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Persistent organic pollutants (POPs) affect human health through the aryl hydrocarbon receptor (AhR) pathway and are implicated in mitochondrial dysfunction. Using data from the PIVUS study, we investigated the associations of serum AhR ligand (POP)-mediated luciferase activity (AhRL), mitochondrial ATP production inhibiting substances (MIS-ATP), and those affecting reactive oxygen species (MIS-ROS) with several metabolic syndrome (MetS) and cardiopulmonary function parameters. These include insulin resistance (HOMA-IR), inflammation, oxidative stress, and cardiopulmonary variables (FVC, FEV1, LV-EF, CCA distensibility). MIS-ATP showed significant correlations with HOMA-IR and pulmonary functions, indicating its direct impact of MIS-ATP on metabolic and pulmonary health. MIS-ROS correlated with oxidative stress markers and CCA distensibility, suggesting a role in systemic inflammatory responses. This study highlights the intricate relationships between environmental pollutant mixture and cardiopulmonary health in MetS as indicated by biomarkers of POP exposure in the elderly population, suggesting POP exposure may influence MetS onset and progression through mitochondrial dysfunction.

Purpose: To investigate whether tibial-sided anterolateral ligament (ALL) injuries are associated with poor healing and residual pivot shift., Methods: Patients who underwent anterior cruciate ligament reconstructions within postinjury 6 weeks from January 2008 to March 2021 were included. They had concomitant ALL injury confirmed by preoperative magnetic resonance imaging (MRI) and were followed for a minimum of 20 months. Preoperative ALL injury was graded by the Muramatsu classification, and postoperative ALL healing were graded by a modification of the Lee classification (good, partial, and nonvisualized). The patients were allocated to an improved group (IG) and an unimproved group (UG) on the basis of a comparison of pre- and postoperative MRI. ALL tear site, postoperative knee stability, Lysholm score, and Tegner activity scale (patient-reported outcomes [PROs]) were compared between the 2 groups., Results: In total, 128 patients were enrolled; 94.5% patients achieved the minimal clinically important difference for PROs, respectively. The ALL was torn at the femoral side in 46.9% patients, at midsubstance in 31.2.%, and at tibial side in 21.9%, Preoperatively, 86 (67.2%) patients had a partial tear, and 42 (32.8%) patients had a complete tear. On the basis of the postoperative MRI appearances, 38 (29.7%) and 90 (70.3%) patients were allocated to the IG and UG, respectively. The tibial-side tears were significantly frequent in the UG (P = .032). Pivot shift showed a significantly greater incidence in the UG than IG (P = .004). Lachman test and PROs did not differ between the 2 groups., Conclusions: Tibial-sided ALL tears occurred in 18.7% of the UG compared with 3.2% of the IG, and 45.6% of the UG had a postoperative grade 1 or 2 pivot shift compared with 15.8% of the IG. Percentages of patients with the minimal clinically important difference for PROs did not differ between the 2 groups. However, the clinical relevance is limited by a high transfer bias., Level of Evidence: Level III, retrospective cohort study., Competing Interests: Disclosures The authors report no conflicts of interest in the authorship and publication of this article. Full ICMJE author disclosure forms are available for this article online, as supplementary material., (Copyright © 2024 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background Active surveillance (AS) is an accepted strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). While previous studies have evaluated the prognostic value of US features, results have been inconsistent. Purpose To determine if US features can help predict tumor progression in patients with low-risk PTMC undergoing AS. Materials and Methods This prospective study enrolled 1177 participants with PTMC from three hospitals between June 2016 and January 2021. Participants were self-assigned to either immediate surgery or AS, and those with two or more US examinations in the absence of surgery were included in the analysis. A χ 2 test was used to compare estimated tumor progression rate at 4 years between participants stratified according to US features. Multivariable Cox regression analysis was used to assess the association of clinical and US features with overall tumor progression and specific progression criteria. Results Among 699 participants included in the analysis, 68 (mean age, 49 years ± 12 [SD]; 40 female participants) showed tumor progression (median follow-up, 41.4 months ± 16 [SD]). Tumor progression was associated with the US features of diffuse thyroid disease (DTD) (hazard ratio [HR], 2.3 [95% CI: 1.4, 3.7]; P = .001) and intratumoral vascularity (HR, 1.7 [95% CI: 1.0, 3.0]; P = .04) and the participant characteristics of male sex (HR, 2.8 [95% CI: 1.7, 4.6]; P < .001), age less than 30 years (HR, 2.9 [95% CI: 1.2, 6.8]; P = .01), and thyroid-stimulating hormone level of 7 µU/mL or higher (HR, 6.9 [95% CI: 2.7, 17.4]; P < .001). The risk of tumor progression was higher for participants with DTD (14%, P = .001) or intratumoral vascularity (14%, P = .02) than for participants without these features (6%). DTD and intratumoral vascularity were associated with tumor enlargement (HR, 2.7 [95% CI: 1.4, 5.1]; P = .002) and new lymph node metastasis (HR, 5.0 [95% CI: 1.3, 19.4]; P = .02), respectively. Conclusion DTD and intratumoral vascularity were associated with an increased risk of tumor progression in participants with PTMC undergoing AS. Clinical trial registration no. NCT02938702 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Reuter and the review "International Expert Consensus on US Lexicon for Thyroid Nodules" by Durante et al in this issue.

Objective: We evaluated the efficacy and safety of postoperative radiotherapy (PORT) for differentiated thyroid cancer (DTC) with high risk features., Materials and Methods: This retrospective study analyzed 187 patients treated for DTC from 1985 to 2019. DTC referred to nonanaplastic thyroid cancer originating from follicular cells. PORT was defined as the administration of external beam radiation to the thyroid and regional lymph nodes following surgery for initially diagnosed DTC. The patients were included in the analysis if they received PORT or exhibited any of the following features: (a) pT4 or pN1b according to the 8th American Joint Committee on Cancer, (b) poorly differentiated thyroid cancer (PDTC), or (c) unfavourable variants such as anaplastic foci and etc. After 1:1 propensity matching, a total of 108 patients were analyzed according to PORT receipt. The median follow-up duration of the matched group was 10.4 years., Results: After matching, most of the variables became balanced, but the PORT group still had more PDTC and DTC with anaplastic foci. Radioactive iodine (RAI) was less frequently administered in the PORT group. PORT yielded a significantly higher 5-year locoregional recurrence free survival (LRFS) than the No PORT group (5-year LRFS 86.1% vs. 72.7%, p = 0.022), but the 10-year cancer specific survival (CSS) was similar between them (97.8% vs. 85.9%, p = 0.122). The multivariable analysis indicated that PORT was a favourable prognostic factor (Hazard ratio 0.3, 95% Confidence interval 0.1-0.8, p = 0.02) for LRFS, but not for CSS. Among 133 patients without PORT for initial disease, 39 of them received salvage surgery followed by salvage PORT. No severe toxicity after PORT was reported., Conclusion: PORT reduced locoregional recurrence in DTC patients without severe toxicity. PORT can be an effective and safe treatment to improve locoregional control in DTC with high risk features. However, further study is warranted to identify those who can benefit from PORT., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: Subacute thyroiditis (SAT) is a thyroid disease initiated by viral infection. Whether severe acute respiratory syndrome coronavirus 2 infection can cause SAT is unclear. This study investigated changes in the nationwide incidence of SAT during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This is a retrospective, cross-sectional population-based study. Data regarding SAT and related viral diseases, including COVID-19, from 2017 to 2020 were collected from the National Health Insurance Service and Korea Disease Control and Prevention Agency databases. Results: In a total of 15,447 patients, 2484 men and 12,963 women diagnosed with SAT from 2017 to 2020 were included in this study. The incidence of SAT was significantly higher in 2020 than in 2017-2019 (8.30 vs. 7.27 per 100,000 persons, p  < 0.001), while the incidence of SAT-related respiratory viral diseases, except for COVID-19, markedly decreased in 2020. The peak age of SAT incidence in 2020 was 50-59 years, and the women-to-men ratio was 5.4 (similar to that in 2017-2019). Corticosteroids were prescribed more often (72% vs. 58%, p  < 0.001), and the prescription rate exceeding 1 month was significantly higher (45% vs. 40%, p  < 0.01) in 2020 than in 2017-2019. Conclusions: The incidence of SAT increased in 2020 in association with COVID-19. A diagnostic approach to COVID-19 needs to be considered in patients with SAT during the COVID-19 pandemic.

Osimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that was initially developed to overcome the EGFR T790M mutation and is used as a standard therapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR-activating mutations. Despite the remarkable initial efficacy, osimertinib, like other EGFR-TKIs, is limited by the emergence of acquired resistance. As the EGFR mutation C797S has been identified as a key driver of acquired resistance to osimertinib, development of a drug that targets this clinically relevant mutation could help improve patient outcomes. Here, we report the discovery and preclinical efficacy of OBX02-011, a reversible fourth-generation EGFR TKI that overcomes the EGFR C797S mutation. Compared to approved EGFR TKIs, OBX02-011 showed potent anticancer effects and inhibited EGFR-related signaling in various models, including those harboring the EGFR C797S mutation. Additionally, in transgenic mouse models (EGFRL858R/T790M/C797S), OBX02-011 treatment effectively inhibited tumor growth and EGFR activity, leading to enhanced survival. Collectively, these results suggest that OBX02-011 may be a promising new EGFR TKI to overcome C797S-mediated resistance in NSCLC.

Backgruound: Radioactive iodine (RAI) therapy is a successful therapeutic modality for Graves' disease. However, RAI therapy can fail, and RAI therapy after antithyroid drugs (ATDs) has a lower remission rate. Therefore, many patients require repeated RAI therapy. This study investigated the clinical outcomes of repeated RAI therapy for Graves' disease., Methods: Patients who underwent RAI therapy as second-line therapy after failure of ATD treatment between 2001 and 2015 were reviewed. Remission was defined as hypothyroid or euthyroid status without ATD, and with or without levothyroxine at 12 months after RAI therapy., Results: The 1-year remission rate after 2nd RAI therapy (66%, 152/230) is significantly higher than that after 1st RAI therapy (48%, 393/815) or long-term ATD treatment after 1st RAI therapy failure (42%). The clinical response to 2nd RAI therapy was more rapid. The median time intervals from the 2nd RAI therapy to ATD discontinuation (1.3 months) and to the start of levothyroxine replacement (2.5 months) were significantly shorter than those for the 1st RAI therapy. A smaller goiter size, a longer time interval between the 1st and 2nd RAI therapies, and a longer ATD discontinuation period predicted remission after the 2nd RAI therapy. Finally, in 78 patients who failed the 2nd RAI therapy, the mean ATD dosage significantly reduced 5.1 mg over 12 months., Conclusion: Repeated RAI therapy can be a good therapeutic option, especially in patients with smaller goiters and those who are more responsive to the 1st RAI therapy.

Anti-dementia medications are widely prescribed to patients with Alzheimer's dementia (AD) in South Korea. This study investigated the pattern of medical management in newly diagnosed patients with AD using a standardized data format-the Observational Medical Outcome Partnership Common Data Model from five hospitals. We examined the anti-dementia treatment patterns from datasets that comprise > 5 million patients during 2009-2019. The medication utility information was analyzed with respect to treatment trends and persistence across 11 years. Among the 8653 patients with newly diagnosed AD, donepezil was the most commonly prescribed anti-dementia medication (4218; 48.75%), followed by memantine (1565; 18.09%), rivastigmine (1777; 8.98%), and galantamine (494; 5.71%). The rising prescription trend during observation period was found only with donepezil. The treatment pathways for the three cholinesterase inhibitors combined with N-methyl-D-aspartate receptor antagonist were different according to the drugs (19.6%; donepezil; 28.1%; rivastigmine, and 17.2%; galantamine). A 12-month persistence analysis showed values of approximately 50% for donepezil and memantine and approximately 40% for rivastigmine and galantamine. There were differences in the prescribing pattern and persistence among anti-dementia medications from database using the Observational Medical Outcome Partnership Common Data Model on the Federated E-health Big Data for Evidence Renovation Network platform in Korea., (© 2022. The Author(s).)

Objective: In the COVID-19 pandemic era, healthcare workers suffer from psychological problems such as anxiety in response to the viral epidemic and it may decrease their quality of life (QoL). The aim of this study was to explore the influence of healthcare workers' stress and anxiety response to the viral epidemic and their organizational commitment on their QoL. We also explored the mediating effect of resilience on any association. Methods: From January 28, 2021, to January 29, 2021, 389 workers responded to an online survey that included the rating scales Stress and Anxiety to Viral Epidemics-9 items (SAVE-9), Perceived Stress Scale (PSS), Brief Resilience Scale (BRS), Organizational Commitment Questionnaire (OCQ), and the WHO-5 well-being index. Results: A better QoL (WHO well-being index top 25%) of healthcare workers during the COVID-19 pandemic era was predicted by low stress and anxiety in response to the viral epidemic [SAVE-9, adjusted odds ratio (aOR) = 0.92, 95% confidence interval (CI) 0.87-0.97], a high level of resilience (BRS, aOR = 1.26, 95%CI 1.15-1.37), and high organizational commitment (OCQ, aOR = 1.04, 95%CI 1.02-1.07). Mediation analysis showed that resilience partially mediated the effects of stress/anxiety in response to the viral epidemic and the organizational commitment on the quality of life. Conclusion: We observed that the stress and anxiety of healthcare workers in response to the viral epidemic and organizational commitment influenced their QOL. Their resilience mediated the relationship between their psychological problems and QOL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Son, Kim, Cho, Lee, Choi, Kil, Kim, Hong, Ahn and Chung.)

Background: Mitochondrial dysfunction is strongly associated with several kidney diseases. However, no studies have evaluated the potential renal hazards of serum mitochondria-inhibiting substance (MIS) and aryl hydrocarbon receptor ligand (AhRL) levels., Methods: We used serum level of MIS and AhRL and clinical renal outcomes from 1,511 participants of a prospective community-based cohort in Ansung. MIS was evaluated based on intracellular adenosine triphosphate (MIS-ATP) or reactive oxygen species (MIS-ROS) generation measured using cell-based assays., Results: During a mean 6.9-year follow-up, 84 participants (5.6%) developed a rapid decline in kidney function. In the lowest quartile group of MIS-ATP, patients were older and had metabolically deleterious parameters. In multivariate logistic regression analysis, higher MIS-ATP was associated with decreased odds for rapid decline: the odds ratio (OR) of 1% increase was 0.977 (95% confidence interval [CI], 0.957 to 0.998; P=0.031), while higher MIS-ROS was marginally associated with increased odds for rapid decline (OR, 1.014; 95% CI, 0.999 to 1.028; P=0.055). However, serum AhRL was not associated with the rapid decline in kidney function. In subgroup analysis, the renal hazard of MIS was particularly evident in people with hypertension and low baseline kidney function., Conclusion: Serum MIS was independently associated with a rapid decline in kidney function, while serum AhRL was not. The clinical implication of renal hazard on serum MIS requires further evaluation in future studies.

Background and Aims: Current guidelines for chronic hepatitis B (CHB) patients are to undergo surveillance for hepatocellular carcinoma (HCC) with 6-month ultrasonography. We aimed to compare detection rates of very-early-stage HCC in two groups: group A, undergoing 6-month ultrasonography versus group B, undergoing 6-month ultrasonography alternating with dynamic computed tomography (CT)., Methods: This retrospective study assessed 2151 CHB patients under entecavir/tenofovir therapy from 2007 to 2016. Detection rates of very-early-stage HCC were compared between groups A/B at intermediate/high risk based on platelets, age, gender-hepatitis B scores. The primary endpoint was the proportion of patients in each group with very-early-stage HCC. Cox proportional hazards model was used to assess the effect of surveillance modalities to detect very-early-stage HCC., Results: Five-year cumulative HCC incidence rates in group A were 15.0% not significantly different from 18.2% in group B at high risk (P = 0.17). Detection rates of very-early-stage HCC were significantly higher in group B than in group A (P < 0.001), and surveillance using CT alternating with ultrasonography was significantly associated with detection of very-early-stage HCC (hazard ratio 3.89, P < 0.001). Among intermediate-risk patients, difference between detection rates of very-early-stage HCC in groups A and B was not significant (P = 0.30), and surveillance using CT alternating with ultrasonography was not significantly associated with detection of very-early-stage HCC (hazard ratio 1.61, P = 0.23)., Conclusion: In high-risk CHB patients, surveillance using CT alternating with ultrasonography led to higher detection rates of very-early-stage HCC compared to surveillance using ultrasonography., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This paper presents a technique for developing a novel surface for dental implants using a combination of nitriding and anodic oxidation, followed by the deposition of graphene oxide using atmospheric plasma. The effects of various surface treatments on bacterial adhesion and osteoblast activation were also evaluated., Methods: CP titanium (control) was processed into disk-shaped specimens. Nitriding was conducted using vacuum nitriding, followed by anodic oxidation, which was performed in an electrolyte using a DC power supply, to form the novel "mulberry surface." Graphene oxide deposition was performed using atmospheric plasma with an inflow of carbon sources. After analyzing the sample surfaces, antibacterial activity was evaluated using Streptococcus mutans and Porphyromonas gingivalis bacteria. The viability, adhesion, proliferation, and differentiation of osteoblasts were also assessed. Analysis of variance (ANOVA) with Tukey's post-hoc test was used to calculate statistical differences., Results: We observed that the mulberry surface was formed on samples treated with nitriding and anodic oxidation, and these samples exhibited more effective antibacterial activity than the control. We also found that the samples with additional graphene oxide deposition exhibited better biocompatibility, which was validated by osteoblast adhesion, proliferation, and differentiation., Conclusion: The development of the mulberry surface along with graphene oxide deposition inhibits bacterial adhesion to the implant and enhances the adhesion, proliferation, and differentiation of osteoblasts. These results indicate that the mulberry surface and graphene oxide deposition together can inhibit peri-implantitis and promote osseointegration., Competing Interests: Hee-Seon Kim, Min-Kyung Ji, and Woo-Hyung Jang are co-first auhtors. Miss Hee-Sun Kim reports grants from National Research Foundation of Korea (2020R1F1A1076982, 2018R1A6A1A030243340 during the conduct of the study. The authors report no conflicts of interest in this work., (© 2021 Kim et al.)

The aim of study was aimed to investigate associations of platelet-to-neutrophil ratio (PNR) and platelet-to-lymphocyte ratio (PLR) on admission with clinical outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH). A retrospective analysis was performed on patients who were treated for aSAH. Unfavorable clinical outcome was defined as Modified Rankin Scale (mRS) score of 3-6 at 90-days. Receiver operating characteristic curve analysis was performed to detect optimal cutoff values of PNR and PLR for predicting clinical outcomes. Logistic regression was used to explore associations of PNR and PLR with clinical outcomes. A total of 544 patients with aSAH were enrolled. Of them, 152 (29.9%) had unfavorable clinical outcome. Optimal cutoff values of PNR and PLR to predict clinical outcomes at 90 days after aSAH were 25 and 130, respectively (P < 0.001 and <0.001, respectively). In multivariate logistic regression analysis, PNR <25 and PLR ≥ 130 were associated with unfavorable clinical outcome at 90 days after aSAH (odds ratio [OR]: 1.81; 95% confidence interval [CI]: 1.23-3.69; P = 0.018 and OR: 1.56; 95% CI: 1.18-2.62; P = 0.031, respectively). PNR and PLR as novel inflammatory biomarkers could predict the clinical outcome after aSAH. PNR <22 and PLR ≥ 130 were associated with unfavorable clinical outcome at 90 days after aSAH., 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 © 2021 Elsevier Ltd. All rights reserved.)

Background: The management of cytologically indeterminate thyroid nodules is challenging for clinicians. This study aimed to compare the diagnostic performance of the Korean Thyroid Imaging Reporting and Data Systems (K-TIRADS) with that of the American College of Radiology (ACR)-TIRADS for predicting the malignancy risk of indeterminate thyroid nodules., Methods: Thyroid nodules diagnosed by fine-needle aspiration (FNA) followed by surgery or core needle biopsy at a single referral hospital were enrolled., Results: Among 200 thyroid nodules, 78 (39.0%) nodules were classified as indeterminate by FNA (Bethesda category III, IV, and V), and 114 (57.0%) nodules were finally diagnosed as malignancy by surgery or core needle biopsy. The area under the curve (AUC) was higher for FNA than for either TIRADS system in all nodules, while all three methods showed similar AUCs for indeterminate nodules. However, for Bethesda category III nodules, applying K-TIRADS 5 significantly increased the risk of malignancy compared to a cytological examination alone (50.0% vs. 26.5%, P=0.028), whereas applying ACR-TIRADS did not lead to a change., Conclusion: K-TIRADS and ACR-TIRADS showed similar diagnostic performance in assessing indeterminate thyroid nodules, and K-TIRADS had beneficial effects for malignancy prediction in Bethesda category III nodules.

Background: Exposure to air pollution (gaseous pollutants and/or particulate matter) has been associated with the incidence, prevalence, and mortality of type 1 diabetes (T1D)., Purpose: To examine the quantitative relationship between air pollutant emissions and the incidence of T1D., Methods: We examined the association between the incidence of T1D and type 2 diabetes (T2D) in 2017 as well as that of T1D in patients younger than 15 years in 2016 with "emissions of air-polluting substances from stationary and mobile sources by regions of the Russian Federation in 2016" as reported by the Federal Diabetes Register of Russia downloaded from the Russian government website (http://www.mnr.gov.ru/docs/gosudarstvennye&#95;doklady/o&#95;sostoyanii&#95;i&#95;ob&#95;okhrane&#95;okruzhayushchey&#95;sredy&#95;rossiyskoy&#95;federatsii/)., Results: The incidence of T1D across all ages in each region of the Russian Federation correlated with the total air pollutants emitted in the region each year (r=0.278, P=0.013). The incidence of T2D was also correlated with the amount of air pollutants (r=0.234, P=0.037) and the incidence of T1D (r=0.600, P<0.001) in each country. Similarly, the incidence of T1D in patients younger than 15 years correlated with the total air pollutants emitted each year in each region (r=0.300, P=0.011)., Conclusion: The quantitative relationship between the total air pollutants emitted and the incidence of T1D and T2D in the Russian Federation suggests that air pollution contributes to the development of T1D and T2D.

Objectives: Diabetes appears to decrease the risk of subarachnoid hemorrhage. However, it is not clear whether diabetes decreases the risk of aneurysm formation. The aim of our study to evaluate the risk of unruptured cerebral aneurysm in patients with diabetes mellitus., Methods: We used data from participants who underwent brain magnetic resonance angiography (MRA) and laboratory tests at the Healthcare System Gangnam Center of Seoul National University Hospital between January 2010 and December 2013. From the 17,368 participants who underwent brain MRA, we analyzed 16,337 subjects whose diabetes status could be identified., Results: The number of participants with diabetes was 2299 (14.1%). The proportion of participants with cerebral aneurysms was 2.3% in the diabetic group and 2.7% in the non-diabetic group, which was not significantly different (P = 0.225). There were no significant differences in the size, location, and multiplicity of aneurysms between the diabetes and control groups. In multivariate logistic regression, older age showed significant risk effects on cerebral aneurysms, but female sex, hypertension, diabetes, obesity, and smoking did not show significant risk effects., Conclusion: In this study, diabetes did not affect the risk of cerebral aneurysm formation. In addition, neither smoking, nor hypertension was a significant risk factor for unruptured cerebral aneurysms. The lack of association between cerebral aneurysm and the traditional risk factors for subarachnoid hemorrhage requires further study. Risk factors for cerebral aneurysm development and those for cerebral aneurysm rupture may be different., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To determine the effects of graphene oxide (GO) deposition (on a zirconia surface) on bacterial adhesion and osteoblast activation., Methods: An atmospheric pressure plasma generator (PGS-300) was used to coat Ar/CH 4 mixed gas onto zirconia specimens (15-mm diameter × 2.5-mm thick disks) at a rate of 10 L/min and 240 V. Zirconia specimens were divided into two groups: uncoated (control; Zr) group and GO-coated (Zr-GO) group. Surface characteristics and element structures of each specimen were evaluated by field emission scanning electron microscope (FE-SEM), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and contact angle. Additionally, crystal violet staining was performed to assess the adhesion of Streptococcus mutans . WST-8 and ALP (Alkaline phosphatase) assays were conducted to evaluate MC3T3-E1 osteoblast adhesion, proliferation, and differentiation. Statistical analysis was calculated by the Mann-Whitney U -test., Results: FE-SEM and Raman spectroscopy demonstrated effective GO deposition on the zirconia surface in Zr-GO. The attachment and biofilm formation of S. mutans was significantly reduced in Zr-GO compared with that of Zr ( P < 0.05). While no significant differences in cell attachment of MC3T3-1 were observed, both proliferation and differentiation were increased in Zr-GO as compared with that of Zr ( P < 0.05)., Significance: GO-coated zirconia inhibited the attachment of S. mutans and stimulated proliferation and differentiation of osteoblasts. Therefore, GO-coated zirconia can prevent peri-implantitis by inhibiting bacterial adhesion. Moreover, its osteogenic ability can increase bone adhesion and success rate of implants., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Jang et al.)

Background: Thyroid-stimulating hormone (TSH) suppression therapy is an important treatment modality for differentiated thyroid carcinoma (DTC), but it increases fracture risk. The aim of this study was to evaluate changes in bone mineral density (BMD) and trabecular bone score (TBS) in postmenopausal DTC patients receiving TSH suppression therapy., Methods: A total of 410 postmenopausal DTC patients who underwent thyroidectomy and had at least two dual-energy X-ray absorptiometry measurements, including a preoperative measurement, were included. Patients who had osteoporosis medication for more than 1 year were classified as 'patients with osteoporosis'., Results: In patients without osteoporosis, the change in %BMD was similar between TSH suppression (-) and (+) groups, while the decrease in %TBS was significantly greater in the TSH suppression (+) group than that of the TSH suppression (-) group. The relative risk of vertebral fracture was decreased by TBS changes but not by BMD changes. In patients with osteoporosis, both BMD and TBS showed significant increases in the TSH suppression (-) group but not in TSH suppression (+) group. At year 4, TBS was significantly lower in the TSH suppression (+) group than that in the TSH suppression (-) group, while BMD showed no difference between groups., Conclusions: TBS may better reflect bone health than BMD in postmenopausal DTC patients with TSH suppression therapy.

Introduction: This study investigated morphological variations of the intrathoracic nerves and the neural connections of the second and third thoracic sympathetic ganglia to the brachial plexus based on the existence of the intrathoracic nerves and the rami communicantes., Materials and Methods: Fifty thoracic sympathetic trunks from 26 Korean adult cadavers were used., Results: The first intrathoracic nerve connecting the first and second thoracic nerves was observed on 36 sides (72%), and the second intrathoracic nerve connecting the second and third thoracic nerves was found on three sides (6%). There were either one (62%) or two (10%) first intrathoracic nerves, and only one second intrathoracic nerve (6%). The neural connections of the second and third thoracic sympathetic ganglia to the first thoracic nerve were classified into three types based on the existence of the intrathoracic nerves: Type I (68%) had only the first intrathoracic nerve, Type II (26%) had no intrathoracic nerve, and Type III (6%) had both the first and second intrathoracic nerves. Types I, II, and III were further subdivided into 10, 6, and 3 types, respectively, according to the types of the rami communicantes arising from the second and third thoracic sympathetic ganglia., Conclusions: Improved knowledge of the variations in intrathoracic nerves and upper thoracic sympathetic ganglia will be helpful to thoracic surgeons when they are disrupting the sympathetic supply to the hand for treating palmar hyperhidrosis, and contribute to successful diagnoses and treatments., (© 2020 Wiley Periodicals LLC.)

Background: High circulating levels of dioxins and dioxin-like chemicals, acting via the aryl hydrocarbon receptor (AhR), have previously been linked to diabetes. We now investigated whether the serum AhR ligands (AhRL) were higher in subjects with metabolic syndrome (MetS) and in subjects who had developed a worsened glucose tolerance over time., Methods: Serum AhRL at baseline was measured by a cell-based AhRL activity assay in 70-year-old subjects (n=911) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The main outcome measures were prevalent MetS and worsening of glucose tolerance over 5 years of follow-up., Results: AhRL was significantly elevated in subjects with prevalent MetS as compared to those without MetS, following adjustment for sex, smoking, exercise habits, alcohol intake and educational level (P=0.009). AhRL at baseline was higher in subjects who developed impaired fasting glucose or diabetes at age 75 years than in those who remained normoglycemic (P=0.0081). The odds ratio (OR) of AhRL for worsening glucose tolerance over 5 years was 1.43 (95% confidence interval [CI], 1.13 to 1.81; P=0.003, continuous variables) and 2.81 (95% CI, 1.31 to 6.02; P=0.008, in the highest quartile) adjusted for sex, life style factors, body mass index, and glucose., Conclusion: These findings support a large body of epidemiologic evidence that exposure to AhR transactivating substances, such as dioxins and dioxin-like chemicals, might be involved in the pathogenesis of MetS and diabetes development. Measurement of serum AhRL in humans can be a useful tool in predicting the onset of metabolic disorders.

Background: Low 25-hydroxyvitamin D (25OHD) levels are associated with the incidence of type 2 diabetes mellitus (T2DM). However, the association between 25OHD and metabolic health status or diabetic complications is inconclusive. We evaluated this relationship between vitamin D status and metabolic parameters and complications of T2DM., Methods: This study included 1,392 patients with T2DM who visited Eulji and Ewha Diabetes Center between January 2011 and August 2016. Anthropometric parameters and laboratory tests including glycated hemoglobin (HbA1c), lipid profile, liver and kidney function, and urinary albumin-to-creatinine ratio (UACR) were evaluated. Diabetic macro- and microvascular complications were determined through a medical record review. Serum 25OHD concentrations were measured by chemiluminescent immunoassay., Results: The mean 25OHD level was 16.8±9.6 ng/mL. Vitamin D deficiency (&lt;20 ng/mL) and severe deficiency (&lt;10 ng/mL) were observed in 990 (71.1%) and 351 (25.2%) participants, respectively. 25OHD level was positively correlated with age and highdensity lipoprotein cholesterol (HDL-C) level and negatively correlated with HbA1c, triglyceride level, and UACR. HDL-C and UACR were significantly associated with 25OHD after adjusting for other variables. Vitamin D deficiency was independently related to nephropathy after adjusting for confounding variables., Conclusion: Vitamin D deficiency was common among Korean T2DM patients; it was independently associated with microalbuminuria and HDL level, and positively related to diabetic nephropathy.

Background: We sought to explore whether reduced pulmonary function is an independent risk factor for incident diabetes in Koreans., Methods: We conducted a prospective cohort study of pulmonary function as a risk factor for incident diabetes using 10-year follow-up data from 3,864 middle-aged adults from the Ansung cohort study in Korea. The incidence of diabetes was assessed using both oral glucose tolerance tests and glycosylated hemoglobin levels., Results: During 37,118 person-years of follow-up, 583 participants developed diabetes (incidence rate: 15.7 per 1,000 person-years). The mean follow-up period was 8.0±3.7 years. Forced vital capacity (FVC; % predicted) and forced expiratory volume in 1 second (FEV1; % predicted) were significantly correlated with incident diabetes in a graded manner after adjustment for sex, age, smoking, exercise, and metabolic parameters. The adjusted hazard ratio (HR) and confidence interval (CI) for diabetes were 1.408 (1.106 to 1.792) and 1.469 (1.137 to 1.897) in the first quartiles of FVC and FEV1, respectively, when compared with the highest quartile. Furthermore, the FVC of the lowest first and second quartiles showed a significantly higher 10-year panel homeostasis model assessment of insulin resistance index, with differences of 0.095 (95% CI, 0.010 to 0.018; P=0.028) and 0.127 (95% CI, 0.044 to 0.210; P=0.003), respectively, when compared to the highest quartiles., Conclusion: FVC and FEV1 are independent risk factors for developing diabetes in Koreans. Pulmonary factors are possible risk factors for insulin resistance and diabetes.

Background and Aims: Current guidelines for chronic hepatitis B (CHB) patients are to undergo surveillance for hepatocellular carcinoma (HCC) with 6-monthly ultrasonography (US). However, sensitivities of US to detect early-stage HCC in cirrhotic patients are suboptimal. We aimed to compare overall survival and detection rates of very-early-stage HCC in two groups: group A, undergoing 6-monthly US versus group B, undergoing 6-monthly US alternating with dynamic computed tomography (CT)., Methods: This retrospective multicenter study assessed 1235 cirrhotic patients with CHB under entecavir/tenofovir therapy from 2007 to 2016. The primary endpoint was overall survival rates between the two groups. The Cox proportional hazards model and propensity score matching analyses were used to assess the effect of surveillance modalities on overall survival and detection of Barcelona Clinic Liver Cancer stage 0 HCC after balancing., Results: During a median follow-up of 4.5 years, 10-year cumulative HCC incidence rates of 16.3% were significantly higher in group B (n = 576) than 13.7% in group A (n = 659; P < 0.001). However, in patients with HCC, 10-year overall survival rates of 85.1% were significantly higher in group B than 65.6% in group A (P = 0.001 by log-rank test). CT exam alternating with US was independently associated with reduced overall mortality (hazard ratio 0.47, P = 0.02). Cumulative incidence of Barcelona Clinic Liver Cancer stage 0 HCC was significantly higher in group B than in group A (hazard ratio 2.82, P < 0.001)., Conclusion: In cirrhotic patients with CHB, dynamic CT exam alternating with US led to higher detection rates of very-early-stage HCC and benefit of overall survival than did US exams., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Dry sauna treatments improve the quality of life for chronic pain, congestive heart failure, and type 2 diabetes patients. This study aimed to determine whether dry sauna therapy improved the quality of life of obese people., Methods: A total of 38 consecutive participants aged over 20 years with a body mass index of ≥25 kg/m2 were recruited for the study. The participants were treated with a 90°C dry sauna for 15 minutes, twice daily for 4 consecutive days. To assess the quality of life, all participants completed the 5 level EQ-5D questionnaires and the EQ-Visual Analog Scale. Study parameters were measured on the same day prior to commencing the sauna sessions in a fasted state and 2 days after the last sauna session., Results: The average age was 62.3±9.5 years; 84.2% of the participants were female. The mean body mass index was 28.5±2.4 kg/m2. Dry sauna significantly improved the mean 5 level EQ-5D index scores from 0.83±0.12 to 0.89±0.11 and increased the mean EQ-Visual Analog Scale from 79.0±15.2 to 91.1±9.7. However, there were no significant changes in body mass index, blood pressure, heart rate, or body composition before and after the 8-session sauna therapy., Conclusion: Dry sauna improved the health-related quality of life of obese patients without adverse events. Further clinical studies in larger study populations are needed to verify these findings and provide concrete evidence for obesity treatment.

The purpose of this study was to examine the effect of plasma treatment by treating the surface of Co-Cr alloy, Ti-6Al-4V alloy, and CP-Ti alloy as a material for denture metal frameworks with non-thermal atmospheric pressure plasma (NTAPP) and measuring their shear bond strength (SBS) with a heat-cured resin. 20 specimens were prepared for each of Co-Cr, Ti-6Al-4V, and CP-Ti alloys. Each metal alloy group was divided into the following subgroups depending on NTAPP treatment: C (Co-Cr alloy without plasma), T (CP-Ti without plasma), A (Ti-6Al-4V alloy without plasma), CP (Co-Cr alloy with plasma), TP (CP-Ti with plasma) and AP (Ti-6Al-4V alloy with plasma). Specimens were treated with a metal conditioner and bonded to a denture base resin. SBS was measured using a universal testing machine. All data obtained were statistically analyzed using two-way analysis of variance (ANOVA), Tukey's honestly significant difference (HSD) test, and independent t -test. The mean values (SD) of SBS (MPa) were: 10.31 (1.19) for C group; 12.43 (0.98) for T group; 13.75 (2.02) for A group; 13.53 (1.61) for CP group; 16.87 (1.55) for TP group; 17.46 (1.65) for AP group. The SBS of the AP group was the highest while that of the C group was the lowest. SBS of specimen treated with NTAPP was significantly increased regardless of metal alloy types ( p < 0.001). Within the limitations of this study, NTAPP can increases the SBS of Co-Cr alloy, CP-Ti alloy, and Ti-6Al-4V alloy with a denture base resin.

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

Background: Although reversible in some patients, primary hypothyroidism is considered a permanent condition requiring lifelong hormone therapy. This study aimed to investigate the factors predicting the successful discontinuation of levothyroxine (L-T4) therapy in patients with primary hypothyroidism., Methods: A retrospective study was performed in primary hypothyroidism patients who met inclusion criteria: patients who maintained stable L-T4 therapy for more than 1 year, following gradual dose reduction of L-T4 based on the clinical decision (L-T4 tapering); patients receiving either no L-T4 or a fixed minimum dose for more than 1 year after L-T4 tapering. Reduction in L-T4 dosage by 12.5-50 μg within 3 months was considered as L-T4 tapering. Serum free T4, TSH, and clinical symptoms were evaluated before, during and after tapering. Logistic regression and decision tree analyses were performed to predict the successful discontinuation of L-T4., Results: Among 382 patients, 22.5% and 58.4% showed successful discontinuation (T4-Discontinued) and dose reduction (T4-Reduced) of L-T4 therapy, while other did not obtained any reduction of L-T4 dose (T4-Unchanged). The median number of tapering visit was 1.0 (range, 1.0-4.0). In T4-Discontinued group, the TSH level and the positive rate of anti-thyroperoxidase at the time of L-T4 initiation were lower, the duration of L-T4 therapy was shorter, and the maintenance dose of L-T4 at the time of tapering was lower than those in the T4-Unchanged group. In ultrasonography, normal parenchyma was preserved in the T4-Discontinued group while others showed higher rates of heterogeneous or hypoechoic parenchymal changes. Among those different characteristics, the longer duration of L-T4 therapy and the higher maintenance dose of L-T4 at the time of tapering significantly predicted the failure of discontinuation of L-T4 in multivariate analysis. A decision tree showed that patients with a duration of L-T4 therapy >4.6 years had lower success rate of discontinuation., Conclusion: Shorter duration of L-T4 therapy and lower L-T4 dose at the time of tapering are the predictable factors for successful L-T4 tapering in stably maintained primary hypothyroidism patients., Competing Interests: The authors have declared that no competing interests excist.

Exposure to environment-polluting chemicals (EPC) is associated with the development of diabetes. Many EPCs exert toxic effects via aryl hydrocarbon receptor (AhR) and/or mitochondrial inhibition. Here we investigated if the levels of human exposure to a mixture of EPC and/or mitochondrial inhibitors could predict the development of diabetes in a prospective study, the Korean Genome and Epidemiological Study (KoGES). We analysed AhR ligands (AhRL) and mitochondria-inhibiting substances (MIS) in serum samples (n = 1,537), collected during the 2008 Ansung KoGES survey with a 4-year-follow-up. Serum AhRL, determined by the AhR-dependent luciferase reporter assay, represents the contamination level of AhR ligand mixture in serum. Serum levels of MIS, analysed indirectly by MIS-ATP or MIS-ROS, are the serum MIS-induced mitochondria inhibiting effects on ATP content or reactive oxygen species (ROS) production in the cultured cells. Among 919 normal subjects at baseline, 7.1% developed impaired glucose tolerance (IGT) and 1.6% diabetes after 4 years. At the baseline, diabetic and IGT sera displayed higher AhRL and MIS than normal sera, which correlated with indices of insulin resistance. When the subjects were classified according to ROC cut-off values, fully adjusted relative risks of diabetes development within 4 years were 7.60 (95% CI, 4.23-13.64), 4.27 (95% CI, 2.38-7.64), and 21.11 (95% CI, 8.46-52.67) for AhRL ≥ 2.70 pM, MIS-ATP ≤ 88.1%, and both, respectively. Gender analysis revealed that male subjects with AhRL ≥ 2.70 pM or MIS-ATP ≤ 88.1% showed higher risk than female subjects. High serum levels of AhRL and/or MIS strongly predict the future development of diabetes, suggesting that the accumulation of AhR ligands and/or mitochondrial inhibitors in body may play an important role in the pathogenesis of diabetes.

Purpose: Elevated aryl hydrocarbon receptor (AhR) transactivating (AHRT) activity and uremia in chronic kidney disease (CKD) may interact with each other, further complicating the disease course. In this study, we prospectively estimated serum AHRT activity using a highly sensitive cell-based AhR-dependent luciferase activity assay in CKD patients and compared differences therein according to treatment modality., Materials and Methods: Patients undergoing peritoneal dialysis (PD) (n=22) and hemodialysis (HD) (n=38) and patients with pre-dialysis CKD stage IV or V (n=28) were included. AHRT activity and intracellular adenosine triphosphate (ATP) levels were measured. We performed a correlation analysis for AHRT activity, ATP levels, and various clinical parameters., Results: AHRT activity and intracellular ATP levels were inversely correlated and differed according to treatment modalities. AHRT activity was higher in non-dialysis CKD patients than in patients undergoing dialysis and was higher in patients undergoing HD, compared to PD. AHRT activity decreased after HD treatment in HD patients. ATP levels were higher in healthy controls than in patients with pre-dialysis CKD and PD and were further decreased in patients with HD. We noted significant correlations between multiple clinical parameters associated with cardiovascular risk factors and AHRT activity., Conclusion: AHRT activity was elevated in CKD patients, while dialysis treatment reduced AHRT activity. Further studies are warranted to specify AHRT activity and to evaluate the precise roles thereof in patients with CKD., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Background: Thyroid-stimulating hormone (TSH) suppression is recommended for patients who undergo thyroidectomy for differentiated thyroid cancer (DTC). However, the impact of TSH suppression on clinical outcomes in low-risk DTC remains uncertain. Therefore, we investigated the effects of postoperative TSH levels on recurrence in patients with low-risk DTC after thyroid lobectomy., Methods: Patients ( n =1,528) who underwent thyroid lobectomy for papillary thyroid carcinoma between 2000 and 2012 were included in this study. According to the mean and dominant TSH values during the entire follow-up period or 5 years, patients were divided into four groups (<0.5, 0.5 to 1.9, 2.0 to 4.4, and ≥4.5 mIU/L). Recurrence-free survival was compared among the groups., Results: During the 5.6 years of follow-up, 21 patients (1.4%) experienced recurrence. Mean TSH levels were within the recommended low-normal range (0.5 to 1.9 mIU/L) during the total follow-up period or 5 years in 38.1% or 36.0% of patients. The mean and dominant TSH values did not affect recurrence-free survival. Adjustment for other risk factors did not alter the results., Conclusion: Serum TSH levels did not affect short-term recurrence in patients with low-risk DTC after thyroid lobectomy. TSH suppression should be conducted more selectively., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019 Korean Endocrine Society.)

Context: Thyroid nodules are very common, and 7% to 15% of them are diagnosed as thyroid cancer. However, the inherited genetic risk factors for thyroid nodules and their associations with thyroid cancer remain unknown., Objective: To identify the genetic variants associated with susceptibility to thyroid nodules in comparison with thyroid cancer., Design and Setting: We performed a three-stage genome-wide association study for thyroid nodules. The discovery stage involved a genome-wide scan of 811 subjects with thyroid nodules and 691 subjects with a normal thyroid from a population-based cohort. Replication studies were conducted in an additional 1981 cases and 3100 controls from the participants of a health checkup. We also performed expression quantitative trait loci analysis of public data., Results: The most robust association was observed in TRPM3 (rs4745021) in the joint analysis (OR, 1.26; P = 6.12 × 10-8) and meta-analysis (OR, 1.28; P = 2.11 × 10-8). Signals at MBIP/NKX2-1 were replicated but did not reach genome-wide significance in the joint analysis (rs2415317, P = 4.62 × 10-5; rs944289, P = 8.68 × 10-5). The expression quantitative trait loci analysis showed that TRPM3 expression was associated with the rs4745021 genotype in thyroid tissues., Conclusions: To the best of our knowledge, we have performed the first genome-wide association study of thyroid nodules and identified a susceptibility locus associated with thyroid nodules, suggesting that thyroid nodules have a genetic predisposition distinct from that of thyroid cancer.

A novel mutation in intron 9-exon 10 boundary of the GCK gene was detected in a male patient with clinical features of GCK-MODY and situs inversus. This case highlights the value of sequencing the GCK gene in individuals with GCK-MODY phenotype and no family history of monogenic diabetes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of this study was to determine the association between subclinical hypothyroidism and cardiovascular (CVD) events, and mortality using the atherosclerotic CVD risk score. We carried out an observational study in a prospective cohort that was followed up for 12 years. The study included 3,021 participants aged ≥ 40 years at baseline from the Ansung cohort, part of the Korean Genome and Epidemiology Study. Cox regression models were constructed to evaluate the hazards ratio (HR) and 95% confidence interval (CI) for all-cause mortality and CVD events in groups classified according to thyroid status. Subgroup analysis was performed with a cut-off age of 65 years or 7.5% of the 10-year atherosclerotic CVD risk score. The subclinical hypothyroidism group in the highest quartile of thyroid-stimulating hormone (>6.57 mIU/L) had a significantly increased risk of all-cause mortality (HR 2.12, 95% CI 1.27 to 3.56) and CVD events (HR 1.92, 95% CI 1.21 to 3.04) compared with euthyroid participants. Subgroup analysis by CVD risk revealed that participants with high CVD risk only had a high risk of all-cause mortality (HR 2.18, 95% CI 1.22 to 3.87) and CVD events (HR 2.42, 95% CI 1.35 to 4.33). Further analysis showed that participants aged <65 years with high CVD risk had the highest risk of all-cause mortality (HR 3.50, 95% CI 1.50 to 8.16) and CVD events (HR 3.37, 95% CI 1.46 to 9.57). Our results demonstrated that high thyroid-stimulating hormone levels were associated with a greater risk of mortality and new CVD risks, particularly among subjects with high CVD risk., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aims: We evaluated the prevalence and characteristics of thyroid nodules detected by thyroid ultrasound (US) at health checkups and the associated clinical parameters., Methods: A total of 72,319 subjects who underwent thyroid US at three health checkup centers in Korea from January 2004 to December 2010 were included in this study. The correlations between the presence of thyroid nodules and other clinical parameters were analyzed., Results: The prevalence of thyroid nodules and cysts was 34.2% (n = 24,757). Thyroid nodules were more prevalent in women and older age groups. Among the subjects with thyroid nodules with size information (n = 24,686), 18,833 (76.3%) had nodules measuring ≤ 1.0 cm. Women and older age groups showed higher proportion of larger nodules. Percentage of women, age, body mass index (BMI), waist circumference, body fat composition, blood pressure, and the level of fasting glucose, total cholesterol, and low density lipoprotein cholesterol were higher in the subjects with thyroid nodules compared to those without nodules. The prevalence of metabolic syndrome and overt/subclinical thyrotoxic state was higher in the subjects with thyroid nodules. In the multivariable logistic regression analysis, women, age, BMI, metabolic syndrome, and thyrotoxicosis were independently associated with the presence of thyroid nodules., Conclusions: The high prevalence of thyroid nodules in people who underwent thyroid US at a health checkup suggests that increased detection of thyroid nodules resulted in an increased prevalence in the general population. However, metabolic disturbances may also have contributed to the increase in thyroid nodule prevalence in Korea.

Background: Despite the beneficial effect of fibroblast growth factor 21 (FGF21) on metabolic disease, there are concerns about adverse effects on bone metabolism, supported by animal studies. However, a recent human study showed the positive association between serum FGF21 level and bone mineral density (BMD) in healthy premenopausal women. We undertook this study to examine the association between FGF21 level and BMD in healthy postmenopausal Korean women who are susceptible to osteoporosis., Methods: We used data of 115 participants from a cohort of healthy postmenopausal women (>50 years old) to examine the association between serum FGF21 level and BMD. The clinical characteristics were obtained from the participants, and blood testing and serum FGF21 testing were undertaken. BMD of the lumbar spine, femoral neck and total hip area, and bone markers were used in the analyses., Results: The mean age of the participants was 60.2±7.2 years. Serum FGF21 levels showed negative correlation with BMD and T-scores in all three areas, but there were no statistically significant differences. Multivariate analyses with adjustment for age and body mass index also did not show significant association between serum FGF21 level and BMD. In addition, serum FGF21 level also showed no correlation with osteocalcin and C-telopeptide levels., Conclusion: In our study, serum FGF21 level showed no significant correlation with BMD and T-scores., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018 Korean Endocrine Society.)

The aim of this study was to investigate the specific thyroid condition and thyroid autoantibodies in adult moyamoya disease (MMD) according to clinical presentation (ischemia vs. hemorrhage stroke). In addition, a meta-analysis was performed to reveal the association between adult MMD and elevated thyroid function, or autoantibodies. Prospectively collected data on 169 consecutive patients with MMD at a single institution were analyzed. Community-based controls matched for age and sex were selected for comparison. Penalized multinomial logistic regression analysis was used for factors affecting stroke. For meta-analysis, heterogeneity was evaluated by using the I 2 test. If I 2 < 50%, a fixed effect model was used. Fifty-four cases (32.0%) presented with ischemic stroke and 37 cases (21.9%) with hemorrhage stroke. Hyperthyroidism had a marginally increased risk of MMD with ischemic stroke with reference value of MMD without stroke [odds ratio (OR), 2.53; P = 0.055]. Anti-thyroperoxidase antibody (TPOAb) increased the risk of MMD presenting with ischemic stroke significantly (OR, 2.99; P = 0.020). A meta-analysis revealed that adult MMD was significantly associated with elevated autoantibodies (OR, 7.663; P = 0.002) and hyperthyroidism (OR, 10.936; P < 0.001). Elevated TPOAb and hyperthyroidism may play important roles in adult MMD with ischemic stroke. Studies focusing on targeted hyperthyroidism and thyroid autoantibodies are necessary in treating adult MMD patients in the future.

Objective: Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer (FTC) over time have not been reported. Moreover, the prognostic effects of RAS and TERT promoter mutations in FTC have not been clearly elucidated. We investigated changes in the clinicopathological characteristics of patients with FTC over four decades, as well as the clinical significance of genetic mutations of FTC., Design and Methods: This retrospective study included 690 patients with FTC who underwent thyroidectomy between 1973 and 2015 at the Seoul National University Hospital. In 134 samples, genetic tests for N/H/KRAS and TERT promoter mutations and PAX8/PPARγ rearrangement were performed., Results: The age at diagnosis has increased ( P  < 0.001) in recent decades and extrathyroidal extension of the tumor has become less common ( P  = 0.033). Other clinicopathological characteristics and prognosis of FTC have not significantly changed. The prevalence of RAS mutations decreased ( P  = 0.042) over time, whereas that of TERT promoter mutations remained stable. RAS mutations were associated with distant metastasis and persistent disease, and TERT promoter mutations were associated with distant metastasis, advanced TNM stage, recurrence and disease-specific mortality. FTC patients with coexistent RAS and TERT promoter mutations showed a higher recurrence risk than those with only one mutation., Conclusions: The age at diagnosis of FTC and the frequency of extrathyroidal extension have changed over four decades. Moreover, the prevalence of RAS mutations decreased. RAS and TERT promoter mutations may be associated with poor clinical outcomes in FTC, especially when the two mutations coexist., (© 2017 European Society of Endocrinology.)

Objective: There is debate whether hemithyroidectomy is sufficient for patients with papillary thyroid cancer (PTC) sized 1-4 cm. Therefore, we investigated whether hemithyroidectomy affects recurrence rate compared with thyroidectomy in patients with PTC sized 1-4 cm., Design: Retrospective observational study., Patients: We included 147 patients with 1-4 cm PTC who underwent hemithyroidectomy between 2004 and 2008. They were matched with 298 patients who underwent thyroidectomy, comparing age, sex, tumour size, multiplicity, extrathyroidal extension status and lymph node (LN) metastasis status., Measurements: Recurrence-free survival (RFS) was compared between hemithyroidectomy and thyroidectomy groups., Results: Median follow-up length was 7 years, during which there were nine (6.1%) and 17 (5.7%) recurrences in hemithyroidectomy and thyroidectomy groups, respectively. Recurrence-free survival in the hemithyroidectomy group was not different from that in the thyroidectomy group regardless of variant, multifocality, LN metastasis and radioactive iodine treatment. However, in subgroup analysis, hemithyroidectomy significantly increased the risk of recurrence in patients with contralateral nodules on the preoperative imaging., Conclusions: Recurrence after hemithyroidectomy was not different from that after thyroidectomy during a median follow-up of 7 years. However, because thyroidectomy might be favoured in patients with contralateral nodules at preoperative evaluation, a thorough evaluation of the contralateral thyroid lobe is necessary., (© 2017 John Wiley & Sons Ltd.)

Glucokinase maturity-onset diabetes of the young (GCK-MODY) represents a distinct subgroup of MODY that does not require hyperglycemia-lowering treatment and has very few diabetes-related complications. Three patients from two families who presented with clinical signs of GCK-MODY were evaluated. Whole-exome sequencing was performed and the effects of the identified mutations were assessed using bioinformatics tools, such as PolyPhen-2, SIFT, and in silico modeling. We identified two mutations: p.Leu30Pro and p.Ser383Leu. In silico analyses predicted that these mutations result in structural conformational changes, protein destabilization, and thermal instability. Our findings may inform future GCK-MODY diagnosis; furthermore, the two mutations detected in two Korean families with GCK-MODY improve our understanding of the genetic basis of the disease., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017 Korean Endocrine Society.)

Background: Anti-thyroid drug therapy is considered a treatment of choice for Graves' disease; however, treatment response varies among individuals. Although several studies have reported risk factors for relapse after initial treatment, few have assessed responsiveness during the early treatment period. Our study aimed to identify the clinical characteristics for responsiveness to methimazole., Methods: We included 99 patients diagnosed with Graves' disease for the first time. Drug responsiveness was defined as the correlation coefficients between decreasing rates of free thyroxine level per month and methimazole exposure dose. According to their responsiveness to treatment, the patients were classified into rapid or slow responder groups, and age, sex, free thyroxine level, and thyrotropin binding inhibiting immunoglobulin (TBII) titers were compared between groups., Results: The mean patient age was 44.0±13.5 years and 40 patients were male (40%). The mean TBII titer was 36.6±74.4 IU/L, and the mean free thyroxine concentration was 48.9±21.9 pmol/L. The rapid responder group showed higher TBII titer and free thyroxine level at diagnosis, while age, sex, smoking, and presence of goiter did not differ between the two groups. Logistic regression analyses revealed that high level of serum thyroxine, high titer of TBII, and absence of goiter were significantly associated with a rapid response, while age, sex, and smoking were not significant factors for the prediction of responsiveness., Conclusion: In patients with new onset Graves' disease, high level of free thyroxine, high titer of TBII, and absence of goiter were associated with rapid responsiveness to methimazole treatment., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017 Korean Endocrine Society)

Background: Antithyroid drug (ATD) is a widely used treatment for Graves' disease (GD). However, its long-term efficiency remains unclear. This study investigated the long-term disease prognosis and predictive factors for relapse in ATD-treated GD patients., Methods: Newly diagnosed, ATD-treated GD patients with at least four years of follow-up were recruited (n = 187). Remission was defined as maintaining a euthyroid status for more than one year after ATD withdrawal., Results: During 11.1 years (range 4.0-23.7 years) of median follow-up, overall, 51.9% of the newly diagnosed ATD-treated GD patients achieved remission, 32.1% continued ATD treatment, and 13.4% underwent other ablation treatments. The 10-year remission rates were higher in the first (34.2%) and second (25.5%) ATD courses than in any of the other subsequent ATD courses, and decreased as ATD treatments were repeated. The 10-year relapse rate was the highest after the third ATD treatment (71.4%) compared with that after the first (60.5%) and second (58.3%) courses. Longer duration of ATD treatment (odds ratio [OR] = 1.4 [confidence interval (CI) 1.2-1.7], p < 0.001), higher number of relapses (OR = 4.7 [CI 2.3-9.8], p < 0.001), and moderate to severe Graves' ophthalmopathy (OR = 4.1 [CI 1.1-15.2], p = 0.032) were associated with persistent disease status., Conclusions: A second course of ATD can be considered for GD patients after the first relapse because the chance of remission and the relapse rate are similar to the one after the first ATD treatment course. For GD patients with more than two relapses, or with an ATD treatment duration of more than four to five years, low-dose maintenance of ATD or ablative treatment needs to be considered.

Background: Multipotent mesenchymal stem cells can differentiate into adipocytes or osteoblasts through closely regulated lineage-control processes. However, adipocyte precursor cells release preadipocyte factor 1 (Pref-1), which inhibits the differentiation of mesenchymal stem cells into mature adipocytes and osteoblasts. Previous studies have also reported an inverse association between Pref-1 levels and bone mineral density (BMD) among patients with anorexia nervosa., Methods: In this retrospective study, we examined the correlations between Pref-1 levels and BMD among 124 healthy postmenopausal women (>50 years old). The patients had provided information regarding their clinical characteristics, and underwent blood testing and serum Pref-1 testing., Results: The subjects' mean age was 59.9±7.1 years and the median time since menopause onset was 9.1 years. A history of osteoporotic fracture was identified in 23 subjects (19%). Serum Pref-1 levels were not significantly correlated with BMD values at the lumbar spine (R²=0.038, P=0.109), femur neck (R²=0.017, P=0.869), and total hip (R²=0.041, P=0.09), and multivariate analyses with adjustment for age and body mass index also did not detect any significant correlations. Subgroup analyses according to a history of fracture also did not detect significant associations between Pref-1 levels and BMD values., Conclusion: In our study population, it does not appear that serum Pref-1 levels are significantly associated with BMD values and osteoporosis., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017 Korean Endocrine Society)

Background: This study aimed to evaluate the recurrence and survival after initial curative-intent surgery of resectable anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC)., Methods: A retrospective analysis was conducted on patients with ATC and PDTC who had been treated between 1985 and 2013. Among them, 119 patients who had undergone surgery with curative intent were included in this study. The outcome measures included the clinical response to treatment and the recurrence rates of three separate thyroid cancer groups: ATC, differentiated thyroid cancer (DTC) with anaplastic foci, and PDTC., Results: Initial remission was achieved in 100 (84.0%) patients, with higher percentages in patients with DTC with anaplastic foci (97.8%) and PDTC (96.7%) compared with ATC (60.5%). The overall recurrence rate after initial remission was 30.8% in ATC, 25.9% in PDTC, and 6.7% in DTC with anaplastic foci. Pathologic diagnosis, preexisting goiter or tumors, along with tracheal and lymphatic/vascular invasion were correlated with recurrence (p < 0.001; p = 0.001, 0.006, 0.003, and 0.016, respectively). All patients without initial remission died due to local failure, and most patients with recurrence, apart from two PDTC patients, had distant metastasis. Overall mortality after initial curative-intent surgery was 58.1% in ATC, 8.7% in DTC with anaplastic foci, and 20% in PDTC., Conclusions: The initial remission of resectable tumors was higher and the recurrence rate was lower in DTC with anaplastic foci and PDTC compared with ATC. Careful monitoring of the development of distant metastasis is necessary, especially in patients with aggressive pathology with tracheal and lymphovascular invasion.

Background: Simultaneous PET/MR imaging depends on MR-derived attenuation maps (mu-maps) for accurate attenuation correction of PET data. Currently, these maps are derived from gradient-echo-based MR sequences, which are sensitive to susceptibility changes. Iron oxide magnetic nanoparticles have been used in the measurement of blood volume, tumor microvasculature, tumor-associated macrophages, and characterizing lymph nodes. Our aim in this study was to assess whether the susceptibility effects associated with iron oxide nanoparticles can potentially affect measured (18)F-FDG PET standardized uptake values (SUV) through effects on MR-derived attenuation maps., Methods: The study protocol was approved by the Institutional Animal Care and Use Committee. Using a Siemens Biograph mMR PET/MR scanner, we evaluated the effects of increasing concentrations of ferumoxytol and ferumoxytol aggregates on MR-derived mu-maps using an agarose phantom. In addition, we performed a baboon experiment evaluating the effects of a single i.v. ferumoxytol dose (10 mg/kg) on the liver, spleen, and pancreas (18)F-FDG SUV at baseline (ferumoxytol-naïve), within the first hour and at 1, 3, 5, and 11 weeks., Results: Phantom experiments showed mu-map artifacts starting at ferumoxytol aggregate concentrations of 10 to 20 mg/kg. The in vivo baboon data demonstrated a 53% decrease of observed (18)F-FDG SUV compared to baseline within the first hour in the liver, persisting at least 11 weeks., Conclusions: A single ferumoxytol dose can affect measured SUV for at least 3 months, which should be taken into account when administrating ferumoxytol in patients needing sequential PET/MR scans. Advances in knowledge 1. Ferumoxytol aggregates, but not ferumoxytol alone, produce significant artifacts in MR-derived attenuation correction maps at approximate clinical dose levels of 10 mg/kg. 2. When performing simultaneous whole-body (18)F-FDG PET/MR, a single dose of ferumoxytol can result in observed SUV decreases up to 53%, depending on the amount of ferumoxytol aggregates in the studied tissue. Implications for patient care Administration of a single, clinically relevant, dose of ferumoxytol can potentially result in changes in observed SUV for a prolonged period of time in the setting of simultaneous PET/MR. These potential changes should be considered in particular when administering ferumoxytol to patients with expected future PET/MR studies, as ferumoxytol-induced SUV changes might interfere with therapy assessment.

Context: Previous studies on the extent to which radioactive iodine (RAI) therapy for thyroid cancer increases the risk of subsequently developing breast cancer have given conflicting results., Objective: This study aimed to evaluate the effect of RAI treatment on breast cancer development and recurrence among female patients with primary thyroid cancer., Design: This was a retrospective cohort study. The risk of subsequent breast cancer associated with RAI and its dose in hazard ratios (HRs) with 95% confidential intervals (CIs) were calculated using time-dependent Cox proportional hazard models., Patients: A total of 6150 patients with thyroid cancer enrolled between 1973 and 2009 were followed until December 2012. Of these, 3631 (59.0%) received RAI therapy. During the follow-up period, 99 primary breast cancers were diagnosed., Main Outcome Measure: Risk of breast cancer development according to RAI therapy and RAI dose during treatment for primary thyroid cancer., Results: RAI therapy did not significantly increase the incidence of subsequent breast cancer among female patients (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.22-1.06) when a 2-year latency period was accounted for. High-dose RAI (≥120 mCi) was associated with a reduced incidence of subsequent breast cancer (HR, 0.17; 95% CI, 0.05-0.62) in the cohort with a 2-year latency period., Conclusions: The long-term follow-up results of this study suggest that RAI treatment for patients with thyroid cancer may not increase the risk or recurrence of breast cancer.

Background: The aim of this study was to investigate the risk factors for second primary malignancy (SPM) diagnosed after differentiated thyroid cancer (DTC)., Methods: A total of 2468 DTC patients who underwent thyroidectomy were reviewed. SPM was defined as a non-thyroidal malignancy, diagnosed at least 1 year after the diagnosis of thyroid cancer. Patients were divided into five groups according to cumulative (131)I dose: very high-activity (≥ 37.0 GBq), high-activity (22.3-36.9 GBq), intermediate-activity (5.56-22.2 GBq), low-activity (1.1-5.55 GBq) and no RAI., Results: Among the 2468 patients, 61 (2.5%) had SPMs during 7.0 (1.0-33.0) years of median follow-up. Age above 40 years, male sex and very high-activity RAI were independent risk factors for the development of SPM. SPM-related mortality was highest in the very high-activity group, while DTC-related mortality was highest in the high-activity group. The overall mortality both from SPM and DTC was highest in the high-activity group., Conclusion: A cumulative (131)I dose <37.0 GBq did not increase the risk of SPM. A cumulative (131) I dose ≥ 37.0 GBq increased the risk of SPM and SPM-related mortality and decreased the DTC-specific mortality, resulting in a similar all-cause mortality compared with the low-activity RAI group. Using repeated high-dose RAI for treating RAI-responsive but persistent DTC patients needs careful consideration of the individual benefits from RAI vs the risk of developing SPM., (© 2014 John Wiley & Sons Ltd.)