Search

Sang-In Park,1,* Su-Hak Heo,2,3,* Gihwan Kim,2 Seokhoon Chang,2 Keon-Hyoung Song,3 Min-Gul Kim,4 Eun-Heui Jin,5 JaeWoo Kim,5 SeungHwan Lee,1 Jang Hee Hong5,6 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2R&D Center, C.L. Pharm Co., Ltd, Seoul, Republic of Korea; 3Department of Pharmaceutical Engineering, College of Medical Science, Soonchunhyang University, Asan, Republic of Korea; 4Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea; 5Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea; 6Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea *These authors contributed equally to this work Background: An orodispersible film (ODF) of tadalafil may provide increased convenience for erectile dysfunction (ED) patients as compared to conventional tablet formulations. In this study, we aimed to compare the pharmacokinetic, safety, and tolerability profiles of a newly developed ODF formulation of tadalafil to those of a film-coated tablet (FCT) of tadalafil.Materials and methods: This study was conducted in healthy male subjects using an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to one of two sequences of the two formulations: both the test drug (ODF) and the reference drug (FCT) contained 20 mg of tadalafil. Blood samples were collected up to 72 h after administration. Plasma concentrations of tadalafil were analyzed using liquid chromatography–tandem mass spectrometry. Geometric mean ratios (GMRs) of the ODF to FCT formulations and their 90% CIs for the pharmacokinetic parameters were estimated. Safety and tolerability were assessed throughout the study.Results: Forty healthy male subjects were enrolled, and 36 of these completed the study. The GMRs (90% CIs) of the maximum plasma concentration and the area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration for tadalafil were 0.927 (0.882–0.974) and 0.972 (0.918–1.029), respectively. Both ODF and FCT formulations were well tolerated, and no clinically significant changes from the baseline were observed after dosing.Conclusion: The pharmacokinetics of the tadalafil ODF formulation did not differ significantly from those of the FCT formulation. Furthermore, the safety and tolerability profiles of the ODF formulation were comparable to those of the FCT formulation. Therefore, this tadalafil ODF formulation offers a convenient treatment option for patients with erectile dysfunction. Keywords: erectile dysfunction, orodispersible film, tadalafil, pharmacokinetics

Takayasu's arteritis is a chronic inflammatory disease of the aorta and its main branches, and a well known cause of stroke. Pathogenesis of ischaemic stroke has been attributed to intracranial vasculitic involvement or emboli from either stenoocclusive extracranial vessels or cardiac disease such as aortic regurgitation. We present a patient with Takayasu's arteritis and recurrent cerebral infarctions associated with intracranial atherosclerosis. We postulate that the intracranial atherosclerotic process is an important mechanism in Takayasu's arteritis-related ischaemic stroke. [ABSTRACT FROM AUTHOR]

Background: Vascular diseases, including atherosclerosis and thrombosis, are leading causes of morbidity and mortality worldwide, often resulting in vessel stenosis that impairs blood flow and leads to severe clinical outcomes. Traditional mechanical interventions, such as balloon angioplasty and bare-metal stents, provided initial solutions but were limited by restenosis and thrombosis. The advent of drug-eluting stents improved short-term outcomes by inhibiting vascular smooth muscle cell proliferation, however, they faced challenges including delayed reendothelialization and late-stage thrombosis., Methods: This review highlights the progression from mechanical to biological interventions in treating vascular stenosis and underscores the need for integrated approaches that combine mechanical precision with regenerative therapies., Results: To address long-term complications, bioresorbable stents were developed to provide temporary scaffolding that gradually dissolves, yet they still encounter challenges with mechanical integrity and optimal degradation rates. Consequently, emerging therapies now focus on biological approaches, such as gene therapy, extracellular vesicle treatments, and cell therapies, that aim to promote vascular repair at the cellular level. These strategies offer the potential for true vascular regeneration by enhancing endothelialization, modulating immune responses, and stimulating angiogenesis., Conclusion: Integrating mechanical precision with regenerative biological therapies offers a promising future for treating vascular stenosis. A comprehensive approach combining these modalities could achieve sustainable vascular health., Competing Interests: Declarations. Conflict of interest: There are no conflicts to declare. Ethical statement: There are no animal experiments carried out for this article., (© 2025. Korean Tissue Engineering and Regenerative Medicine Society.)

Background: Non-invasive approach other than conventional endoscopy could be effectively used for screening and monitoring esophageal variceal bleeding (EVB)., Purpose: To retrospectively investigate the role of four-dimensional (4D) flow magnetic resonance imaging (MRI) as an add-on tool to endoscopy for predicting EVB in cirrhotic patients with esophageal varices (EVs)., Material and Methods: A cohort of 109 cirrhotic patients with EVs was divided into four groups: A = negative red color [RC] sign, no EVB, n = 60; B = negative RC sign, EVB, n = 13; C = positive RC sign, no EVB, n = 10; and D = positive RC sign, EVB, n = 26. All patients underwent laboratory assessments and 4D flow MRI using a 3-T scanner to analyze hemodynamic parameters within the main portal vein (PV), splenic vein, and superior mesenteric vein. Comparative analysis of 4D flow parameters among the groups was performed using the Mann-Whitney U-test, and diagnostic accuracy was assessed through the area under the receiver operator characteristic curve (AUC)., Results: In the main PV, all 4D flow parameters were significantly lower in patients with a positive RC sign compared to those with a negative RC sign ( P  < 0.05). Patients with EVB had lower parameters than those without EVB ( P  < 0.05). The AUC values predicting actual variceal bleeding was 0.762 for endoscopy alone and 0.770-0.787 for 4D flow MRI. Integrating the endoscopic classification with the 4D flow MRI significantly improved the AUC value to 0.871 ( P  < 0.05)., Conclusion: Four-dimensional flow MRI may be useful as an add-on tool to endoscopy for predicting actual bleeding in cirrhotic patients with EVs., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Nelonemdaz selectively antagonizes the 2B subunit of the N-methyl-d-aspartate glutamate receptor and scavenges free radical species., Objective: To evaluate whether nelonemdaz enhances the clinical outcomes of patients with acute ischemic stroke undergoing emergent reperfusion therapy., Design, Setting, and Participants: This multicenter double-blind placebo-controlled randomized phase 3 trial (December 25, 2021, to June 30, 2023, in South Korea) recruited patients with acute ischemic stroke who met the following criteria: National Institutes of Health Stroke Scale score greater than or equal to 8, Alberta Stroke Program Early Computed Tomography score greater than or equal to 4, and endovascular thrombectomy within 12 hours after stroke onset., Intervention: Patients were assigned in a 1:1 ratio to receive intravenous infusions of nelonemdaz twice a day for 5 days or a matching placebo., Main Outcomes and Measures: The primary end point was a favorable shift in the modified Rankin scale (mRS) 12 weeks after stroke onset. The secondary end points included various composites of the mRS at 5 and 12 weeks, symptomatic intracranial hemorrhage, and infarct volume. Both intention-to-treat and per-protocol analyses were conducted., Results: A total of 496 patients were enrolled across 24 Korean stroke centers, of whom 39 dropped out (254 men [55.6%]; mean [SD] age, 72.9 [12.1] years). Baseline characteristics of study participants did not significantly differ. For the primary end point, the distribution of the mRS scores at 12 weeks did not significantly differ between the nelonemdaz and placebo groups (common odds ratio, 0.95; 95% CI, 0.69-1.31). For the secondary end points, a median of mRS at 5 weeks (3 vs 3) and mRS 0 at 12 weeks (18.1% vs 18.2%) did not differ substantially between groups. The occurrence of symptomatic intracranial hemorrhage (2.7% vs 0.9%) and infarct volume within 24 hours of the last trial drug infusion (42 vs 38 mL) did not differ significantly between groups. No serious adverse events were reported regarding the trial drug and placebo., Conclusions and Relevance: In this randomized clinical trial, nelonemdaz did not meet the primary efficacy end point compared with placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT05041010.

Purpose: Determining the extent of radical lymphadenectomy at clinical early stage is challenging. We aimed to investigate the appropriate extent of lymphadenectomy in clinical early-stage right colon cancer., Methods: Patients with clinical stage 0 or I right colon cancer who underwent curative surgery from January 2007 to December 2021 were included in this retrospective study. The extent of lymph node (LN) metastases based on the distribution of LN metastases (LND: LND1 pericolic nodes, LND2 intermediate nodes, LND3 apical nodes), along with the depth of submucosal (SM) invasion (classed into SM1-3), were analyzed., Results: Of the 348 patients, distribution across pathologic stages was as follows: 30 patients (8.6%) at stage 0, 207 (59.5%) at stage I, 52 (14.9%) at stage II, and 59 (17.0%) at stage III. In pT1 tumor patients, LN metastases varied by SM invasion depth: 3.6% in SM1 (all LND1), 5.1% in SM2 (all LND1), and 17.5% in SM3 (LND1 10%, LND2 5%, LND3 2.5%). For pT2, pT3, and pT4 stages, LN metastasis rates were 16.2% (LND1 11.3%, LND2 3.8%, LND3 1.3%), 39.7% (LND1 28.9%, LND2 8.4%, LND3 2.4%), and 50% (LND1 25%, LND2 25%), respectively. Tumor invasion depth and lymphovascular invasion were identified as significant risk factors for LN metastasis extending to LND2-3., Conclusion: Complete mesocolic excision should be considered for right-sided colon cancer because tumor infiltration deeper than SM2 could metastasize to LND2 or further. If preoperative endoscopy confirms SM1 or SM2 invasion, D2 lymphadenectomy could be a limited surgical option., Competing Interests: Conflict of Interest: Soo Young Lee, serving as the editor board of Annals of Surgical Treatment and Research, did not participate in the review process of this article. No other potential conflicts of interest pertinent to this article were reported., (Copyright © 2025, the Korean Surgical Society.)

Background: Dysregulated cellular metabolism is known to be associated with drug resistance in cancer treatment. Methods: In this study, we investigated the impact of cellular adaptation to lactic acidosis on intracellular energy metabolism and sensitivity to docetaxel in prostate carcinoma (PC) cells. The effects of curcumin and the role of hexokinase 2 (HK2) in this process were also examined. Results: PC-3AcT and DU145AcT cells that preadapted to lactic acid displayed increased growth behavior, increased dependence on glycolysis, and reduced sensitivity to docetaxel compared to parental PC-3 and DU145 cells. Molecular analyses revealed activation of the c-Raf/MEK/ERK pathway, upregulation of cyclin D1, cyclin B1, and p-cdc2Thr161, and increased levels and activities of key regulatory enzymes in glycolysis, including HK2, in lactate-acclimated cells. HK2 knockdown resulted in decreased cell growth and glycolytic activity, decreased levels of complexes I-V in the mitochondrial electron transport chain, loss of mitochondrial membrane potential, and depletion of intracellular ATP, ultimately leading to cell death. In a xenograft animal model, curcumin combined with docetaxel reduced tumor size and weight, induced downregulation of glycolytic enzymes, and stimulated the upregulation of apoptotic and necroptotic proteins. This was consistent with the in vitro results from 2D monolayer and 3D spheroid cultures, suggesting that the efficacy of curcumin is not affected by docetaxel. Conclusions: Overall, our findings suggest that metabolic plasticity through enhanced glycolysis observed in lactate-acclimated PC cells may be one of the underlying causes of docetaxel resistance, and targeting glycolysis by curcumin may provide potential for drug development that could improve treatment outcomes in PC patients.

Background: Particulate matter (PM) and air pollution have been suggested to be associated with chronic obstructive pulmonary disease (COPD), contributing significantly to global respiratory disease-related mortality. This study aimed to investigate whether seasonal exposure to PM influences dysbiosis in the respiratory microbiota of patients with COPD., Methods: Sputum samples were collected four times over 1 year from 102 patients with COPD, and 16S rRNA sequencing was performed. The dynamics of the airway microbiota were analyzed depending on PM exposure levels and season., Results: The PM-low exposure group had higher α-diversity compared to the PM-high exposure group, particularly noted in spring. Some bacterial groups, including seven species such as Treponema socranskii, were more abundant in the low exposure group. Additionally, the bacterial community structure in summer significantly differed from that in other seasons, with significantly increased α-diversity in this season. The difference in the airway microbiome due to PM exposure was prominent in patients with moderate COPD., Conclusions: PM exposure may influence changes in the sputum microbiome depending on exposure levels and seasonal variations. Our results suggest that airway microbiomes could vary with PM exposure according to seasonal trends., 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 © 2024 Elsevier B.V. All rights reserved.)

Purpose: Autologous arteriovenous fistulas (AVFs) are considered the gold standard for hemodialysis access, with outcomes largely dependent on the surgeon's experience. Nevertheless, few studies have been conducted on the learning curve of junior vascular surgeons in AVF creation. This study aims to address this by examining the development of surgical skills among junior vascular surgeons., Materials and Methods: A retrospective analysis was conducted on 100 patients who underwent autologous AVF procedures performed by five junior surgeons between January 2018 and December 2023. To establish the cutoff number of cases for the learning curve, we examined the cubic spline curve using the hazard ratio for primary failure., Results: The cutoff number for operation cases was 15.33, and we divided the analysis into a pre-learning curve period (≤15 cases of AVF) and a post-learning curve period (>15 cases of AVF). The 1-year primary patency rate for AVF during the post-learning curve period was 84.0%, which was higher than the 65.5% rate observed during the pre-learning curve period. In a subgroup analysis based on AVF type, the radiocephalic fistula patient group demonstrated a significant increase in 1-year primary patency in the post-learning curve period compared to that in the pre-learning curve period (80.0% vs. 43.0%, log-rank P=0.033). In contrast, there was no significant difference in the primary patency rates between the post- and pre-learning curve periods in the brachiocephalic fistula patient group (90.0% vs. 89.2%, log-rank P=0.930)., Conclusion: Junior vascular surgeons demonstrated improved primary AVF patency beyond the learning curve benchmark in 15 patients, with particularly notable enhancements in radiocephalic fistulas.

The widespread adoption of halide perovskites for application in thermoelectric devices, DC power generators, and lasers is hindered by their low charge carrier concentration. In particular, increasing their charge carrier concentration is considered the main challenge to serve as a promising room-temperature thermoelectric material. Efforts have been devoted to enhancing the charge carrier concentration by doping and composition engineering. However, the coupling between charge carrier concentration and mobility, along with the poor stability of these materials, impedes their development for thermoelectric applications. Herein, we demonstrate the successful increase in the charge carrier concentration of CsPbI 2 Br by forming a heterojunction structure with Cu 2 S via a facile spin-coating method. The excellent band alignment between two materials combined with a charge-transfer mechanism realizes the modulation doping, resulting in 8 orders of magnitude increase in carrier concentration from 10 12 to 10 20 cm -3 without detrimental effect on the carrier mobility of CsPbI 2 Br. The thermoelectric power factor of the heterostructured CsPbI 2 Br reached 6.6 μW/m·K 2 , which is 330 times higher than that of pristine CsPbI 2 Br. Furthermore, these films showed higher humidity stability than the control films. This study offers a promising avenue for increasing the charge carrier concentration of halide perovskites, thereby enhancing their potential for various applications.

Arterial stenosis caused by atherosclerosis often requires stent implantation to increase the patency of target artery. However, such external devices often lead to in-stent restenosis due to inadequate re-endothelialization and subsequent inflammatory responses. Therefore, re-endothelialization strategies after stent implantation have been developed to enhance endothelial cell recruitment or to capture circulating endothelial progenitor cells. Notably, recent research indicates that coating stent surfaces with biogenic materials enhances the long-term safety of implantation, markedly diminishing the risk of in-stent restenosis. In this review, we begin by describing the pathophysiology of coronary artery disease and in-stent restenosis. Then, we review the characteristics and materials of existing stents used in clinical practice. Lastly, we explore biogenic materials aimed at accelerating re-endothelialization, including extracellular matrix, cells, and extracellular vesicles. This review helps overcome the limitations of current stents for cardiovascular disease and outlines the next phase of research and development.

Background: After carotid artery angioplasty with stenting (CAS), it is unclear which risk factors are related to long-term outcomes, including in-stent restenosis (ISR). This study aimed to assess the factors associated with restenosis after CAS with a median follow-up of 35.7 months., Materials and Methods: Patients who underwent CAS from January 2013 to December 2018 were included if they had symptomatic or asymptomatic carotid artery stenosis. The carotid Doppler ultrasonography (CDU) was followed up after the procedure. We defined at least 50% restenosis using the criteria that the internal carotid artery (ICA) peak systolic velocity (PSV) was greater than 224 cm/s or the ICA to common carotid artery PSV ratio was higher than 3.4. The risk factors for ISR were also assessed., Results: Of the 189 patients, 122 had symptomatic carotid artery stenosis, and 67 had asymptomatic carotid artery stenosis. Patients were evaluated by CDU for a median of 35.7 months (interquartile range 19.5 to 70.0). Kaplan-Meier analysis showed that the longest time to ISR was 39 months, and ISR-free was better in the asymptomatic CAS group. In all groups, ISR was independently associated with current smoker [adjusted odds ratio (aOR), 3.425; 95% confidence interval (CI), 1.086 to 10.801] and elevated ICA PSV at baseline (aOR, 1.004; 95% CI, 1.001 to 1.007)., Conclusion: Independent risk factors for ISR in the CAS group included current smoking and elevated ICA PSV at baseline. In the symptomatic CAS group, alcohol was independently associated with the ISR. ISR did not occur after 39 months from the CAS procedure in our study patients. Future studies with extended follow-up are necessary to fully understand the long-term outcomes of CAS., 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 Park, Kim, Choi, Chang, Woo and Heo.)

Purpose: This study aimed to assess metabolic changes to monitor the progression from normal liver to hepatitis B virus (HBV)-related hepatitis and liver fibrosis using hyperpolarized 13 C magnetic resonance imaging (MRI)., Procedures: Hepatitis was induced in mice (n = 16) via hydrodynamic injection of HBV 1.2 plasmid (25 μg). Among them, liver fibrosis was induced in the mice (n = 8) through weight-adapted administration of thioacetamide with ethanol. Normal control mice (n = 8) were injected with a phosphate buffer solution. Subsequently, a hyperpolarized 13 C MRI was performed on the mouse liver in vivo. The level of hepatitis B surface antigen (HBsAg) in blood serum was measured. Statistical analysis involved comparing the differential metabolite ratios, blood biochemistry values, and body weight among the three groups using the Kruskal-Wallis one-way analysis of variance., Results: HBsAg was absent in the normal and fibrosis groups, while it was detected in the hepatitis group. The ratios of [1- 13 C] lactate/pyruvate, [1- 13 C] alanine/pyruvate, [1- 13 C] lactate/total carbon, and [1- 13 C] alanine/total carbon were significantly lower in the normal control group than in the hepatitis and fibrosis groups (p < 0.05). Moreover, these ratios were significantly higher in the fibrosis group than in the hepatitis group (p < 0.05). However, no significant differences were observed in either [1- 13 C] pyruvate-hydrate/pyruvate or [1- 13 C] pyruvate-hydrate/total carbon among the three groups., Conclusions: The levels of [1- 13 C] lactate and [1- 13 C] alanine in vivo may serve as valuable indicators for differentiating between HBV-related hepatitis, liver fibrosis, and normal liver., (© 2024. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Introduction: Humanized mouse models to recapitulate human biological systems still have limitations, such as the onset of lethal graft-versus-host disease (GvHD), a variable success rate, and the low accessibility of total body irradiation (TBI). Recently, mice modified with the CD47-SIRPA axis have been studied to improve humanized mouse models. However, such trials have been rarely applied in NOD mice. In this study, we created a novel mouse strain, NOD-CD47 null Rag2 null IL-2rγ null (RTKO) mice, and applied it to generate humanized mice., Methods: Four-week-old female NOD-Rag2 null IL-2rγ null (RID) and RTKO mice pre-conditioned with TBI or busulfan (BSF) injection were used for generating human CD34+ hematopoietic stem cell (HSC) engrafted humanized mice. Clinical signs were observed twice a week, and body weight was measured once a week. Flow cytometry for human leukocyte antigens was performed at intervals of four weeks or two weeks, and mice were sacrificed at 48 weeks after HSC injection., Results: For a long period from 16 to 40 weeks post transplantation, the percentage of hCD45 was mostly maintained above 25% in all groups, and it was sustained the longest and highest in the RTKO BSF group. Reconstruction of human leukocytes, including hCD3, was also most prominent in the RTKO BSF group. Only two mice died before 40 weeks post transplantation in all groups, and there were no life-threatening GvHD lesions except in the dead mice. The occurrence of GvHD has been identified as mainly due to human T cells infiltrating tissues and their related cytokines., Discussion: Humanized mouse models under all conditions applied in this study are considered suitable models for long-term experiments based on the improvement of human leukocytes reconstruction and the stable animal health. Especially, RTKO mice pretreated with BSF are expected to be a valuable platform not only for generating humanized mice but also for various immune research fields., 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 Kim, Lee, Baek, Song, Jo, Ryu, Ryu, Seo, Kim and Heo.)

Objectives: Adherent perinephric fat (APF) poses significant challenges to surgical procedures. This study aimed to evaluate the usefulness of machine learning algorithms combined with MRI-based radiomics features for predicting the presence of APF., Materials and Methods: Patients with renal cell carcinoma who underwent surgery between April 2019 and February 2022 at Chonnam National University Hwasun Hospital were retrospectively screened, and 119 patients included. Twenty-one and seventeen patients were set aside for the internal and external test sets, respectively. Pre-operative T1-weighted MRI acquired at 60 s following a contrast injection (T1w-60) were collected. For each T1w-60 data, two regions of interest (ROIs) were manually drawn: the perinephric fat tissue and an aorta segment on the same level as the targeted kidney. Preprocessing steps included resizing voxels, N4 Bias Correction filtering, and aorta-based normalization. For each patient, 851 radiomics features were extracted from the ROI of perinephric fat tissue. Gender and BMI were added as clinical factors. Least Absolute Shrinkage and Selection Operator was adopted for feature selection. We trained and evaluated five models using a 4-fold cross validation. The final model was chosen based on the highest mean AUC across four folds. The performance of the final model was evaluated on the internal and external test sets., Results: A total of 15 features were selected in the final set. The final model achieved the accuracy, sensitivity, specificity, and AUC of 81% (95% confidence interval, 61.9-95.2%), 72.7% (42.9-100%), 90% (66.7-100%), and 0.855 (0.615-1.0), respectively on the internal test set, and 88.2% (70.6-100%), 100% (100-100%), 80% (50%-100%), 0.971 (0.871-1.0), respectively on the external test set., Conclusions: Our study demonstrated the feasibility of machine learning algorithms trained with MRI-based radiomics features for APF prediction. Further studies with a multi-center approach are necessary to validate our findings., 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 © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: In young patients (aged 18-60 years) with patent foramen ovale (PFO)-associated stroke, percutaneous closure has been found to be useful for preventing recurrent ischemic stroke or transient ischemic attack (TIA). However, it remains unknown whether PFO closure is also beneficial in older patients., Methods: Patients aged ≥60 years who had a cryptogenic stroke and PFO from ten hospitals in South Korea were included. The effect of PFO closure plus medical therapy over medical therapy alone was assessed by a propensity-score matching method in the overall cohort and in those with a high-risk PFO, characterized by the presence of an atrial septal aneurysm or a large shunt., Results: Out of the 437 patients (mean age, 68.1), 303 (69%) had a high-risk PFO and 161 (37%) patients underwent PFO closure. Over a median follow-up of 3.9 years, recurrent ischemic stroke or TIA developed in 64 (14.6%) patients. In the propensity score-matched cohort of the overall patients (130 pairs), PFO closure was associated with a significantly lower risk of a composite of ischemic stroke or TIA (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.24-0.84; P=0.012), but not for ischemic stroke. In a subgroup analysis of confined to the high-risk PFO patients (116 pairs), PFO closure was associated with significantly lower risks of both the composite of ischemic stroke or TIA (HR: 0.40; 95% CI: 0.21-0.77; P=0.006) and ischemic stroke (HR: 0.47; 95% CI: 0.23-0.95; P=0.035)., Conclusion: Elderly patients with cryptogenic stroke and PFO have a high recurrence rate of ischemic stroke or TIA, which may be significantly reduced by device closure.

The dynamic interaction between the brain and the skin is termed the 'skin-brain axis.' Changes in the skin not only reflect conditions in the brain but also exert direct and indirect effects on the brain. Interestingly, the connection between the skin and brain is crucial for understanding aging and neurodegenerative diseases. Several studies have shown an association between Alzheimer's disease (AD) and various skin disorders, such as psoriasis, bullous pemphigoid, and skin cancer. Previous studies have shown a significantly increased risk of new-onset AD in patients with psoriasis. In contrast, skin cancer may reduce the risk of developing AD. Accumulating evidence suggests an interaction between skin disease and AD; however, AD-associated pathological changes mediated by the skin-brain axis are not yet clearly defined. While some studies have reported on the diagnostic implications of the skin-brain axis in AD, few have discussed its potential therapeutic applications. In this review, we address the pathological changes mediated by the skin-brain axis in AD. Furthermore, we summarize (1) the diagnostic implications elucidated through the role of the skin-brain axis in AD and (2) the therapeutic implications for AD based on the skin-brain axis. Our review suggests that a potential therapeutic approach targeting the skin-brain axis will enable significant advances in the treatment of AD.

Sodium bicarbonate is used as an ergogenic supplement to enhance people's performances in various exercises. This study aimed to evaluate the effects of intestinal delivery of sodium bicarbonate on bicarbonate absorption and associated side effects in an experimental human trial. After preparing and assessing enteric-coated and uncoated sodium bicarbonate tablet formulations, pharmacokinetic analysis and gastrointestinal symptom tests were performed after oral administration in the human body. The dose required to increase blood bicarbonate concentration over 5 mmol∙L -1 for the purpose of improving performance during high-intensity exercise was also determined. Enteric-coated tablet formulation protects sodium bicarbonate under acidic conditions and releases bicarbonate in the intestine. Enteric-coated tablet formulation also reduced the oral dose required to achieve a blood bicarbonate concentration over 5 mmol∙L -1 from 300 mg∙kg -1 of uncoated tablet formulation to 225 mg∙kg -1 . Gastrointestinal discomfort was significantly decreased for the group given 225 mg∙kg -1 enteric-coated tablets compared to that given 300 mg∙kg -1 uncoated tablets. These results suggest that enteric-coated tablet formulation could reduce the oral dose required in order to achieve a blood bicarbonate concentration over 5 mmol∙L -1 by 25%, from 300 mg∙kg -1 to 225 mg∙kg -1 , along with its ability to reduce gastrointestinal discomfort associated with the dosage.

Radish ( Raphanus sativus L.), a root vegetable belonging to the Brassicaceae family, is considered one of the representative crops displaying sporophytic self-incompatibility (SSI). The utilization of a self-incompatibility system in F 1 breeding can improve the efficiency of cross-combinations, leading to a reduction in breeding time and aiding in the development of novel F 1 varieties. The successful implementation of this system necessitates the rapid and accurate identification of S haplotypes in parental lines. In this study, we identified a total of nine S haplotypes among 22 elite radish lines through Sanger sequencing. Subsequently, we obtained sequences for showing a 95% similarity to nine S haplotypes, along with sequences identified by other researchers using BLAST. Following this, multiple sequence alignment (MSA) was conducted to identify SRK and SLG sequence similarities, as well as polymorphisms within the class I and II groups. Subsequently, S haplotype-specific marker sets were developed, targeting polymorphic regions of SRK and SLG alleles. These markers successfully amplified each of the nine S haplotypes. These markers will play a crucial role in the rapid and precise identification of parental S haplotypes in the radish F 1 breeding process, proving instrumental in the radish F 1 purity test.

Competing Interests: Authors YL, MJ, SS, and YS were employed by Insilicogen Inc. Authors SH and BP were employed by DASAN Co., Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Our study retrospectively investigated differential patterns of the functional connectivity (FC) of core brain regions synchronous with morphometric changes associated with sexual dysfunction in menopausal women, and their correlations with sexual hormones. Twenty-three premenopausal women (mean age: 41.52 ± 7.38 years) and 21 menopausal women (mean age: 55.52 ± 2.80 years) underwent sex hormone level measurements with high-resolution T1 and functional magnetic resonance imaging (MRI) during rest, neutral, and sexual arousal conditions. Analysis of covariance adjusted for age was used to compare the FC and gray matter (GM) volume between the two groups. Menopausal women showed lower GM volumes in the superior frontal gyrus (SFG), superior temporal pole, parahippocampal gyrus (PHG), hippocampus (Hip), amygdala (Amg), and cerebellum (Cb) compared to premenopausal women ( p < 0.05). In addition, compared to premenopausal women, menopausal women showed decreased FC of seed regions involved in the SFG, frontal eye fields, and Amg, as well as target regions involved in the PHG, Hip, inferior frontal gyrus, Cb, and vermis ( p < 0.005). Furthermore, the FC between the right Amg and right Cb and between the left Amg and right Cb during sexual arousal in both groups was positively correlated with total estrogen and estradiol levels, respectively ( p < 0.01). The GM volume values in the right Amg and right Cb were positively correlated with total estrogen and estradiol levels ( p < 0.05). Our study demonstrated an association between menopause-related differential FC and GM volume variations and fluctuating sex hormones. Our findings highlight that overlapping brain regions with functional alterations and morphometric changes are closely linked with menopausal symptom-related decreases in sexual arousal and hormone levels.

Three-dimensional (3D) microprinting is considered a next-generation manufacturing process for the production of microscale components; however, the narrow range of suitable materials, which include mainly polymers, is a critical issue that limits the application of this process to functional inorganic materials. Herein, we develop a generalised microscale 3D printing method for the production of purely inorganic nanocrystal-based porous materials. Our process is designed to solidify all-inorganic nanocrystals via immediate dispersibility control and surface linking-induced interconnection in the nonsolvent linker bath and thereby creates multibranched gel networks. The process works with various inorganic materials, including metals, semiconductors, magnets, oxides, and multi-materials, not requiring organic binders or stereolithographic equipment. Filaments with a diameter of sub-10 μm are printed into designed complex 3D microarchitectures, which exhibit full nanocrystal functionality and high specific surface areas as well as hierarchical porous structures. This approach provides the platform technology for designing functional inorganics-based porous materials., (© 2023. The Author(s).)

Superoxide dismutase (SOD) can convert active oxygen to oxygen or hydrogen peroxide, and recent research has suggested that it can protect against lung damage and fibrosis. Clinical applications based on SOD remain limited however due to costs and low stability. We here investigated a potential new therapeutic delivery system for this enzyme in the form of SOD-overexpressing Bacillus amyloliquefaciens spores which we introduced into a bleomycin-induced pulmonary fibrosis mouse model. This treatment significantly alleviated the disease, as quantified using a hydroxyproline assay, at 10 7 colony forming unit (CFU) of Bacillus spores per day. Exposure of the mice to the spores was further found to decrease the lung mRNA levels of CTGF, Col1a1, α-SMA, TGF-β, TNF-α, and IL-6, and the protein levels of TGF-β, Smad2/3, αSMA and Col1a1, all major indicators of pulmonary fibrosis. Survival benefits, and reduced byproducts of lipid peroxidase such as malondialdehyde and 4-hydroxynen, were also noted in the treated animals. The beneficial effects of these Bacillus spores on pulmonary fibrosis were further found to be greater than the equivalent free SOD concentration. Immunofluorescence staining of primary pulmonary fibroblasts extracted from the bleomycin-induced model showed decreased αSMA expression following the in vivo treatment with SOD-overexpressing Bacillus. Our treatment approach SOD through Bacillus spores shows beneficial effects against pulmonary fibrosis, combined with the suppression of the SMAD/TGF-β pathway, suggesting that it is an effective novel delivery route for antioxidants., Competing Interests: Declaration of Competing Interest The authors declare no competing financial or other interests in relation to this study., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Diet has a crucial role in the gut microbiota, and dysbiosis in the gut and lungs has been suggested to be associated with chronic obstructive pulmonary disease. We compared the diet, microbiome and metabolome between asymptomatic smokers and those with emphysema., Methods: We enrolled 10 asymptomatic smokers with preserved lung function and 16 smokers with emphysema with severe airflow limitation. Dietary intake information was gathered by a self-reported questionnaire. Sputum and faecal samples were collected for microbial and metabolomics analysis. A murine model of emphysema was used to determine the effect of metabolite supplementation., Results: Despite having a similar smoking history with emphysema patients, asymptomatic smokers had higher values of body mass index, fibre intake and faecal acetate level. Linear discriminant analysis identified 17 microbial taxonomic members that were relatively enriched in the faeces of asymptomatic smokers. Analysis of similarity results showed dissimilarity between the two groups (r=0.287, p=0.003). Higher acetate level was positively associated with forced expiratory volume in one second in the emphysema group (r=0.628, p=0.012). Asymptomatic smokers had a greater number of species associated with acetate and propionate (r>0.6) than did those with emphysema (30 vs 19). In an emphysema mouse model, supplementation of acetate and propionate reduced alveolar destruction and the production of proinflammatory cytokines, and propionate decreased the CD3 + CD4 + IL-17 + T-cell population in the lung and spleen., Conclusion: Smokers with emphysema showed differences in diet, microbiome and short-chain fatty acids compared with asymptomatic smokers. Acetate and propionate showed therapeutic effects in a smoking-induced murine model of emphysema., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In this study, we aimed to compare the long-term therapeutic outcomes of drug-eluting bead transarterial chemoembolization (DEB-TACE) with those of radiofrequency ablation (RFA) for the initial treatment of a single small (≤ 3 cm) hepatocellular carcinoma (HCC)., Methods: From January 2010 to December 2021, 259 consecutive patients who underwent DEB-TACE (67 patients) or RFA (192 patients) as a first-line treatment for a single small HCC were enrolled in this retrospective study. The therapeutic outcomes, including cumulative intrahepatic local tumor progression (LTP), progression-free survival (PFS), and long-term overall survival (OS) rates, were compared between the two groups before and after propensity score (PS) matching. Multivariate Cox proportional hazard models were used to evaluate the prognostic factors and differences in OS and PFS between the two groups for all 92 patients after PS matching., Results: After PS matching, the 1-, 2-, 3-, and 5-year LTP rates were lower in the RFA group than those in the DEB-TACE group ( P < 0.001), and the 1-, 2-, 3-, and 5-year PFS rates in the RFA group were higher than those in the DEB-TACE group ( P = 0.007). However, the 1-, 2-, 3-, and 5-year OS rates were not significantly different between the RFA and DEB-TACE groups ( P = 0.584). Moreover, the OS was not significantly different between the RFA and DEB-TACE groups in the univariate and multivariate analyses, with a hazard ratio (HR) of 0.81. The PFS was significantly higher in the RFA group than that in the DEB-TACE group in the univariate analyses, with a HR of 0.44 ( P = 0.009). Multivariate Cox regression analysis showed that albumin ( P = 0.019) was an independent prognostic factor for OS. Additionally, the major complication rates were not significantly different between the DEB-TACE and RFA groups ( P = 1.000)., Conclusion: The LTP and PFS rates of RFA were superior to those of DEB-TACE in the initial treatment of single small HCC after PS matching. However, the OS rates were not significantly different between RFA and DEB-TACE. Therefore, DEB-TACE may be considered an efficient substitute for RFA in some patients with a single small HCC who are ineligible for RFA., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: Stroke is rarely accompanied with peripheral facial paralysis and supranuclear palsy of the hypoglossal nerve. Both sides of the motor cortex innervate the hypoglossal nucleus; therefore, unilateral lesions of the upper motor neurons rarely result in contralateral lingual paresis. We report a rare case of crossed syndrome with associated hyperacute peripheral hemifacial paralysis and contralateral lingual paresis after a lower pontine tegmentum ischemic stroke., Case Presentation: A 73-year-old man presented with symptoms of hyperacute peripheral hemifacial paralysis. Upon protrusion, the patient's tongue deviated to the contralateral side, without fasciculation or atrophy. Brain imaging showed focal ischemic stroke in the pontine tegmentum. However, lingual hemiparesis and multimodal neuroimaging findings differed., Conclusions: We suggest that cortico-hypoglossal fibers pass through the dorsal pontine. This case of crossed syndrome is a rare report of a lower pontine tegmentum ischemic stroke resembling an upper motor neuron lesion of the contralateral hypoglossal nerve., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The interaction between the microbial environment and the host is important for immune homeostasis. Recent research suggests that microbiota dysbiosis can be involved in respiratory diseases. Emphysema is a chronic inflammatory disease, but it is unclear whether dysbiosis caused by antibiotics can affect disease progression. Here, we tried to elucidate the effect of systemic antibiotics on smoking-exposed emphysema models. In this study, the antibiotic mixture caused more alveolar destruction and airspace expansion in the smoking group than in the smoking only or control groups. This emphysema aggravation as a result of antibiotic exposure was associated with increased levels of inflammatory cells, IL-6, IFNγ and protein concentrations in bronchoalveolar lavage fluid. Proteomics analysis indicated that autophagy could be involved in antibiotic-associated emphysema aggravation, and increased protein levels of LC3B, atg3, and atg7 were identified by Western blotting. In microbiome and metabolome analyses, the composition of the gut microbiota was different with smoking and antibiotic exposure, and the levels of short-chain fatty acids (SCFAs), including acetate and propionate, were reduced by antibiotic exposure. SCFA administration restored emphysema development with reduced inflammatory cells, IL-6, and IFNγ and decreased LC3B, atg3, and atg7 levels. In conclusion, antibiotics can aggravate emphysema, and inflammation and autophagy may be associated with this aggravation. This study provides important insight into the systemic impact of microbial dysbiosis and the therapeutic potential of utilizing the gut microbiota in emphysema., (© 2023. The Author(s).)

Purpose: To prospectively evaluate the potential of four-dimensional (4D) flow magnetic resonance imaging (MRI) in predicting treatment responses after transcatheter arterial chemoembolization (TACE) in cirrhotic patients with hepatocellular carcinoma (HCC)., Methods: A total of 195 patients were classified into four groups (A-D): A, cirrhotic patients without HCC (n = 30); B, cirrhotic patients with HCC before TACE (n = 75); C, cirrhotic patients with HCC showing an incomplete response following TACE (n = 56); and D, cirrhotic patients with HCC achieving a complete response (CR) following TACE (n = 34). The patients were subjected to routine laboratory tests and 4D flow MRI using a 3-T MRI system to measure the quantitative parameters of blood flow in the portal vein (PV), splenic vein (SV), and superior mesenteric vein. The data collected by 4D flow MRI were compared among the groups using one-way analysis of variance. A multivariate analysis was performed to verify the association of clinical characteristics and 4D flow parameters with CR after TACE treatment., Results: The average through-plane velocity, peak velocity magnitude, average net flow, peak flow, and net forward volume in the PV and SV were significantly lower in groups B and C (P < 0.05) compared to those in group A. Moreover, average through-plane velocity and peak velocity magnitude in the PV in groups B and C were significantly lower than those in group D (P < 0.05). The multivariate analysis demonstrated that the average through-plane velocity and peak velocity magnitude in the PV were independently associated with CR in HCC patients after TACE (P < 0.05)., Conclusion: The quantitative flow data obtained by 4D flow MRI may be useful for predicting CR after TACE in cirrhotic patients with HCC., (© 2023. Italian Society of Medical Radiology.)

Introduction: The D-dimer to fibrinogen ratio (DFR) is a good indicator of clot-producing activity in thrombotic disease, but its clinical usefulness in stroke patients with nonvalvular atrial fibrillation (NVAF) has not been studied. We evaluated the association between the DFR and early neurological deterioration (END) in acute ischemic stroke (AIS) patients with NVAF., Methods: We included consecutive AIS patients with NVAF between 2013 and 2015 from the registry of a real-world prospective cohort from 11 large centers in South Korea. END was defined as an increase ≥2 in the total NIHSS score or ≥ 1 in the motor NIHSS score within the first 72 h of admission. The DFR was calculated as follows: DFR = D-dimer (mg/L)/fibrinogen (mg/dL) x 100., Results: A total of 1018 AIS patients with NVAF were evaluated. In multivariable logistic regression analysis, the highest DFR tertile was closely associated with END (adjusted odds ratio [aOR] = 2.14, 95 % confidence interval [CI]: 1.24-3.69). Hypertension (aOR = 1.71, 95 % CI: 1.09-2.70), initial NIHSS score (aOR = 1.05, 95 % CI: 1.02-1.07) and use of anticoagulants (aOR = 0.41, 95 % CI: 0.28-0.60) were also correlated with END. In addition to END, the DFR was correlated with discharge NIHSS and modified Rankin Scale (mRS) scores and the 3-month mRS score., Conclusions: High DFR values were associated with END in AIS patients with NVAF. As the DFR is an indicator directly related to the main pathological mechanism of NVAF patients (fibrinolysis and coagulation), it may be useful in predicting their prognosis., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Brain plasticity plays a significant role in functional recovery after stroke, but the specific benefits of hand rehabilitation robot therapy remain unclear. Evaluating the specific effects of hand rehabilitation robot therapy is crucial in understanding how it impacts brain activity and its relationship to rehabilitation outcomes. This study aimed to investigate the brain activity pattern during hand rehabilitation exercise using functional magnetic resonance imaging (fMRI), and to compare it before and after 3-week hand rehabilitation robot training. To evaluate it, an fMRI experimental environment was constructed to facilitate the same hand posture used in rehabilitation robot therapy. Two stroke survivors participated and the conjunction analysis results from fMRI scans showed that patient 1 exhibited a significant improvement in activation profile after hand rehabilitation robot training, indicative of improved motor function in the bilateral motor cortex. However, activation profile of patient 2 exhibited a slight decrease, potentially due to habituation to the rehabilitation task. Clinical results supported these findings, with patient 1 experiencing a greater increase in FMA score than patient 2. These results suggest that hand rehabilitation robot therapy can induce different brain activity patterns in stroke survivors, which may be linked to patient-specific training outcomes. Further studies with larger sample sizes are necessary to confirm these findings.

Background and Purpose: The congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack (CHA 2 DS 2 -VASc) and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol (HAS-BLED) scores have been validated in estimating the risks of ischemic stroke and major bleeding, respectively, in patients with atrial fibrillation (AF). This study investigated stroke-specific predictors of major bleeding in patients with stroke and AF who were taking oral anticoagulants (OACs)., Methods: Subjects were selected from patients enrolled in the Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) nationwide multicenter registry between 2013 and 2015. Patients were excluded if they were not taking OACs, had no brain imaging data, or had intracranial bleeding directly related to the index stroke. Major bleeding was defined according to International Society of Thrombosis and Haemostasis criteria. Cox regression analyses were performed to assess the associations between clinical variables and major bleeding and Kaplan-Meier estimates were performed to analyze event-free survival., Results: Of a total of 3,213 patients, 1,414 subjects (mean age of 72.6 years, 52.5% males) were enrolled in this study. Major bleeding was reported in 34 patients during the median follow-up period of 1.73 years. Multivariable analysis demonstrated that initial National Institutes of Health Stroke Scale scores (hazard ratio [HR] 1.07, p =0.006), hypertension (HR 3.18, p =0.030), persistent AF type (HR 2.51, p =0.016), and initial hemoglobin level (HR 0.74, p =0.001) were independently associated with major bleeding risk. Except for hypertension, these associations remained significant after adjusting for the HAS-BLED score. Intracranial atherosclerosis presented a trend of association without statistical significance (HR 2.21, p =0.050)., Conclusions: This study found that major bleeding risk was independently associated with stroke-specific factors in anticoagulated patients with stroke and AF. This has the clinical implication that baseline characteristics of patients with stroke and AF should be considered in secondary prevention, which would bring the net clinical benefit of balancing recurrent stroke prevention with minimal bleeding complications., Competing Interests: Woo-Keun Seo received honoraria for lectures from Sanofi-Aventis, Otsuka Korea, Dong-A Pharmaceutical Co, Ltd; study grants from Daiichi Sankyo Korea Co, Ltd; a consulting fee from OBELAB, Inc; and a stock option from JLK Inspection. The other authors report no conflicts., (Copyright © 2023 Korean Neurological Association.)

Blood viscosity may affect the mechanisms of stroke and early neurological deterioration (END). We aimed to investigate the relationship between blood viscosity, stroke mechanisms, and END in patients with middle cerebral artery (MCA) infarction. Patients with symptomatic MCA atherosclerosis (≥ 50% stenosis) were recruited. Blood viscosity was compared across patients with different mechanisms of symptomatic MCA disease: in situ thrombo-occlusion (sMCA-IST), artery-to-artery embolism (sMCA-AAE), and local branch occlusion (sMCA-LBO). END was defined as four points increase in the National Institutes of Health Stroke Scale score from baseline during the first week. The association between blood viscosity and END was also evaluated. A total of 360 patients (76 with sMCA-IST, 216 with sMCA-AAE, and 68 with sMCA-LBO) were investigated. Blood viscosity was highest in patients with sMCA-IST, followed by sMCA-AAE and sMCA-LBO (P < 0.001). Blood viscosity was associated with END in patients with MCA disease. Low shear viscosity was associated with END in patients with sMCA- LBO (adjusted odds ratio, aOR 1.524; 95% confidence interval, CI 1.035-2.246), sMCA- IST (aOR 1.365; 95% CI 1.013-1.839), and sMCA- AAE (aOR 1.285; 95% CI 1.010-1.634). Blood viscosity was related to END in patients with stroke caused by MCA disease., (© 2023. The Author(s).)

A high dependence on aerobic glycolysis, known as the Warburg effect, is one of the metabolic features exhibited by tumor cells. Therefore, targeting glycolysis is becoming a very promising strategy for the development of anticancer drugs. In the present study, it was investigated whether pre‑adaptation of malignant mesothelioma (MM) cells to an acidic environment was associated with a metabolic shift to the Warburg phenotype in energy production, and whether apigenin targets acidosis‑driven metabolic reprogramming. Cell viability, glycolytic activity, Annexin V‑PE binding activity, reactive oxygen species (ROS) levels, mitochondrial membrane potential, ATP content, western blot analysis and spheroid viability were assessed in the present study. MM cells pre‑adapted to lactic acid were resistant to the anticancer drug gemcitabine, increased Akt activation, downregulated p53 expression, and upregulated rate‑limiting enzymes in glucose metabolism compared with their parental cells. Apigenin treatment increased cytotoxicity, Akt inactivation and p53 upregulation. Apigenin also reduced glucose uptake along with downregulation of key regulatory enzymes in glycolysis, increased ROS levels with loss of mitochondrial membrane potential, and downregulated the levels of complexes I, III and IV in the mitochondrial electron transport chain with intracellular ATP depletion, resulting in upregulation of molecules mediating apoptosis and necroptosis. Apigenin‑induced alterations of cellular responses were similar to those of Akt inactivation by Ly294002. Overall, the present results provide mechanistic evidence supporting the anti‑glycolytic and cytotoxic role of apigenin via inhibition of the PI3K/Akt signaling pathway and p53 upregulation.

Purpose: To investigate the utility of preoperative multiparametric magnetic resonance imaging (mpMRI)-based clinical-radiomic analysis combined with machine learning (ML) algorithms in predicting the expression of the Ki-67 proliferative index and p53 tumor suppressor protein in patients with meningioma., Methods: This multicenter retrospective study included 483 and 93 patients from two centers. The Ki-67 index was classified into high (Ki-67≥5%) and low (Ki-67<5%)-expressed groups, and the p53 index was classified into positive (p53≥5%) and negative (p53<5%)-expressed groups. Clinical and radiological features were analyzed using univariate and multivariate statistical analyses. Six ML models were performed with different types of classifiers to predict Ki-67 and p53 status., Results: In the multivariate analysis, larger tumor volumes (p<0.001), irregular tumor margin (p<0.001), and unclear tumor-brain interface (p<0.001) were independently associated with a high Ki-67 status, whereas the presence of both necrosis (p=0.003) and the dural tail sign (p=0.026) were independently associated with a positive p53 status. A relatively better performance was yielded from the model constructed by combined clinical and radiological features. The area under the curve (AUC) and accuracy of high Ki-67 were 0.820 and 0.867 in the internal test, and 0.666 and 0.773 in the external test, respectively. Regarding p53 positivity, the AUC and accuracy were 0.858 and 0.857 in the internal test, and 0.684 and 0.718 in the external test., Conclusion: The present study developed clinical-radiomic ML models to non-invasively predict Ki-67 and p53 expression in meningioma using mpMRI features, and provides a novel non-invasive strategy for assessing cell proliferation., 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 Moon, Lee, Kim, Yoon, Baek, Park, Heo, Shin and Kim.)

Purpose: To develop and validate deep learning-based automatic brain segmentation for East Asians with comparison to data for healthy controls from Freesurfer based on a ground truth., Methods: A total of 30 healthy participants were enrolled and underwent T1-weighted magnetic resonance imaging (MRI) using a 3-tesla MRI system. Our Neuro I software was developed based on a three-dimensional convolutional neural networks (CNNs)-based, deep-learning algorithm, which was trained using data for 776 healthy Koreans with normal cognition. Dice coefficient (D) was calculated for each brain segment and compared with control data by paired t -test. The inter-method reliability was assessed by intraclass correlation coefficient (ICC) and effect size. Pearson correlation analysis was applied to assess the relationship between D values for each method and participant ages., Results: The D values obtained from Freesurfer (ver6.0) were significantly lower than those from Neuro I. The histogram of the Freesurfer results showed remarkable differences in the distribution of D values from Neuro I. Overall, D values obtained by Freesurfer and Neuro I showed positive correlations, but the slopes and intercepts were significantly different. It was showed the largest effect sizes ranged 1.07-3.22, and ICC also showed significantly poor to moderate correlations between the two methods (0.498 ≤ ICC ≤ 0.688). For Neuro I, D values resulted in reduced residuals when fitting data to a line of best fit, and indicated consistent values corresponding to each age, even in young and older adults., Conclusion: Freesurfer and Neuro I were not equivalent when compared to a ground truth, where Neuro I exhibited higher performance. We suggest that Neuro I is a useful alternative for the assessment of the brain volume., Competing Interests: K-EH was employed by Neurozen Inc. The remaining 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 Moon, Lee, Hyeong, Yoon, Baek, Heo, Shin and Kim.)

Aging process is associated with gradual change of liver function and structure. The goal of this study was to evaluate age-related hemodynamic changes in the portal vein (PV) using four-dimensional (4D) flow MRI in healthy adults. A total of 120 healthy subjects were enrolled and categorized into groups A (n = 25, 30-39 years), B (n = 31, 40-49 years), C (n = 34, 50-59 years), and D (n = 30, 60-69 years). All subjects underwent 4D flow data acquisition using a 3-T MRI system to measure the hemodynamic parameters in the main PV. The clinical characteristics and 4D flow parameters were compared among the groups using analysis of variance and analysis of covariance after controlling for significant covariates, accordingly. The outcome metric applying the age-related quadratic model to estimate the age at which 4D flow parameters are the highest (the peak age) as well as the rates of age-related 4D flow changes was estimated. The average area, average through-plane velocity, peak velocity magnitude, average net flow, peak flow, and net forward volume in group D were significantly lower than those in groups A, B and C (P < 0.05). Group C showed significantly lower values of the average through-plane velocity and peak velocity magnitude than those of group B (P < 0.05). The peak age computed was approximately 43-44 years of age for all 4D flow parameters. The rates of age-related 4D flow changes for all 4D flow parameters were negatively correlated with age (P < 0.05). The volume and velocity of the blood flow through the PV peaked at approximately 43-44 years of age and decreased significantly after 60 years of age., (© 2023. The Author(s).)

Background and Purpose: Moderate-intensity statin plus ezetimibe versus high-intensity statin alone may provide a greater low-density lipoprotein cholesterol (LDL-C) reduction in patients with recent ischemic stroke., Methods: This randomized, open-label, controlled trial assigned patients with recent ischemic stroke <90 days to rosuvastatin/ezetimibe 10/10 mg once daily (ROS10/EZT10) or to rosuvastatin 20 mg once daily (ROS20). The primary endpoint was LDL-C reduction ≥50% from baseline at 90 days. Key secondary endpoints were LDL-C <70 mg/dL and multiple lipid goal achievement, and composite of major vascular events., Results: Of 584 randomized, 530 were included in the modified intention-to-treat analysis. The baseline LDL-C level was 130.2±34.7 mg/dL in the ROS10/EZT10 group and 131.0±33.9 mg/dL in the ROS20 group. The primary endpoint was achieved in 198 patients (72.5%) in the ROS10/EZT10 group and 148 (57.6%) in the ROS20 group (odds ratio [95% confidence interval], 1.944 [1.352-2.795]; P= 0.0003). LDL-C level <70 mg/dL was achieved in 80.2% and 65.4% in the ROS10/EZT10 and ROS20 groups (P=0.0001). Multiple lipid goal achievement rate was 71.1% and 53.7% in the ROS10/EZT10 and ROS20 groups (P<0.0001). Major vascular events occurred in 1 patient in the ROS10/EZT10 group and 9 in the ROS20 group (P=0.0091). The adverse event rates did not differ between the two groups., Conclusion: Moderate-intensity rosuvastatin plus ezetimibe was superior to high-intensity rosuvastatin alone for intensive LDL-C reduction in patients with recent ischemic stroke. With the combination therapy, more than 70% of patients achieved LDL-C reduction ≥50% and 80% had an LDL-C <70 mg/dL at 90 days.

Objective: Limb salvage is an important concern following complete oncologic resection for extremity soft tissue sarcoma (STS). Vascular reconstruction is essential for limb salvage. The purpose of this study was to evaluate the outcomes of vascular reconstruction in patients with extremity STS., Methods: This is a retrospective, multi-center, case series of consecutive patients who underwent vascular reconstruction during extremity STS resection at 2 major centers in Korea. Demographics, reconstruction methods, type of conduit, surgical complications, graft patency, limb salvage rate, and patient survival were reviewed., Results: From March 2005 to December 2020, 43 patients underwent vascular reconstructions during STS resection. Among the patients, 22 (51.2%) received arterial only, and 21 (48.8%) received simultaneous arterial and venous reconstructions. For the types of conduits, autologous saphenous veins (56.2%), artificial grafts (26.3%), and cryopreserved allografts (15.8%) were used. During a median follow-up of 23.8 months (interquartile range; 7.7-54.5), the overall primary patency of the reconstructed vessels was significantly higher in arteries than in veins (82.5% vs 56.3% at 12 months, P < .001). According to the type of conduit, the primary patency rate of autogenous vein seemed higher in venous reconstruction, however, there was no statistical significance in both arterial and venous reconstruction. There was no significant difference in primary arterial patency rate ( P = .132) or incidence of surgical complications including postoperative edema or wound problem whether or not simultaneous venous reconstruction was performed with arterial reconstruction. The overall limb salvage rate and patient survival were 97.4%, 95.1%, and 89.4% and 91.9%, 81.7%, and 65.4% at 12, 24, and 36 months, respectively., Conclusions: Patency rates were poorer in venous reconstruction than in arterial reconstruction. In terms of arterial patency and postoperative complication, the role of simultaneous arterial and venous reconstruction seems not essential, however, it needs to be evaluated in future studies.

Background: Oxiracetam may have a modest effect on preventing cognitive decline. Exercise can also enhance cognitive function. This trial aims to investigate the effect of oxiracetam on post-stroke cognitive impairment and explore whether this effect is modified by exercise. Furthermore, the mechanisms that mediate this effect will be investigated through a neural network analysis., Methods: This is a multicenter, randomized, double-blind, placebo-controlled phase IV trial. Patients who complained of cognitive decline 3 months after stroke and had a high risk of cognitive decline were eligible. Patients were randomly assigned to receive either 800 mg of oxiracetam or placebo twice daily for 36 weeks. After randomization, a predetermined exercise protocol was provided to each participant, and the degree of physical activity was assessed using wrist actigraphy at 4, 12, 24, and 36 weeks. Resting-state functional MRI was obtained in baseline and 36-week follow-up. Co-primary endpoints are changes in the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Secondary endpoints include changes in the NINDS-CSN VCIHS-Neuropsychology Protocol, Euro QoL, patient's global assessment, and functional network connectivity. If there is a significant difference in physical activity between the two groups, the interaction effect between physical activity and the treatment group will be examined. A total of 500 patients were enrolled from February 2018, and the last patient's final follow-up was completed in September 2022., Conclusion: This trial is meaningful not only to prove the efficacy of oxiracetam, but also evaluate whether exercise can modify the effects of medication and how cognitive function can be restored. Trial registrationhttp://cris.nih.go.kr (KCT0005137)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 ( HPRT1 ). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disability, and self-harm. Although uric acid overproduction can be modulated with the xanthine oxidase inhibitor allopurinol, there exists no treatment for behavioral and neurological manifestations of LNS. In the current study, CRISPR-mediated base editors (BEs) and prime editors (PEs) were utilized to generate LNS-associated disease models and correct the disease models for therapeutic approach. Cytosine BEs (CBEs) were used to induce c.430C>T and c.508C>T mutations in HAP1 cells, and then adenine BEs (ABEs) were used to correct these mutations without DNA cleavage. PEs induced a c.333&#95;334ins(A) mutation, identified in a Korean patient with LNS, in HAP1 cells, which was corrected in turn by PEs. Furthermore, improved PEs corrected the same mutation in LNS patient-derived fibroblasts by up to 14% without any unwanted mutations. These results suggest that CRISPR-mediated BEs and PEs would be suggested as a potential therapeutic strategy of this extremely rare, devastating genetic disease., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Introduction: Suboptimal sleep duration and poor sleep quality have been proposed to increase stroke risk. However, their significance in young ischemic stroke is unclear. We aimed to investigate the importance of sleep duration and quality on young ischemic stroke patients., Methods: A multicenter matched case-control study was performed to evaluate under-recognized risk factors in young (&lt;45 years) ischemic stroke patients in 8 tertiary hospitals in Korea. A total of 225 patients and 225 age- and sex-matched controls were enrolled in the same period. Detailed information about patients' demographics, socioeconomic state, and traditional and nontraditional risk factors including sleep-related factors were obtained using structured questionnaires. Risk of ischemic stroke was estimated using conditional logistic regression analysis., Results: Although average sleep duration was similar in patients and controls, patients were more likely to have long (≥9 h) or extremely short (&lt;5 h) sleep durations. In addition, the proportion of subjects with dissatisfaction with sleep quality was higher in patients than controls (66.2 vs. 49.3%, p &lt; 0.001). In multivariable conditional logistic regression analysis, long sleep duration (OR: 11.076, 95% CI: 1.819-67.446, p = 0.009) and dissatisfaction with sleep quality (OR: 2.116, 95% CI: 1.168-3.833, p = 0.013) were independently associated with risk of ischemic stroke., Conclusions: Long sleep duration and dissatisfaction with sleep quality may be associated with increased risk of ischemic stroke in young adults. Improving sleep habit or quality could be important for reducing the risk of ischemic stroke., (© 2023 S. Karger AG, Basel.)

Background and Purpose: Various mechanisms are involved in the etiology of stroke caused by atherosclerosis of the middle cerebral artery (MCA). Here, we compared differences in plaque nature and hemodynamic parameters according to stroke mechanism in patients with MCA atherosclerosis., Methods: Consecutive patients with asymptomatic and symptomatic MCA atherosclerosis (≥50% stenosis) were enrolled. MCA plaque characteristics (location and plaque enhancement) and wall shear stress (WSS) were measured using high-resolution vessel wall and four-dimensional flow magnetic resonance imaging, respectively, at five points (initial, upstream, minimal lumen, downstream, and terminal). These parameters were compared between patients with asymptomatic and symptomatic MCA atherosclerosis with infarctions of different mechanisms (artery-to-artery embolism vs. local branch occlusion)., Results: In total, 110 patients (46 asymptomatic, 32 artery-to-artery embolisms, and 32 local branch occlusions) were investigated. Plaques were evenly distributed in the MCA of patients with asymptomatic MCA atherosclerosis, more commonly observed in the distal MCA of patients with artery-to-artery embolism, and in the middle MCA of patients with local branch occlusion. Maximum WSS and plaque enhancement were more prominent in the minimum lumen area of patients with asymptomatic MCA atherosclerosis or those with local branch occlusion, and were more prominent in the upstream area in those with artery-to-artery embolism. The elevated variability in the maximum WSS was related to stroke caused by artery-to-artery embolism., Conclusion: Stroke caused by artery-to-artery embolism was related to plaque enhancement and the highest maximum WSS at the upstream point of the plaque, and was associated with elevated variability of maximum WSS.

Caffeine, a methylxanthine derivative, affects various physiological conditions such as cell growth, proliferation, and energy metabolism. A genome-wide screening for genes required for caffeine resistance in Schizosaccharomyces pombe revealed several candidates, including Pap1 and downstream target genes involved in caffeine efflux. We found that Yap1, a budding yeast AP-1 homolog required for oxidative stress response, has a caffeine tolerance function. Although the Yap1 mutant is not sensitive to caffeine, overexpression of Yap1 renders cells resistant to high concentrations of caffeine. Caffeine sensitivity of mutants lacking two multidrug transporters, Pdr5 or Snq2, is completely recovered by Yap1 overexpression. Among Yap1-dependent target genes, FLR1 , a fluconazole-resistant gene, is necessary but not sufficient for caffeine tolerance. Low concentrations of hydrogen peroxide induce Yap1 activation, which restores cell viability against caffeine toxicity. Intriguingly, oxidative stress-mediated cellular adaptation to caffeine toxicity requires Yap1, but not Flr1. Moreover, caffeine is involved in reduction of intracellular reactive oxygen species (ROS), as well as mutation rate and Rad52 foci formation. Altogether, we identified novel reciprocal crosstalk between ROS signaling and caffeine resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Choi, Heo and Chung.)

Background: In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment strategies for gastric cancer patients receiving neoadjuvant chemotherapy., Patients and Methods: A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed., Results: The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (P < 0.01). PFS and OS were also different according to the ypStage (P < 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (P < 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively., Conclusions: Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)