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The skin acts as a vital barrier, shielding the body from external threats that can trigger dryness, itching, and inflammation. Pilea mongolica, a traditional Chinese medicinal herb, holds promise for various ailments, yet its anti-inflammatory properties remain understudied. This study aimed to explore the potential anti-inflammatory effects of the methanol extract of P. mongolica (MEPM) and its underlying molecular mechanisms and active compounds in LPS-stimulated human keratinocytes. MEPM treatment, at concentrations without cytotoxicity, significantly decreased NO productions and the iNOS, IL-6, IL-1β, and TNF-α levels in LPS-induced HaCaT cells. Moreover, MEPM suppressed IRAK4 expression and phosphorylation of JNK, ERK, p38, p65, and c-Jun, suggesting that the anti-inflammatory effects of MEPM result from the inhibition of IRAK4/MAPK/NF-κB/AP-1 signaling pathway. Through LC/MS/MS analysis, 30 compounds and 24 compounds were estimated in negative and positive modes, respectively, including various anti-inflammatory compounds, such as corilagin and geraniin. Through HPLC analysis, geraniin was found to be present in MEPM at a concentration of 18.87 mg/g. Similar to MEPM, geraniin reduced iNOS mRNA expression and inhibited NO synthesis. It also decreased mRNA and protein levels of inflammatory cytokines, including IL-6 and TNF-α, and inhibited IRAK4 expression and the phosphorylation of MAPKs, NF-κB, and AP-1 pathways. Therefore, it can be inferred that the anti-inflammatory effects of MEPM are attributable to geraniin. Thus, MEPM and its active compound geraniin are potential candidates for use in natural functional cosmetics., 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.)

Although the efficacy of trastuzumab deruxtecan (T-DXd) against HER2-positive gastric cancers (GCs) has driven its clinical application, the precise mechanisms governing its immunomodulatory role remain unclear. In this study, we examined the immune-related mechanisms of action of T-DXd in GC cells. T-DXd exhibited potent antitumor effects in GC cells across diverse HER2 expression levels by inducing DNA damage and apoptosis. Activation of the DNA damage response by T-DXd led to increased PD-L1 expression. RNA-Seq analysis revealed that T-DXd modulated immune-related pathways, resulting in the upregulation of genes associated with inflammation and IFN signaling. Importantly, T-DXd activated the cGAS-STING pathway, inducing an IFN-I response in HER2-positive GC cells. Furthermore, T-DXd activated dendritic cells via the cancer cell-intrinsic cGAS-STING-IFN axis and enhanced PBMC-mediated tumor cell killing by activating CD8 + T cells. These findings provide valuable insights into the role of the cytosolic DNA sensing pathway in the action of T-DXd and offer a compelling rationale for combining T-DXd with immune checkpoint blockade therapies in GC treatment., (© 2024. The Author(s).)

Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione 11 and 7-amino-2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}quinoline-5,8-dione 23 exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC 50 values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)oxy] phenyl}quinoline-5,8-dione 22 inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.

We describe a new species, Chrysospleniuminsularis J.E.Jang, K.H.Lee & H.Y.Gil, belonging to the family Saxifragaceae, from the southern islands of the Republic of Korea. Chrysospleniuminsularis is morphologically similar to C.japonicum (Maxim.) Makino but can be distinguished by fairly persistent bulbils, green to yellowish-green sepals, four stamens, and cylindrical papillose seeds. Chrysospleniuminsularis is also distinguished from C.alternifolium L., which is distributed in Europe, northern Russia, and the Caucasus, by the absence of stolons and green bracts. Phylogenetic analyses, based on one nuclear ribosomal (ITS) and two chloroplast ( rbc L, mat K) regions, confirmed that the new species was monophyletic and that C.insularis and C.alternifolium formed a sister relationship with robust support. Herein, we provide a detailed morphological description of C.insularis with its corresponding geographical distribution and comparison table and figures of related species., Competing Interests: The authors have declared that no competing interests exist., (Ju Eun Jang, Beom Kyun Park, Kang-Hyup Lee, Hyuk-Jin Kim, Hee-Young Gil.)

Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis., (© 2024. The Author(s).)

Study Design: Retrospective cohort study., Objectives: To evaluate whether different radiographic clusters of adult spinal deformity identified using artificial intelligence-based clustering are associated with distinct surgical outcomes., Methods: Patients were classified based on the results of a previously conducted analysis that examined clusters of deformity, including Moderate Sagittal (Mod Sag), Severe Sagittal (Sev Sag), Coronal, and Hyper-Thoracic Kyphosis (Hyper-TK). The surgical data, HRQOL, and complication outcomes of these clusters were then compared., Results: The final analysis included 1062 patients. Similar to published results on a different patient sample, Mod Sag and Sev Sag patients were older, more likely to have a history of previous spine surgery, and more disabled. By 2-year, all clusters improved in HRQOL and reached a similar rate of minimal clinically important difference (MCID).The Sev Sag cluster had the highest rate major complications (53% vs 34-40%), and complications leading to reoperation (29% vs 17-23%), implant failures (20% vs 8-11%), and operative complications (27% vs 10-17%). Coronal patients had the highest rate of pulmonary complications (9% vs 3-6%) but the lowest rate of X-ray imbalance (10% vs 19-21%). No significant differences were found in neurological complications, infection rate, gastrointestinal, or cardiac events (all P > .1). Kaplan-Meier survival curves demonstrated a lower time to first complications for the Sev Sag cluster., Conclusions: All clusters of adult spinal deformity benefit similarly from surgery as they all achieved similar rates of MCID. Although the rates of complications varied among the clusters, the types of complications were not significantly different., 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.

Despite the significant impact of the COVID-19 pandemic on various factors related to adolescent mental health problems such as stress, sadness, suicidal ideation, and suicide attempts, research on this topic has been insufficient to date. This study is based on the Korean Youth Risk Behavior Web-based Survey from 2006 to 2022. We analyzed the mental health problems of adolescents based on questionnaires with medical interviews, within five income groups and compared them with several risk factors. A total of 1,138,804 participants were included in this study, with a mean age (SD) of 15.01 (0.75) years. Of these, 587,256 were male (51.57%). In 2022, the recent period from the study, the weighted prevalence of stress in highest income group was 40.07% (95% CI, 38.67-41.48), sadness was 28.15% (26.82-29.48), suicidal ideation was 13.92% (12.87-14.97), and suicide attempts was 3.42% (2.90-3.93) while the weighted prevalence of stress in lowest income group was 62.77% (59.42-66.13), sadness was 46.83% (43.32-50.34), suicidal ideation was 31.70% (28.44-34.96), and suicide attempts was 10.45% (8.46-12.45). Lower income groups showed a higher proportion with several risk factors. Overall proportion had decreased until the onset of the pandemic. However, a significant increase has been found during the COVID-19 pandemic. Our study showed an association between household income level and the prevalence of mental illness in adolescents. Furthermore, the COVID-19 pandemic has exacerbated mental illness among adolescents from low household income level, underscoring the necessity for heightened public attention and measures targeted at this demographic., (© 2024. The Author(s).)

Background and Purpose: To train and validate a deep learning (DL)-based segmentation model for cerebral microbleeds (CMB) on susceptibility-weighted MRI; and to find associations between CMB, cognitive impairment, and vascular risk factors., Materials and Methods: Participants in this single-institution retrospective study underwent brain MRI to evaluate cognitive impairment between January-September 2023. For training the DL model, the nnU-Net framework was used without modifications. The DL model's performance was evaluated on independent internal and external validation datasets. Linear regression analysis was used to find associations between log-transformed CMB numbers, cognitive function (mini-mental status examination [MMSE]), white matter hyperintensity (WMH) burden, and clinical vascular risk factors (age, sex, hypertension, diabetes, lipid profiles, and body mass index)., Results: Training of the DL model (n = 287) resulted in a robust segmentation performance with an average dice score of 0.73 (95% CI, 0.67-0.79) in an internal validation set, (n = 67) and modest performance in an external validation set (dice score = 0.46, 95% CI, 0.33-0.59, n = 68). In a temporally independent clinical dataset (n = 448), older age, hypertension, and WMH burden were significantly associated with CMB numbers in all distributions (total, lobar, deep, and cerebellar; all P <.01). MMSE was significantly associated with hyperlipidemia (β = 1.88, 95% CI, 0.96-2.81, P <.001), WMH burden (β = -0.17 per 1% WMH burden, 95% CI, -0.27-0.08, P <.001), and total CMB number (β = -0.01 per 1 CMB, 95% CI, -0.02-0.001, P = .04) after adjusting for age and sex., Conclusions: The DL model showed a robust segmentation performance for CMB. In all distributions, CMB had significant positive associations with WMH burden. Increased WMH burden and CMB numbers were associated with decreased cognitive function., Abbreviations: CMB = cerebral microbleed; DL = deep learning, DSC = dice similarity coefficient; MMSE = mini-mental status examination; SVD = small vessel disease; SWI = susceptibility-weighted image; WMH = white matter hyperintensity., Competing Interests: The authors declare no conflicts of interest related to the content of this article, (© 2024 by American Journal of Neuroradiology.)

Purpose: Understanding the mechanism and extent of preoperative deformity in revision procedures may provide data to prevent future failures in lumbar spinal fusion patients., Methods: ASD patients without prior spine surgery (PRIMARY) and with prior short (SHORT) and long (LONG) fusions were included. SHORT patients were stratified into modes of failure: implant, junctional, malalignment, and neurologic. Baseline demographics, spinopelvic alignment, offset from alignment targets, and patient-reported outcome measures (PROMs) were compared across PRIMARY and SHORT cohorts. Segmental lordosis analyses, assessing under-, match, or over-correction to segmental and global lordosis targets, were performed by SRS-Schwab coronal curve type and construct length., Results: Among 785 patients, 430 (55%) were PRIMARY and 355 (45%) were revisions. Revision procedures included 181 (23%) LONG and 174 (22%) SHORT corrections. SHORT modes of failure included 27% implant, 40% junctional, 73% malalignment, and/or 28% neurologic. SHORT patients were older, frailer, and had worse baseline deformity (PT, PI-LL, SVA) and PROMs (NRS, ODI, VR-12, SRS-22) compared to primary patients (p < 0.001). Segmental lordosis analysis identified 93%, 88%, and 62% undercorrected patients at LL, L1-L4, and L4-S1, respectively. SHORT patients more often underwent 3-column osteotomies (30% vs. 12%, p < 0.001) and had higher ISSG Surgical Invasiveness Score (87.8 vs. 78.3, p = 0.006)., Conclusions: Nearly half of adult spinal deformity surgeries were revision fusions. Revision short fusions were associated with sagittal malalignment, often due to undercorrection of segmental lordosis goals, and frequently required more invasive procedures. Further initiatives to optimize alignment in lumbar fusions are needed to avoid costly and invasive deformity corrections., Level of Evidence: IV: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Seeding activities of disease-associated α-synuclein aggregates (αSyn D ), a hallmark of Parkinson's disease (PD), are detectable by seed amplification assay (αSyn-SAA) and being developed as a diagnostic biomarker for PD. Sensitive and accurate αSyn-SAA for blood or saliva would greatly facilitate PD diagnosis. This prospective diagnostic study conducted αSyn-SAA analyses on serum and saliva samples collected from patients clinically diagnosed with PD or healthy controls (HC). 124 subjects (82 PD, 42 HC) donated blood and had extensive clinical assessments, of whom 74 subjects (48 PD, 26 HC) also donated saliva at the same visits. An additional 57 subjects (35 PD, 22 HC) donated saliva and had more limited clinical assessments. The mean ages were 69.21, 66.55, 69.58, and 64.71 years for PD serum donors, HC serum donors, PD saliva donors, and HC saliva donors, respectively. αSyn D seeding activities in either sample type alone or both sample types together were evaluated for PD diagnosis. Serum αSyn-SAA data from 124 subjects showed 80.49% sensitivity, 90.48% specificity, and 0.9006 accuracy (AUC of ROC); saliva αSyn-SAA data from 131 subjects attained 74.70% sensitivity, 97.92% specificity, and 0.8966 accuracy. Remarkably, the combined serum and saliva αSyn-SAA from 74 subjects with both sample types achieved better diagnostic performance: 95.83% sensitivity, 96.15% specificity, and 0.98 accuracy. In addition, serum αSyn D seeding activities correlated inversely with Montreal Cognitive Assessment in males and positively with Hamilton Depression Rating Scale in females and in the < 70 age group, whereas saliva αSyn D seeding activities correlated inversely with age at diagnosis in males and in the < 70 age group. Our data indicate that serum and saliva αSyn-SAA together can achieve high diagnostic accuracy for PD comparable to that of CSF αSyn-SAA, suggesting their potential utility for highly sensitive, accurate, and minimally invasive diagnosis of PD in routine clinical practice and clinical studies., (© 2024. The Author(s).)

Diabetic nephropathy (DN), a leading cause of chronic kidney disease and end-stage kidney disease (ESKD), poses global health challenges given its increasing prevalence. DN increases the risk of mortality and cardiovascular events. Early identification and appropriate DN management are crucial. However, current diagnostic methods rely on general traditional markers, highlighting the need for DN-specific diagnostics. Metabolomics, the study of small molecules produced by metabolic activity, promises to identify specific biomarkers that distinguish DN from other kidney diseases, decode the underlying disease mechanisms, and predict the disease course. Profound changes in metabolic pathways are apparent in individuals with DN, alterations in the tricarboxylic acid cycle and amino acid and lipid metabolism, suggestive of mitochondrial dysfunction. Metabolomics aids prediction of chronic kidney disease progression; several metabolites serve as indicators of renal functional decline and the risk of ESKD. Integration of such information with other omics data will further enhance our understanding of DN, paving the way to personalized treatment. In summary, metabolomics and multi-omics offer valuable insights into DN and are promising diagnostic and prognostic tools.

Background: North Korean refugees (NKRs) exhibit alarmingly high levels of depression prior to or immediately after entering South Korean society, which is likely attributable to their pre-migration traumatic experiences. However, prior research on NKRs has simply examined the cumulative effect of trauma on depression. Despite calls for research identifying trauma exposure patterns that co-occur among refugees, to date, no study has investigated distinct profiles of NKRs' pre-migration trauma exposure and their associations with depression in this high-risk population. To better understand the unique mental health needs of NKRs and provide them with tailored care, it is imperative to identify meaningful subgroups of NKRs with distinct profiles of trauma exposure., Aims: Using latent class analysis (LCA), which is a person-centered approach, this study aimed to identify subgroups of NKRs based on trauma exposure and their associations with sociodemographic characteristics and depression levels., Methods: A sample of NKRs ( N  = 405) in South Korea were assessed for depression, pre-migration trauma, and sociodemographic covariates through a self-administered survey. LCA was conducted to identify trauma exposure classes and multivariate ordinary least squares regression analysis was performed to examine associations between trauma exposure classes and depression., Results: The prevalence of clinically significant depression was 47.2% for our study sample. Three classes of trauma were identified: deprivation trauma and witnessing death (59.3%), complex and pervasive trauma (23.7%), and low exposure (17.0%). Members in the complex and pervasive trauma class demonstrated very high probabilities of exposure to all traumatic events and had the strongest association with elevated depression., Conclusions: Our findings underscore the importance of identifying subgroups of NKRs to unravel heterogeneity in trauma exposure and provide more nuanced explanations for different risk profiles regarding depression. These findings also provide evidence for a framework for clinicians to provide individualized resources and trauma-informed services to NKRs., Competing Interests: Conflict of interestThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Modern graphics processing units (GPUs) provide an unprecedented level of computing power. In this study, we present a high-performance, multi-GPU implementation of the analytical nuclear gradient for Kohn-Sham time-dependent density functional theory (TDDFT), employing the Tamm-Dancoff approximation (TDA) and Gaussian-type atomic orbitals as basis functions. We discuss GPU-efficient algorithms for the derivatives of electron repulsion integrals and exchange-correlation functionals within the range-separated scheme. As an illustrative example, we calculate the TDA-TDDFT gradient of the S 1 state of a full-scale green fluorescent protein with explicit water solvent molecules, totaling 4353 atoms, at the ωB97X/def2-SVP level of theory. Our algorithm demonstrates favorable parallel efficiencies on a high-speed distributed system equipped with 256 Nvidia A100 GPUs, achieving >70% with up to 64 GPUs and 31% with 256 GPUs, effectively leveraging the capabilities of modern high-performance computing systems.

The gut microbiota can play an important role in enhancing the host's complex immune system. In this regard, many studies indicate that probiotics consumption has a beneficial impact on alterations in the composition of the gut microbiota. Our previous study demonstrated that the oral administration of Lacticaseibacillus rhamnosus HDB1258 (HDB1258) enhances immune cell activity and alters the composition of gut microbiota in C57BL/6 mice, thereby showing its potential as a novel immunostimulatory ingredient. Therefore, this clinical trial assessed the effects of HDB1258 on human natural killer (NK) cell activity and changes in gut microbiota. It also investigated the correlation between gut microbiota and NK cell activity following HDB1258 supplementation. Participants ( n = 71) were randomized into placebo and HDB1258 groups, and NK cell activity and gut microbiota were investigated at baseline (week 0) and endline (week 8). The present study showed that HDB1258 significantly increased NK cell activity and resulted in positive regulatory effects on the gut microbial balance in subjects compared to the placebo group. HDB1258 affected the gut microbial balance by inducing the growth of beneficial bacteria such as Lactococcus and Sutterella . Especially, the changes in Escherichia - Shigella composition were negatively correlated with the changes in NK cell activity after HDB1258 consumption. There was also a positive correlation between the NK cell activity in the HDB1258 group and the composition of Prevotella 9 and Adlercreutzia . These findings suggest that HDB1258 may improve the host's intestinal environment by regulating gut bacteria related to immune response and promote NK cell activation. This study was registered at clinical research information service (CRIS: KCT0008204).

Objective: We conducted this study to assess the efficacy and safety of taltirelin hydrate (TH) in spinocerebellar degeneration (SCD)., Methods: Patients were randomly assigned to either the taltirelin group (5 mg orally, twice daily) or the control group. The primary endpoint was changes in the Korean version of Scale for the Assessment and Rating of Ataxia (K-SARA) scores at 24 weeks. The secondary endpoints include changes in the K-SARA scores at 4 and 12 weeks, the Clinical Global Impression, Five-level version of the EuroQol five-dimensional questionnaire, Tinetti balance test and gait analysis at 4, 12 and 24 weeks., Results: A total of 149 patients (hereditary:non-hereditary = 86:63) were enrolled. There were significant differences in changes in K-SARA scores at 24 weeks from baseline between the taltirelin group and the control group (-0.51 ± 2.79 versus 0.36 ± 2.62, respectively; p = 0.0321). Of the K-SARA items, both 'Stance' and 'Speech disturbance' had significantly lower subscores in the taltirelin group as compared with the control group (-0.04 ± 0.89 versus 0.23 ± 0.79 and -0.07 ± 0.74 versus 0.18 ± 0.67; p = 0.0270 and 0.0130, respectively). But there were no significant differences in changes in other secondary efficacy outcome measures at 24 weeks from baseline between the two treatment arms (p > 0.05)., Conclusion: Clinicians might consider using TH in the treatment of ataxia due to SCD.

Background: The impact of blood-brain barrier (BBB) leakage on white matter hyperintensity (WMH) subtypes (location) and its association with clinical factors and cognition remains unclear., Purpose: To investigate the relationship between WMH volume, permeability, clinical factors, and cognition in older individuals across the cognitive spectrum., Study Type: Prospective, cross-sectional., Subjects: A total of 193 older adults with/without cognitive impairment; 128 females; mean age 70.1 years (standard deviation 6.8)., Field Strength/sequence: 3 T, GE Dynamic contrast-enhanced, three-dimensional (3D) Magnetization-prepared rapid gradient-echo (MPRAGE T1WI), 3D fluid-attenuated inversion recovery (FLAIR)., Assessment: Periventricular WMH (PWMH), deep WMH (DWMH), and normal-appearing white matter (NAWM) were segmented using FMRIB automatic segmentation tool algorithms on 3D FLAIR. Hippocampal volume and cortex volume were segmented on 3D T1WI. BBB permeability (Ktrans) and blood plasma volume (Vp) were determined using the Patlak model. Vascular risk factors and cognition were assessed., Statistical Tests: Univariate and multivariate analyses were performed to identify factors associated with WMH permeability. Logistic regression analysis assessed the association between WMH imaging features and cognition, adjusting for age, sex, apolipoprotein E4 status, education, and brain volumes. A P-value <0.05 was considered significant., Results: PWMH exhibited higher Ktrans (0.598 ± 0.509 × 10 -3  minute -1 ) compared to DWMH (0.496 ± 0.478 × 10 -3  minute -1 ) and NAWM (0.476 ± 0.398 × 10 -3  minute -1 ). Smaller PWMH volume and cardiovascular disease (CVD) history were significantly associated with higher Ktrans in PWMH. In DWMH, higher Ktrans were associated with CVD history and cortical volume. In NAWM, it was linked to CVD history and dyslipidemia. Larger PWMH volume (odds ratio [OR] 1.106, confidence interval [CI]: 1.021-1.197) and smaller hippocampal volume (OR 0.069; CI: 0.019-0.253) were independently linked to worse global cognition after covariate adjustment., Data Conclusion: Elevated BBB leakage in PWMH was associated with lower PWMH volume and prior CVD history. Notably, PWMH volume, rather than permeability, was correlated with cognitive decline, suggesting that BBB leakage in WMH may be a consequence of CVD rather than indicate disease progression., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 3., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Study Design: Retrospective cohort study., Objectives: This study aimed to evaluate the survival period in patients with a single spinal metastasis (SSM), subsequently comparing those with isolated-single spinal metastasis (I-SSM) and single spinal metastasis with other metastasis (O-SSM) after surgery, and to identify prognostic factors affecting their survival., Methods: A total of 135 patients were included, with 24 patients in the I-SSM group and 111 in the O-SSM group. Survival analysis was utilized to assess the survival of SSM patients, followed by a comparison of survival rates between the two groups. Univariate and multivariate analyses were conducted to identify significant prognostic factors for survival., Results: The overall median survival period for patients with single spinal metastasis (SSM) was 10.2 ± 1.8 months. Specifically, the median survival was 15.7 ± 5.7 months in the I-SSM group and 10.2 ± 1.5 months in the O-SSM group. The difference in survival periods between the two groups was not statistically significant ( P = 0.345). Significant independent prognostic factors for survival included preoperative Karnofsky Performance Status (KPS) of 50 - 70 (OR 0.51, P = 0.017) and 80 - 100 (OR 0.46, P = 0.012), postoperative ambulatory status (OR 1.19, P = 0.028), and primary malignancy site [Group B (OR 2.67, P = 0.021), Group C (OR 2.90, P = 0.016)]., Conclusions: Patients with SSM have a median survival of 10.2 months, with no significant difference in postoperative survival between the I-SSM and O-SSM groups. Significant prognostic factors influencing the survival period after surgery include preoperative KPS, postoperative ambulatory status, and the primary malignancy site., 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.

Infrared spectroscopy is a valuable tool for forensic examinations because it realizes nondestructive and rapid analysis. Recent advancements in machine learning have facilitated the development of chemometrics, extending to applications in questioned document examination. In this study, support vector machine (SVM), feedforward neural network (FNN), and random forest (RF) models were constructed using the infrared spectral data of document paper samples to identify the manufacturer of document paper products. For model training, the infrared (IR) spectral regions were selected based on their variable importance as determined by the RF models. Narrowing the IR spectral data within the range of 1500-800 cm -1 (selected according to variable importance measures) proved effective in terms of enhancing model performance while minimizing computational costs. The FNN and RF models trained on the second-derivative IR spectra in this range obtained F1-scores of 0.978 and 1.000, respectively. The findings of this study confirm the potential of machine learning methods for extracting and examining forensic features in document paper, resulting in robust models with low computational overhead., 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.)

Indigo is a unique blue dye that has been used in the textile industry for centuries and is currently mass-produced commercially through chemical synthesis. However, the use of toxic substrates and reducing agents for chemical synthesis is associated with environmental concerns, necessitating the development of eco-friendly alternatives based on microbial production. In this study, a robust industrial strategy for indigo production was developed using Pseudomonas putida KT2440 as the host strain, which is characterized by its excellent ability to degrade aromatic compounds and high resistance to environmental stress. By introducing the genes tryptophanase (tnaA) and Flavin-containing monooxygenase (FMO), a P. putida HI201 strain was constructed to produce indigo from tryptophan. To enhance the indigo yield, culture conditions, including medium composition, temperature, tryptophan concentration, and shaking speed, were optimized. Under optimal conditions such as TB medium, 15 mM tryptophan, 30°C, 200 rpm, P. putida HI201 biosynthesized 1.31 g/L indigo from tryptophan in a fed-batch fermentation system. The introduction of tnaA and FMO genes also enabled the production of indigo in various P. putida species, and the indigo-producing strain had a blue color, which served as a visual indicator. This study presents a strategy for using P. putida as a host for robust and sustainable microbial production of indigo, highlighting the strain's applicability and efficiency in environment friendly dye synthesis., 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 Inc. All rights reserved.)

There is no comprehensive umbrella review exploring the connection between schizophrenia and various health outcomes. Therefore, we aimed to systematically review existing meta-analyses about schizophrenia-associated comorbid health outcomes and validate the evidence levels. We performed an umbrella review of meta-analyses of observational studies to explore comorbid health outcomes in individuals with schizophrenia. Searches were conducted across PubMed/MEDLINE, EMBASE, ClinicalKey, and Google Scholar up to September 5, 2023, targeting meta-analyses of observational studies related to comorbid health outcomes in individuals with schizophrenia. We applied AMSTAR2 for data extraction and quality assessment, adhering to PRISMA guidelines. Evidence credibility was evaluated and categorized by evidence quality. Our protocol was registered with PROSPERO (CRD42024498833). Risk and protective factors were analyzed and presented through equivalent odds ratios (eRR). In this umbrella review, we analyzed 9 meta-analyses, including 88 original articles, covering 21 comorbid health outcomes with over 66 million participants across 19 countries. Patients with schizophrenia showed significant associations with multiple health outcomes, including asthma (eRR, 1.71 [95% CI, 1.05-2.78], class and quality of evidence [CE] = non-significant), chronic obstructive pulmonary disease (1.73 [1.25-2.37], CE = weak), pneumonia (2.63 [1.11-6.23], CE = weak), breast cancer of female patients (1.31 [1.04-1.65], CE = weak), cardiovascular disease (1.53 [1.12-2.11], CE = weak), stroke (1.71 [1.30-2.25], CE = weak), congestive heart failure (1.81 [1.21-2.69], CE = weak), sexual dysfunction (2.30 [1.75-3.04], CE = weak), fracture (1.63 [1.10-2.40], CE = weak), dementia (2.29 [1.19-4.39], CE = weak), and psoriasis (1.83 [1.18-2.83] CE = weak). Our study underscores the imperative for an integrated treatment approach to schizophrenia, highlighting its broad impact across respiratory, cardiovascular, sexual, neurological, and dermatological health domains. Given the predominantly non-significant to weak evidence levels, further studies are needed to reinforce our understanding., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Adult isthmic spondylolisthesis(AIS) results in the anterior translation of the vertebral body with neural encroachment. Although oblique lumbar interbody fusion(OLIF) is minimally invasive technique that use a retroperitoneal plane to achieve indirect decompression compared to transforaminal lumbar interbody fusion(TLIF), research on OLIF for AIS remains limited. Therefore, we aimed to compare the clinical and radiological outcomes of these two surgical techniques for AIS., Methods: We analyzed the details of 62patients with AIS who were treated with either OLIF(n=26) or TLIF(n=36) between 2019 and 2022, with a minimum 2-year follow-up. The two surgical techniques were compared in terms of perioperative surgical, radiological, and clinical outcomes. The correlation between the severity of foraminal stenosis and clinical outcomes was evaluated., Results: The OLIF group experienced significantly less blood loss, shorter operative times, and shorter hospital stay than the TLIF group. Radiological assessments showed no significant preoperative differences in disc height or slippage ratios, but postoperative slippage correction was significantly greater in the OLIF group than in the TLIF group(13.5±8.0 versus 5.0±8.9; p<0.001). The clinical outcome improvement ratios did not differ significantly between the two groups. The correlation between preoperative severity of foraminal stenosis and clinical outcomes in the OLIF group was not significant., Conclusion: OLIF is more advantageous than TLIF in terms of blood loss, operative time, hospital stay and anterolisthesis correction. In addition, good clinical outcomes were obtained with indirect decompression alone, regardless of the severity of foraminal stenosis. Therefore, OLIF is a good surgical option for the treatment of AIS., (Copyright © 2024. Published by Elsevier Inc.)

The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

2-Mercaptomethylbenzo[ d ]imidazole (2-MMBI) derivatives were designed and synthesized as tyrosinase (TYR) chelators using 2-mercaptomethylimidazole scaffolds. Seven of the ten 2-MMBI derivatives exhibited stronger inhibition of mushroom TYR activity than kojic acid. Their ability to chelate copper ions was demonstrated through experiments using the copper chelator pyrocatechol violet and assays measuring TYR activity in the presence or absence of exogenous CuSO 4 . The inhibition mechanisms of derivatives 1 , 3 , 8 , and 9 , which showed excellent TYR inhibitory activity, were elucidated through kinetic studies and supported by the docking simulation results. Derivatives 3 , 7 , 8 , and 10 significantly inhibited cellular TYR activity and melanin production in B16F10 cells in a dose-dependent manner, with stronger potency than kojic acid. Furthermore, in situ, derivatives 7 and 10 showed stronger inhibitory effects on B16F10 cell TYR activity than kojic acid. Six derivatives, including 8 , showed highly potent depigmentation in zebrafish larvae, outpacing kojic acid even at 200-670 times lower concentrations. Additionally, all derivatives could scavenge for reactive oxygen species without causing cytotoxicity in epidermal cells. These results suggested that 2-MMBI derivatives are promising anti-melanogenic agents., Competing Interests: The authors declare no conflicts of interest.

Ultraviolet (UV) exposure triggers skin aging primarily by disrupting skin barrier function, resulting in dry skin and wrinkle formation. Oyster hydrolysate (OH), as a functional food, has been reported for anti-cancer, anti-oxidant and anti-apoptotic effects. This study investigated the underlying mechanism of OH effect on UVB-induced skin aging in SKH1 hairless mice. Mice were exposed to UVB three times per week while they were fed with a normal diet or diet containing OH for 10 weeks. Additionally, a randomized, double-blind, and placebo-controlled clinical trial was performed to investigate the OH effect on human skin moisturizing to evaluate its efficacy and safety. UVB exposure increased parameters of skin aging; dehydration, transepidermal water loss, and macroscopic dorsal skin lesions. OH significantly reduced these features of skin aging. Histological analysis demonstrated that OH decreased skin epidermal and dermal thickness and collagen degradation induced by UVB. OH significantly reduced ROS production, suppressed macrophage activation and neutrophil infiltration, and downregulated pro-inflammatory cytokine production. OH improved skin barrier function by increasing the expression of filaggrin, aquaporin-3, and hyaluronic acid synthesis enzymes and promoting recovery from skin damage. Importantly, the results from a human clinical trial demonstrated that OH improved skin moisturization and integrity with no side effects. Taken together, OH supplementation ameliorates skin damage via anti-oxidant and anti-inflammatory properties and enhances skin hydration and barrier function. OH has a therapeutic potential for skin photoaging., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative cognitive dysfunction (POCD) is one of the major complications after surgery, with devastating clinical outcomes. Although POCD is a condition with a multifactorial pathophysiology, blood-brain barrier (BBB) dysfunction and neuronal injury have been shown to play a critical role, especially in the elderly. Previous studies have demonstrated that the choice of anesthetics affect BBB permeability and neuroinflammation. However, most studies are carried out on animals, with limited research undertaken on humans. Therefore, we will compare the effect of intravenous anesthetics and inhaled anesthetics on BBB dysfunction and the change of inflammatory markers after surgery., Methods: One hundred and fifty-four patients who are 60 years of age or older undergoing major surgery for more than 2 h will be randomly allocated to two anesthetics groups (intravenous, inhaled) in a 1:1 ratio. In the intravenous anesthetics group (group P), propofol will be infused with a target-controlled infusion (TCI) system throughout the entire surgery. In the inhaled anesthetics group (group G), bolus injection of propofol will be administered for loss of consciousness, and simultaneously sevoflurane will be initiated for the maintenance of anesthesia. The primary outcome is the change in serum S100 calcium binding protein β (S100β) at four time points: before induction of anesthesia, at the end of surgery, 4 h after surgery, postoperative day 1. Secondary outcomes include changes in the inflammatory markers, serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and C-reactive protein; the incidence of delirium; and the change in the cognitive function between groups. In patients pre-scheduled for postoperative intensive care unit admission, the cerebrospinal fluid/serum albumin quotient (Qalb) between the two groups will be compared before and after surgery, and change in inflammatory markers in serum and CSF will be analyzed in relation to the Qalb., Discussion: The current study will compare the effect of intravenous versus inhaled anesthetics on blood-brain barrier permeability and, as a result, the difference in neuroinflammation in elderly patients. Also, the study results will provide additional information to develop intraoperative anesthetic strategies to reduce POCD., Trial Registration: The trial was prospectively registered at Clinical Trials protocol registration with identifier 2310-117-126 on April 9, 2024., (© 2024. The Author(s).)

Preeclampsia is a hypertensive disorder of pregnancy that can lead to stillbirth and preterm birth if not treated promptly. Currently, the diagnosis of preeclampsia relies on clinical symptoms such as hypertension and proteinuria, along with invasive blood tests. Here, we investigate the role of soluble proteins and exosomes in noninvasive diagnosing preeclampsia non-invasively using maternal urine and urine-derived exosomes. We quantified the levels of particles and the presence of TSG101 and CD63 in urine and urinary exosomes via the biologically intact exosome separation technology (BEST) platform. Then, we obtained higher levels of soluble proteins such as fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) from urine as it was than urinary exosomes. Compared to commercial blood tests, the sensitivity of the sFlt-1/PlGF ratio was found to be 4.0 times higher in urine tests and 1.5 times higher in tests utilizing urine-derived exosomes. Our findings offer promising possibilities for the early and non-invasive identification of high-risk individuals at risk of preeclampsia, allowing for comprehensive preventive management., (© 2024. The Author(s).)

We report the mechanical performance and chemical recycling advantages of implementing alkyl-substituted poly(ε-caprolactones) (PCLs) as soft segments in thermoplastic poly(urethane-urea) (TPUU) materials. Poly(4-methylcaprolactone) (P4MCL) and poly(4-propylcaprolactone) (P4PrCL) were prepared, reacted with isophorone diisocyanate, and chain-extended with water to form TPUUs. The resulting materials' tensile properties were similar or superior to a commercially available polyester thermoplastic poly(urethane) and had superior elastic recovery properties compared to a PCL analogue due to the noncrystalline nature of P4MCL and P4PrCL. Additionally, monomers were recovered from the TPUU materials in high yields via ring-closing depolymerization using a reactive distillation approach at an elevated temperature and a reduced pressure (240-260 °C, 25-140 mTorr) with zinc chloride (ZnCl 2 ) as the catalyst. The thermodynamics of polymerization were estimated using Van't Hoff analyses for 4MCL and 4PrCL; these results indicated that the propyl group in 4PrCL results in a lower practical ceiling temperature ( T c ) for P4PrCL.

Study Design: Retrospective cohort., Objective: To evaluate factors associated with the long-term durability of cost-effectiveness (CE) in ASD patients., Background: A substantial increase in costs associated with the surgical treatment for adult spinal deformity (ASD) has given precedence to scrutinize the value and utility it provides., Methods: We included 327 operative ASD patients with five-year (5 yr) follow-up. Published methods were used to determine costs based on CMS.gov definitions and were based on the average DRG reimbursement rates. The utility was calculated using quality-adjusted life-years (QALY) utilizing the Oswestry Disability Index (ODI) converted to Short-Form Six-Dimension (SF-6D), with a 3% discount applied for its decline in life expectancy. The CE threshold of $150,000 was used for primary analysis., Results: Major and minor complication rates were 11% and 47%, respectively, with 26% undergoing reoperation by five years. The mean cost associated with surgery was $91,095±$47,003, with a utility gain of 0.091±0.086 at one years, QALY gained at 2 years of 0.171±0.183, and at five years of 0.42±0.43. The cost per QALY at two years was $414,885, which decreased to $142,058 at five years.With the threshold of $150,000 for CE, 19% met CE at two years and 56% at five years. In those in which revision was avoided, 87% met cumulative CE till life expectancy. Controlling analysis depicted higher baseline CCI and pelvic tilt (PT) to be the strongest predictors for not maintaining durable CE to five years [CCI OR: 1.821 (1.159-2.862), P =0.009] [PT OR: 1.079 (1.007-1.155), P =0.030]., Conclusions: Most patients achieved cost-effectiveness after four years postoperatively, with 56% meeting at five years postoperatively. When revision was avoided, 87% of patients met cumulative cost-effectiveness till life expectancy. Mechanical complications were predictive of failure to achieve cost-effectiveness at two years, while comorbidity burden and medical complications were at five years., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To develop an accurate mortality risk predictive model among patients with lung cancer., Methods: The development cohort included 96,255 patients with lung cancer aged ≥19 years, who underwent a Korean National Health Insurance Service health check-up from 2005 to 2015. The validation cohort consisted of 18,432 patients (≥19 years) with lung cancer from another region. The outcome was all-cause mortality between January 1, 2005, and December 31, 2020., Results: Approximately 60.5% of the development cohort died within a median follow-up period of 2.32 (0.72-5.00) years. Risk score was highest in participants aged ≥65 years, followed by those who underwent treatment, had a history of emergency room visits, and were current smokers. Participants treated by surgery had the lowest risk score, followed by combined surgery and chemotherapy, combined surgery and radiation therapy, women, and regular exercisers. The C statistic in the development and validation cohorts was 0.78 (95% confidence interval, 0.77-0.78) and 0.81 (95% confidence interval, 0.78-0.84), respectively., Conclusion: Advanced age, lung cancer stage, and treatment type were strong risk factors of mortality in lung cancer patients, while being a woman and exercise were preventive factors. These will aid in the prediction of mortality and management of lung cancer patients., 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 Huh, Kim, Kim and Son.)

Study Design: Secondary data analysis of the NIH sponsored study on Adult Symptomatic Lumbar Scoliosis (ASLS)., Objectives: The purpose of this study is to perform a cost-effectiveness analysis comparing operative versus non-operative care for ASLS eight years after enrollment., Summary of Background Data: A prior cost-effectiveness analysis of the current cohort comparing operative to non-operative care at five years after enrollment showed and ICER of $44,033 in the As-Treated analysis and a ICER of $27,480 in the Intent-to-treat analysis., Methods: Data was collected every three months for the first two years, then every six months for the remainder of the study. Data included use of non-operative modalities, medications and employment status. Costs for index and revision surgeries and non-operative modalities were determined using Medicare Allowable rates. Medication costs were determined using the RedBook and indirect costs were calculated based on reported employment status and income. Quality Adjusted Life Years (QALY) was determined using the SF6D., Results: There were 101 cases in the Operative (Op) and 103 in the Non-operative (Non-Op) group with complete eight year data. Thirty-eight patients (37%) in the Non-Op group had surgery from 3 to 72 months after enrollment. An As-Treated analysis including only cases who never had surgery (N=65) or cases with complete eight-year post-operative data (N=101) showed that operative treatment was favored with an ICER of $20,569 per QALY gained which is within Willingness-to-Pay (WTP) thresholds. An Intent-to-Treat analysis demonstrated greater QALY gains and lower cost in the Op group (ICER = $-13,911). However, Intent-to-Treat analysis is influenced by Non-Op patients who crossed over to operative treatment at variable times during follow-up., Conclusion: Operative treatment was more cost-effective than non-operative treatment for ASLS at eight-year follow-up. The ICER continued to improve as compared to the five-year values ($20,569 vs. $44,033)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The evaluation of bridge safety is closely related to structural stiffness, with dynamic characteristics and displacement being key indicators. Displacement is a significant factor as it is a physical phenomenon that bridge users can directly perceive. However, accurately measuring displacement generally necessitates the installation of displacement meters within the bridge substructure and conducting load tests that require traffic closure, which can be cumbersome. This paper proposes a novel method that uses wireless accelerometers to measure ambient vibration data from bridges, extracts mode shapes and natural frequencies through the time domain decomposition (TDD) technique, and estimates static displacement under specific loads using the flexibility matrix. A field test on a 442.0 m cable-stayed bridge was conducted to verify the proposed method. The estimated displacement was compared with the actual displacement measured by a laser displacement sensor, resulting in an error rate of 3.58%. Additionally, an analysis of the accuracy of displacement estimation based on the number of measurement points indicated that securing at least seven measurement points keeps the error rate within 5%. This study could be effective for evaluating the safety of bridges in environments where load testing is difficult or for bridges that require periodic dynamic characteristics and displacement analysis due to repetitive vibrations, and it is expected to be applicable to various types of bridge structures.

We aimed to assess the association of tramadol use with the risk of dementia. This population-based retrospective cohort study using the Korean National Health Insurance Service database included a total of 1,865,827 older adult patients aged 60 years or older with common musculoskeletal pain between January 1, 2003, and December 31, 2007. Individuals who were newly dispensed tramadol (N = 41,963) were identified and propensity score-matched with those who were not (N = 41,963). Over a maximum of 14-year follow-up, the incidence rates (events per 1000 person-years) of all-cause dementia were 6.1 for nonusers, 6.2 for those with cumulative tramadol use of 1-14 days, 7.7 for those with 15-90 days of use, and 8.0 for those with > 90 days of use. Longer cumulative duration of tramadol use was associated with an increased risk of all-cause dementia compared with nonuse (1 to 14 days: aHR 1.06, 95% CI 0.96-1.17; 15 to 90 days: aHR 1.14, 95% CI 1.10-1.35; and more than 90 days: aHR 1.18, 95% CI 1.00-1.39; test for trend: P < 0.001). The results showed a similar pattern for Alzheimer's disease and were robust across subgroup and sensitivity analyses, but not for vascular dementia. This study found that exposure to tramadol was associated with an increased risk of dementia. Taking this potential risk into consideration, clinicians should carefully weigh potential benefits and risks when prescribing tramadol to older adults with musculoskeletal pain., (© 2024. The Author(s).)

Purpose: Previous studies have reported that migraine headaches may be one of the possible risk factors for open-angle glaucoma (OAG); however, a consensus has not been reached regarding the association between OAG and migraine. In this study, we examined the risk of developing OAG in migraine patients using a 12-year nationwide cohort., Materials and Methods: In this study, data from the Korean National Health Insurance Service-National Sample Cohort database from 2002 to 2015 was used to perform a retrospective cohort study. The study included 1,103,302 subjects, out of which 41,148 were diagnosed with migraine during 2003-2008 and were categorized as the migraine group, while 205,741 patients were selected as controls through propensity score matching at a 1:5 ratio. Subjects with migraine or OAG was ascertained based on KCD code. Multivariate Cox regression analysis was used to evaluate the hazard rate of OAG onset in the migraine group, and subgroup analysis was performed to identify any differences based on sex and age., Results: Multivariate Cox regression analysis showed that the incidence of OAG was significantly greater among patients with migraine than among patients in the comparison group (hazard ratio [HR] 1.238; 95% confidence interval [CI] 1.160-1.132, P < 0.001). Moreover, the risk of developing OAG compared to subjects without migraine did not differ according to the presence of an aura (migraine with aura: HR 1.235; 95% CI 1.137-1.342, P < 0.001; migraine without aura: HR 1.248; 95% CI 1.143-1.363, P < 0.001). In subgroup analyses, the patients with migraine under 40-year-old were found to have a greater hazard rate (HR 1.576, 95% CI: 1.268-1.957) of developing OAG in contrast with patients with migraine and over 40-year-old (HR 1.167, 95%CI: 1.089-1.250) when compared to the corresponding non-migraine patients., Conclusion: This study showed that migraine is a significant risk factor for OAG onset in Korean population, and the presence of aura did not affect the hazard rate of OAG development., Prcis: Patients with migraine showed significantly increased risk of developing OAG in Korean population, without significant differences according to the presence of aura. Our results suggest presence of migraine as a possible risk factor for OAG., Competing Interests: Conflicts of Interest: All authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The exorbitant presence of heavy metals has emerged as one of the most serious ecological issues facing the world. The treatment processes currently employed are not effective for removing all of the contaminants completely. Therefore, it is necessary for better operational technology to be developed. Here, we fabricated effective and inexpensive kaolin-based ceramic membranes with the addition of dolomite using a simple dry compaction method. Moreover, we applied the obtained adsorptive membranes to the removal of lead, copper, zinc, and cadmium from aqueous solutions. The membranes prepared with dolomite addition (sintered at different temperatures) exhibited a high water flux between 246.78 and 1738.56 L/h·m 2 at an extremely low operating pressure (0.03 MPa). Furthermore, the optimal membrane showed high removal efficiencies of 99.12, 99.82, 85.62, and 65.94% for Pb(II), Cu(II), Zn(II), and Cd(II), respectively. The utilization of dolomite enhanced the removal efficiency of the adsorptive membranes by around 32-54% in a multielement system. This work reveals that enhanced adsorptive membranes with high fluxes and strong removal abilities have great potential as a synergized system with practical applications in the removal of heavy-metal contaminants from wastewater in the future., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Kidney transplantation significantly improves the quality of life for those with end-stage renal failure, yet allograft rejection resulting from immune cell interactions remains a persistent challenge. Although T cell-directed immunosuppressive drugs effectively contain graft rejection in most patients, a notable proportion still experiences acute T cell-mediated rejection (TCMR). Despite an emphasis on suppressing T cell-mediated immune responses, successful control over TCMR is not always achieved, suggesting the potential involvement of factors beyond T cells., Methods: Biopsy samples from suspicious (borderline) for acute TCMR (borderline TCMR) and non-TCMR patients were obtained 9 d postsurgery, and spatial transcriptomics profiling was conducted using the GeoMx Digital Spatial Profiler platform. Regions of interest in the glomerulus and interstitium were selected on the basis of immunohistochemistry staining anti-CD3 to identify areas with T-lymphocyte infiltration. Differential gene expression analysis was performed using unpaired t tests., Results: Unbiased clustering of transcriptional profiles across all regions of interest showed distinct transcriptional profiles between glomeruli and interstitium in non-TCMR samples, whereas borderline TCMR samples displayed no distinct transcriptional profiles between these regions. Contrary to the prevailing T cell-centric view, we observed pathways and genes associated with innate immunity-related inflammatory conditions expressed in glomerular regions of borderline TCMR biopsies. Immunofluorescence staining for CD68 confirmed the presence of macrophages in the glomeruli of the post-TCMR sample in a validation cohort, indicating macrophage involvement in the glomerular response after TCMR., Conclusions: Activation of the innate immune response in borderline TCMR appears to impact not only the interstitium but also the glomerulus. Glomerulus-specific immune signatures suggest the role of the innate immune system in rejection. This nuanced understanding proposes the necessity for tailored therapeutic interventions targeting both innate and adaptive immune pathways to enhance transplant outcomes., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Chronic mental stress accelerates atherosclerosis through complicated neuroimmune pathways, needing for advanced imaging techniques to delineate underlying cellular mechanisms. While histopathology, ex vivo imaging, and snapshots of in vivo images offer promising evidence, they lack the ability to capture real-time visualization of blood cell dynamics within pulsatile arteries in longitudinal studies., Methods: An electrically tunable lens was implemented in intravital optical microscopy, synchronizing the focal plane with heartbeats to follow artery movements. ApoE -/- mice underwent 2 weeks of restraint stress before baseline imaging followed by 2 weeks of stress exposure in the longitudinal imaging, while nonstressed mice remained undisturbed. The progression of vascular inflammation was assessed in the carotid arteries through intravital imaging and histological analyses., Results: A 4-fold reduction of motion artifact, assessed by interframe SD, and an effective temporal resolution of 25.2 Hz were achieved in beating murine carotid arteries. Longitudinal intravital imaging showed chronic stress led to a 6.09-fold ( P =0.017) increase in myeloid cell infiltration compared with nonstressed mice. After 3 weeks, we observed that chronic stress intensified vascular inflammation, increasing adhered myeloid cells by 2.45-fold ( P =0.031), while no significant changes were noted in nonstressed mice. Microcirculation imaging revealed increased circulating, rolling, and adhered cells in stressed mice's venules. Histological analysis of the carotid arteries confirmed the in vivo findings that stress augmented plaque area, myeloid cell and macrophage accumulation, and necrotic core volume while reducing fibrous cap thickness indicating accelerated plaque formation. We visualized the 3-dimensional structure of the carotid artery and 4-dimensional dynamics of the venules in the cremaster muscle., Conclusions: Dynamic focusing motion compensation intravital microscopy enabled subcellular resolution in vivo imaging of blood cell dynamics in beating arteries under chronic restraint stress in real time. This novel technique emphasizes the importance of advanced in vivo imaging for understanding cardiovascular disease.

Benign enlargement of the parotid gland hypertrophy results in a bulky lateral facial contour and esthetic appearance. This study aimed to determine the depth from the skin surface to the parotid fascia, which encompasses the parotid gland. The anatomical properties of the parotid glands were evaluated in 40 patients using ultrasonography. An up-to-date understanding of the localization of botulinum neurotoxin (BoNT) injection based on anatomy could lead to better localization of the injection into the parotid gland through morphological measurements using data previously published from cadaveric studies. Measurement using the otobasion inferius as a landmark revealed parotideomasseteric fascia thickness averaging 4-6 mm from the skin surface, with the parotid gland extending approximately 15 mm anteriorly. Analysis showed a 3-7 mm thickness range, indicating an optimal injection depth for safety and efficacy in BoNT procedures. Utilizing the otobasion inferius as an anatomical landmark offers a practical approach for measuring parotideomasseteric fascia thickness, addressing cadaveric study limitations. These guidelines aim to maximize the effects of BoNT therapy, which can be useful in clinical settings, by minimizing its deleterious effects.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which leads to demyelination, axonal loss, and neurodegeneration. Increased oxidative stress and neurodegeneration have been implicated in all stages of MS, making neuroprotective therapeutics a promising strategy for its treatment. We previously have reported vinyl sulfones with antioxidative and anti-inflammatory properties that activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of cytoprotective genes against oxidative stress. In this study, we synthesized vinyl sulfoximine derivatives by modifying the core structure and determined therapeutic potential as Nrf2 activators. Among them, 10v effectively activated Nrf2 (EC 50 = 83.5 nM) and exhibited favorable drug-like properties. 10v successfully induced expression of Nrf2-dependent antioxidant enzymes and suppressed lipopolysaccharide (LPS)-induced inflammatory responses in BV-2 microglial cells. We also confirmed that 10v effectively reversed disease progression and attenuated demyelination in an experimental autoimmune encephalitis (EAE) mouse model of MS.

Background: Recent studies assessing the importance of various preoperative factors on postoperative outcomes following spine surgery have uncovered several important variables that influence subjective and objective outcomes following cervical spine surgery, but it is still unclear which patients are most likely to benefit from operative management., Purpose: The objective of this study was to assess whether preoperative patient-reported outcome measures (PROMs) can be used to predict which patients achieve "normal" levels of pain and function after surgery., Study Design: This was a prospective cohort study., Patient Sample: This study included all adult patients undergoing cervical spine surgery by 1 of 7 senior spine surgeons at our institution between 2016 and 2018. Of the 164 patients who were eligible for 6-month follow-up at the time that study data were collected, 139 had available follow-up data and were included in our analysis., Outcomes Measures: Patients completed the Neck Disability Index (NDI) as well as the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) and Pain Interference computer adaptive tests preoperatively and at 6 months postoperatively., Methods: Patients who achieved postoperative patient-acceptable symptom state (PASS) for NDI (≤17) and the normative mean (50) for PROMIS were identified. The relationship between preoperative PROMs and the probability of achieving PASS and the normative mean was assessed., Results: One hundred thirty-nine patients met inclusion criteria with diagnoses of myelopathy ( n = 36), radiculopathy ( n = 48), and myeloradiculopathy ( n = 49). For NDI, a 1-point worsening in the preoperative score resulted in an OR of achieving PASS of 0.96 ( P < 0.001) in the overall population. This association held true for patients with radiculopathy (OR 0.96; P = 0.022) but not myelopathy (OR 0.98; P = 0.35). For PROMIS PF, a 1-point improvement in the preoperative score resulted in an OR of achieving the normative mean of 1.10 ( P < 0.001). This association held true for patients with radiculopathy (OR 1.14; P = 0.033) but did not reach statistical significance for patients with myelopathy (OR 1.03; P = 0.515)., Conclusions: Preoperative PROMs can predict postoperative benefit for patients undergoing cervical spine surgery, with worse baseline function associated with a lower likelihood of attaining PASS for NDI and the normative mean for PROMIS PF, especially for patients with radiculopathy., Clinical Relevance: Baseline symptoms and function, including myelopathy or radiculopathy-dominant symptoms and preoperative PROMs, may predict postoperative outcomes., Competing Interests: Declaration of Conflicting Interests: The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2024 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

The detoxification process of transforming arsenite (As(III)) to arsenate (As(V)) through bacterial oxidation presents a potent approach for bioremediation of arsenic-polluted soils in abandoned mines. In this study, twelve indigenous arsenic-oxidizing bacteria (AOB) were isolated from arsenic-contaminated soils. Among these, Paenibacillus xylanexedens EBC-SK As2 (MF928871) and Ochrobactrum anthropi EBC-SK As11 (MF928880) were identified as the most effective arsenic-oxidizing isolates. Evaluations for bacterial arsenic resistance demonstrated that P. xylanexedens EBC-SK As2 (MF928871) could resist As(III) up to 40 mM, while O. anthropi EBC-SK As11 (MF928880) could resist As(III) up to 25 mM. From these bacterial strains, genotypes of arsenic resistance system (ars) were detected, encompassing ars leader genes (arsR and arsD), membrane genes (arsB and arsJ), and aox genes known to be crucial for arsenic detoxification. These ars genotypes in the isolated AOBs might play an instrumental role in arsenic-contaminated soils with potential to reduce arsenic contamination., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background : This study aimed to assess the reproducibility and reliability of Chat-Based GPT (ChatGPT)'s responses to 19 statements regarding the management of hip fractures in older adults as adopted by the American Academy of Orthopaedic Surgeons' (AAOS) evidence-based clinical practice guidelines. Methods : Nineteen statements were obtained from the 2021 AAOS evidence-based clinical practice guidelines. After generating questions based on these 19 statements, we set a prompt for both the GPT-4o and GPT-4 models. We repeated this process three times at 24 h intervals for both models, producing outputs A, B, and C. ChatGPT's performance, the intra-ChatGPT reliability, and the accuracy rates were assessed to evaluate the reproducibility and reliability of the hip fracture-related guidelines. Regarding the strengths of the recommendation compared with the 2021 AAOS guidelines, we observed accuracy of 0.684, 0.579, and 0.632 for outputs A, B, and C, respectively. Results : The precision was 0.740, 0.737, and 0.718 in outputs A, B, and C, respectively. For the reliability of the strengths of the recommendation, the Fleiss kappa was 0.409, indicating a moderate level of agreement. No statistical differences in the strengths of the recommendation were observed in outputs A, B, and C between the GPT-4o and GPT-4 versions. Conclusion : ChatGPT may be useful in providing guidelines for hip fractures but performs poorly in terms of accuracy and precision. However, hallucinations remain an unresolved limitation associated with using ChatGPT to search for hip fracture guidelines. The effective utilization of ChatGPT as a patient education tool for the management of hip fractures should be addressed in the future.

Background/Objective: Limited data exist regarding the long-term clinical outcomes and related factors after adult spinal deformity (ASD) surgery. This study aims to characterize patients who experienced poor clinical outcomes during long-term follow-up after ASD surgery. Methods: Patients who underwent ASD surgery with ≥5-vertebra fusion including the sacrum and ≥5-year follow-up were included. They were divided into two groups according to the Oswestry Disability Index (ODI) at the last follow-up: group P (poor outcome, ODI > 40) and group NP (non-poor outcome, ODI ≤ 40). Clinical variables, including patient factors, surgical factors, radiographic parameters, and mechanical complications (proximal junctional kyphosis [PJK] and rod fracture), were compared between the groups. Results: A total of 105 patients were evaluated, with a mean follow-up of 100.6 months. The mean age was 66.3 years, and 94 patients (89.5%) were women. There were 52 patients in group P and 53 patients in group NP. Univariate analysis showed that low T-score, postoperative correction relative to age-adjusted pelvic incidence-lumbar lordosis, T1 pelvic angle (TPA) at last follow-up, and PJK development were significant factors for poor clinical outcomes. Multivariate analysis identified PJK as the single independent risk factor (odds ratio [OR] = 3.957 for PJK development relative to no PJK, OR = 21.141 for revision surgery for PJK relative to no PJK). Conclusions: PJK development was the single independent factor affecting poor clinical outcomes in long-term follow-up. Therefore, PJK prevention appears crucial for achieving long-term success after ASD surgery.

Introduction: Recent epidemiological and aetiological data on adolescent idiopathic scoliosis (AIS) among military draftees are scarce in nationwide and population-based databases. This retrospective, nationwide and population-based study aims to assess national and regional trends in the prevalence of AIS among military draftees in South Korea from 2013 to 2022., Methods: A total of 3 166 669 Korean males were screened at regional Military Manpower Administration (MMA) offices between 2013 and 2022. Based on routine chest radiographs, individuals with Cobb's angle of ≥10° were screened and diagnosed with AIS using whole spine radiographs after excluding surgically treated AIS patients. Data from the MMA were retrospectively collected and the annual prevalence of the total and neglected AIS cases, along with 95% CIs, was assessed. Spearman correlation analysis was performed to evaluate the correlation between the prevalence of AIS and several aetiological factors., Results: The prevalence rate of AIS in the male adolescent population gradually increased from 2013 (0.44%, 95% CI 0.42% to 0.46%) to 2022 (1.33%, 95% CI 1.28% to 1.37%). The AIS rate increased overall in both capital/metropolitan areas and provinces but showed a fluctuating pattern in the capital/metropolitan area. The prevalence rate of neglected AIS showed a very slight increased trend during the same period (mean 0.05%, 95% CI 0.04% to 0.06%) and exhibited a similar pattern in both capital/metropolitan areas and provinces. Using correlation analysis with aetiological factors, the prevalence rate of AIS correlated with overweight or obesity rate (r=0.90, p<0.001) and growth hormone use (r=0.83, p<0.001)., Conclusions: The prevalence of AIS in the male population has increased, with a similar trend observed between capital/metropolitan areas and provinces in South Korea. Our correlation results support both the multifactorial cascade concepts for altered body composition effects and biomechanical progression based on the Hueter-Volkmann effect as the pathomechanisms of AIS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Radiation therapy (RT) is a typical treatment for head and neck cancers. However, prolonged irradiation of the esophagus can cause esophageal fibrosis due to increased reactive oxygen species and proinflammatory cytokines. The objective of this study was to determine whether myogenic gene-transfected mesenchymal stem cells (MSCs) could ameliorate damage to esophageal muscles in a mouse model of radiation-induced esophageal fibrosis. We cloned esophageal myogenic genes (MyoD, MyoG, and Myf6) using plasmid DNA. Afterward, myogenic genes were transfected into Human Mesenchymal Stem Cells (hMSCs) using electroporation. Gene transfer efficiency, stemness, and myogenic gene profile were examined using flow cytometry, quantitative polymerase chain reaction, and RNA sequencing. In vivo efficacy of gene-transfected hMSCs was demonstrated through histological and gene expression analyses using a radiation-induced esophageal fibrosis animal model. We have confirmed that the gene transfer efficiency was high (∼75%). Pluripotency levels in gene-transfected MSCs were significantly decreased compared with those in the control (vector). Particularly, myogenesis-related genes such as OAS2, OAS3, and HSPA1A were overexpressed in the group transfected with three genes. At 4 weeks after injection, it was found that thickness collagen layer and esophageal muscle in MSCs transfected with all three genes were significantly reduced compared to those in the saline group. Muscularis mucosa was observed prominently in the gene combination group. Moreover, expression levels of myogenin, Myf6, calponin, and SM22α known to be specific markers of esophageal muscles tended to increase in the group transfected with three genes. Therefore, using gene-transfected MSCs has the potential as a promising therapy against radiation-induced esophageal fibrosis.

Background: In this narrative review, we assess published data on subclinical hyperthyroidism (SCHyper) and its association with cardiovascular disease (CVD) in the general population. Summary: We present data on the risk of SCHyper in relation to CVD outcomes, including atrial fibrillation (AF), heart failure, stroke, coronary heart disease (CHD), major adverse cardiac events (MACE), CVD mortality, and all-cause mortality. Evidence indicates that SCHyper is associated with an elevated risk of AF, heart failure, MACE, CVD mortality, and all-cause mortality. SCHyper appears to have little association with stroke risk and has shown conflicting results regarding CHD risk. Regarding the degree of serum TSH suppression, evidence shows a higher risk of CVD in SCHyper individuals with suppressed TSH (<0.1 mIU/L) compared with those with low TSH (0.1-0.4 mIU/L). Despite evidence that older individuals are inherently at a higher risk for CVD, no studies have yet demonstrated an age-related increase in the relative risk of CVD in SCHyper. Conclusion: The studies indicate that SCHyper is associated with an increased risk of AF, heart failure, MACE, CVD mortality, and all-cause mortality. Considering the importance of the degree of serum TSH suppression and age as risk factors for CVD, treatment decisions should be individualized based on their specific risk factors.

Introduction: Carotid artery stenting is an alternative interventional treatment to carotid endarterectomy. However, preprocedural considerations and anatomical risk factor analyses for carotid artery stenting are currently insufficient. Therefore, we investigated the high-risk anatomical appearance of carotid artery stenting from the neurointerventionist perspective to predict periprocedural complications., Materials and Methods: We retrospectively reviewed patients with carotid stenosis who underwent carotid artery stenting at a comprehensive stroke center between January 2012 and December 2021. We compared the demographic characteristics, medical history, and anatomical appearance of the stenotic segment in patients with and without complications., Results: We analyzed a total of 148 patients (64 women [43.2%]; median age, 73.0 [interquartile range, 65.5-79.0]). Complications occurred in 39 of the 148 patients, primarily minor and transient. Of baseline or procedural characteristics, a high initial National Institutes of Health Stroke Scale score ( p = 0.04), symptomatic stenosis ( p = 0.01), and curve-centered plaque of the proximal ICA ( p  = 0.01) were significantly associated with carotid artery stenting complications in unadjusted analysis. Curve-centered plaque remained an independent risk factor for carotid artery stenting complications after adjustment (odds ratio 2.23[1.02-4.88], p = 0.04)., Conclusion: High-risk vascular anatomical features, such as curve-centered plaque, are associated with a high frequency of periprocedural complications of carotid artery stenting. Tailored patient selection for carotid stenosis is crucial to prevent complications. Patients with curve-centered plaque should consider alternative treatment options such as carotid endarterectomy to achieve optimal clinical results., 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 Kang, Rhim, Kim, Choi and Kim.)

Background: CSF1R-related leukoencephalopathy is a type of autosomal dominant leukodystrophy caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene. Subcortical ischemic vascular dementia (SIVaD), which is caused by cerebral small vessel disease, is similar to CSF1R-related leukoencephalopathy in that it mainly affects subcortical white matter. In this study, we compared the patterns of white matter hyperintensity (WMH) and cortical thickness in CSF1R-related leukoencephalopathy with those in SIVaD., Methods: Fourteen patients with CSF1R-related leukoencephalopathy and 129 with SIVaD were retrospectively recruited from three tertiary medical centers. We extracted and visualized WMH data using voxel-based morphometry to compare the WMH distributions between the two groups. Cortical thickness was measured using a surface-based method. Statistical maps of differences in cortical thickness between the two groups were generated using a surface model, with age, sex, education, and intracranial volume as covariates., Results: Predominant distribution of WMH in the CSF1R-related leukoencephalopathy group was in the bilateral frontal and parietal areas, whereas the SIVaD group showed diffuse WMH involvement in the bilateral frontal, parietal, and temporal areas. Compared with the SIVaD group, the CSF1R-related leukoencephalopathy group showed more severe corpus callosum atrophy (CCA) and widespread cortical thinning., Conclusions: To our knowledge, this is the first study using the automated MR measurement to capture WMH, cortical thinning, and CCA with signal changes in CSF1R-related leukoencephalopathy. It provides new evidence regarding differences in the patterns of WMH distribution and cortical thinning between CSF1R-related leukoencephalopathy and SIVaD., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Polynucleotide (PN) filler often causes pain and can lead to delivery inaccuracies when applied via intradermal injection using a traditional needle., Aims: To evaluate the efficacy of treatment and the pain during the procedure using conventional needle injection versus a needle-free jet system for intradermal PN filler application., Methods: In this split-face clinical trial, 10 Korean subjects were enrolled. Each subject received an intradermal injection of PN filler on one side of the face and a needle-free jet injection using CureJet on the other side. Assessments included global and 3D skin imaging at each visit. Pain intensity was evaluated using visual analogue scale (VAS) scores during the injection. Additionally, patient satisfaction and adverse events were documented., Results: Findings revealed that Global Aesthetic Improvement Scale scores and patient satisfaction were significantly higher with the CureJet compared to the needle injection method. VAS scores were notably lower on the CureJet side. Improvements in both pore and wrinkle indices were observed from baseline, with a more pronounced improvement rate on the CureJet side compared to the needle injection side., Conclusions: Needle-free injection of PN for aging skin was found to be effective in enhancing pore and wrinkle improvement, while reducing associated discomfort., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: This study aimed to investigate the association of the grit scale, a personality trait characterized by perseverance and passion, with both the presence and the severity of insomnia in the Korean adult population., Methods: A nationwide population-based cross-sectional survey was conducted through face-to-face interviews using structured questionnaires between September and December 2018 in Korea. Grit was assessed by using the 8-item Short Grit Scale. Participants were categorized into insomnia and non-insomnia groups based on a threshold of 10 on the Insomnia Severity Index (ISI). The association between girt and insomnia was analyzed using multiple linear regression and multivariable logistic regression, controlling for sociodemographic factors, lifestyles, and comorbidities., Results: A total of 2453 participants (49.9 % male; aged 19-92 years) were enrolled in the study. Individual grit scores ranged from 1.75 to 5.00 points (mean [SD], 3.27 [0.42]), and insomnia was present in 16.5 % of the population. The insomnia group exhibited lower grit score compared to the non-insomnia group (3.11 [0.40] vs. 3.30 [0.42], p < 0.001, Cohen's d = 0.46). Grit was negatively associated with ISI scores (β = -0.15, 95 % CI = -0.19, -0.11, p < 0.001) and with having insomnia (OR 0.40, 95 % CI = 0.30, 0.55, p < 0.001), after controlling for covariates., Conclusions: Individuals with higher grit were less likely to have insomnia. Clinicians should consider personality traits, such as grit, in the evaluation and the management of insomnia., 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.)