was associated with growth restriction in weight (OR 1.43) and head circumference (OR 1.33). Periventricular leukomalacia infants had relatively small head circumferences (OR 1.91) and poor developmental screening results (OR 2.89).Conclusion: Catch-up growth remains a major issue in infants born under 1500 g, especially those with some morbidities from preterm birth. Regular checkups to monitor and early intervention to achieve normal growth are essential. What is Known: • Growth in preterm infants has long-term implications for neurodevelopmental and cardiometabolic outcomes. • Data are lacking on the time-serial effects of many preterm morbidities simultaneously on long-term growth outcomes. What is New: • All growth parameters of VLBW infants, including weight, height, and head circumference, fell within the 30-40th percentile of normal growth for infants at 60 months of age, indicating that catch-up growth for VLBW infants remains an issue. • VLBW infants with major preterm morbidities, including BPD, PVL, and sepsis, showed difficulties in achieving normal catch-up growth and neurodevelopment at 60 months of age., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Colonoscopy surveillance guidelines set the surveillance schedule based on polyp characteristics. Polyps with high-grade dysplasia (HGD) require 3 years of follow-up regardless of size. However, it is unclear whether patients with diminutive polyps (≤5 mm) with HGD have a higher risk. We evaluated the effect of diminutive adenoma with HGD on adenoma occurrence., Methods: From January 2015 to December 2017, patients who underwent index and surveillance colonoscopy were retrospectively screened. The patients were grouped into no adenoma group, low-risk (patients with ≤2 low-grade dysplasia [LGD]), diminutive HGD, and high-risk (HGD >5 mm, ≥3 adenomas) groups according to the index colonoscopy results. Each group was analyzed using logistic analysis., Results: The mean follow-up period was 22.47 months. Altogether, 610 (50.45%) patients had LGD and 152 (12.5%) had HGD. Among them, 61 (5.0%) patients had a diminutive polyp with HGD. Analysis of the risks of developing advanced adenoma in the surveillance colonoscopy showed that compared to the no adenoma group, the diminutive HGD group did not show a significant risk (odds ratio [OR] = 1.503 [0.449-5.027], p = 0.509), while the high-risk group showed a significant risk (OR = 2.044 [1.015-4.114], p = 0.045)., Conclusions: Diminutive adenoma with HGD increased the risk of adenoma on surveillance colonoscopy, and in the case of advanced adenoma, the risk was increased, but it was not statistically significant., (© 2021 S. Karger AG, Basel.)

We aimed to evaluate risk factors for growth failure in very low birth weight (VLBW) infants at 18-24 months of corrected age (follow-up1, FU1) and at 36 months of age (follow-up2, FU2). In this prospective cohort study, a total of 2,943 VLBW infants from the Korean Neonatal Network between 2013 and 2015 finished follow-up at FU1. Growth failure was defined as a z-score below -1.28. Multiple logistic regression was used to analyze risk factors for growth failure after dividing the infants into small for gestational age (SGA) and appropriate for gestational age (AGA) groups. Overall, 18.7% of infants were SGA at birth. Growth failure was present in 60.0% at discharge, 20.3% at FU1, and 35.2% at FU2. Among AGA infants, male sex, growth failure at discharge, periventricular leukomalacia, treatment of retinopathy of prematurity, ventriculoperitoneal shunt status and treatment of rehabilitation after discharge were independent risk factors for growth failure at FU1. Among SGA infants, lower birth weight, pregnancy-induced hypertension, and treatment of rehabilitation after discharge were independent risk factors for growth failure at FU1. Mean weight z-score graphs from birth to 36 month of age revealed significant differences between SGA and non-SGA and between VLBW infants and extremely low birth weight infants. Growth failure remains an issue, and VLBW infants with risk factors should be closely checked for growth and nutrition., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in HSCs have recently been reported in various liver diseases; however, the mechanism linking the glutamine/glutamate metabolism and mGluR5 in liver fibrosis remains unclear. Here, we report that mGluR5 activation in natural killer (NK) cells attenuates liver fibrosis through increased cytotoxicity and interferon-γ (IFN-γ) production in both mice and humans., Approach and Results: Following 2-week injection of carbon tetrachloride (CCl 4 ) or 5-week methionine-deficient and choline-deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild-type mice. Consistently, NK cell-specific mGluR5 knockout mice had aggravated CCl 4 -induced liver fibrosis with decreased production of IFN-γ. Conversely, in vitro activation of mGluR5 in NK cells significantly increased the expression of anti-fibrosis-related genes including Ifng, Prf1 (perforin), and Klrk1 (killer cell lectin like receptor K1) and the production of IFN-γ through the mitogen-activated extracellular signal-regulated kinase/extracellular signal-related kinase pathway, contributing to the increased cytotoxicity against activated HSCs. However, we found that the uptake of glutamate was increased in activated HSCs, resulting in shortage of extracellular glutamate and reduced stimulation of mGluR5 in NK cells. Consequently, this could enable HSCs to evade NK cell cytotoxicity in advanced liver fibrosis. In vivo, pharmacologic activation of mGluR5 accelerated CCl 4 -induced liver fibrosis regression by restoring NK cell cytotoxicity. In humans, mGluR5 activation enhanced the cytotoxicity of NK cells isolated from healthy donors, but not from patients with cirrhosis with significantly reduced mGluR5 expression in NK cells., Conclusions: mGluR5 plays important roles in attenuating liver fibrosis by augmenting NK cell cytotoxicity, which could be used as a potential therapeutic target for liver fibrosis., (© 2021 by the American Association for the Study of Liver Diseases.)

Circulating tumor cells (CTCs) are extremely low-frequency cells in the bloodstream. As those cells have detached from the primary tumor tissues and it circulates throughout the whole body, they are considered as promising diagnostic biomarkers for clinical application. However, the analysis of CTC is often restricted due to their rarity and heterogeneity, as well as their short-term presence. Here we proposed formalin-fixed, paraffin-embedded (FFPE) CTC block method, in combination manner with the hydrogel core-mediated CTC accumulation and conventional paraffin tissue block preparation. The hydrogel core specifically captures and releases cancer cells with high efficiency with an immunoaffinity manner. An additional shell structure protects the isolated cancer cells during the FFPE CTC block preparation process. The fabricated FFPE CTC block was sectioned and cytopathologically investigated just the same way as the conventional tissue block. Our results demonstrate that rare cells such as CTCs can also be prepared for FFPE cell blocks and shows great promise for cytopathological CTC studies.

Background: Circulating tumor DNA (ctDNA) and exosome have been widely researched in the field of medical technology and diagnosis platforms. The purpose of our study was to improve the capturing properties of ctDNA and exosome, which involved combining two beads using approaches that may provide a new method for cancer diagnoses., Methods: We present a dual isolation system including a polydopamine (PDA)-silica-coated alginate bead for circulating tumor DNA (ctDNA) capture and an anti-CD63 immobilized bead for exosome capture. We examined the ctDNA mutation in pre-operative plasma samples obtained from 91 colorectal cancer (CRC) patients using a droplet digital PCR (ddPCR)., Results: The area under the curve (AUROC) of ctKRAS G12D mutation in the buffy coat was 0.718 (95% CI: 0.598-0.838; p = 0.001). Patients with CRC that had unmethylation of MLH1 and MSH2 showed significantly higher buffy coat ctKRAS G12D mutations, ascites ctKRAS G12D mutations, miR-31-5, and mixed scores than the patients with a methylation of MLH1 and MSH2., Conclusion: Our proposed alginate bead using the specific gravity-free method suggests that the screening of mutated ctKRAS DNA and miR-31-5 by liquid biopsy aids in identifying the patients, predicting a primary tumor, and monitoring in the early detection of a tumor.

During microbial infection, bystander CD8 + T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8 + T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8 + T cells and their migration. IL-15 upregulates CCR5 in memory CD8 + T cells in the absence of T cell receptor (TCR) stimulation and enhances CCR5-dependent migration. IL-15-induced CCR5 upregulation is abrogated by TCR stimulation, indicating that CCR5 is upregulated in bystander-activated CD8 + T cells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8 + T cells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8 + T cells is associated with severe liver injury in patients with acute hepatitis A. Altogether, the results indicate that CCR5 upregulation by IL-15 mediates the migration of bystander-activated CD8 + T cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Backgrounds: The clinical significance of subepithelial (SE) spread from early gastric cancer (EGC) is poorly understood. Thus, we evaluated the proportion and extent of SE spread from EGC, as well as related risk factors., Methods: We reviewed medical records and pathological specimens from patients with EGC who underwent surgery or endoscopic resection between January 2016 and December 2016 at Chungnam National University Hospital., Results: A total of 404 patients were reviewed and SE spread was identified for 142 patients (35.1%). The presence of SE spread was associated with gender, histological type, location, endoscopic appearance, color change, presence of lymphovascular invasion, and invasion depth. Multivariable analysis revealed that SE spread was only independently associated with histological type. The distance of SE spread was significantly different between histological types, and the maximum distance was 17 mm., Conclusion: More than 30% of our patients with EGC had SE spread, which could reach up to 17 mm. Given the proportion of SE spread in these cases, a wider resection margin may be safe during endoscopic resection or surgery.

To evaluate national epidemiologic data on infants treated for patent ductus arteriosus (PDA) in Korea and analyze outcomes associated with different PDA treatments. We retrospectively evaluated data on 12,336 patients diagnosed with PDA (International Classification of Diseases-10 code: Q250) between 2015 and 2018 from the Health Insurance Review and Assessment database. Among them, 1623 patients underwent surgical ligation (code: O1671). We used birth certificate data from Statistics Korea to estimate the prevalence, diagnosis, and treatment of PDA. The prevalence of infants with PDA was 81 infants per 10,000 live births and 45.2% in very low birth weight (VLBW) infants, which increased from 2015 to 2018. PDA ligation was performed in 2571 infants and 22% VLBW infants. Medical treatment was administered to 4202 infants, which decreased significantly, especially in VLBW infants (62% to 53%). The proportion of treatment was as follows: conservative treatment (53.1%), intravenous ibuprofen (24.4%), surgery (20.4%), and oral ibuprofen (10.7%); that among 4854 VLBW infants was as follows: intravenous ibuprofen (46.3%), conservative treatment (33.2%), surgery (22.2%), and oral ibuprofen (14.2%). Surgical treatment had a significantly higher risk (odds ratio 1.36) of mortality than conservative treatment. Surgical and/or medical treatments were associated with a higher risk of morbidity. Recently, increased use of conservative management of PDA has contributed to improved neonatal outcomes in VLBW infants. Select patients may still benefit from surgical ligation following careful consideration.

The improvement of delivery room care, according to the 2015 International Consensus, may affect neonatal outcome, especially in very-low-birth-weight infants. We aimed to investigate the current practice of neonatal resuscitation by year and analyze the association with neonatal outcomes. A total of 8142 very-low-birth-weight infants, registered in the Korean Neonatal Network between 2014 and 2017 were included. A significant decreasing trend of intubation (64.5% vs 55.1%, P < 0.0001) and markedly increasing trend of positive pressure ventilation (PPV) (11.5% vs 22.9%, P < 0.0001) were noted. The annual PPV rate differed significantly by gestation (P < 0.0001). The highest level of resuscitation was also shown as an independent risk factor for mortality within 7 days and for bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and periventricular leukomalacia. PPV and intubation were associated with significantly decreased risk of mortality and morbidities compared to epinephrine use. When considering association, the incidence of mortality within 7 days, IVH, PVL, and BPD or mortality showed significant differences by combination of year, gestational age, and level of resuscitation. According to updated guidelines, changes in the highest level of resuscitation significantly associated with reducing mortality and morbidities. More meticulous delivery room resuscitation focusing on extreme prematurity is needed.

Background/aims: Current evidence suggests that liver cirrhosis (LC) causes severe psychological stress and depression, which are risk factors for suicide. Although previous studies reported the association between LC and suicidal thoughts, little is known of its effect on suicidal deaths. Therefore, this study was undertaken to investigate the effect of new-onset LC on suicide., Methods: From the National Health Insurance Service-National Sample Cohort of South Korea, 5,809 incident LC patients and 11,618 risk-set controls matched by propensity score were selected for follow-up. The incidence rate of suicide was estimated using a generalized estimating equation with a Poisson distribution. Effect size was presented as a hazard ratio (HR) using Cox's proportional hazards model., Results: The incidence rate of suicide was 143.3 cases per 100,000 person years (95% confidence interval [CI], 100.2-205.1) among the LC cohort. The LC patients were 2.37 times more likely to commit suicide compared with matched controls (HR, 2.37; 95% CI, 1.44-3.88). Increased suicide risk was evident within the first 2 years of the follow-up period (HR, 2.59; 95% CI, 1.20-5.60) and among the 18-49-year-old age group (HR, 3.72; 95% CI, 1.45-9.56)., Conclusion: Our study found increased risk of suicide in patients with new onset LC, especially during the early period following diagnosis and in younger patients. To decrease this suicide risk, a regular and continuous social support system is required.

Background: In neonatal intensive care unit (NICU) patients with intubation status, fluoroscopic evaluation for the bowel is limited. This study was to evaluate the utility of bedside upper gastrointestinal (UGI) series with delayed radiographs (DR) for assessing duodenojejunal junction (DJJ) and small bowel passage in NICU patients with nonspecific bowel ultrasonography and contrast enema findings., Methods: We reviewed clinical and imaging data for bedside UGI with DR of NICU patients from 2014 to 2019. Five abdominal radiographs were obtained at fixed time intervals of immediately after, 1 min, 5 min, 1 h, and 2 h following the administration of 5 cc/kg isotonic water-soluble contrast agent via the nasogastric tube., Results: Twenty bedside UGI with DR were performed in 17 patients (weight range: 520-3620 g, age range: 0-4 months). Confidence identifying the DJJ was either good (n = 7) or equivocal (n = 8) at immediate or 1 min radiographs. The DJJ could not be evaluated in five from four delayed passage (including two meconium plug syndrome and one gastric volvulus) and one inadequate timing. There was only one case of intestinal malrotation, which was not detected on ultrasonography, but detected at the first UGI examination with good DJJ confidence., Conclusions: Bedside UGI with DR can evaluate intestinal malrotation using immediate and 1 min delay and small bowel passage using 1 and 2 h delay images in NICU patients with nonspecific ultrasonographic and contrast enema findings. The majority with delayed contrast passages can have bowel pathology. Because of a small number of patients in this study, further studies with more infants are needed.

This study aimed to investigate the nationwide growth pattern of infants in Korea according to the birth-weight group and to analyze the effect of growth on development. A total of 430,541 infants, born in 2013 and who received the infant health check-up regularly from 6 months to 60 months of age, were included. The weight, height, head circumferences percentiles, and neurodevelopment using screening tests results were compared among the birth-weight groups. Using longitudinal analysis, the study found a significant difference in height, weight, and head circumference, respectively, according to age at health check-up, birth weight group, and combination of age and birth weight ( p < 0.001). The growth parameters at 60 months of age showed a significant correlation with those at 6 months of age especially in extremely low birth weight infants. The incidence of suspected developmental delay was significantly higher in infants with growth below the 10th percentiles than in those with growth above the 10th percentiles. Among 4571 (1.6%) infants with suspected developmental delay results at 60 months of age, birth weight, sex, and poor growth parameters were confirmed as associated factors. This nationwide Korean study shows that poor growth and neurodevelopment outcomes persisted among low-birth-weight infants at 60 months of age. Our findings provide guidance for developing a nationwide follow-up program for infants with perinatal risk factors in Korea.

Background: Despite the expansion of antenatal syphilis screening programs, congenital syphilis (CS) remains a concern., Purpose: This study aimed to analyze the manifestation and progress of CS, including treatment and follow-up, based on a nationwide study., Methods: From the Korean National Health Insurance Service database, a total of 548 infants were examined for CS during their first year of life from 2013 to 2018. Neurosyphilis and complications were investigated using the International Classification of Diseases-10 codes., Results: The birth rate of infants from mothers with syphilis was 2.8 per 10,000 live births for 5 years, which is not indicative of a decreasing trend. Overall, 148 infants were proven or highly probable or possible of having CS with treatment for 10 days; 66 infants were possible or less likely of having CS with only 1-day treatment. Jaundice (56 %) was common, followed by hearing impairment (14 %), renal disease (8 %), and mental retardation (8 %). Fourteen cases of neurosyphilis occurred. Infants with complications, including mental retardation, eye involvement, hearing impairment, or renal disease, were significantly associated with neurosyphilis (OR 8.49, P < 0.0001). Of 250 patients who received treatment, 92.8 % were treated with one medication: benzathine penicillin was used in 73 % of patients. Only four patients were re-treated due to treatment failure. In addition to the treponemal test, fluorescent treponemal antibody-absorption was the most utilized tool for diagnosis and follow-up., Conclusions: Establishing standardized guidelines for the evaluation of CS, as well as the establishment of treatment regimens and follow up-plans for the disease, at a national level would help improve maternal and neonatal care and facilitate the eradication of CS in Korea.

Although circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of various tumors, clinical correlation of cfDNA with gastric cancer has not been fully understood. To address this, we developed a highly sensitive cfDNA capture system by integrating polydopamine (PDA) and silica. PDA-silica hybrids incorporated different molecular interactions to a single system, enhancing cfDNA capture by 1.34-fold compared to the conventional silica-based approach (p = 0.001), which was confirmed using cell culture supernatants. A clinical study using human plasma samples revealed that the diagnostic accuracy of the new system to be superior than the commercially available cfDNA kit, as well as other serum antigen tests. Among the cancer patients, plasma cfDNA levels exhibited a good correlation with the size of a tumor. cfDNA was also predicative of distant metastasis, as the median cfDNA levels of metastatic cancer patients were ~60-fold higher than those without metastasis (p = 0.008). Furthermore, high concordance between tissue biopsy and cfDNA genomic analysis was found, as HER2 expression in cfDNA demonstrated an area under ROC curve (AUC) of 0.976 (p <0.001) for detecting patients with HER2-positive tumors. The new system also revealed high prognostic capability of cfDNA, as the concentration of cfDNA was highly associated with the survival outcomes. Our novel technology demonstrates the potential to achieve efficient detection of cfDNA that may serve as a reliable biomarker for gastric tumor., Competing Interests: This study was partially supported by Sponsored Research Program (SRP) from Capio Biosciences, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. S. Hong is one of the cofounders of Capio Biosciences, Inc., a biotech startup that is commercializing CapioCyte. This does not alter the adherence to PLOS ONE policies on sharing data and materials. All other authors declare no financial or non-financial competing interests potentially interfering with the submitted research article.

Purpose: The purpose of this study was to identify the optimal timing for screening spinal cord ultrasonography (US) to detect filum terminale lipoma in infants., Methods: We retrospectively reviewed infants (<12 months old) who underwent repeated spinal cord US between April 2011 and January 2019. We excluded infants if they only had one US examination, or if they had lesions other than filum terminale lipoma. Infants with filum terminale lipoma on magnetic resonance imaging were included in the lipoma group and the others in the control group. A linear mixed model was used to assess differences in the growth pattern of filum terminale thickness by age and group. The cutoff thickness on US and its diagnostic performance were assessed according to age., Results: Among 442 infants with 901 US examinations, 46 were included in the lipoma group and 58 in the control group. Sixty-seven infants had unmeasurable filum terminale thickness on initial US, including 55 neonates (82.1%) before 1 month of age. The lipoma group had significantly greater filum terminale thickness than the control group (P<0.001). Thickness increased with age in the lipoma group (P=0.027). The sensitivity of US was 87.5% and the area under the receiver operating characteristic curve was 0.949 (95% confidence interval, 0.849 to 0.991) with a cutoff value of 1.1 mm in 4- to 6-month-old infants., Conclusion: Screening spinal cord US could effectively diagnose filum terminale lipoma in 4- to 6-month-old infants with a cutoff thickness of 1.1 mm. Spinal cord US can be used to screen young infants with intraspinal abnormalities.

Background: Pulmonary surfactant (PS) replacement therapy, as a safe and effective treatment for respiratory distress syndrome (RDS) may have further increased with the extended insurance coverage since 2011 in Korea. Thus, this study aimed to investigate the epidemiologic data of PS replacement therapy for RDS in Korea and to analyze the complications associated with RDS., Methods: We included 19,442 infants who were treated with PS and diagnosed with RDS (International Classification of Diseases-10 codes: P22.0) between 2014 and 2018 from the Health Insurance Review and Assessment database. Birth certificate data from Statistics Korea were used to estimate the incidence of RDS., Results: The average incidence of RDS within the study period was 0.99% among live births. Repeated doses of PS were administered to 1,688 infants (8.7%), ranging from 2 doses in 929 infants (4.8%) to 9 doses in 1 infant (0.01%). The incidence of RDS in term infants markedly increased over 5 years from 0.2% to 0.34%. The incidence was similarly increased among the preterm infants. The RDS mortality rate was 6.3% and showed a decreasing trend according to year. The mortality rate was significantly higher in the lower gestational age group. A decreasing trend was observed in the incidence of the complications, such as patent ductus arteriosus, intraventricular hemorrhage, and bronchopulmonary dysplasia, except for pneumothorax in term infants. The complications were also higher in the lower gestational age group and the lower birth weight group. However, pneumothorax was the most frequent complication in the term infant group and in infants with birth weight ≥ 2,500 g., Conclusion: Advancements in neonatal care and extended insurance coverage have increased the use of PS replacement therapy for RDS. This, in turn, decreased neonatal mortality and the incidence of the associated complications. The appropriate therapeutic strategy for RDS should be decided according to the gestational age and lung pathology., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Background and Aims: Mitochondrial double-stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol-associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll-like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)-17A (IL-17A) production in ALD., Approach and Results: Following binge ethanol (EtOH) drinking, IL-17A production primarily increased in γδ T cells of wild-type (WT) mice, whereas the production of IL-17A was mainly facilitated by CD4 + T cells in acute-on-chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell-depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA-restricting enzyme, was significantly decreased in EtOH-exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH-treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small-sized RNAs were enriched in EtOH-treated Exos (EtOH-Exos) rather than EtOH-treated microvesicles in hepatocytes of WT mice and humans. Quantitative real-time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH-Exos from mice and humans. After direct treatment with EtOH-Exos, IL-1β expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL-17A production of γδ T cells in mice and humans., Conclusions: EtOH-mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL-1β expression in Kupffer cells triggers IL-17A production in γδ T cells at the early stage that may accelerate IL-17A expression in CD4 + T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD., (© 2019 by the American Association for the Study of Liver Diseases.)

TEA Domain Transcription Factors (TEADs) are important in development and serve essential roles in tumorigenesis; however, the role of TEAD2 expression in hepatocellular carcinoma (HCC) has not been widely examined. The present study was conducted to investigate the expression status of TEAD2 in HCC and to evaluate whether the expression of TEAD2 is associated with the prognosis of patients with HCC. mRNA expression data was retrieved for Hippo pathway genes of 50 normal control and 377 HCC samples from The Cancer Genome Atlas data portal. Gene set enrichment, GeneNeighbors, ClassNeighbors and survival analyses were then performed based on the gene expression levels. The mRNA expression of TEAD2 and VGLL4 was significantly higher in HCC compared with the normal control samples, and the mRNA expression of TEAD2 was higher in advanced stages than in early stages. Specifically, survival analysis revealed that higher mRNA expression of TEAD2 was significantly associated with a less favorable overall survival rate (P=0.0067) and there was a trend towards significance between higher mRNA expression of VGLL4 and poor overall survival rate (P=0.051). According to the gene set enrichment analysis, patients with higher mRNA expression of TEAD2 and VGLL4 had strongly enhanced epithelial‑mesenchymal transition and angiogenesis, which are associated with tumor progression. In conclusion, increased mRNA expression of TEAD2 is associated with a poor prognosis in patients with HCC. TEAD2 may serve as a prognostic factor for HCC and a novel therapeutic target.

For acute lower gastrointestinal bleeding (LGIB), lower gastrointestinal endoscopy is the preferred initial diagnostic test. However, it is difficult to perform urgently. Computed tomography (CT) is a convenient alternative.This study aimed to determine the diagnostic performance of CT compared to lower endoscopy as an initial test for evaluating acute LGIB.The medical records of 382 patients who visited our emergency department with hematochezia between January 2012 and January 2017 were retrospectively analyzed. Of them, 112 underwent CT, 65 underwent colonoscopy, and 205 underwent sigmoidoscopy as an initial test. For each method, sensitivity, specificity, positive predictive value, and negative predictive value were calculated upon active bleeding site detection and LGIB etiology diagnosis.The sensitivity, specificity, positive predictive value, and negative predictive value of CT for active bleeding site detection were 85.7%, 100%, 100%, and 96.9%, respectively, while those for identifying the etiology of LGIB were 87.4%, 40.0%, 83.5, and 47.6%, respectively.CT was not inferior to lower endoscopy for active bleeding site detection. Early localization and the exclusion of active bleeding were possible with CT. Etiology was diagnosed with high sensitivity and PPV by CT. Thus, CT can be an alternative initial diagnostic tool for evaluating acute LGIB.