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Changhee Ha,1 Eun Sil Kim,2 Yiyoung Kwon,2 Yon Ho Choe,2 Mi Jin Kim,2 Soo-Youn Lee1,3 1Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 2Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 3Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KoreaCorrespondence: Mi Jin KimDepartment of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, KoreaTel +82 2 3410 0951Fax +82 2 3410 0043Email mijin1217.kim@samsung.comSoo-Youn LeeDepartment of Laboratory Medicine and Genetics, Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, KoreaTel +82 2 3410 1834Fax +82 2 3410 2719Email suddenbz@skku.eduAbstract: Pediatric Crohn’s disease (CD) carries a higher genetic susceptibility and an increased risk of a more aggressive disease course than adult CD. Treatment of CD is based on immunomodulatory drugs, such as thiopurines. The enzyme mainly involved in drug metabolism is thiopurine S-methyltransferase (TPMT). An increased concentration of drug metabolites can cause adverse drug effects, such as myelosuppression and hepatotoxicity; therefore, assessing the activity of TPMT is essential both before and during treatment. TPMT genotyping result is not affected by previous thiopurine dose and currently is the primary component of TPMT activity and disease monitoring. Until now, more than 40 allelic variants of the TPMT gene have been reported, with most of them having an uncertain or no enzyme function. In this article, we report the first case of a novel TPMT allele, TPMT*45, that was identified in a Korean girl with CD whose findings suggested decreased TPMT activity. This newly observed variant is caused by a single nucleotide polymorphism resulting in nonsense mutation (c.676C>T, p.R226*) and the partial loss of amino acids in the TPMT protein. Initially, the patient began azathioprine at a standard dosage (1.5 mg/kg/day), and her laboratory results, including red blood cell (RBC) TPMT activity (6-methylmercaptopurine 2.68 nmol/mL/h and 6-methylmercaptopurine riboside 4.82 nmol/mL/h) along with thiopurine metabolite levels (6-thioguanine nucleotides 479.3 pmol/8× 108 RBC), suggested an enzyme deficiency. The thiopurine dose was reduced to half (0.7 mg/kg/day), and the follow-up metabolite results as well as the associated inflammatory markers were continuously within reference ranges. Along with an improvement in the patient’s subjective reports and clinical symptoms, the patient demonstrated a good treatment response to the adjusted dose. The results of our report illustrate the importance of TPMT genotyping and pharmacogenetic-based thiopurine dose adjustment. Further research should focus on the functional characterization and impact on this novel allele’s treatment effect.Keywords: TPMT*45, Crohn’s disease, thioupurine, single nucleotide polymorphism, TPMT activity, drug metabolism

Background: Recently developed digital tomosynthesis has shown improved detection of pulmonary lesions with a radiation dose comparable to conventional CR but with a much lower radiation dose than CT. Purpose: To compare the diagnostic performance of digital tomosynthesis (DT) with that of chest radiography (CR) for the detection of aortic arch calcification (AAC). Material and Methods: The study included 100 patients who underwent multidetector computed tomography (MDCT), DT, and CR (DT and CR were obtained within one week of CT examination). We evaluated and compared the diagnostic performances of DT and CR for the detection of AAC with MDCT as the reference standard. The extent (four grades 0-3) of AAC on DT and CR was also compared with CT calcium score. Inter-observer agreement was analyzed by using kappa statistics. Results: On DT, overall accuracy for AAC was superior to that of CR (94% and 71%, respectively, P < 0.01). Inter-observer agreement was good with DT and CR (kappa values = 0.74 and 0.62, respectively) for the presence of AAC, and good with DT and moderate with CR (kappa value = 0.64 and 0.53, respectively) for AAC grading. The overall correlation coefficient on AAC grading between DT and CT (calcium score) was superior to that between CR and CT (0.90 and 0.60, respectively). Conclusion: DT is superior to CR for detection and extent evaluation of AAC. [ABSTRACT FROM AUTHOR]

Background: Effects of high iodine-concentration contrast material on the image quality of coronary CT angiography (CCTA) have not been well evaluated.Purpose: To compare the image quality and attenuation values of CCTA between patients administered iopromide 370 and iomeprol 400 with the use of 64-slice multidetector CT.Material and Methods: Patients were prospectively enrolled and were randomized into two groups (group A, 151 patients received iopromide 370, iodine flux = 1.48 g I/s; group B, 146 patients received iomeprol 400, iodine flux = 1.60 g I/s). CT attenuation was measured in the coronary arteries and great arteries and measurements were standardized based on an iodine flux of 1.50 g I/s. The image quality of 15 coronary artery segments was graded by two radiologists in consensus with the use of a four-point scale (1 = excellent to 4 = poor enhancement). Non-parametric statistical approaches were used to compare the two groups.Results: The median attenuation values in the coronary arteries were 454 HU and 464 HU for iopromide 370 and iomeprol 400, respectively, and they did not differ (P = 0.26). When standardizing for an iodine flux, significantly higher attenuation values were found for iopromide 370 (median = 460 HU, range = 216–791 HU) compared with iomeprol 400 (median = 435 HU, range = 195–758 HU) (P = 0.006). The median image quality score of coronary arterial segments was 1 (range 1–2) for both groups (P = 0.84).Conclusion: The attenuation values in the coronary arteries after injection of the same amount of two high iodine-concentration contrast materials at the same flow rate with different iodine fluxes are similar with no difference in image quality. With standardization for an iodine flux, the attenuation is significantly higher when using iopromide 370. [ABSTRACT FROM AUTHOR]

Background: Patient empowerment is receiving increasing attention in cancer care, and its relevance has led to a growing body of literature. Empowerment-related evidence, however, has not been comprehensively reviewed., Objective: The purpose of this scoping review was to summarize the available evidence on patient empowerment in cancer care. Specifically, we examined how patient empowerment has been defined and measured and what we have learned., Methods: We searched 6 databases (MEDLINE, PubMed, CINAHL, EMBASE, Cochrane Library, and PsycINFO), adapting key search terms (eg, "neoplasm," "empowerment") to each. Extracted data included author, publication year, country of data collection, main study purpose, study design, sampling method, setting, cancer trajectory, definition of empowerment and its source, measurement of empowerment, correlates, intervention (if applicable), and major results., Results: Of the 2987 articles we initially identified, we included 64 studies (18 quantitative, 9 qualitative, 9 psychometric validation, 8 mixed methods, 6 reviews, and 14 others). Across designs, randomized controlled trials were the most frequent. A comprehensive summary by study designs was provided., Conclusions: The review highlights the importance of defining the empowerment concept, which is generally vague. There is a paucity of research on examining the relationship between empowerment and its related concepts. More nonexperimental studies (eg, cross-sectional, longitudinal, case-control studies) are required., Implications for Practice: Nurses are in an optimal position to engage in the process of empowerment, leading to its benefits. To achieve the best outcomes, nurses need to clarify the definition, select an appropriate measurement, and be trained in empowerment strategies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Biologics are important therapeutic agents for pediatric Crohn's disease. Discontinuation of biologics is known to increase the relapse rate up to 71.4% in these patients; however, their long-term use increases the risk of opportunistic infections and causes economic burden and psychological fatigue. Therefore, taking a drug holiday is meaningful, even if the biologics cannot be completely discontinued. This study aimed to analyze the risk factors affecting relapse after discontinuation of biologics in children with Crohn's disease., Methods: We retrospectively reviewed the data of 435 children with Crohn's disease who visited a single health center between March 2013 and March 2021. Subsequently, we analyzed data from the patients who discontinued biologics after deep remission., Results: Among the enrolled patients, 388 were followed up for ≥2 years, and of these, 357 were administered biologics. A total of 103 patients discontinued biologics after deep remission, subsequently 31 maintained remission and 72 relapsed. The shorter the duration of biologic treatment (odds ratio of 0.444, P  = 0.029), the higher the ESR (odds ratio of 1.294, P  = 0.009) and fecal calprotectin (odds ratio of 1.010, P  = 0.032), and the less histological remission at the time of discontinuation of biologics (odds ratio of 0.119, P  = 0.026), the greater the risk of relapse after discontinuation of biologics., Conclusions: We identified factors associated with relapse after discontinuation of biologics. The results suggest that biologics can be discontinued in the absence of these factors after deep remission. However, because the relapse rate may increase after the discontinuation of biologics, close monitoring is important, and if necessary, re-administration of biologics should be actively considered., 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., (© 2024 Kim, Kim, Kim, Choe and Kim.)

Fibroblasts are cells that reside within the fibrous or loose connective tissues of most mammalian organs. For research purposes, fibroblasts are often subjected to long-term culture under defined conditions, during which their properties can significantly change. It is essential to understand and document these changes to obtain reliable outcomes. For the quantification of specific gene expressions, the most reliable and widely used technique is quantitative real-time polymerase chain reaction (qRT-PCR). Here, we assessed the impact of a reference gene's stability on a qRT-PCR analysis of long-term cultured canine skin fibroblasts. After successfully isolating the fibroblasts from canine skin tissues, they were cultured and evaluated for proliferation and β-galactosidase activity at different passage numbers. With extended culture, the fibroblasts showed a long doubling time and elevated β-galactosidase activity. Using three widely used algorithms, geNorm, Normfinder, and Bestkeeper, we identified HPRT1, YWHAZ, and GUSB as the most stable reference genes for both early- and late-passage fibroblasts. Conventional reference genes such as GAPDH were found to be less stable than those genes. The normalization of Vimentin by the stable genes showed statistical differences, whereas normalization by an unstable gene did not. Collectively, this study indicates that using stable reference genes is essential for accurately and reliably measuring gene expression in both early- and late-passage fibroblasts. These findings provide valuable insights into internal controls for gene expression studies and are expected to be utilized for analyzing gene expression patterns in molecular biology research.

Geothermal features in Antarctica provide favorable conditions for diverse microorganisms, yet their genomic diversity remains poorly understood. Here, we present an integrated dataset comprising PacBio HiFi and Hi-C metagenomic sequencing, along with single-cell amplified genomes (SAGs) from two high-altitude geothermal sites, Mount Melbourne and Mount Rittmann, in Antarctica. The long-read HiFi sequencing, coupled with Hi-C, enhances the understanding of microbiome diversity and functionality in this unique ecosystem by providing more complete and accurate genomic information. SAGs complement this by recovering rare microbial taxa and offering a strain-resolved perspective. This dataset aims to deepen our understanding of microbial evolution and ecology in Antarctic geothermal environments, and facilitate cross-comparison with other geothermal environments globally., (© 2024. The Author(s).)

Background: Coronary computed tomography angiography-derived fractional flow reserve (FFR CT ) is a per-vessel index reflecting cumulative hemodynamic burden while coronary events occur in focal lesions., Objectives: The authors sought to evaluate the additive prognostic value of the local gradient of FFR CT (FFR CT gradient) in addition to FFR CT to predict future coronary events., Methods: The current study included 245 patients (634 vessels) who underwent coronary computed tomography angiography within 6 to 36 months before the index angiography, of which 209 vessels had future coronary events and 425 vessels did not. Future coronary events were defined as a composite of vessel-specific myocardial infarction or urgent revascularization during a mean interval of 1.5 years. Pre-existing disease patterns were classified according to FFR CT of ≤0.80 and FFR CT gradient of ≥0.025/mm., Results: Both FFR CT (per 0.01 decrease; adjusted HR: 1.040; 95% CI: 1.029-1.051; P  < 0.001) and FFR CT gradient (per 0.01 increase; adjusted HR: 1.144; 95% CI: 1.101-1.190; P  < 0.001) were significantly associated with the risk of future coronary events. Lesions with FFR CT gradient of ≥0.025/mm showed significantly higher risk of future coronary events than those with FFR CT gradient of <0.025/mm in both the FFR CT >0.80 (49.2% vs 30.1%; HR: 2.069; 95% CI: 1.265-3.385; P  = 0.004) and FFR CT  ≤0.80 groups (60.9% vs 38.3%; HR: 1.988; 95% CI: 1.317-2.999; P =0 .001). Adding FFR CT gradient into the model with FFR CT alone showed significantly increased predictability of future coronary events (global chi-square: 45.8 vs 39.9; P  = 0.015)., Conclusions: Patients with high FFR CT gradient showed increased risk of future coronary events irrespective of FFR CT . Integrating both FFR CT and FFR CT gradient showed incremental predictability of future coronary events compared with FFR CT alone. (Prediction and Validation of Clinical Course of Coronary Artery Disease With CT-Derived Non-Invasive Hemodynamic Phenotyping and Plaque Characterization [DESTINY Study]; NCT04794868)., Competing Interests: The current study was supported by the internal research funds provided from the Heart Vascular Stroke Institute, Samsung Medical Center (OTX0004011). Other than providing financial support, the sponsors were not involved with design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Dr Hahn has received institutional research grants from the National Evidence-Based Healthcare Collaborating Agency, Ministry of Health and Welfare, Korea; Abbott Vascular; Biosensors; Boston Scientific; Daiichi-Sankyo; Donga-ST; Hanmi Pharmaceutical; and Medtronic Inc. Dr Gwon has received institutional research grants from Boston Scientific, Genoss, and Medtronic Inc. Dr J.-M. Lee has received institutional research grants from Abbott Vascular, Boston Scientific, Philips Volcano, Terumo Corporation, Zoll Medical, and Donga-ST. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Glioblastoma is a common brain tumor that poses considerable challenges in drug delivery. In this study, we investigated the potential of cell-based nanoparticles for targeted drug delivery to the glioblastoma sites. The anticancer drug of temozolomide (TMZ)-loaded T7-cholesterol nanoparticle micelles efficiently delivered nanoparticles to neutrophils and, subsequently, to the tumors. T7 is a cell-penetrating peptide that enhances the delivery of T7/TMZ to the target cells. T7 also serves as a transferrin target peptide, enabling targeted delivery to tumors. T7-conjugated cholesterol can self-assemble into micelles in aqueous solution and attach to the membrane of neutrophils. We confirmed that T7/TMZ nanoparticle micelles were efficiently located inside the neutrophils. Thereafter, T7/TMZ-conveyed neutrophils were administered to a glioblastoma mouse model, enabling neutrophils to penetrate the blood-brain barrier and deliver drugs directly to the tumor site. We evaluated the drug delivery efficiency and therapeutic effects of intravenous injection of T7/TMZ-conveyed neutrophils to a glioblastoma mouse model. These results demonstrate the promising role of neutrophil-based nanoparticle delivery systems in the targeted therapy of glioblastoma.

Low-dose radiotherapy (LDRT) has been explored as a treatment option for various inflammatory diseases; however, its application in the context of rheumatoid arthritis (RA) is lacking. This study aimed to elucidate the mechanism underlying LDRT-based treatment for RA and standardize it. LDRT reduced the total numbers of immune cells, but increased the apoptotic CD4 + T and B220 + B cells, in the draining lymph nodes of collagen induced arthritis and K/BxN models. In addition, it significantly reduced the severity of various pathological manifestations, including bone destruction, cartilage erosion, and swelling of hind limb ankle. Post-LDRT, the proportion of apoptotic CD4 + T and CD19 + B cells increased significantly in the PBMCs derived from human patients with RA. LDRT showed a similar effect in fibroblast-like synoviocytes as well. In conclusion, we report that LDRT induces apoptosis in immune cells and fibro-blast-like synoviocytes, contributing to attenuation of arthritis., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Background: Therapeutic drug monitoring of infliximab (IFX) can improve treatment outcomes; however, the temporal gap between drug concentration monitoring and subsequent availability restricts its practical application. To address this issue, an automated monitoring method, AFIAS IFX, was developed to rapidly and accurately analyze IFX concentration in blood. The analytical and clinical performances of this method were assessed to establish its clinical utility., Methods: The analytical performance of AFIAS IFX was evaluated according to Clinical and Laboratory Standard Institute guidelines. For clinical validation, AFIAS IFX was compared with 3 established enzyme-linked immunosorbent assay kits (LISA TRACKER, RIDASCREEN, and ImmunoGuide) using 100 consecutive samples from 28 patients treated with IFX. Passing-Bablok regression and Bland-Altman analyses were performed to compare the methods., Results: The detection and quantification limits of AFIAS IFX were 0.12 and 0.20 mcg/mL, respectively. Furthermore, AFIAS IFX analyzed samples within 10 minutes for concentrations up to 50 mcg/mL, exhibiting reproducibility (coefficient of variation [CV] ≤7.8%) and accuracy (recovery 98%-101%) with serum, plasma, and whole blood samples. Clinically, it exhibited a good correlation with the 3 established enzyme-linked immunosorbent assay kits. For patients treated with Remicade (IFX), the Passing-Bablok regression slope was 1.001-1.259, with a mean difference of -1.48 to 0.28 mcg/mL. For patients treated with CT-P13, the Passing-Bablok regression slope was 0.974-1.254, with a mean difference of -2.44 to 0.15 mcg/mL., Conclusions: AFIAS IFX, a novel fluorescence-based lateral flow assay, exhibited excellent performance in analyzing IFX trough levels and is a potentially powerful tool for therapeutic drug monitoring in clinical settings, with opportunities for further development., Competing Interests: M.L. and H.C. have been involved in the development of the product discussed in this paper, only. Their involvement was limited and not extend to any other aspects of this study. The remaining authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Context.—: Therapeutic drug monitoring is recommended to optimize infliximab use and improve outcome in chronic inflammatory disorders., Objective.—: To describe a simple and affordable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure infliximab in serum., Design.—: Infliximab was measured using winged stable isotope-labeled peptides as internal standards. Linearity, lower limit of measuring interval, limit of detection, precision, accuracy, carryover, and ion suppression were evaluated. Method comparison against 2 enzyme-linked immunosorbent assay (ELISA) methods (Remsima Monitor and IDKmonitor Infliximab) and anti-drug antibody (ADA) interference were evaluated using clinical specimens from inflammatory bowel disease patients (N = 237)., Results.—: Analytical run time and sample preparation time were 5 minutes per sample and 3 hours per batch, respectively. Analytical measurement interval and limit of detection were 0.50 to 50.0 μg/mL (R2 = 0.998) and 0.25 μg/mL, respectively. The intraday and interday imprecision percentage coefficients of variation were less than 6.1%. Accuracy was 94.2% to 98.7%. No significant ion suppression or carryover was observed. Infliximab concentrations measured by LC-MS/MS showed good agreement with those measured by Remsima Monitor (mean percentage difference, 5.7%; 95% CI, -1.2% to 12.6%) but were markedly lower than those measured by IDKmonitor (-32.6%; -35.8% to -29.4%), demonstrating significant bias between ELISAs. Although a good agreement between LC-MS/MS and ELISA was observed for ADA-negative samples (-3.5%; -12.8% to 5.9%), a significant bias was observed for ADA-positive samples (13.6%; 1.7% to 25.6%)., Conclusions.—: This simple, fast, and affordable LC-MS/MS method for infliximab quantitation could improve standardization of infliximab quantitation and optimization of infliximab use in patients with high-titer ADA., (© 2024 College of American Pathologists.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons and neuroinflammation. Recent studies have identified a role of T cells in the pathogenesis of PD. Additionally, these studies suggested that α-synuclein (α-Syn) is related to abnormal T-cell responses and may act as an epitope and trigger autoimmune T-cell responses. However, it is unclear whether the α-Syn-mediated autoimmune response occurs and whether it is related to neuronal cell death and glial cell activation. In this study, we investigated the autoimmune T-cell response induced by α-Syn peptides and evaluated the neurotoxic effect of the α-Syn peptide-mediated autoimmune response. The immunization of mice with α-Syn peptides resulted in enhanced autoimmune responses, such as the peptide recall response, polarization toward Th1/Th17 cells, and regulatory T cell imbalance. Furthermore, the α-Syn autoimmune response led to the death of primary neurons cocultured with splenocytes. Treatment with conditioned media from α-Syn peptide-immunized splenocytes induced microglia and toxic A1-type astrocyte activation. Taken together, our results provide evidence of the potential role of the α-Syn-initiated autoimmune response and its contribution to neuronal cell death and glial cell activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Studies on somatic mutations in cloned animals have revealed slight genetic variances between clones and their originals, but have yet to identify the precise effects of these differences within the organism. Somatic mutations contribute to aging and are implicated in tumor development and other age-related diseases. Thus, we compared whole genome sequencing data from an original dog with that of cloned dogs, identifying candidate somatic mutations that were disproportionately located within genes previously implicated in aging. The substitutional signature of cloning-specific somatic mutations mirrored the uniform distribution characteristic of the signature associated with human aging. Further analysis of genes revealed significant enrichment of traits associated with body size as well as the molecular mechanisms underlying neuronal function and tumorigenesis. Overall, the somatic mutations found in cloned dogs may indicate a conserved mechanism driving aging across species and a broad spectrum of pathway alterations.

Adipose tissue, well known for its endocrine function, plays an immunological role in the body. The inflamed adipose tissue under LPS-induced systemic inflammation is characterized by the dominance of pro-inflammatory immune cells, particularly neutrophils. Although migration of macrophages toward damaged or dead adipocytes to form a crown-like structure in inflamed adipose tissue has been revealed, the neutrophilic interaction with adipocytes or the extracellular matrix remains unknown. Here, we demonstrated the involvement of adhesion molecules, particularly integrin α6β1, of neutrophils in adipocytes or the extracellular matrix of inflamed adipose tissue interaction. These results suggest that disrupting the adhesion between adipose tissue components and neutrophils may govern the accumulation of excessive neutrophils in inflamed tissues, a prerequisite in developing anti-inflammatory therapeutics by inhibiting inflammatory immune cells., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disorder in dogs with a high prevalence, accounting for approximately 75% of all canine heart disease cases. MMVD is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. However, the molecular mechanisms and age-related changes that govern disease progression, especially at the early stage (B1) before the development of discernable clinical signs, remain poorly understood. In this prospective study, we aimed to compare gene expression differences between blood samples of aged beagle dogs with stage B1 MMVD and those of healthy controls using RNA sequencing. Clinical evaluation was also conducted, which revealed minimal differences in radiographic and echocardiographic measurements despite distinct biomarker variations between the two groups. Comparative transcriptomics revealed differentially expressed genes associated with extracellular matrix remodeling, prostaglandin metabolism, immune modulation, and interferon-related pathways, which bear functional relevance for MMVD. In particular, the top 10 over- and under-expressed genes represent promising candidates for influencing pathogenic changes in MMVD stage B1. Our research findings, which include identified variations in clinical markers and gene expression, enhance our understanding of MMVD. Furthermore, they underscore the need for further research into early diagnosis and treatment strategies, as, to the best of our knowledge, no prior studies have explored the precise molecular mechanisms of stage B1 in MMVD through total RNA sequencing., Competing Interests: The authors have declared no conflicts of interest in relation to the research, authorship or publication of this article, (Copyright: © 2024 Kim 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.)

Objective: Biliary atresia (BA) patients develop chronic liver disease after the Kasai operation and are eventually indicated for liver transplantation (LT). The purposes of this study were to analyze long-term outcomes after LT and risk factors that affect complications to reduce graft failure., Study Design: Overall, 145 pediatric patients who underwent LT between June 1996 and June 2020 after a diagnosis of BA were included. We performed a retrospective analysis of medical records and evaluated patient and graft survival, cumulative incidence of complications, risk factors, and the results of policy changes., Results: Patient and graft survival rates in over 20 years were 95.8% and 91.0%, respectively. Post-transplantation lymphoproliferative disease was frequently observed in the early period of immunosuppression within the first 1-2 years after LT. The incidence of cholangitis and rejection steadily increased over time. Weight-to-portal vein size was evaluated as a risk factor for cholangitis and bile duct strictures (OR = 12.82, p  = 0.006 and OR = 16.54, p  = 0.015, respectively). When evaluated using 2013 as a reference point, the split graft indication was expanded and the group that received LT after 2013 had a significantly lower survival over time compared with that of the group that received LT before 2013 ( p  = 0.006)., Conclusion: This study revealed time differences in prevalence of complications. The evaluation of weight-to-duct or vessel size is a more important factor in considering complications than the graft-to-recipient weight ratio. Survival outcomes may have been altered by a policy change that affects the donor type ratio in transplantation., 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., (© 2024 Kwon, Ahn, Yang, Kim, Choe, Lee and Kim.)

Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: A substantial number of cancer survivors have poor quality of life (QOL) even after completing cancer treatment. Thus, in this study, we used machine learning (ML) to develop predictive models for poor QOL in post-treatment cancer survivors in South Korea., Methods: This cross-sectional study used online survey data from 1,005 post-treatment cancer survivors in South Korea. The outcome variable was QOL, which was measured using the global QOL subscale of the European Organization of Cancer and Treatment for Cancer Quality of Life Questionnaire, where a global QOL score < 60.4 was defined as poor QOL. Three ML models (random forest (RF), support vector machine, and extreme gradient boosting) and three deep learning models were used to develop predictive models for poor QOL. Model performance regarding accuracy, area under the receiver operating characteristic curve, F1 score, precision, and recall was evaluated. The SHapely Additive exPlanation (SHAP) method was used to identify important features., Results: Of the 1,005 participants, 65.1% had poor QOL. Among the six models, the RF model had the best performance (accuracy = 0.85, F1 = 0.90). The SHAP method revealed that survivorship concerns (e.g., distress, pain, and fatigue) were the most important factors that affected poor QOL., Conclusions: The ML-based prediction model developed to predict poor QOL in Korean post-treatment cancer survivors showed good accuracy. The ML model proposed in this study can be used to support clinical decision-making in identifying survivors at risk of poor QOL., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Inflammation in vascular structures due to external factors such as injury or infection inevitably leads to blood leakage. Therefore, measuring blood infiltrated into tissue may serve as an indication for the extent of an inflammatory reaction or injury. There are various methods of confirming vascular permeability in vivo and in vitro; for example, using a blood vessel permeable dye, the dye efflux can be quantitatively measured with a spectrophotometer. Although the aforementioned commonly used methods can measure leaked dye without difficulty, substantial limitations exist regarding the time points of blood leakage that can be measured. Here, we describe the details of a novel protocol to identify and analyze the real-time progression of blood leakage in vivo. This method, by combining existing methods with real-time imaging, is expected to immensely improve the visualization and evaluation of vascular permeability., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This study aimed to develop and validate a deep learning-based method that allows for segmental analysis of myocardial late gadolinium enhancement (LGE) lesions., Methods: Cardiac LGE data from 170 patients with coronary artery disease and non-ischemic heart disease were used for training, validation, and testing. Short-axis images were transformed to polar space after identification of the left ventricular (LV) center point and anterior right ventricular (RV) insertion point. Images were obtained after dividing the polar transformed images into segments based on the 16-segment LV model. Five different deep convolutional neural network (CNN) models were developed and validated using the labeled data, where the image after the division corresponded to a segment, and the lesion labeling was based on the 16-segment LV model. Unseen testing data were used to evaluate the performance of the lesion classification., Results: Without manual lesion segmentation and annotation, the proposed method showed an area under the curve (AUC) of 0.875, and a precision, recall, and F1-score of 0.723, 0.783, and 0.752, respectively for the lesion class when the pretrained ResNet50 model was tested for all slice images. The two pretrained models of ResNet50 and EfficientNet-B0 outperformed the three non-pretrained CNN models in terms of AUCs (0.873-0.875 vs. 0.834-0.841)., Conclusion: The proposed method is based on learning a deep CNN model from polar transformed images to predict LGE lesions with good accuracy and does not require time-consuming annotation procedures such as lesion segmentation., 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 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: Pulmonary paragonimiasis, a food-borne zoonotic helminthiasis, is a parasitic disease of the lung caused by infection with trematodes species of the genus Paragonimus. Although pneumothorax has been reported as occuring with paragonimiasis, to date no study has been performed concerning the clinical features and predictive risk factors for this condition., Methods: This retrospective study, which aims to fill this gap, was conducted at Jeonbuk National University Hospital. All patients (aged ≥19 years) were diagnosed with paragonimiasis between May 2011 and December 2021. Medical records were reviewed and information concerning age, sex, vital signs, underlying diseases, clinical signs and symptoms, laboratory findings, radiologic findings, treatment, and clinical outcomes was collected. An odds ratio (OR) for the risk factors associated with pneumothorax was calculated using the binary logistic regression model., Results: Among 179 consecutive patients diagnosed with pulmonary paragonimiasis, the postive rate of pneumothorax was 10.6% (19/179). Pneumothorax occurred mostly in the right lung (78.9%, 15/19), and intrapulmonary parenchymal lesions showed an ipsilateral relationship with pneumothorax (94.7%, 18/19). Fifteen patients (78.9%, 15/19) of pneumothorax associated with pulmonary paragonimiasis are accompanied by pleural effusion. Most of patients with pneumothorax (89.5%, 17/19) underwent chest tube insertion as a first treatment. Three patients (15.8%) showed relapses but in no case was a death recorded. Asthma (odds ratio [OR] 8.10, 95% confidence interval [CI] 1.43-45.91), chest pain (OR 8.15, 95% CI 2.70-24.58), and intrapulmonary lesions (OR 8.94, 95% CI 1.12-71.36) were independent risk factors for pulmonary paragonimiasis-associated pneumothorax., Conclusions: Our findings suggest that clinicians should keep in mind the possibility of pneumothorax when approached by patients with pulmonary paragonimiasis complaining of chest pain, accompanied by intrapulmonary lesions or with asthma as an underlying disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Song 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: Myocardial perfusion reserve index (MPRI) in magnetic resonance imaging (MRI) is an important indicator of ischemia, and its measurement typically involves manual procedures. The purposes of this study were to develop a fully automatic method for estimating the MPRI and to evaluate its performance., Methods: The method consisted of segmenting the myocardium in dynamic contrast-enhanced (DCE) myocardial perfusion MRI data using Monte Carlo dropout U-Net, dividing the myocardium into segments based on landmark localization with machine learning, and estimating the MPRI after the calculation of the left ventricular and myocardial contrast upslopes. The proposed method was compared with a reference method, which involved manual adjustments of the myocardial contours and upslope ranges., Results: In test subjects, MPRIs measured by the proposed technique correlated with those by the manual reference in segmental assessment [intraclass correlation coefficient (ICC) =0.75, 95% CI: 0.70-0.79, P<0.001]. The automatic and reference MPRI values showed a mean difference of -0.02 and 95% limits of agreement of (-0.86, 0.82)., Conclusions: The proposed automatic method is based on deep learning segmentation and machine learning landmark detection for MPRI measurements in DCE perfusion MRI. It holds the potential to efficiently and quantitatively assess myocardial ischemia without any user's interaction., 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-23-840/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: There is a strong correlation between risk factors for coronary artery disease (CAD) and aortic aneurysm (AA). We aimed to investigate the prevalence and prognostic impact of CAD and AA in patients who underwent coronary aorta computed tomography (CACT) protocol, which allowed simultaneous evaluation of coronary artery and aorta., Methods: Between 2010 and 2021, 1,553 patients who underwent CACT were enrolled from a tertiary center. The presence and location of AA and the presence of CAD were identified from CT. The primary outcome was a composite of cardiovascular death, acute coronary syndrome requiring urgent revascularization, and stroke at 3 years after the index CT scan., Results: Out of 1,553 enrolled patients, 179 (11.5%) had AA. The prevalence of CAD was significantly higher in patients with AA than those without (47.5% vs. 18.3%, P < 0.001). Among patients with AA, the prevalence of comorbid CAD was higher in those with abdominal AA than thoracic AA (57.3% vs. 37.8%, P = 0.014), respectively. In multivariable analysis, the presence of CAD was an independent predictor of primary outcome at 3 years (hazard ratio [HR], 2.58; 95% CI, 1.47-4.51; P = 0.001), while AA was not (HR, 1.00; 95% CI, 0.48-2.07; P = 0.993)., Conclusion: In this cohort of patients undergoing simultaneous evaluation of coronary artery and aorta using CACT protocol, patients with AA had an increased risk of comorbid CAD compared to those without AA. CAD was independently associated with adverse clinical outcomes at 3 years., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Purpose: This study aimed to compare the diagnostic performance of cardiac CT and transthoracic echocardiogram (TTE) depending on the degree of valvular calcification and bicuspid aortic valve (BAV) subtype., Materials and Methods: This retrospective study included 266 consecutive patients (106 with BAV and 160 with tricuspid aortic valve) who underwent cardiac CT and TTE before aortic valve replacement. Cardiac CT was used to evaluate the morphology of the aortic valve, and a calcium scoring scan was used to quantify valve calcium. The aortic valves were classified into fused and two-sinus types. The diagnostic accuracy of cardiac CT and TTE was calculated using a reference standard for intraoperative inspection., Results: CT demonstrated significantly higher sensitivity, negative predictive value, and accuracy than TTE in detecting BAV ( p < 0.001, p < 0.001, and p = 0.003, respectively). The TTE sensitivity tended to decrease as valvular calcification increased. The error rate of TTE for CT was 10.9% for the two-sinus type of BAV and 28.3% for the fused type ( p = 0.044)., Conclusion: Cardiac CT had a higher diagnostic performance in detecting BAV than TTE and may help diagnose BAV, particularly in patients with severe valvular calcification., Competing Interests: Conflicts of Interest: The authors have no potential conflicts of interest to disclose., (Copyrights © 2023 The Korean Society of Radiology.)

Mesenchymal stem cells derived from rheumatoid arthritis patients (RA-MSCs) provide an understanding of a variety of cellular and immunological responses within the inflammatory milieu. Sustained exposure of MSCs to inflammatory cytokines is likely to exert an influence on genetic variations, including reference genes (RGs). The sensitive effect of cytokines on the reference genes of RA-SF-MSCs may be a variation factor affecting patient-derived MSCs as well as the accuracy and reliability of data. Here, we comparatively evaluated the stability levels of nine RG candidates, namely GAPDH , ACTB , B2M , EEF1A1 , TBP , RPLP0 , PPIA , YWHAZ , and HPRT1 , to find the most stable ones. Alteration of the RG expression was evaluated in MSCs derived from the SF of healthy donors (H-SF-MSCs) and in RA-SF-MSCs using the geNorm and NormFinder software programs. The results showed that TBP , PPIA , and YWHAZ were the most stable RGs for the normalization of H-SF-MSCs and RA-SF-MSCs using RT-qPCR, whereas ACTB, the most commonly used RG, was less stable and performed poorly. Additionally, the sensitivity of RG expression upon exposure to proinflammatory cytokines (TNF-α and IL-1β) was evaluated. RG stability was sensitive in the H-SF-MSCs exposed to TNF-α and IL-1β but insensitive in the RA-SF-MSCs. Furthermore, the normalization of IDO expression using ACTB falsely diminished the magnitude of biological significance, which was further confirmed with a functional analysis and an IDO activity assay. In conclusion, the results suggest that TBP , PPIA , and YWHAZ can be used in SF-MSCs, regardless of their exposure to inflammatory cytokines.

Background: The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD., Methods: In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX ( n = 15) (15 mg/body surface area (BSA) per week) or oral AZA ( n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared., Results: Among the 29 patients, there were no significant differences in the biochemical ( p = 1.0 at week 14, p = 0.45 at week 54), endoscopic ( p = 0.968 at week 14, p = 0.05 at week 54), or transmural ( p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences ( p = 0.686, p = 0.389, respectively)., Conclusion: The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.

Introduction: Acute gastrointestinal graft-versus-host disease (GVHD) is a common life-threatening complication after hematopoietic stem cell transplantation (HCT). We aimed to investigate outcomes according to the clinical, endoscopic, and histologic severity of gastrointestinal GVHD in pediatric patients treated with allogeneic HCT., Methods: This retrospective cohort study included pediatric patients who underwent sufficient endoscopic and histopathologic evaluation for clinically suspected acute gastrointestinal GVHD between 2010 and 2020., Results: Fifty-one patients were included (male proportion, 68.6% [35/51]; median age at HCT, 6.4 years). When the patients were classified according to the histologic severity of gastrointestinal GVHD, the severe group had an earlier onset of GVHD symptoms and a higher proportion of patients with severe clinical gastrointestinal GVHD than the mild-to-moderate and "absent" groups. In Cox proportional hazards regression analysis, the groups with more severe clinical and histologic gastrointestinal GVHD showed a higher risk of non-relapse mortality (NRM). The 5-year overall survival (OS) rates were 58.3 and 36.4% in the mild-to-moderate and histologic gastrointestinal GVHD groups, respectively ( p = 0.0384). Patients with higher clinical and histologic grades of gastrointestinal GVHD showed higher cumulative incidence of NRM., Discussion: Our results demonstrated that histologic severity of gastrointestinal GVHD is a relevant factor affecting OS and NRM, and patients with mild-to-moderate or severe histologic gastrointestinal GVHD have worse outcomes than patients without histologic GVHD. These findings support the importance of assessing the histologic grade in the diagnostic evaluation of patients with clinical gastrointestinal GVHD., 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 Kim, Kwon, Choe, Kim and Yoo.)

Background: Identification of factors associated with quality of life (QOL) among cancer survivors is crucial for identifying potential targets for intervention., Objectives: We aimed to provide evidence of factors associated with the QOL among posttreatment cancer survivors in Korea., Methods: We performed a systematic literature search from January 2000 to September 2022 using PubMed, EMBASE, CINAHL, PsycINFO, and Korean databases (RISS, SCIENCEON). We evaluated study quality using the Joanna Briggs Institute Quality Appraisal Checklists for Analytical Cross-sectional Studies and performed statistical analysis using the R 3.0 software (R Foundation for Statistical Computing, Vienna, Austria) package. We analyzed the pooled effect sizes of potential QOL correlates by the random-effects model., Results: This meta-analysis included 31 studies with 8934 participants. The pooled estimates were significantly large for economic status (r = -0.53); significantly medium for fatigue (r = -0.39), anxiety (r = -0.29), depression (r = -0.42), self-efficacy (r = 0.37), and social support (r = 0.30); and significantly small for education level (r = -0.18), job status (r = -0.09), cancer stage (r = -0.20), and time since diagnosis (r = -0.26)., Conclusions: Low education level, having no job, low economic status, advanced cancer stage, short disease period, fatigue, anxiety, and depression were significantly associated with worse QOL, whereas self-efficacy and social support were significantly associated with better QOL., Implications for Practice: The findings have potential implications for identifying "at-risk survivors" of deteriorated QOL and for suggesting powerful strategies (eg, enhancing self-efficacy or social support) for improving QOL., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

(1) Background: Longitudinal changes in myocardial T1 relaxation time are unknown. We aimed to assess the longitudinal changes in the left ventricular (LV) myocardial T1 relaxation time and LV function. (2) Methods: Fifty asymptomatic men (mean age, 52.0 years) who underwent 1.5 T cardiac magnetic resonance imaging twice at an interval of 54 ± 21 months were included in this study. The LV myocardial T1 times and extracellular volume fractions (ECVFs) were calculated using the MOLLI technique (before and 15 min after gadolinium contrast injection). The 10-year Atherosclerotic Cardiovascular Disease (ASCVD) risk score was calculated. (3) Results: No significant differences in the following parameters were noted between the initial and follow-up assessments: LV ejection fraction (65.0 ± 6.7% vs. 63.6 ± 6.3%, p = 0.12), LV mass/end-diastolic volume ratio (0.82 ± 0.12 vs. 0.80 ± 0.14, p = 0.16), native T1 relaxation time (982 ± 36 vs. 977 ± 37 ms, p = 0.46), and ECVF (24.97 ± 2.38% vs. 25.02 ± 2.41%, p = 0.89). The following parameters decreased significantly from the initial assessment to follow-up: stroke volume (87.2 ± 13.7 mL vs. 82.6 ± 15.3 mL, p = 0.01), cardiac output (5.79 ± 1.17 vs. 5.50 ± 1.04 L/min, p = 0.01), and LV mass index (110.16 ± 22.38 vs. 104.32 ± 18.26 g/m 2 , p = 0.01). The 10-year ASCVD risk score also remained unchanged between the two timepoints (4.71 ± 0.19% vs. 5.16 ± 0.24%, p = 0.14). (4) Conclusion: Myocardial T1 values and ECVFs were stable over time in the same middle-aged men.

We aimed to evaluate the additive value of cardiovascular magnetic resonance imaging (CMR) and cardiopulmonary exercise test (CPET) to predict clinical outcomes in patients with HCM. We enrolled 373 patients with HCM and normal left ventricular systolic function who underwent CPET and CMR. The primary outcome was a clinical composite of all-cause death, cardiac transplantation, stroke, heart failure requiring hospitalization and defibrillator implantation. During a follow-up of 70.70 ± 30.74 months, there were 84 composite clinical events. Peak oxygen consumption during CPET was significantly lower (18.51±13.25 vs. 24.59±13.28 mL/kg/min, p < 0.001) and abnormal hemodynamic response to exercise was more frequently detected (41.7 vs. 20.8%, p<0.001) in the group with composite clinical events. The extent of late gadolinium enhancement was larger in the event group (15.39±10.53 vs. 11.97±9.53%LV, p<0.001). Selective parameters were added stepwise to conventional clinical parameters; the final model, where CPET and CMR parameters were added, was verified to have the highest increment value for clinical outcome prediction (p<0.001). This study demonstrated that CPET and CMR findings may be important clinical tools for risk stratification in HCM. Exercise capacity was an independent predictor of composite outcomes in patients with HCM, with incremental value as a risk factor when added to the alleged parameters. These findings could help physicians monitor and manage patients with HCM in the real clinical field., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hwang 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.)