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Abstract Introduction Plexiform neurofibroma of the larynx is a rare disease. In this report, we present a plexiform neurofibroma in the arytenoids and neurofibroma in the parapharynx detected coincidently. Case presentation A 56-year-old Asian woman presented with respiratory distress and episodes of apnea at night. A solitary mass from the left arytenoids was found to be nearly obstructing the airway and causing the sleep apnea. There was also a parapharynx mass protruding into the pharynx. The parapharynx tumor was removed with the lateral incision approach, and the arytenoid tumor was removed with a transoral carbon dioxide laser. The pathologic diagnosis was plexiform neurofibroma for the arytenoid mass and neurofibroma for the parapharynx mass. Conclusion We have reported an extremely rare case of plexiform neurofibroma in the arytenoids and neurofibroma in the parapharynx. This entity may be considered in the differential diagnosis of all laryngeal and parapharynx masses.

Objectives: This study aimed to identify the prevalence, risk factors, and impact of long COVID in a community-based representative sample of patients with COVID-19 aged 19-64 years., Methods: A total of 975 participants completed online or telephone surveys at 1 and 3 months post-diagnosis, covering persistent symptoms, daily activity limitations, vaccination status, and underlying diseases., Results: Long COVID, as defined by the WHO criteria, had a prevalence of 19.7-24.9% in females and 12.7% in males. Logistic regression revealed that the odds of having long COVID symptoms were higher among females compared to males (OR, 2.43; 95% CI, 1.53-3.87), and higher in those aged ≥ 30 years compared to those aged 19-29 years: 30-39 years (OR, 2.91; 95% CI, 1.59-5.33), 40-49 years (OR, 2.72; 95% CI, 1.51-4.89), and 50-64 years (OR, 1.96; 95% CI, 1.10-3.49). Additionally, patients with underlying diseases had higher odds of long COVID symptoms compared to those without underlying diseases (OR, 1.81; 95% CI, 1.24-2.64). Among those with long COVID, 54.2% experienced daily activity limitations, and 40.6% received treatment. Furthermore, lower income groups faced greater daily activity limitations but had similar treatment rates to higher income groups., Conclusions: These findings emphasize the need for interest in and the development of programs to support these low-income populations.

HT074, a multiherbal mixture containing extracts from Inula britannica flowers and Paeonia lactiflora roots, is used in Korean medicine for gastric disorders. This study investigated the protective mechanisms of HT074 against acute reflux esophagitis (RE) in rats. Nitric oxide (NO) production and mRNA expression of antioxidant-related genes ( Nrf2 , HO-1 , SOD , CAT , and GPx2 ) were evaluated in LPS-induced RAW 264.7 cells. Gastroesophageal reflux (GER) was induced in rats, followed by HT074 (100, 300 mg/kg) or ranitidine (50 mg/kg) administration. Esophageal damage and histological changes were assessed. Gastric pH and protein expression levels of Nrf2, HO-1, SOD, CAT, and GPx-1/2 were measured. HT074 pretreatment reduced NO production and increased the expression of HO-1, CAT, and GPx2 in LPS-induced RAW 264.7 cells. In GER-induced rats, HT074 significantly decreased esophageal lesions and increased the expression of HO-1, SOD, GPx-1/2, and Nrf2. HT074 did not affect gastric pH. These findings suggest that HT074 protects against GER-induced esophagitis by inhibiting NO production and enhancing antioxidant activity. Therefore, HT074 could be a promising therapeutic agent for GER disease.

We aimed to examine changes in daily life due to coronavirus disease 2019 (COVID-19) among younger (≤64 years) and older (≥65 years) individuals and to analyze their association with depressive symptoms. Raw data from the 2020 Korean Community Health Survey were used to analyze 228,485 individuals. Changes in daily life due to COVID-19 were measured using a questionnaire that evaluated changes in physical activity, sleep duration, instant food intake, and drinking and smoking status. Depressive symptoms were assessed using the Patient Health Questionnaire 9 scale, and logistic regression analysis was performed to explore the association between the two variables. This study confirmed a significant association between the two variables and found that the intake of instant food showed the largest difference in odds ratios between the younger (OR: 1.851; 95% CI: 1.720-1.992) and older groups (OR: 1.239; 95% CI: 1.060-1.447). A major finding of this study is that the analysis of the association between the two variables revealed a stronger correlation in more variables in the younger population compared to the older population. To address COVID-19-related depression and prepare for potential mental health crises, countries should expand response measures.

Topiramate [2,3:4,5-bis-o-(1-methylethylidene) β-D-fructo-pyranose sulfamate; TPM] is one of the most used new-generation antiepileptic drugs. It has been reported to regulate the differentiation of human bone cells. However, the molecular mechanism of TPM in osteoblast differentiation is not fully elucidated. In the present study, we examined the effect of TPM on osteogenic differentiation of C3H10T1/2, MC3T3-E1, primary mouse calvarial cells, and primary bone marrow stem cells (BMSCs). Primary cells were isolated from mice calvaria and bone marrow respectively. Expression of the osteogenic gene was determined by RT-PCR. The osteogenic protein levels were measured by Western blot analysis. Alkaline phosphatase (ALP) staining experiment was performed to evaluate ALP activity. Alizarin red s (ARS) staining was performed to measure zebrafish caudal fin regeneration. Treatment of TPM up-regulated the osteogenic genes including distal-less homeobox 5 (Dlx5) and runt-related transcription factor 2 (Runx2). In addition, TPM also increased the Dlx5 and Runx2 protein levels, Smad1/5/9 phosphorylation, and alkaline phosphatase (ALP) activity. Furthermore, TPM activated AMPK, and inhibition of AMPK decreased TPM-induced osteogenic differentiation. In the zebrafish model, osteogenic effect of TPM was identified. TPM was increased amputated caudal fin rays of zebrafish. These results demonstrate that TPM enhances osteogenic differentiation via AMPK-mediated Smad1/5/9 phosphorylation., Competing Interests: Declaration of Competing Interest None of the authors have a conflict of interest., (Copyright © 2023. Published by Elsevier GmbH.)

Rationale & Objective: Metformin has been recommended for some patients with advanced chronic kidney disease. However, the value of metformin in kidney transplant recipients (KTRs) with pretransplant diabetes mellitus (DM) or posttransplant DM is uncertain. We investigated the clinical effects of metformin in KTRs., Study Design: Retrospective cohort study., Setting & Participants: A total of 1,995 KTRs with diabetes from 6 tertiary referral centers in the Republic of Korea., Exposure: Metformin usage was defined as the use of metformin for>90 days after kidney transplantation; 1,193 KTRs were metformin users, and 802 KTRs did not use metformin. Changing usage of metformin among those exposed for >90 days was also characterized., Outcome: Primary outcomes were all-cause mortality and death-censored graft failure (DCGF). Secondary outcomes were biopsy-proven acute rejection (BPAR) and lactic acidosis events., Analytical Approach: Survival analyses were conducted using multivariable Cox regression and competing risk analyses using Fine and Gray models. Changes in metformin use over time were modeled using a time-varying covariate. Metformin usage, mean daily dose, and hemoglobin A 1c (HbA 1c ) changes were considered in the landmark analysis to address time-varying confounding., Results: Metformin use was associated with a lower risk of DCGF (adjusted hazard ratio [AHR], 0.47 [95% CI, 0.23-0.96], P=0.038); there was no significant association with all-cause mortality (AHR, 0.94 [95% CI, 0.32-2.76], P=0.915) or BPAR (AHR 0.98 [95% CI, 0.62-1.54], P=0.942). In the subgroup analysis, metformin usage was associated with a reduced risk of all-cause mortality and a lower risk of DCGF for both pretransplantation DM and posttransplant DM groups. Metformin usage was associated with a lower risk of BPAR in the posttransplant DM group, although it was less effective in the pretransplantation DM group. There was no confirmed case of metformin-associated lactic acidosis (MALA) in the present cohort. A higher dose of metformin was correlated with lower risks of DCGF and BPAR., Limitations: Data on newer antidiabetic drugs such as SGLT2 inhibitors are limited, and there is potential limited generalizability to other populations., Conclusions: Metformin usage may benefit KTRs, as evidenced by its association with a reduced risk of DCGF and the absence of MALA events. Randomized controlled trials are needed to validate these observational findings., (Copyright © 2023. Published by Elsevier Inc.)

Minimal change disease (MCD) is characterized by edema and nephrotic range proteinuria (NS). However, the fate of MCD without nephrotic proteinuria requires elucidation. We retrospectively reviewed 79 adults diagnosed with primary MCD at their initial renal biopsy at a tertiary hospital between May 2003 and June 2017. Clinicopathologic features were compared between patients with and without NS. The frequency of flaring to nephrotic proteinuria and renal outcomes were assessed during follow-up. There were 20 and 59 patients in the Non-NS and NS groups, respectively. The Non-NS group had a lower frequency of acute kidney injury (AKI) during the follow-up period [5.0% vs. 59.3%, p <0.001]. The response rate to steroid treatment was 100% in the Non-NS group and 92.3% in the NS group (p = 1.000). Except for one patient, the Non-NS group was treated with steroids when their proteinuria increased to a nephrotic level. There were no differences in the frequency of the first relapse or the number of relapses among patients with initial remission from nephrotic range proteinuria. At the final visit, the complete remission rate was 73.4%. The estimated glomerular filtration rate during follow-up was significantly better in the NS group than the Non-NS group, given the higher rates of AKI at renal biopsy. The rates of renal events, end-stage renal disease, and mortality did not differ between the groups. Adult MCD patients with nephrotic and non-nephrotic range proteinuria showed similar outcomes. Accordingly, this population must be carefully managed, regardless of the amount of proteinuria at renal biopsy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Son 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: Alternative complement pathway dysregulation plays a key role in glomerulonephritis (GN) and is associated with C3 deposition. Herein, we examined pathological and clinical differences between cases of primary GN with C3-dominant (C3D-GN) and nondominant (C3ND-GN) deposition., Methods: We extracted primary GN data from the Korean GlomeruloNEphritis sTudy (KoGNET). C3D-GN was defined as C3 staining two grades greater than C1q, C4, and immunoglobulin via immunofluorescence analysis. To overcome a large difference in the number of patients between the C3D-GN and C3ND-GN groups (31 vs. 9,689), permutation testing was used for analysis., Results: The C3D-GN group exhibited higher serum creatinine (p ≤ 0.001), a greater prevalence of estimated glomerular filtration rate of &lt;60 mL/min/1.72 m2 (p ≤ 0.001), higher (but not significantly so) C-reactive protein level, and lower serum C3 level (p ≤ 0.001). Serum albumin, urine protein/creatinine ratio, number of patients who progressed to end-stage renal disease, and all-cause mortality were comparable between groups. Interstitial fibrosis and mesangial cellularity were greater in the C3D-GN group (p = 0.04 and p = 0.01, respectively) than in the C3ND-GN group. C3 deposition was dominant in the former group (p &lt; 0.001), in parallel with increased subendothelial deposition (p ≤ 0.001)., Conclusion: Greater progression of renal injury and higher mortality occurred in patients with C3D-GN than with C3ND-GN, along with pathologic differences in interstitial and mesangial changes.

Background: Patients undergoing hemodialysis are susceptible to sarcopenia. As intracellular reservoirs of water, skeletal muscles are important contributors to intradialytic hypotension. This study was designed to determine the role of skeletal muscle mass in intradialytic hypotension., Methods: In a cross-sectional study, the body composition of 177 patients was measured immediately after hemodialysis using bioelectrical impedance analysis. The parameters measured were skeletal muscle mass, intracellular and extracellular water contents, total body water, and cell-membrane functionality (in phase angle at 50 kHz). Data from laboratory tests, chest radiography, measurements of handgrip strength and mid-arm circumference, and questionnaires were collected. The main outcome was intradialytic hypotension, defined as more than two episodes of hypotension (systolic blood pressure of &lt;90 mmHg) with intervention over the 3 months following enrollment. Logistic regression models including each parameter related to sarcopenia were compared with a clinical model., Results: Patients with a low ratio of skeletal muscle mass to dry body weight (SMM/WT) had a higher rate of intradialytic hypotension (40.7%). Most low-SMM/WT patients were female, obese, diabetic, and had a lower handgrip strength compared with the other patients. In the high-SMM/WT group, the risk of intradialytic hypotension was lower, with an odds ratio of 0.08 (95% confidence interval [CI], 0.02-0.28) and adjusted odds ratio of 0.06 (95% CI, 0.01-0.29)., Conclusion: Measurement and maintenance of skeletal muscle can help prevent intradialytic hypotension in frail patients undergoing hemodialysis.

Background: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been investigated in kidney transplant recipients (KTRs) with diabetes. We evaluated the impact of SGLT2i in a multicenter cohort of diabetic KTRs., Methods: A total of 2083 KTRs with diabetes were enrolled from 6 transplant centers in Korea. Among them, 226 (10.8%) patients were prescribed SGLT2i for >90 d. The primary outcome was a composite outcome of all-cause mortality, death-censored graft failure (DCGF), and serum creatinine doubling. An acute dip in estimated glomerular filtration rate (eGFR) over 10% was surveyed after SGLT2i use., Results: During the mean follow-up of 62.9 ± 42.2 mo, the SGLT2i group had a lower risk of primary composite outcome than the control group in the multivariate and propensity score-matched models (adjusted hazard ratio, 0.43; 95% confidence interval, 0.24-0.78; P = 0.006 and adjusted hazard ratio, 0.45; 95% confidence interval, 0.24-0.85; P = 0.013, respectively). Multivariate analyses consistently showed a decreased risk of DCGF and serum creatinine doubling in the SGLT2i group. The overall eGFR remained stable without the initial dip after SGLT2i use. A minority (15.6%) of the SGLT2i users showed acute eGFR dip during the first month, but the eGFR recovered thereafter. The risk factors for the eGFR dip were time from transplantation to SGLT2i usage and mean tacrolimus trough level., Conclusions: SGLT2i improved a composite of all-cause mortality, DCGF, or serum creatinine doubling in KTRs. SGLT2i can be used safely and have beneficial effects on preserving graft function in diabetic KTRs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Increased viscosity of concentrated contrast media (CM) in the renal tubules can perturb renal hemodynamics and have a detrimental effect on tubular epithelial cells. However, the effects of viscosity on contrast-induced nephropathy (CIN) remain poorly understood. Conventional in vitro culture studies do not reflect the rheological properties of CM. Therefore, we investigated the effects of CM viscosity on renal tubules using a kidney-on-a-chip and two different types of CM. Renal proximal tubule epithelial cells (RPTEC) were cultured in a three-dimensional microfluidic culture platform under bidirectional fluid shear stress. We treated the RPTEC with two types of CM: low- (LOCM, iopromide) and iso-osmolar contrast media (IOCM, iodixanol). Renal tubular cell injury induced by LOCM and IOCM was examined under different iodine concentrations (50-250 mgI/mL) and shear-stress conditions. LOCM showed a significant dose-dependent cytotoxic effect, which was significantly higher than that of IOCM under static and low-to-moderate shear stress conditions. However, high shear-stress resulted in reduced cell viability in IOCM; no difference between IOCM and LOCM was found under high shear-stress conditions. The cytotoxic effects were pronounced at a mean shear stress of 1 dyn/cm 2 or higher. The high viscosity of IOCM slowed the fluid flow rate and augmented fluid shear-stress. We suggest an alternative in vitro model of CIN using the three-dimensional kidney-on-a-chip. Our results indicate a vital role of viscosity-induced nephrotoxicity under high shear-stress conditions, contrary to the findings of conventional in vitro studies.

Background: Organ crosstalk between the kidney and the heart has been suggested. Acute kidney injury (AKI) and acute heart failure (AHF) are well-known independent risk factors for mortality in hospitalized patients. This study aimed to investigate if these conditions have an additive effect on mortality in hospitalized patients, as this has not been explored in previous studies., Methods: We retrospectively reviewed the records of 101,804 hospitalized patients who visited two tertiary hospitals in the Republic of Korea over a period of 5 years. AKI was diagnosed using serum creatinine-based criteria, and AHF was classified using International Classification of Diseases codes within 2 weeks after admission. Patients were divided into four groups according to the two conditions. The primary outcome was all-cause mortality., Results: AKI occurred in 6.8% of all patients (n = 6,920) and AHF in 1.2% (n = 1,244). Three hundred thirty-one patients (0.3%) developed both conditions while AKI alone was present in 6,589 patients (6.5%) and AHF alone in 913 patients (0.9%). Among the 5,181 patients (5.1%) who died, 20.8% died within 1 month. The hazard ratio for 1-month mortality was 29.23 in patients with both conditions, 15.00 for AKI only, and 3.39 for AHF only. The relative excess risk of interaction was 11.85 (95% confidence interval, 2.43-21.27), and was more prominent in patients aged <75 years and those without chronic heart failure., Conclusion: AKI and AHF have a detrimental additive effect on short-term mortality in hospitalized patients.

Study Design: This is an anatomic study using cadaveric material., Objective: To provide anatomic descriptions of the normal lumbar sublaminar ridge in the lateral recess and its potential to impact on the exiting nerve root there, with implications to surgical technique in lumbar spinal stenosis., Summary of Background Data: The lateral extent of the sublaminar ridge-the bony, superior insertion site of the ligamenta flava-and its topological relationship to the nerve root are not described in the literature. In the setting of degenerative lumbar stenosis this structure can hypertrophy and impinge the nerve root within the lateral recess even after excision of the corresponding ligamentum flavum. Failure to address this may contribute to failed lateral recess decompression., Methods: Fifteen lumbar vertebrae, not obviously degenerated, were resected en bloc from three fixed adult human cadavers and then transected through the pedicles, leaving the posterior column and neural elements intact and articulated. The shape of the sublaminar ridge in the lateral recess and its relationship to the exiting nerve root were carefully examined., Results: The exiting nerve root consistently crosses the sublami- nar ridge immediately inferior to the mid-pedicle, lateral to the subarticular gutter, and on the medial aspect of the true intervertebral foramen. A hypertrophic ridge can compress the exiting root by elevating the nerve root superiorly against the bony underside of the pedicle or displacing it anteriorly against the disc or vertebral body., Conclusion: The sublaminar ridge in the lateral recess may contribute to degenerative lumbar stenosis. Comprehensive appreciation of this anatomy may facilitate thorough lateral recess decompression.Level of Evidence: 4., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A laparoscopic approach is widely used in abdominal surgery. Although several studies have compared surgical and oncological outcomes between laparoscopic surgery (LS) and open surgery (OS) in rectal cancer patients, there have been few studies on postoperative renal outcomes., Methods: We conducted a retrospective cohort study involving 1,633 patients who underwent rectal cancer surgery between 2003 and 2017. Postoperative acute kidney injury (AKI) was diagnosed according to the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes classification., Results: Among the 1,633 patients, 1,072 (65.6%) underwent LS. After matching propensity scores, 395 patients were included in each group. The incidence of postoperative AKI in the LS group was significantly lower than in the OS group (9.9% vs. 15.9%; p = 0.01). Operation time, estimated blood loss, and incidence of transfusion in the LS group were significantly lower than those in the OS group. Cox proportional hazard models revealed that LS was associated with decreased risk of postoperative AKI (hazard ratio [HR], 0.599; 95% confidence interval [CI], 0.402-0.893; p = 0.01) and postoperative transfusion was associated with increased risk of AKI (HR, 2.495; 95% CI, 1.529-4.072; p < 0.001). In the subgroup analysis, the incidence of postoperative AKI in patients with middle or high rectal cancer who underwent LS was much lower than in those who underwent OS (HR, 0.373; 95% CI, 0.197-0.705; p = 0.002)., Conclusion: This study showed that LS may have a favorable effect on the development of postoperative AKI in patients with rectal cancer.

Renal fibrosis is a progressive chronic kidney disease that ultimately leads to end-stage renal failure. Despite several approaches to combat renal fibrosis, an experimental model to evaluate currently available drugs is not ideal. We developed fibrosis-mimicking models using three-dimensional (3D) co-culture devices designed with three separate layers of tubule interstitium, namely, epithelial, fibroblastic, and endothelial layers. We introduced human renal proximal tubular epithelial cells (HK-2), human umbilical-vein endothelial cells, and patient-derived renal fibroblasts, and evaluated the effects of transforming growth factor-β (TGF-β) and TGF-β inhibitor treatment on this renal fibrosis model. The expression of the fibrosis marker alpha smooth muscle actin upon TGF-β1 treatment was augmented in monolayer-cultured HK-2 cells in a 3D disease model. In the vascular compartment of renal fibrosis models, the density of vessels was increased and decreased in the TGF-β-treated group and TGF-β-inhibitor treatment group, respectively. Multiplex ELISA using supernatants in the TGF-β-stimulating 3D models showed that pro-inflammatory cytokine and growth factor levels including interleukin-1 beta, tumor necrosis factor alpha, basic fibroblast growth factor, and TGF-β1, TGF-β2, and TGF-β3 were increased, which mimicked the fibrotic microenvironments of human kidneys. This study may enable the construction of a human renal fibrosis-mimicking device model beyond traditional culture experiments.

Background: Copeptin is secreted in equimolar amounts as arginine vasopressin, main hormone regulating body fluid homeostasis. A recent study reported a copeptin-based classification of osmoregulatory defects in syndromes of inappropriate antidiuresis that may aid in prediction of therapeutic success. We investigated usefulness of copeptin for differentiating etiologies of hyponatremia and predicting efficacy and safety of hypertonic saline treatment in hyponatremic patients., Methods: We performed a multicenter, prospective cohort study of 100 inpatients with symptomatic hyponatremia (corrected serum sodium [sNa] ≤ 125 mmol/L) treated with hypertonic saline. Copeptin levels were measured at baseline and 24 hours after treatment initiation, and patients were classified as being below or above median of copeptin at baseline or at 24 hours, respectively. Correlations between target, under correction, and overcorrection rates of sNa within 24 hours/24-48 hours and copeptin levels at baseline/24 hours were analyzed., Results: Mean sNa and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. Ratio of copeptin-to-urine sodium allowed for an improved differentiation among some (insufficient effective circulatory volume), but not all hyponatremia etiologic subgroups. Patients with below-median copeptin levels at baseline achieved a higher target correction rate in 6/24 hours (odds ratio [OR], 2.97; p = 0.02/OR, 6.21; p = 0.006). Patients with below-median copeptin levels 24 hours after treatment showed a higher overcorrection rate in next 24 hours (OR, 18.00, p = 0.02)., Conclusion: There is a limited diagnostic utility of copeptin for differential diagnosis of hyponatremia. However, copeptin might be useful for predicting responses to hypertonic saline treatment in hyponatremic patients.

Cancerous inhibitor of protein phosphatase 2A (Cip2A) is an oncoprotein that promotes the development of several types of cancer. However, its molecular function in osteoblast differentiation remains unclear. In this study, we found that Cip2A was upregulated under osteogenic conditions in MG63 cells. Besides, overexpression of Cip2A significantly increased the expression of Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). Inversely, the knockdown of Cip2A in MG63 cells suppressed osteoblast differentiation. Cip2A expression during osteogenic differentiation was mediated by extracellular signal-regulated kinase (ERK) activation. Taken together, our results suggest that Cip2A plays important role in regulating osteoblast differentiation by inducing ERK phosphorylation in MG63 cells., (© 2021 International Union of Biochemistry and Molecular Biology.)

Backgrounds: Recently, alternative surrogate endpoints such as a 30% or 40% decline in estimated glomerular filtration rate (eGFR) or eGFR slope over 2 to 3 years have been proposed for predicting renal outcomes. However, the impact of GFR estimation methods on the accuracy and effectiveness of surrogate markers is unknown., Methods: We retrospectively enrolled participants in health screening programs at three hospitals from 1995 to 2009. We defined two different participant groups as YR1 and YR3, which had available 1-year or 3-year eGFR values along with their baseline eGFR levels. We compared the effectiveness of eGFR percentage change or slope to estimate end-stage renal disease (ESRD) risk according to two estimating equations (modified Modification of Diet in Renal Disease equation [eGFRm] and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation [eGFRc]) for GFR., Results: In the YR1 and YR3 groups, 9,971 and 10,171 candidates were enrolled and ESRD incidence during follow-up was 0.26% and 0.19%, respectively. The eGFR percentage change was more effective than eGFR slope in estimating ESRD risk, regardless of the method of estimation. A 40% of decline in eGFR was better than 30%, and a 3-year baseline period was better than a 1-year period for prediction accuracy. Although some diagnostic indices from the CKD-EPI equation were better, we found no significant differences in the discriminative ability and hazard ratios for incident ESRD between eGFRc and eGFRm in either eGFR percentage change or eGFR slope., Conclusion: There were no significant differences in the prediction accuracy of GFR percentage change or eGFR slope between eGFRc and eGFRm in the general population.

Background: Acute kidney injury (AKI) is commonly encountered in clinical practice and is associated with poor patient outcomes and increased health care costs. Despite it posing significant challenges for clinicians, effective measures for AKI prediction and prevention are lacking. Previously published AKI prediction models mostly have a simple design without external validation. Furthermore, little is known about the process of linking model output and clinical decisions due to the black-box nature of neural network models., Objective: We aimed to present an externally validated recurrent neural network (RNN)-based continuous prediction model for in-hospital AKI and show applicable model interpretations in relation to clinical decision support., Methods: Study populations were all patients aged 18 years or older who were hospitalized for more than 48 hours between 2013 and 2017 in 2 tertiary hospitals in Korea (Seoul National University Bundang Hospital and Seoul National University Hospital). All demographic data, laboratory values, vital signs, and clinical conditions of patients were obtained from electronic health records of each hospital. We developed 2-stage hierarchical prediction models (model 1 and model 2) using RNN algorithms. The outcome variable for model 1 was the occurrence of AKI within 7 days from the present. Model 2 predicted the future trajectory of creatinine values up to 72 hours. The performance of each developed model was evaluated using the internal and external validation data sets. For the explainability of our models, different model-agnostic interpretation methods were used, including Shapley Additive Explanations, partial dependence plots, individual conditional expectation, and accumulated local effects plots., Results: We included 69,081 patients in the training, 7675 in the internal validation, and 72,352 in the external validation cohorts for model development after excluding cases with missing data and those with an estimated glomerular filtration rate less than 15 mL/min/1.73 m2 or end-stage kidney disease. Model 1 predicted any AKI development with an area under the receiver operating characteristic curve (AUC) of 0.88 (internal validation) and 0.84 (external validation), and stage 2 or higher AKI development with an AUC of 0.93 (internal validation) and 0.90 (external validation). Model 2 predicted the future creatinine values within 3 days with mean-squared errors of 0.04-0.09 for patients with higher risks of AKI and 0.03-0.08 for those with lower risks. Based on the developed models, we showed AKI probability according to feature values in total patients and each individual with partial dependence, accumulated local effects, and individual conditional expectation plots. We also estimated the effects of feature modifications such as nephrotoxic drug discontinuation on future creatinine levels., Conclusions: We developed and externally validated a continuous AKI prediction model using RNN algorithms. Our model could provide real-time assessment of future AKI occurrences and individualized risk factors for AKI in general inpatient cohorts; thus, we suggest approaches to support clinical decisions based on prediction models for in-hospital AKI., (©Kipyo Kim, Hyeonsik Yang, Jinyeong Yi, Hyung-Eun Son, Ji-Young Ryu, Yong Chul Kim, Jong Cheol Jeong, Ho Jun Chin, Ki Young Na, Dong-Wan Chae, Seung Seok Han, Sejoong Kim. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 16.04.2021.)

Vitexin (apigenin-8-C-d-glucopyranoside) is a flavonoid isolated from natural sources. It has been employed as an anti-oxidant, anti-inflammatory, and anti-cancer agent, and is used as a traditional Chinese medicine to treat a variety of illnesses. The present study investigated the effect of vitexin on osteoblast differentiation of C3H10T1/2 mesenchymal stem cells, MC3T3-E1 preosteoblast, mouse calvarial primary cells, and primary bone marrow stem cells (BMSCs). RT-PCR and quantitative PCR demonstrated that vitexin increased mRNA expression of the osteogenic genes distal-less homeobox 5 (Dlx5) and Runxt-related transcription factor 2 (Runx2). Vitexin also increased the Dlx5 and Runx2 protein levels, Smad1/5/9 phosphorylation, and alkaline phosphatase (ALP) activity. In addition, vitexin increased Runx2-luciferase activity. Moreover, knockdown of Runx2 attenuated the increase in ALP activity induced by vitexin. These results demonstrate that vitexin enhances osteoblast differentiation via Runx2.

Background: Serum uric acid (SUA) is recognized as a risk factor for chronic kidney disease (CKD) and mortality. However, there is controversy as to whether a high or low level of SUA is related to the risk of CKD progression or death, and whether it differs between males and females., Methods: We included 143,762 adults who underwent voluntary health screening between 1995 and 2009 in Korea. For each sex, we divided participants into sex-specific quintiles according to SUA levels and compared end-stage renal disease (ESRD) incidence and mortality between the groups with low and high SUA levels and those with middle SUA levels. Sex-specific Cox proportional hazard analyses were performed for ESRD and all-cause mortality., Results: Among the 143,762 participants, 0.2% (n = 272) developed ESRD. The hazard ratio (HR) of ESRD was higher in the highest (adjusted HR, 2.13; 95% confidence interval [CI], 1.18-3.84) and lowest (adjusted HR, 1.90; 95% CI, 1.02-3.51) SUA quintiles than in the middle SUA quintile in males and the highest SUA quintile in females (adjusted HR, 2.31; 95% CI, 1.10-4.84). Four-point three percent (n = 6,215) of participants died during a mean follow-up period of 157 months. The hazard ratio (HR) of all-cause mortality was higher in the highest SUA quintile than in the middle SUA quintile in males (adjusted HR, 1.15; 95% CI, 1.03-1.28) and females (adjusted HR, 1.17; 95% CI, 1.01-1.35)., Conclusion: Elevated levels of SUA are associated with increased risk for ESRD and all-cause mortality in both sexes. Low levels of SUA might be related to ESRD and death only in males, showing U-shaped associations. Our findings suggest sex-specific associations between SUA levels and ESRD development and mortality., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Background: The association between glomerulonephritis (GN) and cancer has been well known for decades. However, studies evaluating long-term de novo cancer development in patients with GN are limited. This study aimed to evaluate the incidence of cancer development among patients with renal biopsy-proven GN during post-biopsy follow-up and the differences in outcomes according to cancer occurrence., Methods: We conducted a retrospective cohort study of adult patients who underwent renal biopsy at Seoul National Bundang Hospital between 2003 and 2017. After excluding 778 patients with age < 18 years, cancer diagnosis before or within 6 months after renal biopsy, immunosuppressant therapy before renal biopsy, or pathologic diagnoses other than GN, 822 patients were included in the analysis. Data on baseline clinical characteristics, renal biopsy results, and types and doses of immunosuppressant agents were collected from electronic medical records. The incidence of cancer was censored on the date when the first cancer was diagnosed. We evaluated rates of mortality and end-stage renal disease (ESRD) development during follow-up., Results: During a mean follow-up period of 58.9 ± 44.5 months, 45 subjects (5.5%) developed de novo cancer. A comparison of clinical characteristics between subjects who did and did not develop cancer revealed that cancer patients were older and had higher comorbidities and immunosuppressant use. Overall, patients with GN had an elevated standardized incidence ratio (SIR) of 7.16 (95% confidence interval (CI): 5.22-9.61) relative to the age- and sex-matched general population. In particular, the SIR was significantly higher in GNs such as membranous nephropathy (MN), IgA nephropathy, lupus nephritis, and focal segmental glomerulosclerosis. Multivariable Cox proportional hazard model revealed that patients with MN had an increased risk of cancer development, with a hazard ratio of 2.30 [95% CI: 1.06-4.98]. Patients with MN who developed cancer had a significantly higher risk of mortality (hazard ratio: 6.59; 95% CI: 1.22-35.56, P = 0.03) than those without cancer, but there was a non-significant difference in ESRD development., Conclusions: Patients with GN without concurrent cancer, particularly those with MN, have significantly higher risks of cancer development and subsequent mortality and should remain aware of the potential development of malignancy during follow-up.

Our study examined the association between chronotype, daily physical activity, and the estimated risk of dementia in 170 community-dwelling older adults. Chronotype was assessed with the Horne-Östberg Morningness-Eveningness Questionnaire (MEQ). Daily physical activity (of over 3 METs) was measured with a tri-axial accelerometer. The Korean version of the Mini-Mental State Examination (K-MMSE) was used to measure the estimated risk of dementia. The evening chronotype, low daily physical activity, and dementia were positively associated with each other. The participants with low physical activity alongside evening preference had 3.05 to 3.67 times higher estimated risk of developing dementia, and participants with low physical activity and morning preference had 1.95 to 2.26 times higher estimated risk than those with high physical activity and morning preference. Our study design does not infer causation. Nevertheless, our findings suggest that chronotype and daily physical activity are predictors of the risk of having dementia in older adults aged 70 years and above.

Alpha-pinene (α-pinene) is an organic compound, found in the oils of many species of coniferous trees, especially pine. α-Pinene reportedly has antioxidant and anti-inflammatory activities; however, its effects on osteoblasts are unknown. This study investigated the effects of α-pinene on osteoblast differentiation and tumour necrosis factor-alpha (TNFα)-induced inhibition of osteogenesis. Culture in control or osteogenic medium containing α-pinene increased osteogenic marker expression. Alkaline phosphatase staining and alizarin red S staining confirmed that α-pinene enhanced osteoblast differentiation. Also, α-pinene attenuated TNFα-induced inhibition of Smad1/5/9 phosphorylation and extracellular matrix mineralization. Taken together, our findings suggest that α-pinene enhances osteoblast differentiation and mineralization in MC3T3-E1 pre-osteoblasts., (© 2019 John Wiley & Sons Australia, Ltd.)

Background: The significance of ambulatory blood pressure (ABP) in Korean patients with chronic kidney disease (CKD) in relation to renal outcome or death remains unclear. We investigated the role of ABP in predicting end-stage renal disease or death in patients with CKD., Methods: We enrolled 387 patients with hypertension and CKD who underwent ABP monitoring and were followed for 1 year. Data on clinical parameters and outcomes from August 2014 to May 2018 were retrospectively collected. The composite endpoint was end-stage renal disease or death. Patients were grouped according to the mean ABP., Results: There were 66 endpoint events, 52 end-stage renal disease cases, and 15 mortalities. Among all patients, one developed end-stage renal disease and died. Mean ABP in the systolic and diastolic phases were risk factors for the development of composite outcome with hazard ratios of 1.03 (95% confidence interval [CI], 1.01-1.04; P < 0.001) and 1.04 (95% CI, 1.02-1.07; P = 0.001) for every 1 mmHg increase in BP, respectively. Patients with mean ABP between 125/75 and 130/80 mmHg had a 2.56-fold higher risk for the development of composite outcome (95% CI, 0.72-9.12; P = 0.147) as compared to those with mean ABP ≤ 125/75 mmHg. Patients with mean ABP ≥ 130/80 mmHg had a 4.79-fold higher risk (95% CI, 1.68-13.70; P = 0.003) compared to those with mean ABP ≤ 125/75 mmHg. Office blood pressure (OBP) was not a risk factor for the composite outcome when adjusted for covariates., Conclusion: In contrast to OBP, ABP was a significant risk factor for end-stage renal disease or death in CKD patients.

Fat mass and obesity-associated (FTO) gene helps to regulate energy homeostasis in mammals by controlling energy expenditure. In addition, FTO functions in the regulation of obesity and adipogenic differentiation; however, a role in osteogenic differentiation is unknown. This study investigated the effects of FTO on osteogenic differentiation of C3H10T1/2 cells and the underlying mechanism. Expression of osteogenic and endoplasmic reticulum (ER) stress markers were characterized by reverse-transcriptase polymerase chain reaction and western blotting. Alkaline phosphatase (ALP) staining was performed to assess ALP activity. BMP2 treatment increased mRNA expression of osteogenic genes and FTO. Overexpression of FTO increased expression of the osteogenic genes distal-less homeobox5 (Dlx5) and runt-related transcription factor 2 (Runx2). Activation of adenosine monophosphate-activated protein kinase (AMPK) increased FTO expression, and there was a positive feedback loop between FTO and p-AMPK. p-AMPK and FTO induced mild ER stress; however, tunicamycin-induced severe ER stress suppressed FTO expression and AMPK activation. In summary, FTO induces osteogenic differentiation of C3H10T1/2 cells upon BMP2 treatment by inducing mild ER stress via a positive feedback loop with p-AMPK. FTO expression and AMPK activation induce mild ER stress. By contrast, severe ER stress inhibits osteogenic differentiation by suppressing FTO expression and AMPK activation.

The retinoic acid receptor-related orphan receptor alpha (RORα) is a member of the nuclear hormone receptor superfamily. Several studies show that estradiol is related to RORα expression. However, the link between estradiol and RORα in osteoblast differentiation remains unknown. Here, we showed that estradiol induces RORα expression in C3H10T1/2 and MC3T3-E1 cells. RORα overexpression increased the expression of osteogenic genes including bone morphogenetic protein 2 (BMP2), distal-less homeobox 5, inhibitor of DNA binding, runt-related transcription factor 2 (Runx2), and osteocalcin. In addition, RORα increased phosphorylation of smad1/5/9. Furthermore, RORα knockdown suppressed estradiol-induced BMP2 and Runx2 protein level. Also, we confirmed that estradiol-induced ALP staining and matrix mineralization was attenuated in RORα knockdown. Summarily, these results suggest that estradiol-induced RORα promotes osteoblast differentiation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although C1q nephropathy (C1qN) was introduced three decades ago, the clinical significance and renal outcomes of C1qN remain unclear. This study aimed to evaluate the clinical characteristics of C1qN, including renal outcomes, by performing a matched comparison within a multicenter cohort. We enrolled 6,413 adult patients who underwent kidney biopsy between January 2000 and January 2018 at three tertiary hospitals in Korea. We compared the clinical characteristics of 23 patients with C1qN with those of patients with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) who were matched by age, sex, diabetic status, and a period of biopsy. Histological and clinical parameters in patients with C1qN were also evaluated according to the different pathological phenotypes. For a mean follow-up period of 92 months, 4 patients with C1qN (17.4%) developed end-stage renal disease (ESRD). None of the matched patients with MCD had ESRD, but 7 (30.4%) of patients with FSGS progressed to ESRD, which was not different from that of C1qN patients (p = 0.491). Laboratory and pathological findings, except segmental glomerulosclerosis, were not notably different between FSGS and C1qN. The presence of segmental glomerulosclerosis, mesangial hypercellularity, and podocyte effacement did not affect both the short- and long-term renal outcomes in patients with C1qN. Our study showed that the renal outcomes of C1qN are comparable with those of FSGS, and not with MCD. Specific pathological findings, including segmental glomerulosclerosis in C1qN, were not associated with renal outcomes, which may suggest homogeneity in the clinical features of C1qN., Competing Interests: The authors have declared that no competing interests exist.

Kisspeptin-10 (KP-10) acts as a tumor metastasis suppressor via its receptor, G-protein-coupled receptor 54 (GPR54). The KP-10-GPR54 system plays an important role in embryonic kidney development. However, its function in osteoblast differentiation is unknown. Osteoblast differentiation is controlled by a range of hormones and cytokines, such as bone morphogenetic protein (BMPs), and multiple transcription factors, such as Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and Distal-less homeobox 5 (Dlx5). In the present study, KP-10-treatment significantly increased the expression of osteogenic genes, including mRNA and protein levels of BMP2, in C3H10T1/2 cells. Moreover, KP-10 induced BMP2-luc activity and increased phosphorylation of Smad1/5/9. In addition, NFATc4 specifically mediated KP-10-induced BMP2 gene expression. However, KP-10 treatment did not induce expression of the BMP2 and Runx2 genes in GPR54 -/- cells. To examine whether KP-10 induced secretion of BMP2 to the culture medium, we used the conditioned-medium (C.M) of KP-10 treated medium on C3H10T1/2 cells. Dlx5 and Runx2 expressions were higher in GPR54 -/- cells treated with C.M than in those treated with KP-10. These results demonstrate that BMP2 protein has an autocrine effect upon KP-10 treatment. Taken together, these findings suggest that KP-10/GPR54 signaling induces osteoblast differentiation via NFATc4-mediated BMP2 expression.

Aims: Curcumin (diferuloylmethane or [1E,6E]-1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6heptadiene-3,5-dione) is a phenolic natural product derived from the rhizomes of the turmeric plant, Curcuma longa. It is reported to have various biological actions such as anti-oxidative, anti-inflammatory, and anti-cancer effects. However, the molecular mechanism of osteoblast differentiation by curcumin has not yet been reported., Main Methods: The cytotoxicity of curcumin was identified using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Expression of osteogenic markers and endoplasmic reticulum (ER) stress markers in C3H1-T1/2 cells were measured using reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blotting. Alkaline phosphatase (ALP) staining was performed to assess ALP activity in C3H10T1/2 cells. Transcriptional activity was detected using a luciferase reporter assay., Key Findings: Curcumin increased the expression of genes such as distal-less homeobox 5 (Dlx5), runt-related transcription factor 2 (Runx2), ALP, and osteocalcin (OC), which subsequently induced osteoblast differentiation in C3H10T1/2 cells. In addition, ALP activity and mineralization was found to be increased by curcumin treatment. Curcumin also induced mild ER stress similar to bone morphogenetic protein 2 (BMP2) function in osteoblast cells. Next, we confirmed that curcumin increased mild ER stress and osteoblast differentiation similar to BMP2 in C3H10T1/2 mesenchymal stem cells. Transient transfection studies also showed that curcumin increased ATF6-Luc activity, while decreasing the activities of CREBH-Luc and SMILE-Luc. In addition, similar to BMP2, curcumin induced the phosphorylation of Smad 1/5/9., Significance: Overall, these results demonstrate that curcumin-induced mild ER stress increases osteoblast differentiation via ATF6 expression in C3H10T1/2 cells., (Copyright © 2017. Published by Elsevier Inc.)

Curculactones A and B are rare γ-lactone derivatives obtained from yellow, natural curcumin following γ-irradiation, and are a type of small molecules with a moderate anti-obesity effect. However, the exact role of curculactones A and B in osteoblast differentiation is unknown. In this study, the effects of curculactones A and B on the differentiation of the mesenchymal cell line C3H10T1/2 and pre-osteoblast cell line MC3T3-E1 to osteoblasts were examined. Curculactones A or B could markedly increase the mRNA levels of osteogenic marker genes and alkaline phosphatase (ALP) activity. Collectively, our findings indicate that curculactones A or B induced osteoblast differentiation through osteogenic expression of genes such as distal-less homeobox 5 (Dlx5), runt-related transcription factor 2 (Runx2), ALP, and osteocalcin (OC)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We aimed to investigate the differences in health screening, including medical checkups and cancer screening, between HBV carriers and non-carriers in the Republic of Korea. In the fifth Korean National Health and Nutrition Examination Survey (KNHANES V), conducted between 2010 and 2012, 17,865 persons who answered regarding their HBV-infection status, medical checkup history, liver cancer screening and general cancer screening within the past years were included in the final analysis. In total, 295 persons were HBV carriers. Logistic regression models were used to compare the health check-up rate between the HBV carriers and non- HBV carriers. The HBV carriers were more likely to have been screened for liver cancer [adjusted odds ratio (OR): 2.83, 95% confidence interval (95%CI): 1.90-4.21] or cancer [OR: 1.44, 95%CI: 1.04-1.99]. The HBV carriers showed a probability of receiving medical checkups that was identical to that of the non-carriers [OR: 0.99, 95%CI: 0.72-1.35]. The HBV carriers, who were at higher risk of developing chronic liver disease, were more likely to be screened for cancer, including liver cancer, than the non-HBV carriers; no difference in the rate of medical checkups was observed between the HBV carriers and non-HBV carriers.

Objective: Paraclinoid segment internal carotid artery (ICA) aneurysms have historically been a technical challenge for neurovascular surgeons. The development of microsurgical approach, advances in surgical techniques, and endovascular procedures have improved the outcome for paraclinoid aneurysms. However, many authors have reported high complication rates from microsurgical treatments. Therefore, the present study reviews the microsurgical complications of the extradural anterior clinoidectomy for treating paraclinoid aneurysms and investigates the prevention and management of observed complications., Methods: Between January 2004 and April 2008, 22 patients with 24 paraclinoid aneurysms underwent microsurgical direct clipping by a cerebrovascular team at a regional neurosurgical center. Microsurgery was performed via an ipsilateral pterional approach with extradural anterior clinoidectomy. We retrospectively reviewed patients' medical charts, office records, radiographic studies, and operative records., Results: IN OUR SERIES, THE CLINICAL OUTCOMES AFTER AN IPSILATERAL PTERIONAL APPROACH WITH EXTRADURAL ANTERIOR CLINOIDECTOMY FOR PARACLINOID ANEURYSMS WERE EXCELLENT OR GOOD (GLASGOWS OUTCOME SCALE : GOS 5 or 4) in 87.5% of cases. The microsurgical complications related directly to the extradural anterior clinoidectomy included transient cranial nerve palsy (6), cerebrospinal fluid leak (1), worsened change in vision (1), unplanned ICA occlusion (1), and epidural hematoma (1). Only one of the complications resulted in permanent morbidity (4.2%), and none resulted in death., Conclusion: Although surgical complications are still reported to occur more frequently for the treatment of paraclinoid aneurysms, the permanent morbidity and mortality resulting from a extradural anterior clinoidectomy in our series were lower than previously reported. Precise anatomical knowledge combined with several microsurgical tactics can help to achieve good outcomes with minimal complications.