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Ji-Hye Byun,1 Sun-Hong Kwon,1 Ji-Hye Ha,2 Eui-Kyung Lee1 1School of Pharmacy, Sungkyunkwan University, Suwon-si, Gyeonggi-do, 2Ministry of Food and Drug Safety, Cheongju-si, Chungcheongbuk-do, South Korea Purpose: The benefit–risk balance for drugs can alter post approval owing to additional data on efficacy or adverse events. This study developed a quantitative benefit–risk assessment (BRA) model for statins using multicriteria decision analysis with discrete choice experiments and compared a recent BRA with that at the time of approval. Patients and methods: Following a systematic review of the literature, the benefit criteria within the statin BRA model were defined as a reduction in the plasma low-density lipoprotein cholesterol level and a reduction in myocardial infarction incidence; the risk criteria were hepatotoxicity (Liv) and fatal rhabdomyolysis (Rha). The scores for these criteria were estimated using mixed treatment comparison methods. Weighting was calculated from a discrete choice experiment involving 203 Korean patients. The scores and weights were integrated to produce an overall value representing the benefit–risk balance, and sensitivity analyses were conducted. Results: In this BRA model, low-density lipoprotein (relative importance [RI]: 37.50%) was found to be a more important benefit criterion than myocardial infarction (RI: 35.43%), and Liv (RI: 16.28%) was a more important risk criterion than Rha (RI: 10.79%). Patients preferred atorvastatin, and the preference ranking of cerivastatin and simvastatin was switched post approval because of the emergence of additional risk information related to cerivastatin. Conclusion: A quantitative statin BRA model confirmed that the preference ranking of statins changed post approval because of the identification of additional benefits or risks. Keywords: multicriteria decision analysis, statin, quantitative benefit–risk assessment, discrete choice experiment

Ji-Hye Byun,1 Sun-Hong Kwon,1 Ji-Eun Lee,1 Ji-Eun Cheon,1 Eun-Jin Jang,2 Eui-Kyung Lee1 1School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 2Information Statistics, Andong National University, Andong, Gyeongsangbuk-do, South Korea Purpose: To elucidate and compare benefit–risk preferences among Korean patients and physicians concerning cyclooxygenase-2 (Cox-2) inhibitor treatments for arthritis.Materials and methods: Subjects included 100 patients with arthritis and 60 board-certified orthopedic surgeon physicians in South Korea. Through a systematic review of the literature, beneficial attributes of using Cox-2 inhibitors were defined as a decrease in the Western Ontario and McMaster Universities Arthritis Index for pain score and improvement in physical function. Likewise, risk attributes included upper gastrointestinal (GI) complications and cardiovascular (CV) adverse events. Discrete choice experiments were used to determine preferences for these four attributes among Korean patients and physicians. Relative importance and maximum acceptable risk for improving beneficial attributes were assessed by analyzing the results of the discrete choice experiment by using a conditional logit model.Results: Patients ranked the relative importance of benefit–risk attributes as follows: pain reduction (35.2%); physical function improvement (30.0%); fewer CV adverse events (21.5%); fewer GI complications (13.4%). The physicians’ ranking for the same attributes was as follows: fewer CV (33.5%); pain reduction (32.4%); fewer GI complications (18.1%); physical function improvement (16.0%). Patients were more willing than physicians to accept risks when pain improved from 20% or 45% to 55% and physical function improved from 15% or 35% to 45%.Conclusion: We confirmed that patients and physicians had different benefit–risk preferences regarding Cox-2 inhibitors. Patients with arthritis prioritized the benefits of Cox-2 inhibitors over the risks; moreover, in comparison with the physicians, arthritis patients were more willing to accept the trade-off between benefits and risks to achieve the best treatment level. To reduce the preference gap and achieve treatment goals, physicians must better understand their patients’ preferences. Keywords: discrete choice experiment, Cox-2 inhibitors, willingness to accept, patient and physicians preference, arthritis

Objectives: To compare findings at dynamic computed tomography (CT), endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiography (MRC) in patients with sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) and periductal infiltrating cancer in the common bile duct (CBD), and to evaluate the diagnostic performance of ERC and MRC in differentiating between the two diseases.Methods: Bile duct changes at dynamic CT, ERC and MRC were compared in 58 patients with SC-AIP and CBD involvement and 93 patients with periductal infiltrating CBD cancer. Two radiologists rated their confidence in differentiating between the two diseases and the diagnostic performances of ERC and MRC were compared.Results: At CT, SC-AIP was more frequently associated with intrapancreatic CBD involvement, thinner CBD walls, concentric wall thickening, smooth outer margins, and lower degrees of upstream ductal dilatation and contrast enhancement (P ≤ 0.05) than CBD cancer. At ERC and MRC, SC-AIP was more frequently associated with smooth margins, gradual and symmetric narrowing, multifocal involvement and hourglass appearance (P ≤ 0.027) than CBD cancer. MRC showed good diagnostic performance comparable to ERC.Conclusions: Dynamic CT, ERC and MRC can be helpful in distinguishing SC-AIP from periductal infiltrating CBD cancer. MRC may be a useful diagnostic alternative to ERC in differentiating between the two diseases.Key Points: • SC-AIP often mimics periductal infiltrating ductal cancer. • Imaging findings of SC-AIP and periductal infiltrating CBD cancer can be similar. • Dynamic CT, ERC and MRC help differentiate between these two diseases. • MRC may be a useful diagnostic alternative to ERC. [ABSTRACT FROM AUTHOR]

Purpose or Objective: Drug concentration-response curves (DRCs) are crucial in pharmacology for assessing the drug effects on biological systems. The widely used sigmoid Emax model, which accounts for response saturation, relies heavily on the effective drug concentration ( E D 50 ). This reliance can lead to validation errors and inaccuracies in model fitting. The Emax model cannot generate multiple DRCs, raising concerns about whether the dataset is fully utilized., Methods: This study formulates an extended Emax (eEmax) model designed to overcome these limitations. The eEmax model generates multiple DRCs from a single dataset by using various estimated α ' s ∈ 0,100 , while keeping E D α fixed, rather than estimating an E D 50 value as in the Emax model., Results: This model effectively captures a broader range of concentration-response behavior, including non-sigmoidal patterns, thus providing greater flexibility and accuracy compared to the Emax model. Validation using various drug-response data and PKPD frameworks demonstrates the eEmax model's improved accuracy and versatility in handling concentration-response data., Conclusions: The eEmax model provides a robust and flexible method for drug concentration-response analysis, facilitating the generation of multiple DRCs from a single dataset and reducing the possibility of validation errors. This model is particularly valuable for its ease of use and its capability to fully utilize datasets, providing its potential in PKPD modeling and drug discovery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The 78-kDa glucose-regulated protein (GRP78) expressed on the cell surface (csGRP78) has been reported to regulate tissue factor (TF) procoagulant activity (PCA) in lesion-resident endothelial cells (ECs), which is further enhanced by circulating anti-GRP78 autoantibodies that bind to the Leu 98 -Leu 115 epitope in GRP78., Objectives: Determine the effects of the engagement of the anti-GRP78 autoantibody to csGRP78 on ECs and the underlying mechanisms that impact TF PCA., Methods: Immunofluorescent staining was used to determine the presence of csGRP78 in tumor necrosis factor α-treated ECs. An established TF PCA assay was used to evaluate human ECs following treatment with anti-GRP78 autoantibodies. The Fura 2-AM assay (Abcam) was used to quantify changes in intracellular Ca 2+ levels. Small molecules predicted to bind GRP78 were identified using artificial intelligence. Enzyme-linked immunosorbent assays were used to assess the ability of these GRP78 binders to mitigate TF activity and interfere with the autoantibody/csGRP78 complex., Results: In tumor necrosis factor α-treated ECs, anti-GRP78 autoantibodies increased TF PCA. This observation was further enhanced by endoplasmic reticulum stress-induced elevation of csGRP78 levels. Anti-GRP78 autoantibody treatment increased intracellular Ca 2+ levels. Sequestering the anti-GRP78 autoantibody with a conformational peptide or blocking with heparin attenuated anti-GRP78 autoantibody-induced TF PCA. We identified B07 ∗ , as a GRP78 binder that diminished anti-GRP78 autoantibody-induced TF PCA on ECs., Conclusion: These findings show how anti-GRP78 autoantibodies enhance TF PCA that contributes to thrombosis and identify novel GRP78 binders that represent a potential novel therapeutic strategy for treating and managing atherothrombotic disease., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement., Methods: This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics., Results: R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91)., Conclusion: The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Statins are a cornerstone in the medical management of cardiovascular disease, yet their efficacy varies greatly between individuals. In this commentary, we outline the evidence for the role of CD4+CD28null T-cell expansion as a critical moderator of the effects of statins in preventing cardiovascular events via the reduction of pathological inflammation. Given this relationship, we argue that T-cell profiles should be considered as a patient characteristic in clinical and preclinical studies examining statin efficacy in other age- and inflammation-related pathologies. We discuss the implications this may have for studies of statin use in numerous disease processes-notably, dementia and neurocognitive dysfunction-and the potential for T-cell profiles to be used as a prognosticator for statin efficacy in rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Kawasaki disease (KD) is a systemic inflammatory disease characterized by vasculitis. In South Korea, some pediatric doctors empirically prescribe steroids to control febrile pediatric patients. This study aimed to evaluate the clinical characteristics of patients with KD after steroid exposure., Methods: This was a single-center, retrospective, observational study. This study included patients (aged ≤15 years) between January 2020 and July 2022. We compared two groups, one group exposed to steroids and the other group who were not, using the Student's t-test or analysis of variance; otherwise, the Mann-Whitney U test or Kruskal-Wallis test was conducted. Statistical significance was set at p < 0.05., Results: In total, 190 patients with KD were enrolled; of these, 64 (33.7 %) had a history of steroid exposure, and 126 (66.3 %) had no history of steroid exposure. In the steroid exposure group, prolonged fever duration (6.72 ± 1.72 versus 5.61 ± 1.19, p-value = <0.001), a lower proportion of complete KD (29.69 % vs. 88.10 %, p-value = <0.001), and a significantly lower level of C-reactive protein were observed. However, no significant correlations were observed between the Transthoracic Echocardiography (TTE) results (coronary artery aneurysm, existence of pericardial effusion) and prognostic factors (days of hospitalization, the number of intravenous immunoglobulin administrations, and Kobayashi score) between the two groups., Conclusions: Patients with KD and previous steroid exposure may exhibit an incomplete KD phenotype with prolonged fever. Although previous steroid exposure does not affect the prognosis of KD, including coronary artery aneurysms, it may mask the classic features of KD, resulting in a delayed diagnosis., Competing Interests: Declaration of competing interest The authors declare no financial or other conflicts of interest., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to identify preoperative magnetic resonance imaging (MRI) findings that can predict the shunt responsiveness in idiopathic normal-pressure hydrocephalus (iNPH) patients and to investigate postoperative outcome and complications., Materials and Methods: A total of 192 patients with iNPH who underwent shunt at our hospital between 2000 and 2021 were included to investigate complications. Of these, after exclusion, 127 (1-month postoperative follow-up) and 77 (1-year postoperative follow-up) patients were evaluated. The preoperative MRI features (the presence of tightness of the high-convexity subarachnoid space, Sylvian fissure enlargement, Evans' index, and callosal angle) of the shunt-response and nonresponse groups were compared, and a systematic review was conducted to evaluate whether preoperative MRI findings could predict shunt response., Results: Postoperative complications within one month after surgery were observed in 6.8% (13/192), and the most common complication was hemorrhage. Changes in corpus callosum were observed in 4.2% (8/192). The shunt-response rates were 83.5% (106/127) in the 1-month follow-up group and 70.1% (54/77) in 1-year follow-up group. In the logistic regression analysis, only Evans' index measuring >0.4 had a significant negative relationship with shunt response at 1-month follow-up; however, no significant relationship was observed at 1-year follow-up. According to our systematic review, it is still controversial whether preoperative MRI findings could predict shunt response., Conclusion: Evans' index measure of >0.4 had a significant relationship with the shunt response in the 1-month follow-up group. In systematic reviews, there is ongoing debate about whether preoperative MRI findings can accurately predict responses to shunt surgery. Postoperative corpus callosal change was observed in 4.2% of iNPH patients., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose ( 18 F-FDG) PET/CT variables to predict recurrence-free survival (RFS) after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: Patients with resectable PDAC who underwent upfront surgery between 2014 and 2017 (development set) or between 2018 and 2019 (test set) were retrospectively evaluated. In the development set, a risk-scoring system was developed using the multivariable Cox proportional hazards model, including variables associated with RFS. In the test set, the performance of the risk score was evaluated using the Harrell C-index and compared with that of the postoperative pathological tumor stage., Results: A total of 529 patients, including 335 (198 male; mean age ± standard deviation, 64 ± 9 years) and 194 (103 male; mean age, 66 ± 9 years) patients in the development and test sets, respectively, were evaluated. The risk score included five variables predicting RFS: tumor size (hazard ratio [HR], 1.29 per 1 cm increment; P < 0.001), maximal standardized uptake values of tumor ≥ 5.2 (HR, 1.29; P = 0.06), suspicious regional lymph nodes (HR, 1.43; P = 0.02), possible distant metastasis on 18 F-FDG PET/CT (HR, 2.32; P = 0.03), and CA 19-9 (HR, 1.02 per 100 U/mL increment; P = 0.002). In the test set, the risk score showed good performance in predicting RFS (C-index, 0.61), similar to that of the pathologic tumor stage (C-index, 0.64; P = 0.17)., Conclusion: The proposed risk score based on preoperative CA 19-9, CT, and 18 F-FDG PET/CT variables may have clinical utility in selecting high-risk patients with resectable PDAC., Competing Interests: Seung Soo Lee, who holds the respective position of Editorial Board Member of the Korean Journal of Radiology, was not involved in the editorial evaluation or decision to publish this article. The remaining author has declared no conflicts of interest., (Copyright © 2024 The Korean Society of Radiology.)

External and internal factors are involved in controlling the growth of fishes. However, little is known about the mechanisms by which external factors trigger stimulus signals. This study explored the physiological roles of melatonin in the transcription of growth-related genes in the brain and liver of Chrysiptera cyanea, a tropical damselfish with long-day preference. In brain samples of this species collected at 4-h intervals, the transcript levels of arylalkylamine N-acetyltransferase2 (aanat2), the rate-limiting enzyme of melatonin synthesis, and growth hormone (gh) peaked at 20:00 and 00:00, respectively. Concomitantly, the transcript levels of insulin-like growth factors (igf1 and igf2) in the brain and liver were upregulated during the scotophase. Levels of iodothyronine deiodinases (dio2 and dio3), enzymes that convert thyroxine (T4) to triiodothyronine (T3) and reverse T3, respectively, increased in the brain (dio2 and dio3) and liver (dio2) during the photophase, whereas dio3 levels in the liver showed the opposite trend. Fish reared in melatonin-containing water exhibited significant increases in the transcription levels of gh and igf1 in the brain and igf1 in the liver, suggesting that growth in this fish is positively regulated by the GH/IGF pathway on a daily basis. Melatonin treatment also stimulated the transcript levels of dio2 and dio3 in the liver, but not in the brain. Fish consuming pellets containing T3, but not T4, showed significant increases in gh and igf1 in the brain and igf1 and igf2 in the liver, suggesting that the intercellular actions of the TH/IGF pathway have an impact on growth on a daily basis. In summary, IGF synthesis and action in the brain and liver undergo dual regulation by distinct hormone networks, which may also be affected by daily, seasonal, or nutritional factors., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Delphinidin (Delp), a natural antioxidant, has shown promise in treating age-related ailments such as osteoarthritis (OA). This study investigates the impact of delphinidin on intervertebral disc degeneration (IVDD) using human nucleus pulposus cells (hNPCs) subjected to hydrogen peroxide. Various molecular and cellular assays were employed to assess senescence, extracellular matrix (ECM) degradation markers, and the activation of AMPK and autophagy pathways. Initially, oxidative stress (OS)-induced hNPCs exhibited notably elevated levels of senescence markers like p53 and p21, which were mitigated by Delp treatment. Additionally, Delp attenuated IVDD characteristics including apoptosis and ECM degradation markers in OS-induced senescence (OSIS) hNPCs by downregulating MMP-13 and ADAMTS-5 while upregulating COL2A1 and aggrecans. Furthermore, Delp reversed the increased ROS production and reduced autophagy activation observed in OSIS hNPCs. Interestingly, the ability of Delp to regulate cellular senescence and ECM balance in OSIS hNPCs was hindered by autophagy inhibition using CQ. Remarkably, Delp upregulated SIRT1 and phosphorylated AMPK expression while downregulating mTOR phosphorylation in the presence of AICAR (AMPK activator), and this effect was reversed by Compound C, AMPK inhibitor. In summary, our findings suggest that Delp can safeguard hNPCs from oxidative stress by promoting autophagy through the SIRT1/AMPK/mTOR pathway.

Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Japanese eel (Anguilla japonica) is a commercially important fish species in Asia. Understanding factors like photoperiod, temperature, and lunar cycles is crucial for successful aquaculture and managing its reproduction. Melatonin and dopamine (DA) are essential for regulating reproduction in vertebrates, including fish. This study investigated the effects of melatonin and DA on the reproductive system of mature male Japanese eels to better understand reproductive regulation in fish. To clarify the effects of these hormones on sexual maturation in eels, a critical stage in the reproductive process, sexual maturation was induced by injecting human chorionic gonadotropin, which stimulates the production of sex hormones. To check the effect of melatonin and DA on sexual maturation, DA, melatonin, and DA + domperidone were intraperitoneally injected into fish from each group (six per treatment) at a dose of 1 mg/kg body weight. The fish were then examined using quantitative RT-PCR by comparing the messenger RNA level of reproduction-related genes (gonadotropin releasing hormone 1; gnrh1, gonadotropin releasing hormone 2; gnrh2, follicle stimulating hormone; fshβ, luteinizing hormone; lhβ and DA receptor 2b; d2b), involved in the gonadotropic axis in eels, to those that received a control injection. The results indicate significant differences in the expression levels of gnrh1, gnrh2 and d2b in the brain and d2b, fshβ, lhβ in the pituitary at different stages of sexual maturation. Melatonin appears to enhance the production of sex gonadotropins, whereas DA inhibits them. These findings suggest an interaction between melatonin and DA in regulating reproduction in Japanese eels., (© 2024 Wiley Periodicals LLC.)

Electrolyte additives with multiple functions enable the interfacial engineering of Li-metal batteries (LMBs). Owing to their unique reduction behavior, additives exhibit a high potential for electrode surface modification that increases the reversibility of Li-metal anodes by enabling the development of a hierarchical solid electrolyte interphase (SEI). This study confirms that an adequately designed SEI facilitates the homogeneous supply of Li + , nonlocalized Li deposition, and low electrolyte degradation in LMBs while enduring the volume fluctuation of Li-metal anodes on cycling. An in-depth analysis of interfacial engineering mechanisms reveals that multilayered SEI structures comprising mechanically robust LiF-rich species, electron-rich P-O species, and elastic polymeric species enabled the stable charge and discharge of LMBs. The polymeric outer SEI layer in the as-fabricated multilayered SEI could accommodate the volume fluctuation of Li-metal anodes, significantly enhancing the cycling stability Li||LiNi 0.8 Co 0.1 Mn 0.1 O 2 full cells with an electrolyte amount of 3.6 g Ah -1 and an areal capacity of 3.2 mAh cm -2 . Therefore, this study confirms the ability of interfacial layers formed by electrolyte additives and fluorinated solvents to advance the performance of LMBs and can open new frontiers in the fabrication of high-performance LMBs through electrolyte-formulation engineering., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Target-mediated drug disposition (TMDD) is a phenomenon characterized by a drug's high-affinity binding to a target molecule, which significantly influences its pharmacokinetic profile within an organism. The comprehensive TMDD model delineates this interaction, yet it may become overly complex and computationally demanding in the absence of specific concentration data for the target or its complexes. Consequently, simplified TMDD models employing quasi-steady state approximations (QSSAs) have been introduced; however, the precise conditions under which these models yield accurate results require further elucidation. Here, we establish the validity of three simplified TMDD models: the Michaelis-Menten model reduced with the standard QSSA (mTMDD), the QSS model reduced with the total QSSA (qTMDD), and a first-order approximation of the total QSSA (pTMDD). Specifically, we find that mTMDD is applicable only when initial drug concentrations substantially exceed total target concentrations, while qTMDD can be used for all drug concentrations. Notably, pTMDD offers a simpler and faster alternative to qTMDD, with broader applicability than mTMDD. These findings are confirmed with antibody-drug conjugate real-world data. Our findings provide a framework for selecting appropriate simplified TMDD models while ensuring accuracy, potentially enhancing drug development and facilitating safer, more personalized treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Byun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Mycobacterium avium complex (MAC), including Mycobacterium intracellulare is a member of slow-growing mycobacteria and contributes to a substantial proportion of nontuberculous mycobacterial lung disease in humans affecting immunocompromised and elderly populations. Adaptation of pathogens in hostile environments is crucial in establishing infection and persistence within the host. However, the sophisticated cellular and molecular mechanisms of stress response in M. intracellulare still need to be fully explored. We aimed to elucidate the transcriptional response of M. intracellulare under acidic and oxidative stress conditions., Results: At the transcriptome level, 80 genes were shown [FC] ≥ 2.0 and p < 0.05 under oxidative stress with 10 mM hydrogen peroxide. Specifically, 77 genes were upregulated, while 3 genes were downregulated. In functional analysis, oxidative stress conditions activate DNA replication, nucleotide excision repair, mismatch repair, homologous recombination, and tuberculosis pathways. Additionally, our results demonstrate that DNA replication and repair system genes, such as dnaB, dinG, urvB, uvrD2, and recA, are indispensable for resistance to oxidative stress. On the contrary, 878 genes were shown [FC] ≥ 2.0 and p < 0.05 under acidic stress with pH 4.5. Among these genes, 339 were upregulated, while 539 were downregulated. Functional analysis highlighted nitrogen and sulfur metabolism pathways as the primary responses to acidic stress. Our findings provide evidence of the critical role played by nitrogen and sulfur metabolism genes in the response to acidic stress, including narGHIJ, nirBD, narU, narK3, cysND, cysC, cysH, ferredoxin 1 and 2, and formate dehydrogenase., Conclusion: Our results suggest the activation of several pathways potentially critical for the survival of M. intracellulare under a hostile microenvironment within the host. This study indicates the importance of stress responses in M. intracellulare infection and identifies promising therapeutic targets., (© 2024. The Author(s).)

Background: Immune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage response and repair (DDR) genes can lead to genetic instability, often accompanied by a high tumor mutation burden (TMB). However, few studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies., Methods: The KM-06 open-label, multicenter, single-arm, phase II trial evaluated the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations assessed by clinically targeted sequencing. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or for 24 months. The primary endpoint was the objective response rate (ORR) as per RECIST V.1.1 criteria., Results: A total of 48 patients were enrolled in the study (median age 61, 58.3% male). The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3% each). Eight patients achieved a partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate was 60.0%. The median progression-free survival was 2.9 months. Treatment-related adverse events of any grade and grade ≥3 occurred in 44 (91.7%) and 4 (8.3%) patients, respectively. Clinically targeted sequencing data inferred both TMB and microsatellite instability (MSI). Using a TMB cut-off of 12 mut/Mb, there were significant differences in overall survival (p=0.00035), progression-free survival (p=0.0061), and the best overall response (p=0.05). In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high epithelial-mesenchymal transition signaling pathway activation. The responders exhibited a marked increase in PD-1-/Ki67+CD8 T cells at the early stage of treatment (C3D1) compared with non-responders (p=0.03)., Conclusions: In this phase II trial, nivolumab demonstrated moderate efficacy and manageable toxicity in patients with solid cancer harboring DDR gene mutations. A high TMB (>12 mut/Mb) and MSI score (>2.5) determined through clinically target sequencing presented significant discriminatory power for the nivolumab response., Trial Registration Number: NCT04761744., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although end stage renal disease patients who undergo hemodialysis frequently experience dialysis-associated thrombotic complications, there remains a paucity of literature comparing the efficacy of different endovascular salvage techniques for grafts and fistulas. This study aims to compare primary patency in dialysis access following salvage mechanical thrombolysis/thrombectomy with a rotational thrombolysis device versus balloon maceration., Methods: Using a database of patient records at a tertiary medical center, all patients who underwent rotational thrombectomy with the Cleaner XT™ Rotational Thrombectomy System for endovascular salvage of arteriovenous fistula or arteriovenous graft from August 2016 to July 2022 were included in the population. Fourteen patients who underwent balloon maceration for endovascular salvage were matched to the patients in the rotational thrombectomy group based on date of procedure. The primary patency of the fistula or graft for the two groups was measured., Results: A total of 13 patients who underwent dialysis access salvage with rotational thrombectomy (10 grafts, 3 fistulas) were matched with 14 patients who underwent balloon maceration for dialysis access salvage (10 grafts, 4 fistulas). Six patients in both groups required additional graft access salvage (46% rotational thrombectomy; 43% balloon maceration). The median time to next dialysis salvage was 51 days for rotational thrombectomy and 43.5 days for balloon maceration (W + 9, critical value 1; compatible with statistically significant difference)., Conclusion: Endovascular access salvage by rotational thrombectomy may provide longer primary patency compared to salvage by balloon maceration. However, a longer follow-up prospective study of a larger study population is necessary to clarify the safety and efficacy of rotational thrombectomy using the Cleaner XT™ device., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Surgically resected grade 1-2 (G1-2) pancreatic neuroendocrine tumors (PanNETs) exhibit diverse clinical outcomes, highlighting the need for reliable prognostic biomarkers. Our study aimed to develop and validate CT-based radiomics model for predicting postsurgical outcome in patients with G1-2 PanNETs, and to compare its performance with the current clinical staging system., Methods: This multicenter retrospective study included patients who underwent dynamic CT and subsequent curative resection for G1-2 PanNETs. A radiomics-based model (R-score) for predicting recurrence-free survival (RFS) was developed from a development set (441 patients from one institution) using least absolute shrinkage and selection operator-Cox regression analysis. A clinical model (C-model) consisting of age and tumor stage according to the 8th American Joint Committee on Cancer staging system was built, and an integrative model combining the C-model and the R-score (CR-model) was developed using multivariable Cox regression analysis. Using an external test set (159 patients from another institution), the models' performance for predicting RFS and overall survival (OS) was evaluated using Harrell's C-index. The incremental value of adding the R-score to the C-model was evaluated using net reclassification improvement (NRI) and integrated discrimination improvement (IDI)., Results: The median follow-up periods were 68.3 and 59.7 months in the development and test sets, respectively. In the development set, 58 patients (13.2%) experienced recurrence and 35 (7.9%) died. In the test set, tumors recurred in 14 patients (8.8%) and 12 (7.5%) died. In the test set, the R-score had a C-index of 0.716 for RFS and 0.674 for OS. Compared with the C-model, the CR-model showed higher C-index (RFS, 0.734 vs. 0.662, p = 0.012; OS, 0.781 vs. 0.675, p = 0.043). CR-model also showed improved classification (NRI, 0.330, p < 0.001) and discrimination (IDI, 0.071, p < 0.001) for prediction of 3-year RFS., Conclusions: Our CR-model outperformed the current clinical staging system in prediction of the prognosis for G1-2 PanNETs and added incremental value for predicting postoperative recurrence. The CR-model enables precise identification of high-risk patients, guiding personalized treatment planning to improve outcomes in surgically resected grade 1-2 PanNETs., (© 2024. The Author(s).)

Although three-dimensional (3D) printing techniques are used to mimic macro- and micro-structures as well as multi-structural human tissues in tissue engineering, efficient target tissue regeneration requires bioactive 3D printing scaffolds. In this study, we developed a bone morphogenetic protein-2 (BMP-2)-immobilized polycaprolactone (PCL) 3D printing scaffold with leaf-stacked structure (LSS) ( 3D-PLSS-BMP ) as a bioactive patient-tailored bone graft. The unique LSS was introduced on the strand surface of the scaffold via heating/cooling in tetraglycol without significant deterioration in physical properties. The BMP-2 adsorbed on 3D-PLSS-BMP was continuously released from LSS over a period of 32 d. The LSS can be a microtopographical cue for improved focal cell adhesion, proliferation, and osteogenic differentiation. In vitro cell culture and in vivo animal studies demonstrated the biological (bioactive BMP-2) and physical (microrough structure) mechanisms of 3D-PLSS-BMP for accelerated bone regeneration. Thus, bioactive molecule-immobilized 3D printing scaffold with LSS represents a promising physically and biologically activated bone graft as well as an advanced tool for widespread application in clinical and research fields., (© 2024 IOP Publishing Ltd.)

Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51 -/- ) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51 -/- , and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51 -/- mice and in ob/ob mice. TDAG51 -/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51 -/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51 -/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Despite the revision of threshold growth (TG) in the Liver Imaging Reporting and Data System (LI-RADS) version 2018, the appropriate time period between the two examinations for TG has not been determined. We compared the accuracy of LI-RADS with TG based on tumor growth rate for the diagnosis of hepatocellular carcinoma (HCC) with that of LI-RADS v2018 based on the original TG., Methods: Patients who underwent preoperative MRI for focal solid lesions (≤ 3.0 cm) were retrospectively evaluated. Three readers measured the size of each lesion on prior CT/MRI and index MRI, with tumor growth rate defined as the percent change in lesion size per month. In addition to the original TG (≥ 50% size increase within ≤ 6 months), the modified TG based on tumor growth rates ≥ 10%/month (TG-10%), ≥ 20%/month (TG-20%), and ≥ 30%/month (TG-30%) were evaluated. The accuracies of these evaluation methods for LI-RADS category 5 HCC were compared using generalized estimation equations., Results: A total of 508 lesions from 370 patients were evaluated. Compared with LI-RADS v2018 with the original TG, the accuracy of LI-RADS with TG-10% was significantly higher (85.0% vs. 80.7%, p < .001), whereas the accuracies of LI-RADS with TG-20% (81.3% vs. 80.7%, p = .404) and TG-30% (79.3% vs. 80.7%, p = .052) were not significant. The sensitivity of LI-RADS with TG-10% was higher than that of LI-RADS v2018 (79.0% vs. 72.5%, p < .001), whereas their specificities were not significantly different (96.6% vs. 96.6%, p > .999)., Conclusion: TG-10% improved the sensitivity of LI-RADS by detecting additional hepatocellular carcinomas underestimated due to short-term follow-up., Clinical Relevance Statement: Threshold growth based on tumor growth rate can be clinically useful in the diagnosis of hepatocellular carcinoma, by improving the sensitivity of LI-RADS., Key Points: • The diagnostic accuracy of Liver Imaging Reporting and Data System (LI-RADS) v2018 was not significantly affected by the time interval between prior and index assessments of threshold growth. • In the 334 hepatocellular carcinomas, the frequency of threshold growth was significantly higher using tumor growth rate ≥ 10%/month (TG-10%) than original threshold growth (53.3% vs. 18.0%, p < .001). • Compared with LI-RADS v2018 with the original threshold growth, LI-RADS with TG-10% had significantly higher accuracy (85.0% vs. 80.7%, p < .001) and sensitivity (79.0% vs. 72.5%, p < .001) but a similar specificity (96.6% vs. 96.6%, p > .999)., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC)., Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC., Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia ( n = 107, 13.2%), neutropenia ( n = 23, 2.8%), anemia ( n = 21, 2.6%), and elevated liver enzyme ( n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively., Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Deception is an inevitable occurrence in daily life. Various methods have been used to understand the mechanisms underlying brain deception. Moreover, numerous efforts have been undertaken to detect deception and truth-telling. Functional near-infrared spectroscopy (fNIRS) has great potential for neurological applications compared with other state-of-the-art methods. Therefore, an fNIRS-based spontaneous lie detection model was used in the present study. We interviewed 10 healthy subjects to identify deception using the fNIRS system. A card game frequently referred to as a bluff or cheat was introduced. This game was selected because its rules are ideal for testing our hypotheses. The optical probe of the fNIRS was placed on the subject's forehead, and we acquired optical density signals, which were then converted into oxy-hemoglobin and deoxy-hemoglobin signals using the Modified Beer-Lambert law. The oxy-hemoglobin signal was preprocessed to eliminate noise. In this study, we proposed three artificial neural networks inspired by deep learning models, including AlexNet, ResNet, and GoogleNet, to classify deception and truth-telling. The proposed models achieved accuracies of 88.5%, 88.0%, and 90.0%, respectively. These proposed models were compared with other classification models, including k-nearest neighbor, linear support vector machines (SVM), quadratic SVM, cubic SVM, simple decision trees, and complex decision trees. These comparisons showed that the proposed models performed better than the other state-of-the-art methods., 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 © 2024 Bhutta, Ali, Zafar, Kim, Byun and Lee.)

Background: Over the last decade, extracorporeal membrane oxygenation (ECMO) use in critically ill children has increased and is associated with favorable outcomes. Our study aims to evaluate the current status of pediatric ECMO in Korea, with a specific focus on its volume and changes in survival rates based on diagnostic indications., Methods: This multicenter study retrospectively analyzed the indications and outcomes of pediatric ECMO over 10 years in patients at 14 hospitals in Korea from January 2012 to December 2021. Four diagnostic categories (neonatal respiratory, pediatric respiratory, post-cardiotomy, and cardiac-medical) and trends were compared between periods 1 (2012-2016) and 2 (2017-2021)., Results: Overall, 1065 ECMO runs were performed on 1032 patients, with the annual number of cases remaining unchanged over the 10 years. ECMO was most frequently used for post-cardiotomy (42.4%), cardiac-medical (31.8%), pediatric respiratory (17.5%), and neonatal respiratory (8.2%) cases. A 3.7% increase and 6.1% decrease in pediatric respiratory and post-cardiotomy cases, respectively, were noted between periods 1 and 2. Among the four groups, the cardiac-medical group had the highest survival rate (51.2%), followed by the pediatric respiratory (46.4%), post-cardiotomy (36.5%), and neonatal respiratory (29.4%) groups. A consistent improvement was noted in patient survival over the 10 years, with a significant increase between the two periods from 38.2% to 47.1% ( P = 0.004). Improvement in survival was evident in post-cardiotomy cases (30-45%, P = 0.002). Significant associations with mortality were observed in neonates, patients requiring dialysis, and those treated with extracorporeal cardiopulmonary resuscitation ( P < 0.001). In pediatric respiratory ECMO, immunocompromised patients also showed a significant correlation with mortality ( P < 0.001)., Conclusion: Pediatric ECMO demonstrated a steady increase in overall survival in Korea; however, further efforts are needed since the outcomes remain suboptimal compared with global outcomes., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objectives: To evaluate the diagnostic performance for hepatocellular carcinoma (HCC) detection of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 on gadoxetic acid-enhanced MRI, comparing liver transplant candidates (LT group) with patients who underwent surgical resection (SR group), and to determine significant clinical factors for diagnostic performance of LI-RADS v2018., Methods: Patients who underwent gadoxetic acid-enhanced MRI and subsequent SR or LT for HCC were retrospectively included between January 2019 and December 2020. The sensitivity and specificity of LI-RADS LR-5 for HCC were compared between the two groups using generalized estimating equations. The accuracy of patient allocation according to the Milan criteria was calculated for the LT group. Univariable and multivariable logistic regression analyses were performed to determine significant clinical factors associated with the sensitivity of LI-RADS., Results: Of the 281 patients, 237 were assigned to the SR group, and 44 were assigned to the LT group. The LT group showed significantly lower per-patient (48.5% vs. 79.6%, p < .001) and per-lesion sensitivity (31.0% vs. 75.9%, p < .001) than the SR group, whereas no significant difference in both per-patient (100.0% vs. 91.7%, p > .99) and per-lesion specificities (100.0% vs. 94.1%, p > .99). The accuracy of patient allocation was 50.0%. Sensitivity was significantly lower in patients with a smaller lesion size (p < .001), a larger lesion number (p = .002), and a higher Child-Pugh score (p = .009)., Conclusion: LI-RADS v2018 on gadoxetic acid-enhanced MRI might be insufficient in liver transplant candidates and other diagnostic imaging tests should be considered in patients with these significant clinical factors., Clinical Relevance Statement: In liver transplant candidates with a smaller lesion size, a larger lesion number, and a higher Child-Pugh score, imaging tests other than gadoxetic acid-enhanced MRI may be clinically useful to determine the transplant eligibility., Key Points: • The sensitivity of the Liver Imaging Reporting and Data System (LI-RADS) was lower in liver transplant candidates than in those who underwent surgical resection. • With the use of gadoxetic acid-enhanced MRI, the accuracy of patient allocation for liver transplantation on the basis of the Milan criteria was suboptimal. • The sensitivity of LI-RADS v2018 was significantly associated with lesion size, lesion number, and Child-Pugh classification., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Introduction: Nusinersen is the first drug approved for spinal muscular atrophy (SMA) treatment. In this study, we aimed to evaluate the long-term safety and efficacy of nusinersen, assess the therapeutic effects based on the treatment initiation timing and baseline motor function, and explore the perception of functional improvement from either parents or patients, utilizing 3-year nationwide follow-up data in South Korea., Methods: We enrolled patients with SMA who were treated with nusinersen under the National Health Insurance coverage, with complete motor score records available and a minimum treatment duration of 6 months. To evaluate the motor function of patients, the Hammersmith Infant Neurological Examination-2 (HINE-2) was used for type 1 and the Expanded Hammersmith Functional Motor Scale (HFMSE) was used for types 2 and 3 patients. A significant improvement was defined as a HINE-2 score gain ≥5 for patients with type 1 and an HFMSE score ≥ 3 for patients with types 2 and 3 SMA. Effects of treatment timing were assessed. Patients with type 2 were further categorized based on baseline motor scores for outcome analysis. We also analyzed a second dataset from five tertiary hospitals with the information on parents/patients-reported impressions of improvement., Results: The study comprised 137 patients, with 21, 103, and 13 patients representing type 1, 2, and 3 SMA, respectively. At the 3-year follow-up, the analysis encompassed 7 patients with type 1, 12 patients with type 2, and none with type 3. Nearly half of all enrolled patients across SMA types (42.8, 59.2 and 46.2%, respectively) reached the 2-year follow-up for analysis. Patients with type 1 SMA exhibited gradual motor function improvement over 1-, 2-, and 3-year follow-ups (16, 9, and 7 patients, respectively). Patients with type 2 SMA demonstrated improvement over 1-, 2-, and 3-year follow-ups (96, 61 and 12 patients, respectively). Early treatment from symptom onset resulted in better outcomes for patients with type 1 and 2 SMA. In the second dataset, 90.7% of 108 patients reported subjective improvement at the 1-year follow-up., Conclusion: Nusinersen treatment for types 1-3 SMA is safe and effective in long-term follow-up. Early treatment initiation was a significant factor affecting long-term motor outcome., 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 Cho, Lee, Kim, Lee, Kim, Lee, Yum, Byun, Lee, Lee, Lee and Chae.)

Endonucleases have recently widely used in molecular diagnostics. Here, we report a strategy to exploit the properties of Argonaute (Ago) proteins for molecular diagnostics by introducing an artificial nucleic acid circuit with Ago protein (ANCA) method. The ANCA is designed to perform a continuous autocatalytic reaction through cross-catalytic cleavage of the Ago protein, enabling one-step, amplification-free, and isothermal DNA detection. Using the ANCA method, carbapenemase-producing Klebsiella pneumoniae (CPKP) are successfully detected without DNA extraction and amplification steps. In addition, we demonstrate the detection of carbapenem-resistant bacteria in human urine and blood samples using the method. We also demonstrate the direct identification of CPKP swabbed from surfaces using the ANCA method in conjunction with a three-dimensional nanopillar structure. Finally, the ANCA method is applied to detect CPKP in rectal swab specimens from infected patients, achieving sensitivity and specificity of 100% and 100%, respectively. The developed method can contribute to simple, rapid and accurate diagnosis of CPKP, which can help prevent nosocomial infections., (© 2023. The Author(s).)

Objectives: To evaluate early- and long-term outcomes of the surgical treatment for coarctation of the aorta based on a new classification system., Methods: A retrospective clinical review of 111 patients with coarctation of the aorta who underwent surgery (March 2011 to August 2020) was performed. We categorised coarctation of the aorta into type I, with all three head vessels tightly packed; type II, with the left subclavian artery separated from the two other head vessels; and type III, with all three head vessels separated from one another. Each type included subtype a, with a short isthmic portion, and subtype b, with a long isthmic portion., Results: The median patient age and weight at operation were 8 (range, 1-1490) days and 3.2 (range, 1.9-18.5) kg, respectively. Extended end-to-end anastomosis was performed via sternotomy in 54, via thoracotomy in 12, end-to-side anastomosis in 31, autologous main pulmonary artery patch augmentation in 12, and modified end-to-end anastomosis combined with subclavian artery flap aortoplasty in two patients. There was one (0.9%) case of early mortality and 12 (10.8%) cases of post-operative complications. Two (1.8%) late deaths occurred during follow-up. Five (4.5%) patients underwent balloon dilatation and three (2.7%) underwent reoperation for restenosis of coarctation of the aorta. All patients with type Ia (21 patients, 18.9%) underwent extended end-to-end anastomosis via sternotomy or thoracotomy., Conclusions: According to the early and late outcomes observed in this study, surgical treatment of coarctation of the aorta using the new classification system could be safe and low risk.

Objective: To investigate the imaging characteristics of large duct pancreatic ductal adenocarcinoma (LD-PDAC) on computed tomography (CT) and magnetic resonance imaging (MRI)., Materials and Methods: Thirty-five patients with LD-PDAC (63.2 ± 9.7 years) were retrospectively evaluated. Tumor morphology on CT and MRI (predominantly solid mass vs. solid mass with prominent cysts vs. predominantly cystic mass) was evaluated. Additionally, the visibility, quantity, shape (oval vs. branching vs. irregular), and MRI signal intensity of neoplastic cysts within the LD-PDAC were investigated. The radiological diagnoses rendered for LD-PDAC in radiology reports were reviewed., Results: LD-PDAC was more commonly observed as a solid mass with prominent cysts (45.7% [16/35] on CT and 37.1% [13/35] on MRI) or a predominantly cystic mass (20.0% [7/35] on CT and 40.0% [14/35] on MRI) and less commonly as a predominantly solid mass on CT (34.3% [12/35]) and MRI (22.9% [8/35]). The tumor morphology on imaging was significantly associated with the size of the cancer gland on histopathological examination ( P = 0.020 [CT] and 0.013 [MRI]). Neoplastic cysts were visible in 88.6% (31/35) and 91.4% (32/35) of the LD-PDAC cases on CT and MRI, respectively. The cysts appeared as branching (51.6% [16/35] on CT and 59.4% [19/35] on MRI) or oval shapes (45.2% [14/35] on CT and 31.2% [10/35] on MRI) with fluid-like MRI signal intensity. In the radiology reports, 10 LD-PDAC cases (28.6%) were misinterpreted as diseases other than typical PDAC, particularly intraductal papillary mucinous neoplasms., Conclusion: LD-PDAC frequently appears as a solid mass with prominent cysts or as a predominantly cystic mass on CT and MRI. Radiologists should be familiar with the imaging features of LD-PDAC to avoid misdiagnosis., Competing Interests: Seung Soo Lee, the editor board member of the Korean Journal of Radiology, was not involved in the editorial evaluation or decision to publish this article. All authors have declared no conflicts of interest., (Copyright © 2023 The Korean Society of Radiology.)

Aims: As the process of bone regeneration is preceded by an inflammatory response, the immune system has long been considered important for fracture healing. Despite many studies on the contribution of immune cells to bone-related diseases, the role of immune cells in the regeneration therapy of lost bone is not well understood. In addition, various types of cells are involved in the clinical bone regeneration environment, but most of the osteo-biology studies are conducted in an osteoblast-only environment., Materials and Methods: Here, we investigated the effects of macrophages and dendritic cells on osteogenic differentiation in a co-culture environment involving human periosteal cell-derived osteoblasts, human monocyte-derived osteoclasts, and myeloid-derived cells. In addition, the cluster of myeloid immune cells involved in the clinical bone regeneration process was analyzed through bone defect rat modeling., Key Findings: We found that specific types of myeloid cells and related cytokines increased osteogenic differentiation. These results were confirmed in experiments using myeloid cells originating from human primitive peripheral blood mononuclear cells and by measuring the colonization of macrophages and dendritic cells in an in vivo bone defect environment. In addition, Next generation sequencing (NGS) analysis was performed through RNA sequencing for osteogenesis caused by macrophages and dendritic cells in vitro, which implemented a clinical bone regeneration environment. The results of these experiments suggest that the role of M2 macrophages or dendritic cells is markedly increased during osteogenic differentiation. Therefore, we propose that the exchange of bioactive factors between macrophages and dendritic cells during the bone formation metabolic process is a crucial step of tissue regeneration rather than limited to the initial inflammatory response., Significance: This study indicates that M2 macrophages, among myeloid cells, can be mediators that play a vital role in the effective bone regeneration process and shows the potential as a useful next-generation advanced cell therapy for bone regeneration treatment., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The emergence of next-generation sequencing (NGS) is currently leading the diagnosis of acute myeloid leukemia (AML) and its treatment using a more genetic-level approach. The study aimed to find clinical and prognostic correlations with genomic mutation profiles in Korean patients with AML using NGS., Methods: This retrospective study enrolled a total of 30 patients who were newly diagnosed with AML from February 2021 to October 2022 in Korea. NGS was used to identify the genetic profiles of 40 genes relevant to AML. The clinical and laboratory data of the patients were analyzed with their genomic mutation profiles., Results: NGS revealed at least one mutation in all patients, with a range of one to seven mutations (median of three mutations). Mutations were commonly associated with TET2, CEBPA, RUNX1, FLT3, IDH2, NPM1, and SRSF2 genes. The TET2 mutation correlated with older (77 vs. 72) patients, and the FLT3 mutation was associated with a higher WBC count (33.4 x 109/L vs. 6.4 x 109/L). The RUNX1 mutation correlated with a lower (44.0 x 109/L vs. 65.5 x 109/L) platelet count, and the NPM1 mutation showed a higher number of blasts in peripheral blood (56.5% vs. 13.0%). Among 16 patients who received induction chemotherapy, mutations in SRSF2, ASXL1, PHF6, SF3B1, and PTPN11 were detected only in patients who failed to achieve complete remission (CR). Meanwhile, mutations in NRAS, TP53, IKZF1, DNMT3A, SH2B3, U2AF1, and WT1 were detected in patients who achieved CR., Conclusions: Clinical and prognostic correlations were observed according to genomic mutation profiles detected by NGS in Korean patients with AML. An NGS study with a larger cohort of patients would be beneficial to establish the significant prognostic impact on patients with AML.

Background: Coronary bifurcation angles influence plaque initiation in the coronary artery, and changes in blood flow caused by tortuosity in the coronary arteries can reduce blood pressure distal to the tortuous portion of the coronary artery, leading to myocardial ischemia. We aimed to describe two factors (coronary artery tortuosity and bifurcation angle) as one descriptor for the evaluation of proximal left anterior descending coronary artery (LAD) disease., Methods: We reviewed the medical records of 133 consecutive patients who underwent computed tomography angiography (CTA) for angina symptoms between November 2019 and January 2020. The patients were divided into two groups according to the presence of significant LAD stenosis on CTA (defined as LAD stenosis >50%). The straight length of the vessel was measured using the central luminal line of the flow path, and, calculated using proprietary algorithms in TeraRecon software. We used three-dimensional volume rendering and two-dimensional axial images to measure the left main coronary artery (LM)-LAD angles., Results: In the univariate analysis, there were significant differences in the linear distance between the endpoints of the 20 mm actual curve of the LAD (d20), cosine value for LM-LAD angle (cosθ) <0.8, age, presence of hypertension or diabetes, and number of pack years [hazard ratio (HR): 2.70, 8.04, 1.05, 3.70, 2.82, and 1.04; P=0.029, P<0.001, P=0.020, P=0.024, P=0.021, and P=0.002, respectively]. However, in the multivariate analysis, the cosθ multiplied by d20 (d20*cosθ) <15.5, presence of hypertension and number of pack years (HR: 11.36, 4.54, and 1.04; P<0.001, P=0.019, and P=0.003, respectively) were predictors of significant proximal LAD stenosis., Conclusions: As the tortuosity and LM-LAD angle increased (d20 and cosθ decreased, respectively), the chance of proximal LAD lesions formation increased. d20*cosθ might be useful as a predictor of proximal LAD stenosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-518/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Purpose: We aimed to evaluate and compare the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) v2018 for hepatocellular carcinoma (HCC) ≤ 3.0 cm on gadoxetic acid-enhanced MRI according to the etiology of cirrhosis., Methods: Thirty-eight patients with alcoholic liver cirrhosis (ALC) and 37 with hepatitis C virus-related cirrhosis (HCV) who underwent preoperative MRI and subsequent surgical resection or transplantation were included. For comparison groups, patients with hepatitis B virus-related cirrhosis (HBV) were included by 1:1 matching with HCV and ALC groups according to age, lesion size, and Child-Pugh classification. The imaging characteristics of background liver and focal lesions were analyzed. The diagnostic performance of LI-RADS was compared between HCV and HBV groups, and between ALC and HBV groups., Results: ALC group showed significantly higher frequency of hepatic steatosis (25.8 % vs. 6.1 %, p =.04) and lower frequency of nonperipheral washout on portal venous-phase in HCC (63.2 % vs. 97.1 %, p <.001) compared with HBV group. ALC group showed significantly lower sensitivity than HBV group (52.6 % vs. 88.6 %, p<.001). No significant differences in diagnostic performance were found between HCV and HBV groups. In ALC group, hepatobiliary-phase hypointensity provided significantly higher sensitivity (76.3 % vs. 52.6 %, p =.008)., Conclusion: The sensitivity of LI-RADS for diagnosing HCC ≤ 3.0 cm was significantly lower in the ALC group than in the HBV group., 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.)

An obligate anaerobic, Gram-negative, rod-shaped and non-spore-forming bacterium, designated as strain GYB001 T , was isolated from the blood of a patient with a sigmoid colon perforation. Taxonomic characterization of the novel isolate was performed using a polyphasic approach. A phylogenetic analysis based on 16S rRNA gene and whole genome sequences revealed that GYB001 T represented a member of the genus Parabacteroides , in the family Tannerellaceae . The closest species, based on 16S rRNA sequence, was Parabacteroides gordonii DSM 23371 T with 97.4 % similarity. Average nucleotide identity and digital DNA-DNA hybridization values between strain GYB001 T and P. gordonii DSM 23371 T were 86.7 and 28.7% and between GYB001 T and Parabacteroides faecis JCM 18682 T were 86.6 and 27.7 %, respectively. The genome was 6.57 Mbp long with 43.3 mol% G+C content. Colonies on Brucella blood agar (BBA) were circular, convex, smooth, grey and small in size. Growth was observed on trypticase soy agar (TSA), TSA +5 % sheep blood and Euglena gracilis agar. Growth occurred at 18-42 °C on BBA in the presence of 0-3 % NaCl (w/v) and at pH 6.0-8.5. The major polar lipids were phosphatidylethanolamine and phospholipids. The major fatty acids in strain GYB001 T were anteiso-C 15 : 0 and iso-C 17 : 0 3-OH, and the predominant respiratory quinones were menaquinone-10 (MK-10) and MK-9. The cell wall contained meso -diaminopimelic acid. Considering these phenotypic features and comparative genome analyses, we propose strain GYB001 T as the type strain of Parabacteroides leei sp. nov. (=KCTC 25738 T =KBN12P06525 T =LMG 32797 T ).

Bone morphogenetic proteins (BMPs) have tremendous therapeutic potential regarding the treatment of bone and musculoskeletal disorders due to their osteo-inductive ability. More than twenty BMPs have been identified in the human body with various functions, such as embryonic development, skeleton genesis, hematopoiesis, and neurogenesis. BMPs can induce the differentiation of MSCs into the osteoblast lineage and promote the proliferation of osteoblasts and chondrocytes. BMP signaling is also involved in tissue remodeling and regeneration processes to maintain homeostasis in adults. In particular, growth factors, such as BMP-2 and BMP-7, have already been approved and are being used as treatments, but it is unclear as to whether they are the most potent BMPs that induce bone formation. According to recent studies, BMP-9 is known to be the most potent inducer of the osteogenic differentiation of mesenchymal stem cells, both in vitro and in vivo. However, its exact role in the skeletal system is still unclear. In addition, research results suggest that the molecular mechanism of BMP-9-mediated bone formation is also different from the previously known BMP family, suggesting that research on signaling pathways related to BMP-9-mediated bone formation is actively being conducted. In this study, we performed a phosphorylation array to investigate the signaling mechanism of BMP-9 compared with BMP-2, another influential bone-forming growth factor, and we compared the downstream signaling system. We present a mechanism for the signal transduction of BMP-9, focusing on the previously known pathway and the p53 factor, which is relatively upregulated compared with BMP-2.