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Objectives: Fatigue is a common clinical manifestation in patients with primary Sjögren's syndrome (pSS). The aims of this study were to investigate the association between fatigue severity and other clinical characteristics in pSS patients and to determine the factors contributing to fatigue.Method: We analysed 257 participants from the Korean Initiative of pSS (KISS), a prospective pSS cohort. Fatigue was assessed according to the fatigue domain of the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-Reported Index (ESSPRI). Health-related quality of life (HRQoL) was evaluated using the EuroQol-5 dimensions (EQ-5D) questionnaire. Multiple linear regression analysis was used to estimate the effect of each variable on fatigue severity.Results: The median total ESSPRI score was 5 [interquartile range (IQR) 4-6]. Thirty-four per cent of patients reported a fatigue score > 5. Younger and premenopausal patients presented with more fatigue (p = 0.013 and p < 0.001, respectively). Higher Xerostomia Inventory (XI) scale (p < 0.001) and Ocular Surface Dryness Index (OSDI) (p < 0.001) scores were observed in patients with a fatigue score > 5. Pain, xerostomia, and age were determined to be significantly associated with fatigue severity after adjusting for depression/anxiety, OSDI score, and the presence of fibromyalgia using a multivariate general linear model. The ESSPRI fatigue score was correlated with the EQ-5D by time trade-off (TTO) values and visual analogue scale (VAS) scores.Conclusions: In Korean patients with pSS, younger age, xerostomia, and pain were correlated significantly with fatigue, and fatigue was associated with HRQoL. [ABSTRACT FROM AUTHOR]

Object: This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1β (IL-1β)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in human rheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway.Methods: IL-1β-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining.Results: IL-1β appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1β. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang-1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38 MAPK, but not that of ERK.Conclusion: This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1β-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

Objective: Angiogenesis may be involved in the pathogenesis of Behçet's disease (BD). Some angiogenic factors such as vascular endothelial growth factor, monocyte chemoattractant protein-1, and endothelin-1 are significantly associated with BD. Here, we investigate whether Angiopoietin contributes to disease activity and clinical manifestations of BD.Methods: We recruited 59 consecutive patients with BD and sex- and age-matched 65 healthy control subjects for this study. We reviewed data regarding clinical features, erythrocyte sediment rate (ESR), and C-reactive protein (CRP) at the time of enrollment. Serum angiopoietin-1 and angiopoietin-2 were estimated by enzyme-linked immunosorbent assay. Statistical analyses were performed using the Student t test and Pearson's correlation coefficient analysis.Results: Levels of serum angiopoietin-1 are significantly increased in BD patients compared to controls (284.5+/-101.2 ng/ml of BD vs 237.1+/-76.4 ng/ml of controls, p=0.012). However, serum angiopoietin-2 levels are similar in both groups (974.2+/-679.3 pg/ml of BD vs 858.3+/-535.3 pg/ml of controls, p=0.562). Serum angiopoietin-1 expression is significantly elevated in patients with skin lesions (p=0.025) and positively correlated with disease duration (r=0.320, p=0.015). ESR levels are closely associated with serum angiopoietin-2 (r=0.306, p=0.018).Conclusion: Angiopoiein-1 expression is enhanced in BD patients compared to controls. This preliminary study identifies that angiopoietin-1 may play an important role in the pathogenesis of BD. [ABSTRACT FROM AUTHOR]

PURPOSE: This article examines functional impairment across global and specific dimensions among youth 3 years after their detention. METHODS: Functional impairment was assessed using the Child and Adolescent Functional Assessment Scale (CAFAS) in a large, stratified, random sample of formerly detained youth (N = 1653). RESULTS: More than one-fifth of the individuals in the sample were scored as having marked impairment that required, at minimum, 'multiple sources of care' (CAFAS Total Score of > or =100); 7.0% required 'intensive intervention' (CAFAS Total Score > or =140). Most of the sample had impairment; only 7.5% had 'no noteworthy impairment' (CAFAS Total Score < or =10). Significantly more males were impaired than females. Among males living in the community at follow-up, African Americans and Hispanics were more likely to be impaired than non-Hispanic whites. In comparison to males living in the community, males who were incarcerated at follow-up were significantly more likely to have impaired thinking and impaired functioning at home (if incarcerated, 'home' is the correctional facility) but less likely to have substance use problems. CONCLUSIONS: Three years after detention, most youth struggle in one or more life domains; more than one in five have marked impairment in functioning. These findings underscore the ongoing costs, to both youth and society, of our failure to provide effective rehabilitation to youth after detention. [ABSTRACT FROM AUTHOR]

Objective: Accelerated atherosclerosis in inflammatory rheumatic diseases such as ankylosing spondylitis (AS) stands out among the leading causes of morbidity and mortality. We assessed the correlation between subclinical carotid atherosclerosis and its related clinical parameters in AS patients.Methods: Twenty-eight patients (23 males, 5 females) with AS and 27 sex- and age-matched controls were consecutively recruited to this study. We estimated the carotid intima-media thickness (IMT) and parameters related to arterial elastic properties, including the distensibility coefficient (DC), stiffness index (beta), and incremental elastic modulus (E(inc)) using high-resolution ultrasonography. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay (ELISA).Results: Carotid IMT values and arterial elastic parameters in AS patients showed no statistical significance compared to those of controls (0.57+/-0.07 vs 0.55+/-0.05, p=0.387 for IMT, 28.45+/-9.23 vs 31.93+/-9.52, p=0.175 for DC, 2.32+/-0.18 vs 2.29+/-0.15, p=0.559 for stiffness index (beta), and 0.14+/-0.05 vs 0.12+/-0.03, p=0.116 for E(inc)). The serum level of IL-6 in AS patients was significantly different compared with controls (p=0.001), but not in serum levels of TNF-alpha and MCP-1 (p=0.162, p=0.087, respectively). Carotid IMT and all arterial elastic parameters calculated in this study were not found to be associated with serum levels of TNF-alpha, IL-6, and MCP-1.Conclusion: This cross-sectional study showed that carotid IMT and parameters related with arterial elastic properties in young AS patients without clinically evident cardiovascular risk factors were not different from those of sex- and age-matched healthy controls. Serum levels of TNF-alpha, IL-6, and MCP-1 did not reflect the degree of carotid subclinical atherosclerosis. However, these findings should be confirmed further in a larger population. [ABSTRACT FROM AUTHOR]

BACKGROUND/AIMS: This study aimed to develop a brief, reliable and valid test for cognitive function of severely demented patients. METHODS: We constructed the Severe Cognitive Impairment Rating Scale, which consisted of 11 items covering memory, language, visuospatial function, frontal function and orientation, and investigated its reliability and validity on 267 subjects [normal: 65, very mild Alzheimer's disease (AD): 42, mild AD: 58, moderate AD: 36, severe AD: 44, profound AD: 22]. RESULTS: The internal consistency obtained by Cronbach's coefficient alpha was 0.93. The interrater reliability and test-retest reliability in the moderately to severely impaired subjects with an MMSE score of

Objective: This review examined U.S. empirical studies published since 1990 of the perpetration of violence and of violent victimization among persons with severe mental illness and their relative importance as public health concerns.Methods: MEDLINE, PsycINFO, and Web of Science were searched for published empirical investigations of recent prevalence or incidence of perpetration or victimization among persons with severe mental illness. Studies of special populations were included if separate rates were reported for persons with and without severe mental illness.Results: The search yielded 31 studies of violence perpetration and ten studies of violent victimization. Few examined perpetration and victimization in the same sample. Prevalence rates varied by sample type and time frame (recall period). Half of the studies of perpetration examined inpatients; of these, about half sampled only committed inpatients, whose rates of perpetration (17%-50%) were higher than those of other samples. Among outpatients, 2% to 13% had perpetrated violence in the past six months to three years, compared with 20% to 34% who had been violently victimized. Studies combining outpatients and inpatients reported that 12% to 22% had perpetrated violence in the past six to 18 months, compared with 35% who had been a victim in the past year.Conclusions: Perpetration of violence and violent victimization are more common among persons with severe mental illness than in the general population. Victimization is a greater public health concern than perpetration. Ironically, the discipline's focus on perpetration among inpatients may contribute to negative stereotypes. [ABSTRACT FROM AUTHOR]

BACKGROUND/AIMS: To compare the prevalence and characteristics of depression in vascular dementia (VaD) and Alzheimer's disease (AD) after adjusting for dementia severity and gender. METHODS: One hundred and eight pairs of VaD and AD patients matched for dementia severity and gender were assessed. RESULTS: Major depressive disorder (MDD) was more prevalent in the VaD group than in the AD group (20.4% in VaD, 10.2% in AD, p = 0.04, Cochran-Mantel-Haenszel, CMH, test) regardless of the dementia severity and gender. The odds ratio for developing MDD in the VaD group versus the AD group was estimated to be 2.20 (95% confidence interval = 1.02-4.74). Neurovegetative symptoms such as 'felt tired and weak all the time' (30.6% in VaD, 13.9% in AD, p = 0.003, CMH test) and 'changed weight without trying' (16.7% in VaD, 6.5% in AD, p = 0.02, CMH test) were more prevalent in the VaD group than in the AD group. CONCLUSION: Depression in VaD was quantitatively and qualitatively different from that in AD regardless of the severity of dementia and gender; depression was more prevalent, severer and more retarded and vegetative in VaD than in AD. [ABSTRACT FROM AUTHOR]

Objective: Resistance to apoptosis of fibroblast-like synoviocytes (FLS) is considered as a major characteristic in RA. This study was designed to identify whether melittin has a pro-apoptotic effect in IL-6/sIL6R-stimulated human FLS by investigating the expression of mitochondrial apoptosis-related genes, nuclear factor-κB (NF-κB), and signal transducer and activators of transcription (STAT) activation.Methods: Cell viability was determined using a MTT assay after melittin treatment. Expressions of STAT3 and mitochondrial apoptosis-related genes induced by the IL-6/sIL-6R complex were determined by real time-polymerase chain reaction and western blotting. The expression of NF-κB p65 following IL-6 stimulation was determined by western blot analysis. The effects of melittin on the expression of apoptosis-related genes and the transcription factors NF-κB p65 and STAT3 were assessed in FLS. Apoptosis of FLS was determined by TUNEL-labeling to detect DNA strand breaks and DNA fragmentation assays. Caspase-3 activity was determined by a colorimetric assay.Results: IL-6/sIL-6R induced the activation of the transcription factors, STAT3, NF-κB p65 (nucleus), and Bcl-2. Melittin increased the expression of pro-apoptosis-related molecules, namely caspase-3, caspase-9, Apaf-1, and cytosolic cytochrome c, in a dose-dependent manner after treatment with IL-6/sIL-6R. Melittin inhibited STAT3 activation, translocation of NF-κB p65 into the nucleus, and expression of anti-apoptotic genes such as Bcl-2 and mitochondrial cytochrome c.Conclusions: The pro-apoptotic effects of melittin likely result from inhibition of the activation of the transcription factors, STAT3 and NF-κB p65, and regulation of mitochondrial apoptosis-related genes. Melittin is thus a promising therapeutic option for RA as it induces apoptosis in apoptosis-resistant synoviocytes. [ABSTRACT FROM AUTHOR]

Background/objectives: The prognostic significance of circumferential resection margin (CRM) or circumferential surface (CS) in pancreatic head cancer is controversial. We investigated the survival outcomes according to CRM or CS involvement in pancreatoduodenectomy specimens of pancreatic ductal adenocarcinoma (PDAC)., Methods: A total of 102 pancreatoduodenectomy specimens after upfront surgery for PDAC between 2014 and 2018 were prospectively collected. The superior mesenteric vein/portal vein or superior mesenteric artery margins were classified as CRM, and the anterior or posterior surfaces as CS. Survival outcomes and recurrence were compared according to the CRM/CS status, which was categorized into R1 0mm , R1 1mm , and R0 (≥1 mm) by the 0 and 1 mm rules., Results: For CRM, R1 0mm had significantly lower overall survival (OS) (P < 0.001) and disease-free survival (P < 0.001) rates than R1 1mm and R0, with no difference between R1 1mm and R0. For CS, R0 had a significantly higher OS rate (P < 0.001) than R1 0mm and R1 1mm , with no difference between R1 0mm and R1 1mm . In multivariable analysis, R1 0mm CRM was an independent risk factor for OS (hazard ratio 2.410, P = 0.003) and DFS (hazard ratio 5.019, P < 0.001). When CRM/CS were analyzed separately, only the R1 0mm superior mesenteric artery margin was significantly associated with local recurrence (P = 0.012)., Conclusions: The results suggest that CRM involvement defined by the 0 mm rule is more appropriate than the 1 mm rule for predicting survival outcomes, but CS involvement defined by the 0 or 1 mm rules is not prognostically significant., 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 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective : Chondrocyte apoptosis has been considered a crucial mechanism that is responsible for cartilage destruction in osteoarthritis (OA). The mechanism of interleukin-37 (IL-37) on chondrocyte apoptosis has not been clearly determined in the pathogenesis of OA. Here, we explored the role of IL-37 in the regulation of cellular apoptosis in rat chondrocytes stimulated by IL-1β. Methods : Rat chondrocytes were used in in vitro study, and were stimulated with IL-1β (10 ng/mL) and/or recombinant IL-37 (rIL-37; 100 ng/mL) after cytotoxicity assessments using these cytokines were conducted. After rIL-37 treatment of chondrocytes stimulated with IL-1β, the cell proliferation assay, apoptosis assays, including expression of mitochondrial apoptosis-related markers, flow cytometry analysis of annexin V-FITC/propidium iodide (PI), cell cycle analysis, and Hoechst 33342 staining, and reactive oxygen species (ROS) measurement were used. Results : IL-1β induced expression of inflammatory cytokines and triggered degradation of the extracellular matrix of rat chondrocytes, but this effect was significantly attenuated by rIL-37 treatment. Enhanced ROS generation following IL-1β stimulation was reduced in a dose-dependent manner after stimulation with rIL-37. IL-1β induced pro-apoptotic markers and suppressed anti-apoptotic markers in rat chondrocytes. Flow cytometry using annexin V-FITC/PI revealed that IL-1β increased the apoptosis rate of rat chondrocytes, and that this effect was markedly reversed by treatment with rIL-37. Conclusions : IL-37 potently attenuated IL-1β-mediated apoptosis of rat chondrocytes by blocking ROS production. This study suggests that IL-37 can serve as a novel anti-cytokine therapy in OA by blocking chondrocyte apoptosis.

Animal models of early life stress/adversity (ELS) have provided a foundation from which our understanding of the psychoneuroimmunology of childhood trauma has expanded over recent decades. Rodent models are a cornerstone of the ELS literature with many studies utilizing paradigms based on early life separation/deprivation protocols and manipulating the cage environment. However, no animal model is perfect. In particular, the lack of standardization across ELS models has led to inconsistent results and raised questions regarding the translational value of common preclinical models. In this chapter, we present an overview of the history of ELS rodent models and discuss considerations relevant to the ongoing efforts to both improve existing models and generate novel paradigms to meet the evolving needs of molecular- and mechanism-based ELS research., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

There is increased awareness among basic and clinical scientists that psychological and social stress can have detrimental effects on physical, cognitive, and mental health. Data have been published indicating that social, economic, psychological, and physical environmental stress can influence behavior that has biological and physiological consequences-yet there are major gaps in understanding the physiological and cellular processes that drive increased morbidity and mortality. The potential role of mitochondria has been highlighted in psychosomatic medicine, as their functionality in various biological and physiological processes has earned recognition. This review outlines the essential role of mitochondria by considering the numerous intracellular, extracellular, and physiological functions it regulates that position the organelle as a central mediator in responses to psychological stress. We then connect these functions to mitochondrial allostasis and allostatic load for further examination of the limitations of mitochondria to an adaptive psychological stress response where mitochondrial allostatic load may eventually lead to systemic pathophysiology. This review emphasizes how chronic social, economic, and psychological stress can contribute to mitochondrial dysfunction and predispose individuals to poorer health outcomes and death. Mitochondrial capacity, function, and activity may therefore serve as biomarkers for identifying individuals at high risk for developing comorbid conditions related to their psychosocial environment., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the risk of cardiovascular disease (CVD) associated with increasing dose of a non-steroidal anti-inflammatory drug (NSAID) in patients with ankylosing spondylitis (AS)., Methods: Using the Korean National Health Insurance database, patients newly diagnosed with AS without prior CVD between 2010 and 2018 were included in this nationwide cohort study. The primary outcome was CVD, a composite outcome of ischaemic heart disease, stroke or congestive heart failure. Exposure to NSAIDs was evaluated using a time-varying approach. The dose of NSAIDs was considered in each exposure period. Cox proportional hazard regression was used to investigate the risk of CVD associated with NSAID use., Results: Of the 19 775 patients (mean age, 36 years; 75% were male), 19 706 received NSAID treatment. During follow-up period of 98 290 person-years, 1663 cases of CVD occurred including 1157 cases of ischaemic heart disease, 301 cases of stroke and 613 cases of congestive heart failure. Increasing dose of NSAIDs was associated with incident CVD after adjusting for confounders (adjusted HR (aHR) 1.10; 95% CI 1.08 to 1.13). Specifically, increasing dose of NSAIDs was associated with incident ischaemic heart disease (aHR 1.08; 95% CI 1.05 to 1.11), stroke (aHR 1.09; 95% CI 1.04 to 1.15) and congestive heart failure (aHR 1.12; 95% CI 1.08 to 1.16). The association between NSAID dose and higher CVD risk was consistent in different subgroups., Conclusion: In a real-world AS cohort, higher dose of NSAID treatment was associated with a higher risk of CVD, including ischaemic heart disease, stroke and congestive heart failure., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Maternal separation with early weaning (MSEW) is a popular early life stress (ELS) model in rodents, which emulates childhood neglect through scheduled mother-offspring separation. Although variations of ELS models, including maternal separation and MSEW, have been published for the mouse species, the reported results are inconsistent. Corticosterone is considered the main stress hormone involved in regulating stress responses in rodents-yet generating a robust and reproducible corticosterone response in mouse models of ELS has been elusive. Considering the current lack of standardization for MSEW protocols, these inconsistent results may be attributed to variations in model methodologies. Here, we compared the effects of select early wean diet sources-which are the non-milk diets used to complete early weaning in MSEW pups-on the immediate stress phenotype of C57BL/6J mice at postnatal day 21. Non-aversive handling was an integral component of our modified MSEW model. The evaluation of body weight and serum corticosterone revealed the early wean diet to be a key variable in the resulting stress phenotype. Interestingly, select non-milk diets facilitated a stress phenotype in which low body weight was accompanied by significant corticosterone elevation. Our data indicate that dietary considerations are critical in MSEW-based studies and provide insight into improving the reproducibility of key stress-associated outcomes as a function of this widely used ELS paradigm.

Objective : The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods : Serum was collected from patients with gout ( n = 40) and from healthy controls ( n = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results : Serum IL-37 levels in gout patients were significantly higher than in controls ( p < 0.001) and was associated with the serum uric acid level ( r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions : This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.

Background/aim: The RNA binding protein quaking (QKI) is associated with the development and progression of tumor suppressors in various cancers. However, the clinical implications of QKI expression have not yet been fully elucidated. In this study, we aimed to investigate the clinicopathological and prognostic significance of QKI expression in hepatocellular carcinoma (HCC)., Materials and Methods: We performed QKI, Zinc finger E-box-binding homeobox 1 (ZEB1), E-cadherin, and glutathione peroxidase 4 (GPX4) immunohistochemical staining on 166 HCC patient tissue samples. X-tile bioinformatics software was used to set the cut-off value for high QKI expression. Correlations between QKI expression and various clinicopathological parameters were assessed., Results: The best cut-off value for high QKI expression was 12.5. High QKI expression was observed in 28 of 166 patients (16.9%) and was an independent prognostic factor for inferior recurrence-free survival (RFS). In addition, high ZEB1 and GPX4 expression correlated with high QKI expression, but not with the loss of E-cadherin expression., Conclusion: High QKI expression was identified in HCCs and associated with poor RFS. QKI might be a prognostic biomarker of HCCs associated with epithelial-to-mesenchymal transition and a potential candidate therapeutic target., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: The objective of this prospective, observational multicenter study (NCT03264703) was to compare the effectiveness of single conventional disease-modifying anti-rheumatic drug (cDMARD) plus anti-tumor necrosis factor (TNF) therapy versus multiple cDMARD treatments in patients with moderate-to-severe rheumatoid arthritis (RA) following cDMARD failure in the real-world setting in South Korea., Methods: At the treating physicians' discretion, patients received single cDMARD plus anti-TNF therapy or multiple cDMARDs. Changes from baseline in disease activity score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), corticosteroid use, and Korean Health Assessment Questionnaire (KHAQ-20) scores were evaluated at 3, 6, and 12 months., Results: Of 207 enrollees, the final analysis included 45 of 73 cDMARD plus anti-TNF and 91 of 134 multiple-cDMARD recipients. There were no significant between-group differences (BGDs) in ANCOVA-adjusted changes from baseline in DAS28-ESR at 3, 6 (primary endpoint), and 12 months (BGDs -0.18, -0.38, and -0.03, respectively). More cDMARD plus anti-TNF than multiple-cDMARD recipients achieved a >50% reduction from baseline in corticosteroid dosage at 12 months (35.7% vs 14.6%; p=0.007). Changes from baseline in KHAQ-20 scores at 3, 6, and 12 months were significantly better with cDMARD plus anti-TNF therapy than with multiple cDMARDs (BGD -0.18, -0.19, and -0.19 points, respectively; all p ≤ 0.024)., Conclusion: In the real-world setting, relative to multiple cDMARDs, single cDMARD plus anti-TNF therapy significantly improved quality-of-life scores and reduced corticosteroid use, with no significant BGD in disease activity, in RA patients in whom previous cDMARD therapy had failed., Competing Interests: CONFLICT OF INTEREST Y.K.S. has received research funding from Bristol Myers Squibb, Eisai Korea Inc., Pfizer Pharmaceuticals, Yuhan Pharmaceuticals, and JW Pharmaceuticals Corporation; and consulting fees from Immunoforge Co. Ltd. M.W.S., S.H.K., D.W.K., J.Y.C., S.I.L., J.W.H., H.S.L., and S.H.L. have received research funding from Eisai Korea Inc. for this study. J.R.K. is an employee of Eisai Korea Inc., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

Objective: To examine the risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large real-world ankylosing spondylitis (AS) cohort., Methods: This nationwide population-based cohort study used data from the Korean National Health Insurance Database. Patients aged ≥18 years old who were newly diagnosed with AS without prior cardiovascular disease between January 2010 and December 2018 were included in this study. Controls without AS were randomly selected by age, sex, and index year. The primary outcome was cardiovascular disease, a composite outcome of ischemic heart disease, stroke, or congestive heart failure. Long-term use of NSAIDs was defined as use of NSAIDs for >365 cumulative defined daily doses. The association between long-term use of NSAIDs and incident cardiovascular disease was examined in both AS and non-AS populations., Results: Among 19 775 patients with AS and 59 325 matched controls without AS, there were 1,663 and 4,308 incident cases of cardiovascular disease, showing an incidence of 16.9 and 13.8 per 1,000 person-years, respectively. Long-term use of NSAIDs was associated with increased risk of cardiovascular disease in non-AS controls (adjusted hazard ratio [aHR], 1.64; 95% CI, 1.48-1.82). In contrast, long-term use of NSAIDs did not increase the risk of cardiovascular disease in AS patients (aHR, 1.06; 95% CI, 0.94-1.20; adjusted for age, sex, socioeconomic status, body mass index, smoking status, hypertension, diabetes, hyperlipidemia, and tumor necrosis factor inhibitor use)., Conclusion: Prolonged NSAID treatment in AS patients may not be as harmful as in the general population regarding cardiovascular risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Although eye movements such as saccades are related to internal cognitive processes and are independent of visual processing, few studies have investigated whether non-visual cognitive tasks simultaneously affect horizontal and vertical saccades in younger and older adults., Methods: We recruited 28 younger adults aged 20-29 years and 26 older adults aged >60 years through advertisements in community settings. All participants were free of major psychiatric, neurological, or ocular diseases. All participants performed the mental arithmetic task (MAT) and verbal fluency task (VFT). The primary measures were saccade parameters, including frequency, mean amplitude, and mean velocity., Results: During MAT and VFT, the frequencies of horizontal and vertical saccades increased ( p  = 0.0005 for horizontal saccade in MAT; p  < 0.0001 for horizontal saccade in VFT; p  = 0.012 for vertical saccade in MAT; p  = 0.001 for vertical saccade in VFT), but were comparable between MAT and VFT. The old group showed a slower vertical saccade than the young group during the tasks ( p  = 0.011 in the MAT phase; p  = 0.006 in the VFT phase). The amplitude of the horizontal saccade decreased in both groups during MAT compared to the resting period ( p  = 0.013), but did not change significantly during VFT., Discussion: Saccade parameters can change during non-visual cognitive tasks with differences between age groups and saccade directions. This study significantly contributes to our understanding of the distinct dynamics of horizontal and vertical saccades across various age group in cognitive aging, despite its restricted focus on specific saccade parameters and cognitive tasks, and inclusion solely of cognitively normal individuals. This study highlights the importance of saccade analysis in elucidating age-related cognitive changes. In conclusion, saccades should be examined in future studies as a potential non-invasive biomarker for early detection of cognitive decline and neurodegenerative diseases., 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 Yang, Choe, Noh, Kim, Han and Kim.)

A hallmark of effective cancer treatment is the prevention of tumor reoccurrence and metastasis to distal organs, which are responsible for most cancer deaths. However, primary tumor resection is expected to be curative as most solid tumors have been shown both experimentally and clinically to accelerate metastasis to distal organs including the lungs. In this study, we evaluated the efficacy of our engineered nasal nano-vaccine (CpG-NP-Tag) in reducing accelerated lung metastasis resulting from primary tumor resection. Cytosine-phosphate-guanine oligonucleotide [CpG ODN]-conjugated nanoparticle [NP] encapsulating tumor antigen [Tag] (CpG-NP-Tag) was manufactured and tested in vivo using a syngeneic mouse mammary tumor model following intranasal delivery. We found that our nasal nano-vaccine (CpG-NP-Tag), compared to control NPs administered after primary mammary tumor resection, significantly reduced lung metastasis in female BALB/c mice subjected to surgery (surgery mice). An evaluation of vaccine efficacy in both surgery and non-surgery mice revealed that primary tumor resection reduces CD11b + monocyte-derived suppressor-like cell accumulation in the lungs, allowing increased infiltration of vaccine-elicited T cells (IFN-γ CD8 + T cells) in the lungs of surgery mice compared to non-surgery mice. These findings suggest that the combination of the target delivery of a nasal vaccine in conjunction with the standard surgery of primary tumors is a plausible adjunctive treatment against the establishment of lung metastasis.

The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that GLUT1 expression increased after M1 polarization stimuli and found that GLUT3 expression increased after M2 stimulation in macrophages. Conditional deletion of Glut3 (LysM-Cre Glut3fl/fl) impaired M2 polarization of bone marrow-derived macrophages. Alternatively activated macrophages from the skin of patients with atopic dermatitis showed increased GLUT3 expression, and a calcipotriol-induced model of atopic dermatitis was rescued in LysM-Cre Glut3fl/fl mice. M2-like macrophages expressed GLUT3 in human wound tissues as assessed by transcriptomics and costaining, and GLUT3 expression was significantly decreased in nonhealing, compared with healing, diabetic foot ulcers. In an excisional wound healing model, LysM-Cre Glut3fl/fl mice showed significantly impaired M2 macrophage polarization and delayed wound healing. GLUT3 promoted IL-4/STAT6 signaling, independently of its glucose transport activity. Unlike plasma membrane-localized GLUT1, GLUT3 was localized primarily to endosomes and was required for the efficient endocytosis of IL-4Rα subunits. GLUT3 interacted directly with GTP-bound RAS in vitro and in vivo through its intracytoplasmic loop domain, and this interaction was required for efficient STAT6 activation and M2 polarization. PAK activation and macropinocytosis were also impaired without GLUT3, suggesting broader roles for GLUT3 in the regulation of endocytosis. Thus, GLUT3 is required for efficient alternative macrophage polarization and function, through a glucose transport-independent, RAS-mediated role in the regulation of endocytosis and IL-4/STAT6 activation.

Objectives: To explore the course of lung function and RA disease activity and predictive factors for deteriorating lung function in patients with RA-interstitial lung disease (ILD)., Methods: The Korean Rheumatoid Arthritis-Interstitial Lung Disease cohort is a multicentre, prospective observational cohort. Patients with RA-ILD were enrolled and followed up annually for 3 years for RA disease activity and ILD status assessment. Group-based modelling was used to cluster a similar predicted percentage of forced vital capacity (FVC%) patterns into trajectories., Results: This study included 140 patients who underwent at least two pulmonary function tests. Four distinctive trajectories for predicted FVC% were 'improving' [n = 11 (7.9%)], 'stable' [n = 68 (38.4%)], 'slowly declining' [n = 54 (48.6%)] and 'rapidly declining' [n = 7 (5.0%)]. Most (77.7%) patients maintained or improved to low RA disease activity. The lung function trajectory was not comparable to the RA disease activity trajectory. Age ≥70 years [relative risk (RR) 10.8 (95% CI 1.30, 89.71)] and early RA diagnosed within the preceding 2 years [RR 10.1 (95% CI 1.22, 84.2)] were associated with increased risk for rapidly declining predicted FVC%. The risk for deterioration or mortality increased in patients with a simultaneous diagnosis of RA and ILD within 24 weeks [RR 9.18 (95% CI 2.05, 41.0)] and the extent of lung involvement [RR 3.28 (95% CI 1.12, 9.60)]., Conclusion: Most patients with RA-ILD experienced stable or slowly declining lung function. In 5% of patients, predicted FVC% deteriorated rapidly, especially in older adults with early RA. The lung function trajectory was not comparable to the RA disease activity trajectory., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: During the coronavirus disease 2019 (COVID-19) period, children spent more time at home, which is where most foreign body ingestions (FBIs) in children occur. We compared the rate of FBI in children in the Daegu-Kyungpook Province during COVID-19 to the rate in the 2 years before the COVID-19 period., Methods: The period from January to December in the year 2020 was defined as the COVID-19 period, and the corresponding time period in 2018 and 2019 was defined as the pre-COVID-19 period. Medical records were analyzed retrospectively for pediatric patients aged 0-15 years who visited outpatient and emergency rooms at seven tertiary referral hospitals in Daegu-Kyungpook Province., Results: The annual occurrence rate of FBIs in patients visiting seven tertiary referral hospitals was not different during COVID-19 compared to that in the pre-COVID-19 period and the median age of these patients during the COVID-19 and pre-COVID-19 periods was similar. However, occurrence rates increased in the groups aged 0-3 and 4-6 years but decreased in the group aged 7-15 years during the COVID-19 period. The proportion of male patients as well as inpatients increased significantly during the COVID-19 period (both P=0.01). The proportion of foreign bodies located in the post-pyloric region increased during the COVID-19 period (P=0.02). The most common symptom, foreign body sensation in the neck, was similar in both groups. There was no significant difference in the foreign body removal method between the two groups. The occurrence rates of swallowing of toys, coins, magnets, button batteries, and superabsorbent polymers non-significantly increased; and the food ingestion rate decreased, while the non-food ingestion rate increased in all age groups during the COVID-19 period., Conclusions: The FBI rate in children did not differ during the COVID-19 period compared to that in the pre-COVID-19 period. The occurrence of FBI in boys, the number of foreign bodies located in the post-pyloric region, and the number of hospitalizations due to FBI increased during the COVID-19 period., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-21/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

The CaV2 voltage-gated calcium channel is the major conduit of calcium ions necessary for neurotransmitter release at presynaptic active zones (AZs). The CaV2 channel is a multimeric complex that consists of a pore-forming α 1 subunit and two auxiliary β and α 2 δ subunits. Although auxiliary subunits are critical for channel function, whether they are required for α 1 trafficking is unresolved. Using endogenously fluorescent protein-tagged CaV2 channel subunits in Caenorhabditis elegans , we show that UNC-2/α 1 localizes to AZs even in the absence of CCB-1/β or UNC-36/α 2 δ, albeit at low levels. When UNC-2 is manipulated to be trapped in the endoplasmic reticulum (ER), CCB-1 and UNC-36 fail to colocalize with UNC-2 in the ER, indicating that they do not coassemble with UNC-2 in the ER. Moreover, blocking ER-associated degradation does not further increase presynaptic UNC-2 channels in ccb-1 or unc-36 mutants, indicating that UNC-2 levels are not regulated in the ER. An unc-2 mutant lacking C-terminal AZ protein interaction sites with intact auxiliary subunit binding sites displays persistent presynaptic UNC-2 localization and a prominent increase of UNC-2 channels in nonsynaptic axonal regions, underscoring a protective role of auxiliary subunits against UNC-2 degradation. In the absence of UNC-2, presynaptic CCB-1 and UNC-36 are profoundly diminished to barely detectable levels, indicating that UNC-2 is required for the presynaptic localization of CCB-1 and UNC-36. Together, our findings demonstrate that although the pore-forming subunit does not require auxiliary subunits for its trafficking and transport to AZs, it recruits auxiliary subunits to stabilize and expand calcium channel signalosomes. SIGNIFICANCE STATEMENT Synaptic transmission in the neuron hinges on the coupling of synaptic vesicle exocytosis with calcium influx. This calcium influx is mediated by CaV2 voltage-gated calcium channels. These channels consist of one pore-forming α 1 subunit and two auxiliary β and α 2 δ subunits. The auxiliary subunits enhance channel function and regulate the overall level of channels at presynaptic terminals. However, it is not settled how these auxiliary subunits regulate the overall channel level. Our study in C. elegans finds that although the auxiliary subunits do not coassemble with α 1 and aid trafficking, they are recruited to α 1 and stabilize the channel complex at presynaptic terminals. Our study suggests that drugs that target the auxiliary subunits can directly destabilize and have an impact on CaV2 channels., (Copyright © 2023 the authors.)

The excessive growth of aquatic macrophytes in a water system has a negative effect on the lake ecosystem. This article presents data on water parameters and sedimentation rates from sites that include different aquatic macrophytes at Tasik Berombak, a freshwater lake on Peninsular Malaysia's eastern coast. Areas with  Hanguana   malayana and  Pandanus helicopus  were selected for sampling, while an area without aquatic macrophytes served as the control. At the lake's surface and bottom, temperature, conductivity, total dissolved solids, dissolved oxygen (D.O.), and pH were measured in situ . The surface water was sampled for chemical analysis in the laboratory (chlorophyll-a, total suspended solids, total carbon, total organic carbon, inorganic carbon, total dissolved nitrogen, total dissolved phosphorus). Settling sediment was collected using cylinder traps deployed under the macrophytes at the bottom of the lake. The presented data includes the water parameters according to plant-base area, depth differentiation (top versus bottom), and variable correlation analysis. Understanding the impact of excessive aquatic plants on the lake ecosystem in a tropical environment requires information on water parameters and sedimentation rates from the aquatic plants. Therefore, these data can be used to monitor the impact of land use change on the aquatic plant community and, ultimately, the lake ecosystem., Competing 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., (© 2023 The Author(s).)

Objective: To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD)., Methods: The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure., Results: Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression., Conclusion: None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: CT-P10 was the first licensed rituximab biosimilar. This Korean post-marketing surveillance study evaluated CT-P10 safety and effectiveness in approved indications., Research Design and Methods: This prospective, open-label, observational, phase 4 study collected routine clinical practice data across 27 centers in the Republic of Korea. Patients received their first CT-P10 treatment, per prescribing information, for non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) during the surveillance period (16 November 2016-15 November 2020). Safety (including adverse events [AEs] and adverse drug reactions [ADRs]) and disease-specific clinical response (by best overall response [NHL/CLL], Disease Activity Score in 28-joints [RA], or Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [GPA/MPA]) were assessed for ≤1 year (NHL/CLL) or ≤24 weeks (RA/GPA/MPA)., Results: The safety population comprised 677 patients (604 NHL, 16 CLL, 42 RA, 7 GPA, 8 MPA). AEs/ADRs were reported for 68.4%/27.7% (NHL/CLL), 31.0%/14.3% (RA), and 86.7%/13.3% (GPA/MPA) of patients. Serious AEs and unexpected ADRs did not raise new safety signals. Pneumonia was the most frequent serious ADR overall. Positive effectiveness outcomes were observed., Conclusions: Findings were consistent with the known CT-P10/reference rituximab safety profile, with high effectiveness observed in NHL/CLL and RA.

Introduction: As of May 2023, 19 and 18 biosimilars have been approved for the treatment of rheumatoid arthritis (RA) by the European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) respectively., Area Covered: Pharmacokinetic results of phase 1 studies of approved biosimilars were reviewed by systematic literature search. The impact of immunogenicity on the pharmacokinetic data and clinical response was assessed, and the potential benefit of monitoring serum concentrations of biologic drugs is discussed. The advantage of subcutaneous CT-P13 (an infliximab biosimilar) in clinical practice is reviewed., Expert Opinion: Biosimilars are approved based on the totality of evidence including comparable physiochemical properties, PK / PD profiles, and clinical efficacy and safety to the originator. To utilize biosimilars more effectively, physicians should be aware of the utility of combination DMARD therapy to reduce immunogenicity and maintain efficacy and PK profile. PK monitoring, however, is not currently recommended in clinical practice. CT-P13 subcutaneous (SC) is the first SC infliximab used for treatment of RA patients. Based on data from clinical studies and the real world, SC-infliximab is an attractive therapeutic option compared to IV formulations of infliximab based on its efficacy, pharmacokinetics, patient-reported outcomes, and safety profile.

Little is known about differences in the therapeutic efficacy of denosumab in subjects with and without rheumatoid arthritis (RA). This study compares the changes in bone mineral density (BMD) between RA patients and controls without RA who had been treated with denosumab for 2 years for postmenopausal osteoporosis. A total of 82 RA patients and 64 controls were enrolled, who were refractory to selective estrogen receptor modulators (SERMs) or bisphosphonates and completed the treatment of denosumab 60 mg for 2 years. The efficacy of denosumab in RA patients and controls was assessed using areal BMD (aBMD) and T-score of the lumbar spine, femur neck, and total hip. A general linear model with repeated measures analysis of variance was used to determine differences in aBMD and T-score between 2 study groups. No significant differences in percent changes in aBMD and T-scores by denosumab treatment for 2 years at the lumbar spine, femur neck, and total hip were evident between RA patients and controls (P > .05 of all), except T-score of the total hip (P = .034). Denosumab treatment equally increased aBMD at the lumbar spine and T-scores at the lumbar spine and total hip between RA patients and controls without statistical differences, but RA patients showed less improvement in aBMD at the femur neck (ptime*group = 0.032) and T-scores at the femur neck and total hip than controls (ptime*group = 0.004 of both). Changes in aBMD and T-scores after denosumab treatment in RA patients were not affected by previous use of bisphosphonates or SERMs. Differences of T-score at the femur neck among previous bisphosphonate users and aBMD and T-score at the femur neck and T-scores at the total hip were evident. This study revealed that 2 years of denosumab treatment in female RA patients achieved comparable efficacy on BMD to controls at the lumbar spine, but showed somewhat insufficient improvement at the femur neck and total hip., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Facilitative carbohydrate transporters (GLUTs, SLC2 gene family) are transmembrane proteins transporting hexoses and other sugars based on cellular metabolic demands. While a direct link between GLUTs and metabolic disorders has framed them as important biological and medicinal targets, targeting disease-relevant GLUTs remains challenging. In this study, we aimed to identify substrate-GLUT interactions that would discriminate between major fructose transporters. We examined the uptake distribution for conformational and configurational isomers of fructose using the corresponding conformationally locked fluorescently labeled mimetics as probes for assessing GLUT preferences in real time. Through comparative analysis of the uptake of the probes in the yeast-based single GLUT expression systems and the multi-GLUT mammalian cell environment, we established the ability of fructose transporters to discriminate between fructose conformers and epimers. We demonstrated that recreating the conformational and configurational mixture of fructose with molecular probes allows for the specific probe distribution, with fructofuranose mimetic being taken up preferentially through GLUT5 and β-d-fructopyranose mimetic passing through GLUT2. The uptake of α-d-fructopyranose mimetic was found to be independent of GLUT5 or GLUT2. The results of this study provide a new approach to analyzing GLUT5 and GLUT2 activity in live cells, and the findings can be used as a proof-of-concept for multi-GLUT activity screening in live cells. The research also provides new knowledge on substrate-GLUT interactions and new tools for monitoring alterations in GLUT activities.

Evaluation of hepatic fibrosis is essential to prevent liver-related morbidity and mortality. Although various types of ultrasound shear wave elastography (SWE) have been used and validated, there are limited studies on the relatively newer technique, two-dimensional SWE (2D-SWE). Therefore, this study aimed to compare the diagnostic performances of 2D-SWE and point SWE (p-SWE) for evaluating liver fibrosis using histology as the reference standard. To measure liver stiffness (LS) values, 87 patients underwent 2D-SWE and p-SWE using the same machine. Technical failures and unreliable measurements were also evaluated. The diagnostic performances of 2D-SWE and p-SWE were compared using area under the receiver operating characteristic (AUROC) curve analysis. No technical failures were observed in either method; however, unreliable measurements were less frequent in 2D-SWE (1/87 [1.1%]) than in p-SWE (8/87 [9.2%]) ( p < 0.001). The AUROC of the LS values of 2D-SWE were significantly higher than those of p-SWE for diagnosing significant fibrosis (0.965 vs. 0.872, p = 0.022) and cirrhosis (0.994 vs. 0.886, p = 0.042). In conclusion, 2D-SWE is more reliable and accurate than p-SWE for diagnosing hepatic fibrosis.

Background: As significant advances in the field of treatment for rheumatoid arthritis (RA), there is a great need to identify the healthcare outcomes such as treatment satisfaction and health-related quality of life (HRQoL) of patients with various treatment options. This study aims to identify the difference in the treatment satisfaction and HRQoL of patients with RA using different treatment options, by comparing the treatment satisfaction and HRQoL in patients with RA treated with tofacitinib and adalimumab in real-world settings in Korea, using propensity score methods., Methods: In this non-interventional, multicenter, cross-sectional study (NCT03703817), a total of 410 patients with RA diagnosis were recruited in 21 university-based hospitals throughout Korea. The treatment satisfaction and HRQoL were assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM) and EQ-5D questionnaires self-reported by the patients. This study compared outcomes between two drug groups in unweighted, greedy matching, and stabilized inverse probability of treatment weight (IPTW) samples using propensity score., Results: In all three samples, tofacitinib group showed higher convenience domain of TSQM than that in the adalimumab group, but not effectiveness, side effects, and global satisfaction domains. Multivariable analysis using the covariates of demographic and clinical characteristics of the participants also showed consistent results in TSQM. No statistical difference in EQ-5D-based HRQoL was identified between two drug groups in all three samples., Conclusions: This study identified that tofacitinib shows higher treatment satisfaction in the convenience domain of TSQM rather than adalimumab, suggesting that various factors such as drug formulation, route or frequency of administration, and storage can have an impact on the treatment satisfaction, especially the convenience domain. These findings may be useful to patients and physicians when determining treatment options., Trial Registration: ClinicalTrials.gov, NCT03703817., (© 2023. The Author(s).)

Introduction: SB4 is the first approved biosimilar of etanercept, a biologic tumor necrosis factor inhibitor, to treat various autoimmune diseases including axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). This post-marketing surveillance (PMS) study of SB4 investigated safety and effectiveness in routine clinical practice and is part of the drug approval process in Korea., Methods: This prospective, multi-center, open-label, observational, phase IV PMS study was designed to enroll patients with axSpA, RA, PsA, and PsO in Korea from September 2015 to September 2019. Both etanercept-naïve patients or patients switched from reference etanercept were included. SB4 was administered weekly via subcutaneous injections using pre-filled syringes. Safety was assessed by the incidence of adverse events (AEs), adverse drug reactions (ADRs) and serious adverse events (SAE). Effectiveness was assessed by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA., Results: Among 316 enrolled patients, 314 were included in the safety analysis (176 with AS and 138 with RA). The overall incidence of AEs, ADRs and serious AEs were 17.8, 9.9, and 1.3%, respectively. Most AEs were mild (66.7%) or moderate (31.1%) and not related to SB4 (58.9%). Most common AEs were injection site pruritus (1.9%) and injection site rash (1.3%). At week 24, mean disease activity scores significantly decreased compared to baseline in naïve patients with AS and RA (BASDAI 2.7 vs. 6.2, p < 0.0001; DAS28 3.8 vs. 5.7, p < 0.0001) and in switched patients with AS and RA (BASDAI 1.0 vs. 1.3, p = 0.0018; DAS28 2.4 vs. 2.9, p = 0.0893)., Conclusion: This first real-world evidence of SB4 from a phase IV PMS study in Korea shows comparable effectiveness to historical SB4 real-world evidence without any new significant safety signals., (© 2022. The Author(s).)

Peroxisome proliferator-activated receptor γ (PPAR-γ) is thought to negatively regulate NLRP3 inflammasome activation. The aim of this study was to identify the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on monosodium urate (MSU) crystal-induced NLRP3 inflammasome activation through the regulation of PPAR-γ in THP-1 cells. The expression of PPAR-γ, NLRP3, caspase-1, and interleukin-1β (IL-1β) in human monocytic THP-1 cells transfected with PPAR-γ siRNA or not and stimulated with MSU crystals was assessed using quantitative a real time-polymerase chain reaction and Western blotting. The expression of those markers in THP-1 cells pretreated with statins (atorvastatin, simvastatin, and mevastatin) was also evaluated. Intracellular reactive oxygen species (ROS) were measured using H 2 DCF-DA and flow cytometry analyses. THP-1 cells treated with MSU crystals (0.3 mg/mL) inhibited PARR-γ and increased NLRP3, caspase-1, and IL-1β mRNA and protein expression, and all those changes were significantly reversed by treatment with atorvastatin, simvastatin, or mevastatin. PPAR-γ activity revealed that MSU crystals suppressed PPAR-γ activity, which was markedly augmented by atorvastatin, simvastatin, and mevastatin. Transfecting cells with PPAR-γ siRNA attenuated the inhibitory effect of statins on MSU crystal-mediated NLRP3 inflammasome activation. Statins also significantly reduced the intracellular ROS generation caused by stimulation with MSU crystals. The inhibitory effects of atorvastatin and simvastatin on intracellular ROS generation were reduced in THP-1 cells transfected with PPAR-γ siRNA. This study demonstrates that PPAR-γ is responsible for suppressing MSU-mediated NLRP3 inflammasome activation. The inhibitory effect of statins on MSU-induced NLRP3 inflammasome activation depends on PPAR-γ activity and production and the inhibition of ROS generation.

Histone deacetylase (HDAC) has been found to play a crucial role in the regulation of osteoclast differentiation and formation. This study was designed to identify the effect of the HDAC6 inhibitor CKD-WID on the receptor for the activation of nuclear factor-κB ligand (RANKL)-mediated osteoclast formation in the presence of monosodium urate (MSU) in RAW 264.7 murine macrophage cells. The expression of osteoclast-specific target genes, calcineurin, and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) was evaluated in RAW 264.7 murine macrophages treated with MSU, RANKL, or CKD-WID by real-time quantitative polymerase chain reaction and Western blot assay. The effect of CKD-WID on osteoclast formation was measured by tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring formation staining, and assays for bone resorption activity. RANKL in the presence of MSU significantly induced HDAC6 gene and protein expression in RAW 264.7 cells. CKD-WID markedly suppressed the expression of osteoclast-related markers such as c-Fos, TRAP, cathepsin K, and carbonic anhydrase II induced by co-stimulation with RANKL and MSU in RAW 264.7 cells. Transcription factor NFATc1 mRNA expression and nuclear NFATc1 protein expression induced by co-stimulation with RANKL and MSU were significantly inhibited by CKD-WID treatment. CKD-WID also decreased the number of TRAP-positive multinuclear cells and F-actin ring-positive cells and attenuated bone resorption activity. Co-stimulation with RANKL and MSU increased calcineurin gene and protein expression, which was significantly blocked by CKD-WID treatment. The HDAC6 inhibitor CKD-WID suppressed MSU-induced osteoclast formation through blocking the calcineurin-NFAT pathway in RAW 264.7 cells. This suggests that HDAC6 is considered a therapeutic target in uric acid-mediated osteoclastogenesis.

The aim of this study was to evaluate the expression of chemokine receptor CXCR4 and its ligand CXCL12 in patients with gout and uric acid-induced inflammation. A total of 40 patients with intercritical gout and 27 controls were consecutively enrolled. The serum levels of interleukin-1β (IL-1β), IL-18, CXCL12, and CXCR4 were assessed using an enzyme-linked immunosorbent assay. The gene and protein expressions for these target molecules were measured in human U937 cells incubated with monosodium urate (MSU) crystals using a real-time reverse transcription polymerase chain reaction and Western blot analysis. Patients with intercritical gout showed higher serum IL-1β, IL-18, and CXCL12 levels, but not the serum CXCR4 level, than in the controls.The serum CXCR4 level in gout patients was associated with the serum IL-18 level, uric acid level, and uric acid/creatinine ratio ( r = 0.331, p = 0.037; r = 0.346, p = 0.028; and r = 0.361, p = 0.022, respectively). U937 cells treated with MSU crystals significantly induced the CXCL12 and CXCR4 mRNA and protein expression in addition to IL-1β and IL-18. In cells transfected with IL-1β siRNA or IL-18 siRNA, the CXCL12 and CXCR4 expression was downregulated compared with the non-transfected cells in MSU crystal-induced inflammation. In this study, we revealed that CXCL12 and CXCR4 were involved in the pathogenesis of uric acid-induced inflammation and gouty arthritis.

Peptidyl arginine deiminases (PAD) enzymes have been investigated in various cancers. Recently, PAD enzyme, in particular PAD2, has been further implicated in cancers. Although the expression of PAD2 was significantly higher in hepatocellular carcinoma (HCC) tissue, its diagnostic or prognostic role of PAD2 in HCC patients is unknown. This study investigated whether the expression of PAD2 affects recurrence and survival in HCC patients who underwent hepatic resection. One hundred and twenty-two HCC patients after hepatic resection were enrolled. The median follow-up was 41 months (range 1-213 months) in enrolled patients. To investigate an association between PAD2 expression level and the clinical characteristics of enrolled patients, the recurrence of HCC following surgical resection and survival of the patients were examined. Ninety-eight cases (80.3%) of HCC demonstrated a higher expression of PAD2. The expression of PAD2 was correlated with age, hepatitis B virus positivity, hypertension, and higher alpha-fetoprotein level. There was no association between PAD2 expression and sex, diabetes mellitus, Child-Pugh class, major portal vein invasion, HCC size or number. The recurrence rates in patients with lower PAD2 expression were higher than those with higher PAD2 expression. The cumulative survival rates of patients with higher PAD2 expression were better than those of patients with lower PAD2 expression, but it was not statistically significant. In conclusion, PAD2 expression is closely associated with recurrence of HCC patients following surgical resection.

Tryptophan serves as an important redox-active amino acid in mediating electron transfer and mitigating oxidative damage in proteins. We previously showed a difference in electrochemical potentials for two tryptophan residues in azurin with distinct hydrogen-bonding environments. Here, we test whether reducing the side chain bulk at position Phe110 to Leu, Ser, or Ala impacts the electrochemical potentials ( E °) for tryptophan at position 48. X-ray diffraction confirmed the influx of crystallographically resolved water molecules for both the F110A and F110L tyrosine free azurin mutants. The local environments of W48 in all azurin mutants were further evaluated by UV resonance Raman (UVRR) spectroscopy to probe the impact of mutations on hydrogen bonding and polarity. A correlation between the frequency of the ω17 mode─considered a vibrational marker for hydrogen bonding─and E ° is proposed. However, the trend is opposite to the expectation from a previous study on small molecules. Density functional theory calculations suggest that the ω17 mode reflects hydrogen bonding as well as local polarity. Further, the UVRR data reveal different intensity/frequency shifts of the ω9/ω10 vibrational modes that characterize the local H-bonding environments of tryptophan. The cumulative data support that the presence of water increases E ° and reveal properties of the protein microenvironment surrounding tryptophan.

Background and Objectives: Hematological indices have been known to be available markers used for evaluating disease activity in rheumatoid arthritis (RA). This study serves to verify the association between four different hematological indices and disease activity measures in patients with RA. Materials and Methods: The study included 257 female RA patients and 71 age-matched female controls. Four hematological indices, namely systemic immune-inflammation index (SII), neutrophil-to-hemoglobin and lymphocyte (NHL) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), were evaluated. Composite measures of RA included Disease Activity Score 28 joints (DAS28), the simplified disease activity index (SDAI), and the clinical disease activity index (CDAI). Results: Patients with RA showed statistically higher SII, NHL score, NLR, and PLR compared with controls. SII and NHL score were significantly associated with DAS28 erythrocyte sedimentation rate (DAS28-ESR), DAS28 C-reactive protein (DAS28-CRP), CDAI, and SDAI, whereas NLR was related to DAS28-CRP, CDAI, and SDAI. SII, NHL score, and NLR tended to increase as disease activity based on DAS28-ESR, DAS28-CRP, and CDAI worsened. In the analysis using receiver operating characteristic curve of hematological indices for diagnostic accuracy, the area under the curve was 0.703 (95% confidence interval, CI 0.637−0.769, p < 0.001) for SII and 0.705 (95% CI 0.639−0.770, p < 0.001) for NHL score, which showed acceptable potential for the diagnosis of RA. Four hematological indices showed weak potential for the detection of remission. Conclusions: The present study results showed that SII and NHL scores might be useful markers that adequately reflect disease activity and lead to more accurate diagnosis in RA.