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Geum Joon Cho,1 Michael S Oh,2 Min-Jeong Oh,1 Keon Vin Park,3 Sung Won Han,3 Young Kwang Chae2,4 1Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea; 2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; 3School of Industrial Management Engineering, Korea University, Seoul, Republic of Korea; 4Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USACorrespondence: Young Kwang ChaeDepartment of Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Avenue, Suite 1006, Chicago, IL 60611, USATel +1 312-926-4248Email ychae@nm.orgBackground: The effect of blood transfusions on the risk of developing primary cancer remains unclear, especially when administered in the peripartum period.Materials and Methods: We conducted a retrospective cohort study of 270,529 pregnant women who delivered between January 1, 2007 and December 31, 2009, with data obtained from three national databases in South Korea. From this cohort, we identified 4569 patients who received peripartum blood transfusions. We calculated hazard ratios (HRs) for new diagnoses of cancer and adjusted them for relevant clinical factors using a Cox proportional hazards model.Results: During follow-up, patients who received peripartum transfusions had an increased risk of developing cancer, with an adjusted HR of 1.16 (95% confidence interval [CI], 1.01– 1.34). In a subgroup analysis, this risk was significant only among patients who received 3 or more units of blood, with an adjusted HR of 1.40 (95% CI, 1.10– 1.79). Increased risk after transfusions were seen with brain, lung, ovarian, and gallbladder cancers. The difference in cancer risk between the transfusion and no-transfusion groups remained significant during both the first (1.29% vs 1.07%, p < 0.01) and second year (0.74% vs 0.56%, p < 0.01) after delivery.Conclusion: Receipt of 3 or more blood transfusions in the peripartum period was associated with a significantly increased risk of developing cancer. Prospective studies should be pursued to further understand the link between blood transfusions and long-term oncologic risks.Keywords: blood transfusion, pregnancy, cancer, immunomodulation

Human adipose-derived mesenchymal stem cells (hAMSCs) are capable of immunomodulation and regeneration after neural injury. For these reasons, hAMSCs have been investigated as a promising stem cell candidate for stroke treatment. However, noninvasive experiments studying the effects of grafted stem cells in the host brain have not yet been reported. Cerebrospinal fluid (CSF), which can be collected without sacrificing the subject, is involved in physiological control of the brain and reflects the pathophysiology of various neurological disorders of the central nervous system (CNS). Following stem cell transplantation in a stroke model, quantitative analysis of CSF proteome changes can potentially reveal the therapeutic effect of stem cells on the host CNS. We examined hAMSC-secreted proteins obtained from serum-free culture medium by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which identified several extracellular matrix proteins, supporting the well-known active paracrine function of hAMSCs. Subsequently, we performed label-free quantitative proteomic analysis on CSF samples from rat stroke models intravenously injected with hAMSC (experimental) or phosphate buffered saline (control). In total, 524 proteins were identified; among them, 125 and 91 proteins were increased and decreased with hAMSC treatment, respectively. Furthermore, gene set enrichment analysis revealed three proteins, 14-3-3 theta, MAG, and neurocan, that showed significant increases in the hAMSC-treated model; these proteins are core members of neurotrophin signaling, nerve growth factor (NGF) signaling, and glycosaminoglycan metabolism, respectively. Subsequent histological and neurologic function experiments validated proliferative neurogenesis in the hAMSC-treated stroke model. We conclude that (i) intravenous injection of hAMSCs can induce neurologic recovery in a rat stroke model and (ii) CSF may reflect the therapeutic effect of hAMSCs. Additionally, proteins as 14-3-3 theta, MAG, and neurocan could be considered as potential CSF biomarkers of neuroregeneration. These CSF proteome profiling results would be utilized as valuable resource in further stroke studies.

Donepezil (DNZ) has been used to treat dementia associated with mild, moderate, or severe Alzheimer's disease (AD). DNZ uptake can alleviate cognitive symptoms in AD patients via acetylcholinesterase (AChE) inhibition. However, oral administration of DNZ has limitations, including first-pass metabolism, difficulties with swallowing, and low patient compliance. In this work, we disclose a novel transdermal DNZ delivery system utilizing T2 polymer, synthesized via the ring-opening polymerization of 2,2,5,5-tetramethyl-2,5-disila-1-oxacyclopentane with trifluoroacetic acid (TFA). In the in vivo studies in an AD animal model, the DNZ-loaded T2 polymer (DNZ@T2) facilitated efficient transdermal DNZ delivery to the bloodstream and improved spatial working memory and long-term memory of the AD mouse model. Both the T2 polymer and DNZ@T2 exhibited low cytotoxicity and non-significant in vivo toxicity. This research highlights a promising transdermal delivery strategy for AD treatment, potentially enhancing therapeutic efficacy and patient compliance.

Background: Depression and memory loss are prevalent neurodegenerative disorders, with diabetic patients facing an elevated risk of brain dysfunction. Methylglyoxal (MGO) formation, which is heightened in diabetes owing to hyperglycemia and gut dysbiosis, may serve as a critical link between diabetes and brain diseases. Despite the high prevalence of MGO, the precise mechanisms underlying MGO-induced depression and memory loss remain unclear., Results: We investigated the effect of MGO stress on depression like-behavior and memory loss to elucidate the potential interplay between MGO-induced tryptophan (Trp) metabolism impairment and oxidative stress in the brain. It demonstrates that MGO induces depression-like behavior in mice, as confirmed by the OFT, TST, FST, SPT, and EPM behavioral tests. MGO led to the depletion of Trp and related neurotransmitters as 5-HT, EPI, and DA in the mouse brain. Additionally, MGO reduced the cell count in the DG, CA1, and CA3 hippocampal regions and modulated TPH2 levels in the brain. Notably, co-treatment with MGO and Trp mirrored the effects observed after Trp-null treatment in neurons, including reduced TPH1 and TPH2 levels and inhibition of neuronal outgrowth. Furthermore, MGO significantly altered the expression of key proteins associated with neurodegeneration, such as p-Tau, p-GSK-3β, APP, oAβ, BDNF, NGF, and p-TrkB. Concurrently, MGO activated MAPKs through ROS induction, triggering a redox imbalance by downregulating Nrf-2, Ho-1, TXNRD1, Trx, Sirt-3, and Sirt-5 expression levels, NAD +, and CAT activity in the mouse brain. This led to an accelerated neuroinflammatory response, as evidenced by increased expression of Iba-1, p-NF-κB, and the secretion of IL-6 and TNF-α. Importantly, Trp treatment ameliorated MGO-induced depression like-behavior and memory loss in mice and markedly mitigated increased expression of p-Tau, APP, p-ERK1/2, p-pJNK, and p-NF-κB in the brain. Likewise, Trp treatment also induced the expression of MGO detoxifying factors GLO-I and GLO-II and CAT activity, suggesting the induction of an antioxidant system and reduced inflammation by inhibiting IL-6 and TNF-α secretion., Conclusions: Our data revealed that MGO-induced depression like-behavior and memory deficits resulted from disturbances in Trp, 5-HT, BDNF, and NGF levels, increased p-Tau and APP expression, neuroinflammation, and impaired redox status (Nrf-2/Ho-1/TXNRD1/Sirt3/5) in the brain., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were performed in compliance with the ethical requirements of the laboratory research center, college of Pharmacy, Gachon University, Korea, and the protocol was approved by the Gachon University Institutional Animal Care and Use Committee (GIACUC-R2020008). This study does not contain any patient samples experiment. Consent for publication: Not applicable. Competing interests: The authors declare no conflict of interest., (© 2024. The Author(s).)

The treatment of non-small cell lung cancer has made major strides with the use of immune checkpoint inhibitors, but there remains a significant need for therapies that can overcome immunotherapy resistance. Dendritic cell (DC) vaccines have been proposed as a therapy that can potentially enhance the antitumor immune response. We have embarked on a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDCs) modified to express the chemokine CCL21 (CCL21-DC) given in combination with pembrolizumab. Here, we report a comprehensive characterization of this CCL21-DC vaccine and interrogate the effects of multiple factors in the manufacturing process. We show that the cellular makeup of the CCL21-DC vaccine is heterogeneous due to the presence of passenger lymphocytes at a proportion that is highly variable among patients. Single cell RNA sequencing of vaccines revealed further heterogeneity within the moDC compartment, with cells spanning a spectrum of DC phenotypes. Transduction with a CCL21-containing adenoviral vector augmented CCL21 secretion by moDCs but otherwise had a minimal effect on vaccine characteristics. A single freeze-thaw cycle for stored vaccines was associated with minor alterations to the DC phenotype, as was the use of healthy donors rather than patient autologous blood. Our results highlight important considerations for the production of DC vaccines and identify underexplored factors that may affect their efficacy and immunologic impact.

Alzheimer's disease (AD) is a representative neurodegenerative disease that is characterized by the overaccumulation of amyloid beta (Aβ) proteins. Since AD is accompanied by excessive oxidative stress, which aggravates neurological pathologies, the use of antioxidants has been considered to prevent disease development. NXP031, a combination of vitamin C (VitC) and an optimized aptamer that binds to VitC and stabilizes the reactivity of VitC, was designed. This study aimed to evaluate the effects of NXP031 on AD pathology, including Aβ accumulation, Aβ-induced oxidative stress, neuronal damage, and neuroinflammation. When NXP031 was administered to 5xFAD transgenic mice, NXP031 exerted a strong inhibitory action on Aβ accumulation, superior to that of VitC, by inducing an increase in Aβ-degrading endopeptidase expression. NXP031 diminished lipid peroxidation levels, activated Nrf2-mediated antioxidant pathways, and suppressed overactivated neuroinflammation. An in vitro study using Neuro2a cells revealed that NXP031 protects the cells against oxidative stress by regulating the MAPK signaling pathway-mediated apoptosis. Additionally, the neuroprotective effects of NXP031 were confirmed in a dose-dependent manner when administered to intrahippocampal Aβ-injected mice, as NXP031 attenuated memory decline, neuronal apoptosis, synaptic degeneration, and excessive glial activation, and reduced NOX-2 expression in the hippocampus. Taken together, NXP031 reduced the Aβ burden by regulating Aβ-degeneration and attenuated memory impairment, neuronal death, synaptic degeneration, and neuroinflammation induced by Aβ toxicity. These results suggest the potential of NXP031 as a therapeutic agent for AD., Competing Interests: Declaration of interests 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 Inc. All rights reserved.)

Alzheimer's disease (AD) presents a growing societal challenge, driven by an aging population. It is characterized by neurodegeneration linked to β-amyloid (Aβ) and tau protein aggregation. Reactive glial cell-mediated neuroinflammation exacerbates disease progression by facilitating the accumulation of Aβ and impairing its clearance, thus highlighting potential therapeutic targets. Aerial parts of Artemisia iwayomogi (AIH), a kind of mugwort, has been consumed as a medicinal herb in East Asia for relieving inflammation-related diseases. Previously, AIH was found to exert potent inhibitory effects on neuroinflammation. This study aimed to examine whether AIH mitigates AD pathogenesis by regulating neuroinflammation and reducing Aβ deposition. AIH treatment to primary mixed glial cultures attenuated the pro-inflammatory responses evoked by Aβ stimulation. When treated to 5 × familial AD (5xFAD) mice, AIH improved learning and cognitive ability and reduced Aβ burden in the brain. AIH suppressed glial overactivation, as well as inhibited the expressions of pro-inflammatory mediators in the brain. Moreover, AIH regulated AKT signaling and elevated the expression of autophagy-lysosomal mediators in vitro. It was confirmed that lysosome-associated membrane protein 1 (LAMP1) was increased in the Aβ-associated microglia in the mouse hippocampus. Finally, it was observed that tau phosphorylation was alleviated, and synaptic protein expression was increased in AIH-treated 5xFAD mice. Overall, this study demonstrated that AIH ameliorated excessive neuroinflammation and Aβ accumulation by regulating microglial activation and autophagy-lysosomal pathway, thereby suggesting AIH as a promising therapeutic candidate for AD treatment., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Electron-transporting transparent conducting oxides (TCOs) are a commercial reality, however, hole-transporting counterparts are far more challenging because of limited material design. Here, we propose a strategy for enhancing the hole conductivity without deteriorating the band gap ( E g ) and workfunction ( Φ ) by Cu incorporation in a strongly correlated NiWO 4 insulator. The optimal Cu-doped NiWO 4 (Cu 0.185 Ni 0.815 WO 4 ) exhibits a resistivity reduction of ∼10 9 times versus NiWO 4 as well as band-like charge transport with the hole mobility approaching 7 cm 2 V -1 s -1 at 200 K, a deep Φ of 5.77 eV, and E g of 2.8 eV. Experimental and theoretical data reveal that the strength of the electron correlation in NiWO 4 is unaffected by Cu incorporation, while the promoted polarizability weakens electron-phonon coupling, promoting the formation of large polarons. Quantum dot light-emitting and oxide p/n junction devices incorporating Cu 0.185 Ni 0.815 WO 4 exhibit remarkable performances, demonstrating that our approach can be deployed to discover new p-type TCOs.

This study aimed to investigate the association between non-traditional lipid profiles and the risk of 1-year vascular events in patients who were already using statins before stroke and had admission LDL-C < 100 mg/dL. This study was an analysis of a prospective, multicenter, nationwide registry of consecutive patients with acute ischemic stroke patients who treated with statin before index stroke and LDL-C < 100 mg/dL on admission. Non-traditional lipid profiles including non-HDL, TC/HDL ratio, LDL/HDL ratio, and TG/HDL ratio were analyzed as a continuous or categorical variable. The primary vascular outcome within one year was a composite of recurrent stroke (either hemorrhagic or ischemic), myocardial infarction (MI) and all-cause mortality. Hazard ratios (95% Cis) for 1-year vascular outcomes were analyzed using the Cox PH model for each non-traditional lipid profiles groups. A total of 7028 patients (age 70.3 ± 10.8years, male 59.8%) were finally analyzed for the study. In unadjusted analysis, no significant associations were observed in the quartiles of LDL/HDL ratio and 1-year primary outcome. However, after adjustment of relevant variables, compared with Q1 of the LDL/HDL ratio, Q4 was significantly associated with increasing the risk of 1-year primary outcome (HR 1.48 [1.19-1.83]). For the LDL/HDL ratio, a linear relationship was observed (P for linearity < 0.001). Higher quartiles of the LDL/HDL ratio were significantly and linearly associated with increasing the risk of 1-year primary vascular outcomes. These findings suggest that even during statin therapy with LDL-C < 100 mg/dl on admission, there should be consideration for residual risk based on the LDL/HDL ratio, following stroke., (© 2024. The Author(s).)

Depression is a debilitating mood disorder that causes persistent feelings of sadness, emptiness, and a loss of joy. However, the clinical efficacy of representative drugs for depression, such as selective serotonin reuptake inhibitors, remains controversial. Therefore, there is an urgent need for more effective therapies to treat depression. Neuroinflammation and the hypothalamic-pituitary-adrenal (HPA) axis are pivotal factors in depression. Inulae Flos (IF), the flower of Inula japonica Thunb, is known for its antioxidant and anti-inflammatory effects. This study explored whether IF alleviates depression in both in vitro and in vivo models. For in vitro studies, we treated BV2 and PC12 cells damaged by lipopolysaccharides or corticosterone (CORT) with IF to investigate the mechanisms of depression. For in vivo studies, C57BL/6 mice were exposed to chronic restraint stress and were administered IF at doses of 0, 100, and 300 mg/kg for 2 weeks. IF inhibited pro-inflammatory mediators, such as nitric oxide, inducible nitric oxide synthase, and interleukins in BV2 cells. Moreover, IF increased the viability of CORT-damaged PC12 cells by modulating protein kinase B, a mammalian target of the rapamycin pathway. Behavioral assessments demonstrated that IF reduced depression-like behaviors in mice. We found that IF reduced the activation of microglia and astrocytes, and regulated synapse plasticity in the mice brains. Furthermore, IF lowered elevated CORT levels in the plasma and restored glucocorticoid receptor expression in the hypothalamus. Collectively, these findings suggest that IF can alleviate depression by mitigating neuroinflammation and recovering dysfunction of the HPA-axis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sex differences in stroke outcomes are notable, with women experiencing higher incidence rates, greater disability-adjusted life years, and poorer recovery compared to men, even after adjusting for age and comorbidities. Despite the disproportionate burden in women, studies have reported that women are less likely to receive appropriate stroke treatment than men., Aim: This study investigated temporal trends of sex differences in acute reperfusion therapy and early outcomes in patients with acute ischemic stroke over 10 years in South Korea., Methods: A retrospective analysis of Korean Stroke Registry included patients with acute ischemic stroke from 2012 to 2021. The study outcomes were the temporal trends of acute reperfusion therapy and early outcomes over 10 years in men and women, respectively. In addition, this study analyzed the temporal trends of sex differences in these parameters during the same period. Early outcomes include the proportions of favorable functional outcomes at discharge, discharge patterns, and in-hospital mortality., Results: A total of 93,692 patients (68.4 years, 40.1% women) with acute ischemic stroke were finally enrolled. Women had a higher age at stroke onset, a higher prevalence of atrial fibrillation, and more severe strokes than men. Women had lower proportion of favorable functional outcomes at discharge and higher proportion of in-hospital mortality compared to men each year. The proportion of patients who received intravenous thrombolysis was lower or similar in women compared to men in most years, and the proportion of patients who received endovascular thrombectomy did not significantly differ between sexes annually. Sex differences in acute reperfusion therapy remained unchanged over 10 years., Conclusion: Women have received acute reperfusion therapy at similar or lower rates than men and experienced poorer outcomes, despite having more stroke risk factors and often more severe strokes., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: W.K.S. received honoraria for lectures from Otsuka Korea, Dong-A Pharmaceutical Co., Ltd., study grants from Dong-A ST.

It is uncertain whether the prognostic power of white matter hyperintensity (WMH) on post-stroke outcomes is modulated as a function of initial neurological severity, a critical determinant of outcome after stroke. This multi-center MRI study tested if higher WMH quintiles were associated with 3-month poor functional outcome (modified Rankin Scale ≥ 3) for mild versus moderate-to-severe ischemic stroke. Mild and moderate-to-severe stroke were defined as admission National Institute of Health Stroke Scale scores of 1-4 and ≥ 5, respectively. Mean age of the enrolled patients (n = 8918) was 67.2 ± 12.6 years and 60.1% male. The association between WMH quintiles and poor functional outcome was modified by stroke severity (p-for-interaction = 0.008). In mild stroke (n = 4994), WMH quintiles associated with the 3-month outcome in a dose-dependent manner for the 2nd to 5th quintile versus the 1st quintile, with adjusted-odds-ratios (aOR [95% confidence interval]) being 1.29 [0.96-1.73], 1.37 [1.02-1.82], 1.60 [1.19-2.13], and 1.89 [1.41-2.53], respectively. In moderate-to-severe stroke (n = 3924), however, there seemed to be a threshold effect: only the highest versus the lowest WMH quintile was significantly associated with poor functional outcome (aOR 1.69 [1.29-2.21]). WMH burden aggravates 3-month functional outcome after mild stroke, but has a lesser modulatory effect for moderate-to-severe stroke, likely due to saturation effects., (© 2024. The Author(s).)

Background: We assessed the influence of prior non-vitamin K antagonist (NOAC) use on stroke outcomes after endovascular treatment (EVT) in patients at a high risk of stroke based on their pre-stroke CHA2DS2-VASc score, and compared them with those who did not use any antithrombotic (NAU) or antiplatelet (APT) agents., Methods: Data were collected from a multicenter database comprising consecutive acute ischemic stroke patients who underwent EVT during a span of 103 months. We evaluated pre-stroke CHA2DS2-VASc scores in enrolled patients and measured instances of successful reperfusion and symptomatic hemorrhagic transformation (SHT) following EVT as the main outcome measures., Results: Among 12 807 patients with acute ischemic stroke, 3765 (29.4%) had a history of atrial fibrillation. Of these, 418 patients with CHA2DS2-VASc scores ≥2 received EVT alone. The prior NOAC group showed higher successful reperfusion rates compared with the prior NAU and APT groups (p=0.04). Multivariate analysis revealed that prior NOAC use increased the likelihood of successful reperfusion after EVT (OR [95% CI] 2.54 [1.34 to 4.83], p=0.004) and improved stroke outcomes, while the prior APT group did not. Furthermore, the prior NOAC use group was not associated with SHT after EVT. Propensity score matching confirmed these findings., Conclusion: Prior use of NOAC is associated with improved outcomes in high-risk stroke patients (pre-stroke CHA2DS2-VASc score ≥2) undergoing EVT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Predicting long-term mortality is essential for understanding prognosis and guiding treatment decisions in patients with ischemic stroke. Therefore, this study aimed to develop and validate the method for predicting 1- and 5-year mortality after ischemic stroke., Methods: We used data from the linked dataset comprising the administrative claims database of the Health Insurance Review and Assessment Service and the Clinical Research Center for Stroke registry data for patients with acute stroke within 7 days of onset. The outcome was all-cause mortality following ischemic stroke. Clinical variables linked to long-term mortality following ischemic stroke were determined. A nomogram was constructed based on the Cox's regression analysis. The performance of the risk prediction model was evaluated using the Harrell's C-index., Results: This study included 42,207 ischemic stroke patients, with a mean age of 66.6 years and 59.2% being male. The patients were randomly divided into training (n = 29,916) and validation (n = 12,291) groups. Variables correlated with long-term mortality in patients with ischemic stroke, including age, sex, body mass index, stroke severity, stroke mechanisms, onset-to-door time, pre-stroke dependency, history of stroke, diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, cancer, smoking, fasting glucose level, previous statin therapy, thrombolytic therapy, such as intravenous thrombolysis and endovascular recanalization therapy, medications, and discharge modified Rankin Scale were identified as predictors. We developed a predictive system named Stroke Measures Analysis of pRognostic Testing-Mortality (SMART-M) by constructing a nomogram using the identified features. The C-statistics of the nomogram in the developing and validation groups were 0.806 (95% confidence interval (CI), 0.802-0.812) and 0.803 (95% CI, 0.795-0.811), respectively., Conclusion: The SMART-M method demonstrated good performance in predicting long-term mortality in ischemic stroke patients. This method may help physicians and family members understand the long-term outcomes and guide the appropriate decision-making process., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This report presents the latest statistics on the stroke population in South Korea, sourced from the Clinical Research Collaborations for Stroke in Korea-National Institute for Health (CRCS-K-NIH), a comprehensive, nationwide, multicenter stroke registry. The Korean cohort, unlike western populations, shows a male-to-female ratio of 1.5, attributed to lower risk factors in Korean women. The average ages for men and women are 67 and 73 years, respectively. Hypertension is the most common risk factor (67%), consistent with global trends, but there is a higher prevalence of diabetes (35%) and smoking (21%). The prevalence of atrial fibrillation (19%) is lower than in western populations, suggesting effective prevention strategies in the general population. A high incidence of large artery atherosclerosis (38%) is observed, likely due to prevalent intracranial arterial disease in East Asians and advanced imaging techniques. There has been a decrease in intravenous thrombolysis rates, from 12% in 2017-2019 to 10% in 2021, with no improvements in door-to-needle and door-to-puncture times, worsened by the coronavirus disease 2019 pandemic. While the use of aspirin plus clopidogrel for non-cardioembolic stroke and direct oral anticoagulants for atrial fibrillation is well-established, the application of direct oral anticoagulants for non-atrial fibrillation cardioembolic strokes in the acute phase requires further research. The incidence of early neurological deterioration (13%) and the cumulative incidence of recurrent stroke at 3 months (3%) align with global figures. Favorable outcomes at 3 months (63%) are comparable internationally, yet the lack of improvement in dependency at 3 months highlights the need for advancements in acute stroke care., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Fluxapyroxad, a persistent fungicide in soil, was investigated for differences in residue dissipation in Chinese cabbage and spring scallion through the application methods of soil, foliar, and systemic treatment. Soil application of 0.4% granule fluxapyroxad resulted in residues up to 0.09 mg kg -1 in the scallion, while it did not contribute to the residues in the harvested cabbage. The 50% dissipation time (DT50) of fluxapyroxad in the scallion was 6.8 days. The residues from systemic treatment were highly correlated with foliar application in both the cabbage and the scallion, and the initial residue and DT50 values were similar for foliar and systemic treatments. In comparing the residues from the systemic treatments between the two crops, the initial residue was 3.11 and 0.22 mg kg -1 in the cabbage and the scallion after the systemic treatment, respectively. The DT50 values were 2.6 and 12.2 days in the cabbage and the scallion, respectively. The theoretical dilution effect due to crop growth was higher for the cabbage (4-fold) than for the scallion (1.2-fold), and the half-lives of fluxapyroxad without considering the dilution effect were 6.4 days in the cabbage and 17.8 days in the scallion. Thus, the residue difference was drastically reduced after 14 days from the last treatment.

Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.

Background and Purpose: To date, only a few small studies have attempted deep learning-based automatic segmentation of white matter hyperintensity (WMH) lesions in patients with cerebral infarction, which is complicated because stroke-related lesions can obscure WMH borders. We developed and validated deep learning algorithms to segment WMH lesions accurately in patients with cerebral infarction, using multisite datasets involving 8,421 patients with acute ischemic stroke., Materials and Methods: We included 8,421 stroke patients from 9 centers in Korea. 2D UNet and SE-Unet models were trained using 2,408 FLAIR MRI from 3 hospitals and validated using 6,013 FLAIR MRIs from 6 hospitals. WMH segmentation performance was assessed by calculating DSC, correlation coefficient, and concordance correlation coefficient compared to a human-segmented gold standard. In addition, we obtained an uncertainty index that represents overall ambiguity in the voxel classification for WMH segmentation in each patient based on the Kullback-Leibler divergence., Results: In the training dataset, the mean age was 67.4±13.0 years and 60.4% were men. The mean (95% CI) DSCs for Unet in internal testing and external validation were respectively 0.659 (0.649-0.669) and 0.710 (0.707-0.714), which were slightly lower than the reliability between humans (DSC=0.744; 95% CI=0.738-0.751; P=.031). Compared with the Unet, the SE-Unet demonstrated better performance, achieving a mean DSC of 0.675 (0.666-0.685; P<.001) in the internal testing and 0.722 (0.719-0.726; P<.001) in the external validation; moreover, it achieved high DSC values (ranging from 0.672 to 0.744) across multiple validation datasets. We observed a significant correlation between WMH volumes that were segmented automatically and manually for the Unet (r=0.917, P<.0001) and even stronger for the SE-Unet (r=0.933, P<.0001). The SE-Unet also attained a high concordance correlation coefficient (ranging from 0.841 to 0.956) in external test datasets. In addition, the uncertainty indices in the majority of patients (86%) in the external datasets were below 0.35, with an average DSC of 0.744 in these patients., Conclusions: We developed and validated deep learning algorithms to segment WMH in patients with acute cerebral infarction using the largest-ever MRI datasets. In addition, we showed that the uncertainty index can be used to identify cases where automatic WMH segmentation is less accurate and requires human review., Abbreviations: WMH = white matter hyperintensity; CNN = convolutional neural networks; SE = squeeze-and-excitation; KL = Kullback-Leibler; ReLU = rectified linear unit; LKW = last known well; mRS = modified Rankin Scale; NIHSS = National Institute of Health Stroke Scale; LAA = large artery atherosclerosis; SVO = small vessel occlusion; CE = cardioembolism., (© 2024 by American Journal of Neuroradiology.)

Background: Alzheimer's disease (AD) is a common type of dementia characterized by amyloid-β (Aβ) accumulation, lysosomal dysfunction, and tau hyperphosphorylation, leading to neurite dystrophy and memory loss. This study aimed to investigate whether Rhei Undulati Rhizoma (RUR), which has been reported to have anti-neuroinflammatory effect, attenuates Aβ-induced memory impairment, neuritic dystrophy, and tau hyperphosphorylation, and to reveal its mode of action., Methods: Five-month-old 5xFAD mice received RUR (50 mg/kg) orally for 2 months. The Y-maze test was used to assess working memory. After behavioral testing, brain tissue was analyzed using thioflavin S staining, western blotting, and immunofluorescence staining to investigate the mode of action of RUR. To confirm whether RUR directly reduces Aβ aggregation, a thioflavin T assay and dot blot were performed after incubating Aβ with RUR., Results: RUR administration attenuated the Aβ-induced memory impairment in 5xFAD mice. Furthermore, decreased accumulation of Aβ was observed in the hippocampus of the RUR-treated 5xFAD group compare to the vehicle-treated 5xFAD group. Moreover, RUR reduced the dystrophic neurites (DNs) that accumulate impaired endolysosomal organelles around Aβ. In particular, RUR treatment downregulated the expression of β-site amyloid precursor protein cleaving enzyme 1 and the hyperphosphorylation of tau within DNs. Additionally, RUR directly suppressed the aggregation of Aβ, and eliminated Aβ oligomers in vitro., Conclusions: This study showed that RUR could attenuate Aβ-induced pathology and directly regulate the aggregation of Aβ. These results suggest that RUR could be an efficient material for AD treatment through Aβ regulation., (© 2024. The Author(s).)

Food processing industries commonly employ organic acids (OAAs) to determine bacterial contamination in acidified and fermented foods. OAAs are believed to possess potent antimicrobial properties by permeating cell membranes, altering proton and anion concentrations in the cytoplasm due to their lipophilic undissociated forms. The bacteriostatic or bactericidal effects of OAAs are influenced by various factors including microbial physiology, environmental pH, and acid dissociation ratios. Despite their utility, the precise mechanisms underlying OAA-mediated inhibition of pathogenic bacteria remain incompletely understood. Therefore, the objectives of this review are to compile a selected area of researches that focus on the current propensity of different OAAs for inactivating food-borne pathogens, and then to present a theoretical insight on the use of OAAs to prevent and control pathogenic bacteria present in acidic/acidified foods and their mode of mechanisms., Competing Interests: Conflict of interestThe authors declare no conflict of interests., (© The Korean Society of Food Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 ​mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Shin-Hye Yu reports a relationship with Paean Biotechnology that includes: employment. Yujin Kim reports a relationship with Paean Biotechnology that includes: employment. Young Cheol Kang reports a relationship with Paean Biotechnology that includes: equity or stocks. Kyuboem Han reports a relationship with Paean Biotechnology that includes: employment. Hong Kyu Lee reports a relationship with Paean Biotechnology that includes: employment. Chun-Hyung Kim reports a relationship with Paean Biotechnology that includes: employment. If there are other authors, they 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Aluminum-incorporated medium-manganese steel (MMnS) has potential for lightweight transport applications owing to its impressive mechanical properties. Increasing the austenite volume fraction and making microstructural changes are key to manufacturing MMnS. However, the grain boundary character and strain distribution of intercritically annealed low-density MMnS have not been extensively scrutinized, and the effects of crystallographic texture orientation on tensile properties remain ambiguous. Therefore, in this study, the microstructure, microtexture, strain distribution, and grain boundary characteristics of a hot-rolled medium-Mn steel (Fe-0.2 C-4.3 Al-9.4 Mn (wt%)) were investigated after intercritical annealing (IA) at 750, 800, or 850 °C for 1 h. The results show that the 800 °C annealed sample exhibited the highest austenite volume fraction among the specimens (60%). The duplex microstructure comprised lath-type γ-austenite, fine α-ferrite, and coarse δ-ferrite. As the IA temperature increased, the body-centered cubic phase orientation shifted from <001> to <111>. At higher temperatures, the face-centered cubic phase was oriented in directions ranging from <101> to <111>, and the sums of the fractions of high-angle grain boundaries and coincidence-site-lattice special boundaries were significantly increased. The 800 °C annealed sample with a high austenite content and strong γ-fiber {111}//RD orientation demonstrated a noteworthy tensile strength (1095 MPa) and tensile elongation (30%).

Background: According to international pediatric urinary tract infection (UTI) guidelines, selecting ampicillin/sulbactam or amoxicillin/clavulanate is recommended as the first-line treatment for pediatric UTI. In Korea, elevated resistance to ampicillin and ampicillin/sulbactam has resulted in the widespread use of third-generation cephalosporins for treating pediatric UTIs. This study aims to compare the efficacy of piperacillin-tazobactam (TZP) and cefotaxime (CTX) as first-line treatments in hospitalized children with UTIs., Materials and Methods: The study, conducted at Jeju National University Hospital, retrospectively analyzed medical records of children hospitalized for febrile UTIs between 2014 and 2017. UTI diagnosis included unexplained fever, abnormal urinalysis, and the presence of significant uropathogens. Treatment responses, recurrence, and antimicrobial susceptibility were assessed., Results: Out of 323 patients, 220 met the inclusion criteria. Demographics and clinical characteristics were similar between TZP and CTX groups. For children aged ≥3 months, no significant differences were found in treatment responses and recurrence. Extended-spectrum beta-lactamase (ESBL)-positive strains were associated with recurrence in those <3 months., Conclusion: In Korea, escalating resistance to empirical antibiotics has led to the adoption of broad-spectrum empirical treatment. TZP emerged as a viable alternative to CTX for hospitalized children aged ≥3 months with UTIs. Consideration of ESBL-positive strains and individualized approaches for those <3 months are crucial., Competing Interests: No conflict of interest., (© 2024 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, The Korean Society for AIDS, and Korean Society of Pediatric Infectious Diseases.)

Objective: This study aimed to investigate the characteristics and epidemiological trends of pediatric injuries among patients visiting emergency departments (EDs) on Jeju Island., Method: Employing a community-level serial cross-sectional analysis, we targeted pediatric patients aged 18 years or younger who visited EDs for injuries over a ten-year period. The data, sourced from the Jeju Injury Surveillance System (JISS), facilitated a comprehensive examination of injury characteristics and epidemiological trends. This included an evaluation of the annual incidence and overall trends in pediatric injury cases., Results: The study found toddlers (42.5% of cases) to be the most frequently injured age group. Males were more prone to injuries, with a male-to-female ratio of 1.7:1. Injuries among visitors accounted for 17.3% of cases, with a seasonal spike in Summer, evenings and weekends. Most incidents occurred at home, predominantly accidental in nature, with adolescents more likely to require EMS services. The common mechanisms of injuries were blunt force (49.2%), slips/falls (22.0%), and motor vehicle collisions (13.2%), leading to bruises, cuts, and sprains. Over the decade, a general increase in pediatric injuries was observed. Accidental injuries initially surged but later stabilized, while self-harm/suicide and assault/violence injuries showed a concerning upward trend. Age-specific analysis revealed increasing trends in infants and adolescents., Conclusion: The study underscores the crucial need for targeted injury prevention and resource allocation strategies, particularly for high-risk groups and times, to effectively mitigate pediatric trauma on Jeju Island.

Background: Recent clinical trials established the benefit of dual antiplatelet therapy with aspirin and clopidogrel (DAPT-AC) in early-presenting patients with minor ischemic stroke. However, the impact of these trials over time on the use and outcomes of DAPT-AC among the patients with nonminor or late-presenting stroke who do not meet the eligibility criteria of these trials has not been delineated., Methods and Results: In a multicenter stroke registry, this study examined yearly changes from April 2008 to August 2022 in DAPT-AC use for stroke patients ineligible for CHANCE/POINT (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events/Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) clinical trials due to National Institutes of Health Stroke Scale >4 or late arrival beyond 24 hours of onset. A total of 32 118 patients (age, 68.1±13.1 years; male, 58.5%) with National Institutes of Health Stroke Scale of 4 (interquartile range, 1-7) were analyzed. In 2008, DAPT-AC was used in 33.0%, other antiplatelets in 62.7%, and no antiplatelet in 4.3%. The frequency of DAPT-AC was relatively unchanged through 2013, when the CHANCE trial was published, and then increased steadily, reaching 78% in 2022, while other antiplatelets decreased to 17.8% in 2022 ( P trend <0.001). From 2011 to 2022, clinical outcomes nonsignificantly improved, with an average relative risk reduction of 2%/y for the composite of stroke, myocardial infarction, and all-cause mortality, both among patients treated with DAPT-AC and patients treated with other antiplatelets., Conclusions: Use of DAPT-AC in stroke patients with stroke ineligible for recent DAPT clinical trials increased markedly and steadily after CHANCE publication in 2013, reaching deployment in nearly 4 of every 5 patients by 2022. The secondary prevention in patients with ischemic stroke seems to be gradually improving, possibly due to the enhancement of risk factor control.

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4 + and CD8 + T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC., Competing Interests: Declaration of interests S.M.D. is a scientific advisory board member for EarlyDiagnostics Inc. and LungLife AI; he has received research funding from Johnson & Johnson and Novartis. R.J.L., R.S.-R., B.L., and S.M.D. are the inventors of a pending patent., (Published by Elsevier Inc.)

Objective: To describe our modifications to the submental island flap (SMIF) in a case series that demonstrates improved reproducibility, shortened length of stay (LOS), and reduced utilization of hospital resources., Study Design: This retrospective case series with chart review included adult patients who underwent resection of malignant or benign tumors resulting in lateral facial, parotid, or temporal bone defects, which were reconstructed with SMIF., Setting: A tertiary-care academic referral center., Methods: Retrospective case series included all adult patients who underwent SMIF reconstruction between March 2020 and August 2021. Patient demographic and clinical data were collected. Primary outcomes were measures of hospital utilization including duration of surgery, LOS, and postoperative outcomes., Results: Twenty-eight patients were included with a mean age of 71.7 years. Eighty percent were male. All patients underwent parotidectomy, and the mean operative time was 347 minutes. The median LOS was 2.5 days (range 0-16 days). Seventy-five percent of the flaps drained into the internal jugular vein, and 25% drained into the external jugular vein. No patients required reoperation or readmission. All flaps survived., Conclusion: SMIFs are a safe and effective option for reconstruction of lateral facial, parotid, and temporal bone defects. Compared to free flap reconstruction, SMIFs offer reduced length of surgery, decreased use of health care resources, and lower rate of reoperation. As health care resource allocation is increasingly important, the SMIF offers an excellent alternative to free flap reconstruction of lateral defects., Competing Interests: Nicole C. Schmitt discloses research funding from Astex Pharmaceuticals and consulting for Sensorion and Checkpoint Surgical (unrelated to this work). The other authors (Melissa S. Oh, Nikhil T. Vettikattu, Harry Michael Baddour, Jennifer H. Gross, Brian J. Boyce, Mihir R. Patel, Clementino Arturo Solares, Azeem S. Kaka) declare that they have no conflicts of interest., (© 2024 The Authors. OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Context: Neurocognitive testing is a critical tool in the management of sport-related concussions. Adversity during childhood and adolescence affects cognitive tasks, behavioral outcomes, and academic performance. Adversity may be important in baseline concussion test validity as well; however, the influence of these experiences is not well understood., Objective: To examine the relationship between individual-level experiences of adversity and baseline test validity of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). We hypothesized that experiences of poverty, maltreatment, or extreme neighborhood deprivation would be associated with lower odds of baseline test validity., Design: Case-control study., Setting: Cuyahoga County, Ohio., Patients or Other Participants: A total of 6495 student-athletes born from 1995 through 2005 who completed a baseline ImPACT test between 10 and 18 years old and were identified in the Child-Household Integrated Longitudinal Data system, a comprehensive data system with demographic and social service usage outcomes for children in Cuyahoga County, Ohio., Main Outcome Measure(s): Baseline concussion test validity was determined using the ImPACT built-in validity measure. Experiences of adversity during the sensitive developmental periods of early childhood and adolescence were key independent variables., Results: Our findings suggested that social mobility may play an important role in baseline validity. Youth with upward social mobility (ie, poverty or neighborhood deprivation in early childhood only) were not different from youth without such experiences (odds ratio [OR] = 0.91, P = .74). Youth with persistent adversity across childhood or downward social mobility (ie, poverty or high neighborhood deprivation in adolescence only) had 50% to 72% lower odds of achieving a valid baseline test (persistent poverty, OR = 0.59, P = .05; adolescent poverty only, OR = 0.50, P = .004; adolescent neighborhood deprivation only, OR = 0.28, P < .001). Maltreatment had no significant effect on test validity., Conclusions: These findings indicated that certain patterns of adversity may predispose youth to invalid baseline testing scores, potentially increasing their risk of inappropriate injury management and poor outcomes., (© by the National Athletic Trainers’ Association, Inc.)

Introduction: Although statin therapy reduces cardiovascular events, statin use is associated with the risk of new-onset diabetes mellitus (NODM). Using a linked dataset, we evaluated the effect of statin treatment on vascular outcomes and NODM development in patients with ischemic stroke., Methods: From the dataset, we identified 20,250 patients with acute ischemic stroke who had neither a prior history of DM nor a previous history of statin use before the index stroke. Patients were divided into statin users and non-users. The outcomes were NODM and vascular outcomes, including recurrent ischemic stroke and acute myocardial infarction (AMI)., Results: Of the 20,250 patients, 13,706 (67.7%) received statin treatment after the index stroke. For the risk of NODM, a time-response relationship was observed between the use of statins and NODM; a longer post-stroke follow-up duration substantially increased the risk of NODM. Among those with ischemic stroke exceeding 3 years, statin users had an approximately 1.7-fold greater risk of NODM than statin non-users. Statin therapy significantly reduced the risk of recurrent ischemic stroke by 54% (HR 0.46, 95% CI, 0.43-0.50, P < 0.001) across all stroke subtypes., Conclusion: Statin therapy following ischemic stroke increased the occurrence of NODM in patients over a period of 3 years. Despite the increased risk of NODM, statin therapy shows a beneficial effect in reducing major cardiovascular events such as recurrent ischemic stroke and AMI in patients with ischemic stroke., (S. Karger AG, Basel.)

Background: Because ischemic stroke is heterogeneous, the associations between low-density lipoprotein (LDL)-cholesterol levels and early vascular outcomes might be different according to the stroke subtype in acute ischemic stroke patients., Methods: This study was an analysis of a prospective, multicenter, stroke registry. Acute ischemic stroke patients previously not treated with statins were included. Admission LDL-cholesterol levels were divided into 7 groups at 20 mg/dl intervals for comparison. The primary early vascular outcome was a composite of stroke, myocardial infarction (MI) and all-cause mortality within 3 months., Results: A total of 38,531 patients (age, 68.5 ± 12.8 yrs; male, 59.6%) were analyzed for this study. The 3-month cumulative incidences of the composite of stroke, MI, and all-cause mortality significantly differed among the LDL-cholesterol level groups, with the highest event rate (11.11%) in the lowest LDL-cholesterol group (<70 mg/dl). After adjustment, the U-shaped associations of LDL-cholesterol levels with primary outcome and all-cause mortality were observed. For the stroke subtypes, there were substantial interactions between the LDL-cholesterol groups and stroke subtype and all-cause mortality (P interaction =0.07). Different patterns, with higher risks of all-cause mortality in the lower LDL-cholesterol in the large artery atherosclerosis subtype (adjusted hazard ratio [aHR] 1.29, 95% confidence interval [CI] 0.98-1.69), but in the higher LDL-cholesterol in the cardioembolism subtype (aHR 1.71 95% CI [1.28-2.29]), were observed among stroke subtypes., Conclusion: We found that there were differential associations of admission LDL-cholesterol levels with all-cause mortality within 3 months among stroke subtypes. These results suggest that admission LDL-cholesterol and early vascular outcomes had complex relationships in patients with ischemic stroke according to the stroke subtypes., (Copyright © 2023. Published by Elsevier Inc.)

Background: Novel oral anticoagulants (NOACs) are currently recommended for the secondary prevention of stroke in patients with acute ischemic stroke (AIS) accompanied by atrial fibrillation (AF). However, the impact of NOACs on clinical outcomes in real-world practice remains ambiguous. This study analyzes the trend of clinical events in patients with AF-related AIS and determines how much the introduction of NOACs has mediated this trend., Methods: We identified patients with AIS and AF between January 2011 and December 2019 using a multicenter stroke registry. Annual rates of NOAC prescriptions and clinical events within 1 year were evaluated. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. To assess the mediation effect of NOACs on the relationship between the calendar year and these outcomes, we used natural effect models and conducted exposure-mediator, exposure-outcome, and mediator-outcome analyses using multivariable regression models or accelerated failure time models, adjusting for potential confounders., Results: Among the 12 977 patients with AF-related AIS, 12 500 (average age: 74.4 years; 51.3% male) were analyzed after excluding cases of valvular AF. Between 2011 and 2019, there was a significant decrease in the 1-year incidence of the primary composite outcome from 28.3% to 21.7%, while the NOAC prescription rate increased from 0% to 75.6%. A 1-year increase in the calendar year was independently associated with delayed occurrence of the primary outcome (adjusted time ratio, 1.10 [95% CI, 1.07-1.14]) and increased NOAC prescription (adjusted odds ratio, 2.20 [95% CI, 2.14-2.27]). Increased NOAC prescription was associated with delayed occurrence of the primary outcome (adjusted time ratio, 3.82 [95% CI, 3.17 to 4.61]). Upon controlling for NOAC prescription (mediator), the calendar year no longer influenced the primary outcome (adjusted time ratio, 0.97 [95% CI, 0.94-1.00]). This suggests that NOAC prescription mediates the association between the calendar year and the primary outcome., Conclusions: Our study highlights a temporal reduction in major clinical events or death in Korean patients with AF-related AIS, mediated by increased NOAC prescription, emphasizing NOAC use in this population., Competing Interests: Disclosures Dr Bae reports grants from Astrazeneca, Bayer Korea, Bristol Myers Squibb, Bristol Myers Squibb Korea, Chong Gun Dang Pharmaceutical Corp, Dong-A ST, Jeil Pharmaceutical Co, Ltd, Korean Drug Co, Ltd, SAMJIN Pharm, Takeda Pharmaceuticals Korea Co, Ltd, and Yuhan Corporation, and personal fees from Amgen Korea, Hanmi Pharmaceutical Co, Ltd, Otsuka Korea, SK Chemicals, and Viatris Korea outside the submitted work. Dr Gorelick received consultative fees for an expert opinion in a medical-legal matter related to stroke in atrial fibrillation.

Redox chemistry involving the quinone/phenol cycling of natural organic matter (NOM) is known to modulate microbial respiration. Complexation with metals or minerals can also affect NOM solubilization and stability. Inspired by these natural phenomena, a new soil amendment approach was suggested to effectively decrease methane emissions in flooded rice paddies. Structurally stable forms of NOM such as lignin and humic acids (HAs) were shown to decrease methane gas emissions in a vial experiment using different soil types and rice straw as a methanogenic substrate, and this inhibitory behavior was likely enhanced by ferric ion-NOM complexation. A mechanistic study using HAs revealed that complexation facilitated the slow release of the humic components. Interestingly, borohydride-based reduction, which transformed quinone moieties into phenols, caused the HAs to lose their inhibitory capacity, suggesting that the electron-accepting ability of HAs is vital for their inhibitory effect. In rice field tests, the humic-metal complexes were shown to successfully mitigate methane generation, while carbon dioxide emissions were relatively unchanged. Microbial community analysis of the rice fields by season revealed a decrease in specific cellulose-metabolizing and methanogenic genera associated with methane emissions. In contrast, the relative abundance of Thaumarchaeota and Actinomycetota, which are associated with NOM and recalcitrant organics, was higher in the presence of Fe-stabilized HAs. These microbial dynamics suggest that the slow release of humic components is effective in modulating the anoxic soil microbiome, possibly due to their electron-accepting ability. Given the simplicity, cost-effectiveness, and soil-friendly nature of complexation processes, Fe-stabilized NOM represents a promising approach for the mitigation of methane emissions from flooded rice paddies., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier B.V.)

The aim of this study was to investigate the prevalence of shoulder pain and analyze its association with socio-demographic factors, agricultural work-related conditions, and biomechanical factors among farmers on Jeju Island. We utilized initial survey data from the Safety for Agricultural Injury of Farmers' cohort study involving adult farmers on Jeju Island. The presence and characteristics of shoulder pain, socio-demographics, agricultural work-related conditions, and biomechanical factors were assessed using semi-structured questionnaires. A total of 1206 participants were analyzed for prevalence and associated risk factors using frequency and multivariate logistic regression analyses. The overall prevalence of shoulder pain was 17%. Multivariate logistic regression analysis, adjusted for significant socio-demographic and agricultural work-related condition variables, revealed that stress level, type of farming, and experiencing an agricultural injury within the preceding year were significantly associated with shoulder pain (stress level: "occasional," adjusted odds ratio [aOR], 1.581; 95% confidence interval [CI], 1.079-2.318; "frequent," aOR, 1.964; 95% CI, 1.205-3.200; and "extreme," aOR, 2.999; 95% CI, 1.480-6.074 vs "rarely"; type of farming: "orchard," aOR, 0.82; 95% CI, 0.597-1.124; "livestock," aOR, 0.225; 95% CI, 0.079-0.641 vs "field"; and experienced an agricultural injury within the past year: "yes," aOR, 2.078; 95% CI, 1.269-3.405). In addition, 3 biomechanical factors significantly contributed to shoulder pain: activities requiring significant power such as shoveling, pickaxing, and hammering; repetitive use of a particular body part; and constant elevation of the arm above the head. The findings highlight the importance of postural education, injury prevention, and psychological support in managing shoulder pain among farmers., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The purpose of this study was to evaluate surgeons' ability to perform or supervise a standard operation with agreed-upon radiologic parameters after being on call., Methods: We reviewed a consecutive series of patients with intertrochanteric hip fractures treated with a fixed angle device at 9 centers and compared corrected tip-apex distance and reduction quality for post-call surgeons versus those who were not. Subgroup analyses included surgeons who operated the night before versus not and attending-only versus resident involved cases. Secondary outcomes included union and perioperative complications., Results: One thousand seven hundred fourteen patients were of average age 77 years. Post-call surgeons treated 823 patients and control surgeons treated 891. Surgical corrected tip-apex distance did not differ between groups: on-call 18 mm versus control 18 mm (P = 0.59). The Garden indices were 160° on the AP and 179° on the lateral in both groups. In 66 cases performed by surgeons who operated the night before, the TAD was 17 mm. No difference was noted in corrected tip-apex distance with and without resident involvement (P = 0.101). No difference was observed in pooled fracture-related complications (P = 0.23)., Conclusion: Post-call surgeons demonstrated no difference in quality and no increase in complications when performing hip fracture repair the next day compared with surgeons who were not on call., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Antibody-based therapeutics (ABTs), including monoclonal/polyclonal antibodies and fragment crystallizable region (Fc)-fusion proteins, are increasingly used in disease treatment, driving the global market growth. Understanding the pharmacokinetic (PK) properties of ABTs is crucial for their clinical effectiveness. This study investigated the PK profile and tissue distribution of efineptakin alfa, a long-acting recombinant human interleukin-7 (rhIL-7-hyFc), using enzyme-linked immunosorbent assay (ELISA) and accelerator mass spectrometry (AMS). Totally, four rats were injected intramuscularly with 1 mg/kg of rhIL-7-hyFc containing 14 C-rhIL-7-hyFc, which was prepared via reductive methylation. Serum total radioactivity (TRA) and serum rhIL-7-hyFc concentrations were quantified using AMS and ELISA, respectively. The TRA concentrations in organs were determined by AMS. Serum TRA peaked at 10 hours with a terminal half-life of 40 hours. The rhIL-7-hyFc exhibited a mean peak concentration at around 17 hours and a rapid elimination with a half-life of 12.3 hours. Peak concentration and area under the curve of TRA were higher than those of rhIL-7-hyFc. Tissue distribution analysis showed an elevated TRA concentrations in lymph nodes, kidneys, and spleen, indicating rhIL-7-hyFc's affinity for these organs. The study also simulated the positions of 14C labeling in rhIL-7-hyFc, identifying specific residues in the fragment of rhIL-7 portion, and provided the explanation of distinct analytes targeted by each method. Combining ELISA and AMS provided advantages by offering sensitivity and specificity for quantification as well as enabling the identification of analyte forms. The integrated use of ELISA and AMS offers valuable insights for the development and optimization of ABT., Competing Interests: Mi-sun Byun and Donghoon Choi are employees of Genexine, Inc. and NeoImmuneTech, Inc., respectively. All other authors declared no competing interests for this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of Antibody Therapeutics.)

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

Background: Although urine drug testing can have vast legal and social ramifications, its interpretation during pregnancy and after birth remains not well understood. Fentanyl metabolism is altered by an individual's genetics, history of opioid use, and liver function. However, little is known about the clearance of fentanyl or its primary metabolite, norfentanyl, in the peripartum period., Objective: We sought to identify and describe cases of delayed urine norfentanyl clearance in the pregnancy and postpartum period within our institution., Study Design: This study described 3 cases of delayed urine norfentanyl clearance in pregnant and postpartum individuals in a colocated obstetrics, postpartum, and addiction medicine program. This program included prescriptions for medication for opioid use disorder and weekly urine drug testing with fentanyl immunoassay with reflex confirmation testing with liquid chromatography-tandem mass spectrometry for positive results with a limit of detection of 2.5 ng/mL., Results: Low levels of norfentanyl (<16.3 ng/mL) were detected in urine 294 days, 126 days, and 231 days after the last fentanyl use. Patient self-reported abstinence was supported by consistently negative urine fentanyl levels throughout the collection period, compliant weekly urine drug tests that were otherwise only positive for buprenorphine, and negative fentanyl and norfentanyl in umbilical cord toxicology., Conclusion: Despite compliance in a medication for opioid use disorder program, the presence of norfentanyl in urine has significant consequences on the maternal-child dyad in the postpartum period. Caution should be used when using low levels of norfentanyl to determine an individual's abstinence, as it can lead to further discrimination against women in medication for opioid use disorder programs., (© 2024 The Authors.)

Background: Cerebral small vessel disease is characterized by white matter hyperintensities (WMH) and acute small vessel occlusion (SVO) stroke. We investigated the effect of prior antiplatelet use (APU) on stroke outcome in 1151 patients with acute SVO stroke patients and moderate to severe WMH., Methods: Using a multicenter database, this retrospective study used quantitative WMH volume measurements and propensity score matching (PSM) for comparisons between patients with prior APU and without APU. Primary outcomes were stroke progression and poor functional outcome (modified Rankin Scale>2) at 3 months. Logistic regression analyses assessed associations between prior APU, WMH burden, and stroke outcomes., Results: Stroke progression was lower in the prior APU group in both the total cohort (14.8% vs. 6.9%, p < 0.001) and the PSM cohort (16.3% vs. 6.9%, p < 0.001). The proportion of poor functional outcomes at 3 months was not significantly different in the total cohort, but the PSM cohort showed a lower proportion in the prior APU group (30.8% vs. 20.2%, p = 0.002). Logistic regression analysis confirmed that prior APU was associated with a reduced risk of stroke progression (OR, 0.39; 95% CI, 0.22-0.70; p = 0.001) and poor functional outcome at 3 months (OR, 0.37; 95% CI, 0.23-0.59; p < 0.001)., Conclusion: Prior APU is associated with reduced stroke progression and improved functional outcome at 3 months in acute SVO stroke patients with moderate to severe WMH. Early treatment of WMH and acute SVO stroke may have potential benefits in improving stroke outcomes., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease (AD), the most common form of dementia, is characterized by memory loss and the abnormal accumulation of senile plaques composed of amyloid-β (Aβ) protein. Trichosanthis Semen (TS) is a traditional herbal medicine used to treat phlegm-related conditions. While TS is recognized for various bioactivities, including anti-neuroinflammatory effects, its ability to attenuate AD remains unknown., Objective: To evaluate the effects of TS extract (TSE) on neuronal damage, Aβ accumulation, and neuroinflammation in AD models., Methods: Thioflavin T and western blot assays were used to assess effects on Aβ aggregation in vitro. TS was treated to PC12 cells with Aβ to assess the neuroprotective effects. Memory functions and histological brain features were investigated in TSE-treated 5×FAD transgenic mice and mice with intracerebroventricularly injected Aβ., Results: TSE disrupted Aβ aggregation and increased the viability of cells and phosphorylation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) in vitro. TSE treatment also suppressed the accumulation of Aβ plaques in the brain of 5×FAD mice, protected neuronal cells in both the subiculum and medial septum, and upregulated Akt/ERK phosphorylation in the hippocampus. Moreover, TSE ameliorated the memory decline and glial overactivation observed in 5×FAD mice. As assessing whether TS affect Aβ-induced neurotoxicity in the Aβ-injected mice, the effects of TS on memory improvement and neuroinflammatory inhibition were confirmed., Conclusions: TSE disrupted Aβ aggregation, protected neurons against Aβ-induced toxicity, and suppressed neuroinflammation, suggesting that it can suppress the development of AD.

The objective of this study was to investigate the effect of a removable physical barrier on the air sparging performance using a lab-scale aquifer model was investigated. The barrier was installed in water-saturated porous media, prior to the air sparging, by injecting calcium chloride aqueous solution into the aquifer with pre-applied alginate solution. Changes in the air flow direction and air flux at the media surface during air sparging were evaluated. With a hydrogel barrier set at the center of the media, the airflow detoured the barrier resulting in a bimodal air flux distribution at the media surface. While employing two gel-formed barriers positioned away from the media's center, the airflow concentrated specifically on the gap between the barriers. The hydrogel was successfully removed using a sodium bicarbonate solution (1.0 mol/L). Using the hydrogel barrier, the performance of air sparging was significantly enhanced for removing contaminants [tetrachloroethene (PCE) and n-hexane mixture] due to increased air flux; 9.8% of PCE applied (7.8 g) was removed during 120 min air sprging for the gel barrier system whereas no PCE was removed for the control. Alginate gel did not show significant sorption capacity for PCE. It was stable in the contaminant up to 68 days with reasonable loss of its mass. Findings of this study present a promising option for air sparging process specifically targeting the contaminant source zone in the aquifer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain., Methods: We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro., Findings: The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells., Interpretation: Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis., Funding: This study was supported by a grant from the National Research Foundation of Korea., Competing Interests: Declaration of interests EH, JGC, DHK and MSO are inventors with a provisional patent, “Method for diagnosing neurodegenerative disease using HpmA” that is licensed to MetaCen Therapeutics. MGP is a co-founder of MetaCen Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: Dr. Alfonso has a consultant agreement with Cochlear Americas. Drs. Oh, Govil, and Todd disclose no conflicts of interest.

Neuroinflammation and synaptic damage are important etiologies associated with the progression of Alzheimer's disease (AD). Linderae Radix (LR) has antioxidant and anti-inflammatory properties. This study investigated whether LR attenuates microglia activation-mediated neuroinflammation and synaptic degeneration and improves AD pathological phenotypes induced by amyloid beta oligomers (AβO) or lipopolysaccharide (LPS) toxicity. For in vitro studies, we treated LR to AβO-stimulated HT22 cells or LR LPS-stimulated BV2 cells. For in vivo studies, we administered LR to mice and AβO was injected by stereotaxic to induce cognitive impairment, neuroinflammation, and synaptic loss. We found that LR increased the cell viability reduced by AβO. Moreover, LR inhibited pro-inflammatory mediators such as nitric oxide (NO), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), and downregulated p38 mitogen-activated protein kinase (MAPK) signaling in BV2 cells. Behavioral assessments demonstrated that LR administration significantly improved cognitive decline induced by AβO-injection. Furthermore, we found that microglia activation increased, and the expression of synaptic proteins decreased in the hippocampus of the AβO-injected group, which was alleviated in the LR-treated group. These findings suggest that LR may be a potential candidate for protection against neuroinflammation and synaptic loss, and may prevent or delay AD progression., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population., Methods: Using a prospective multicenter stroke registry in Korea, young adults (aged 18-50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed., Results: A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years ( P trend =0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%-13.8% and 3.2%-9.2%, respectively; P trend <0.01). Door-to-needle time improved ( P trend <.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%-47.0%), direct oral anticoagulants for atrial fibrillation (0.0%-56.2%), and statins for large artery atherosclerosis (76.1%-95.3%) increased ( P trend <0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011-2013 and 2.3% in 2017-2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%-69.1%) and 0 to 2 (87.6%-86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%-5.5%; P trend =0.04), although the difference was not significant after adjusting for sex and age., Conclusions: Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress., Competing Interests: Disclosures Dr Gorelick reports grants from Amerian Telephysicians, AbbVie, and Pickus Law, outside the submitted work. Dr Bae reports grants from AstraZeneca, Bayer Korea, Bristol Myers Squibb Korea, Dong-A ST, Jeil Pharmaceutical Co, Ltd, Korean Drug Co, Ltd, Samjin Pharm, Takeda Pharmaceuticals Korea Co, Ltd, and Yuhan Corporation and people fees from Amgen Korea, Bayer, Daiichi Sankyo, JW Pharmaceutical, Hanmi Pharmaceutical Co, Ltd, Otsuka Korea, SK Chemicals, and Viatris Korea, outside the submitted work. The other authors report no conflicts.

Aim: While the relationship between impaired kidney function and non-vitamin K antagonist oral anticoagulants (NOACs) is well established, there is limited research exploring the association between an elevated estimated glomerular filtration rate (eGFR) and the efficacy of NOACs, especially concerning the outcomes of acute ischemic stroke (AIS). This study aimed to examine the association between higher-than-normal eGFR and the severity of AIS during the use of NOACs using a nationwide multicenter stroke registry in Korea., Material and Methods: This study utilized data from the Korean Stroke Registry (KSR) database, examining information from 2,379 patients with AIS, who had atrial fibrillation (AF) and a history of utilizing NOACs prior to hospitalization due to incident stroke occurring between 2016 and 2021. Patients with a history involving two or more types of anticoagulants or one or more forms of antiplatelet agents were excluded. Baseline characteristics, medical history, medication usage, CHADS 2 -VASc score, and the anticoagulation and risk factors in atrial fibrillation (ATRIA) score were evaluated. Renal function was assessed using eGFR levels and calculated with the Cockcroft-Gault equation. The severity of stroke was measured by the National Institutes of Health Stroke Scale as an outcome. For sensitivity analysis, further evaluation was performed using eGFR levels according to the modification of diet in renal disease (MDRD) study equation., Results: The mean age of subjects was 76.1 ± 8.9 years. The moderate-to-severe stroke severity group exhibited an elevation in creatinine levels. The eGFR of 60 to 89 mL/min/1.73 m 2 group was associated with a decreased risk of moderate-to-severe stroke severity [hazard ratio (HR)] (0.77, 95% confidence interval (CI) [0.61, 0.98], p = 0.031) compared to the eGFR≥90 mL/min/1.73 m 2 group. An increment of 10 units in eGFR was marginally associated with an increased risk of moderate-to-severe stroke severity (HR: 1.03, 95% CI [1.00, 1.07], p = 0.054)., Conclusion: The study revealed that individuals with eGFR ≥ 90 mL/min/1.73 m 2 had an association linked to an increased risk of moderate-to-severe stroke severity. Our study suggests that patients taking NOACs with higher-than-normal eGFR levels may have an increased severity of AIS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Lee, Oh, Lee, Jeong, Shin, Yoon and Park.)