Remnant cholesterol is an independent risk factor for the incidence of chronic kidney disease in newly-diagnosed type 2 diabetes: A nationwide population-based study.

AIMS: To evaluate the impact of remnant cholesterol (remnant-C) on chronic kidney disease (CKD) incidence in newly-diagnosed type 2 diabetes. METHODS: This retrospective cohort study used Korean National Health Insurance Service data on 212,836 patients with newly-diagnosed type 2 diabetes between 2009 and 2014. We conducted cox regression analysis to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for developing CKD according to remnant-C tertile. RESULTS: During a median follow-up duration of 5.23 years, 6,850 CKD cases developed. In the fully adjusted model, HRs and 95 % CIs for incident CKD increased in the highest tertile of baseline remnant-C compared to the lowest (HR [95 % CI]; 1.234 [1.159-1.314]). This association was more prominent in patients with hypertension or low-income status (P for interaction < 0.05). Increased HRs in the highest tertile of remnant-C was sustained in type 2 diabetes patients within target range of conventional lipid profile such as low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL and < 70 mg/dL (1.165 [1.041-1.304] and 1.308 [1.063-1.609]), high-density lipoprotein cholesterol (HDL-C) (1.243 [1.155-1.338]) and triglyceride (1.168 [1.076-1.268]), respectively. CONCLUSIONS: In newly-diagnosed type 2 diabetes patients, higher remnant-C is independently associated with CKD incidence, even when conventional lipid values are well-controlled.

Cancer Risk in Graves Disease with Radioactive 131I Treatment: A Nationwide Cohort Study.

Radioactive 131I (RAI) therapy has potential effects for the treatment of Graves disease (GD). However, whether RAI therapy for GD increases cancer risk remains controversial in medicine and public health. We aimed to investigate whether the risk of cancer increases in patients with GD receiving RAI therapy compared with those who did not. Methods: We used the Korean National Health Insurance Service's National Health Information Database from 2004 to 2020 and defined GD as prescribing antithyroid drugs, RAI, or thyroidectomy as a treatment for GD (International Classification of Diseases, 10th revision, E05 group). We investigated the hazard ratios (HRs) of overall and site-specific cancers associated with RAI in patients with GD. Subsequent cancer was defined as a primary malignancy treated at least 1 y after RAI therapy. Results: In total, 10,737 patients with GD who received RAI therapy (7,193 women, 67.0%; mean age, 43.7 ± 13.4 y) were matched to 53,003 patients with GD who had never received RAI treatment (35,471 women, 66.9%; mean age, 43.8 ± 13.2 y) in a 1:4-5 ratio by age, sex, and health checkup data. The median follow-up duration was 8.7 y (interquartile range, 5.2-12.1 y), and the median cumulative RAI dose was 555 MBq (interquartile range, 370-630 MBq) in the RAI therapy group. During 2004-2020, the overall subsequent cancer rates were 5.66 and 5.84 per 1,000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted HR of 0.97 (95% CI, 0.88-1.06); this remained at 0.96 (95% CI, 0.83-1.10) after adjustment for multiple clinical confounding factors. For cancer subtypes, the risk of leukemia was significantly increased, with an HR of 2.39 (95% CI, 1.17-4.91). However, a loss of statistical significance was observed after adjusting for confounding factors, which may be attributed to the limited number of absolute events. Moreover, cancer-specific mortality was not different between the RAI and the non-RAI groups, with an adjusted HR of 0.99 (95% CI, 0.66-1.47). Conclusion: This study identified that the overall cancer risk in patients with GD who received RAI therapy compared with those who did not was not significant in Korea. Further long-term studies are needed to determine the risks and advantages of RAI therapy in patients with GD.

Ischaemic stroke in patients with diabetes requiring urgent procedures during the COVID-19 pandemic in South Korea: a retrospective, nationwide, population-based cohort study using data from the National Emergency Department Information System.

OBJECTIVES: The COVID-19 pandemic resulted in suboptimal care for ischaemic stroke. Patients with diabetes mellitus (DM), a high-risk group for stroke, had compromised routine care during the pandemic, which increases the chance of stroke. We examined influence of the COVID-19 pandemic on the management of ischaemic stroke in patients with DM in South Korea. DESIGN: Retrospective, nationwide, population-based cohort study. SETTING: Data from the National Emergency Department Information System. PARTICIPANTS: We analysed 11 734 patients diagnosed with acute ischaemic stroke who underwent intravenous thrombolysis or endovascular thrombectomy between 2019 (the reference year) and 2020 (the pandemic year). Among them, 1014 subjects with DM were analysed separately. OUTCOME MEASURES: The frequency of emergency department (ED) visits, time from symptom onset to ED, from ED visit to admission and in-hospital mortality were compared between two periods in the overall population and in patients with DM. RESULTS: During the pandemic, the incidence of ischaemic stroke requiring urgent procedures increased by 7.57% in total and by 9.03% in patients with DM. Time delay from symptom onset to ED (reference vs pandemic, total: 1.50 vs 1.55 hours; p<0.01) and from ED visit to admission (total: 3.88 vs 3.92 hours; p=0.02) occurred during the pandemic in the overall population, but not significantly in patients with DM specifically. Older patients with DM showed higher chances of intensive care unit (ICU) admission during the pandemic: 53.5% vs 62.8% in age 70-79, 60.5% vs 71.9% in age 80-89 and 20.0% vs 70.8% in age ≥90 years (all p=0.01). There was no significant difference in in-hospital mortality between two periods (total: 8.2% vs 8.4%, p=0.65; DM: 8.1% vs 6.7%, p=0.25). CONCLUSIONS: During the COVID-19 pandemic, the incidence of ischaemic stroke requiring urgent procedures increased, and older patients with DM showed a higher ICU admission rate. However, the pandemic was not associated with an increased in-hospital stroke mortality.

AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent Manner.

BACKGRUOUND: G protein-coupled receptor 40 (GPR40) is a key molecule in diabetes and fatty liver, but its role in endothelial dysfunction remains unclear. Our objective in this study was to determine whether GPR40 agonists protect endothelial cells against palmitatemediated oxidative stress. METHODS: Human umbilical vein endothelial cells (HUVECs) were used to investigate effects of various GPR40 agonists on vascular endothelium. RESULTS: In HUVECs, AM1638, a GPR40-full agonist, enhanced nuclear factor erythroid 2-related factor 2 (NRF2) translocation to the nucleus and heme oxygenase-1 (HO-1) expression, which blocked palmitate-induced superoxide production. Those antioxidant effects were not detected after treatment with LY2922470 or TAK875, GPR40-partial agonists, suggesting that GPR40 regulates reactive oxygen species (ROS) removal in a ligand-dependent manner. We also found that palmitate-induced CCAAT/enhancer-binding protein homologous protein expression; X-box binding protein-1 splicing, nuclear condensation, and fragmentation; and caspase-3 cleavage were all blocked in an NRF2-dependent manner after AM1638 treatment. Both LY2922470 and TAK875 also improved cell viability independent of the NRF2/ROS pathway by reducing palmitate-mediated endoplasmic reticulum stress and nuclear damage. GPR40 agonists thus have beneficial effects against palmitate in HUVECs. In particular, AM1638 reduced palmitate-induced superoxide production and cytotoxicity in an NRF2/HO-1 dependent manner. CONCLUSION: GPR40 could be developed as a good therapeutic target to prevent or treat cardiovascular diseases such as atherosclerosis.

Additive impact of diabetes and sarcopenia on all-cause and cardiovascular mortality: A longitudinal nationwide population-based study.

OBJECTIVE: Diabetes mellitus (DM) and sarcopenia (SP) are growing public health concerns in an aging society, which share common pathophysiological mechanisms and are associated with serious health consequences. We investigated the impact of DM and SP on all-cause and cardiovascular mortalities in a longitudinal nationwide population-based study. METHODS: The study analyzed data from the Korea National Health and Nutrition Examination Survey conducted between 2008 and 2011, including information on appendicular skeletal muscle mass data. Mortality data up to December 2020 were retrieved from the National Death Registry. RESULTS: Among the 17,920 participants, 14,737 (82.2 %) had neither DM nor SP (DM-/SP-), 1349 (7.5 %) had only DM (DM+/SP-), 1425 (8.0 %) had only SP (DM-/SP+), and 409 (2.3 %) had both DM and SP (DM+/SP+). Compared to the DM-/SP- group, the DM-/SP+ and DM+/SP+ groups demonstrated increased all-cause mortality with adjusted hazard ratios (HRs) of 1.47 (95 % confidence interval [CI]: 1.14-1.89) and 1.85 (95 % CI: 1.28-2.69), respectively, while the DM+/SP- group did not (HR 1.29, 95 % CI: 0.97-1.74). The DM+/SP+ group demonstrated the highest risk of overall mortality (p-for-trend <0.001). Compared to the DM-/SP- group, only the DM+/SP+ group demonstrated increased cardiovascular mortality with HRs of 2.10 (95 % CI: 1.11-4.00) while the DM+/SP- (HR 1.35, 95 % CI: 0.79-2.30) and DM-/SP+ (HR 1.42, 95 % CI: 0.84-2.43) groups did not. CONCLUSIONS: The coexistence of DM and SP additively increased the risk of all-cause and cardiovascular mortality. Individuals with either disease may require more careful management to prevent the development of the other disease to reduce mortality.

Concurrent Subacute Thyroiditis and Graves' Disease After COVID-19: A Case Report.

There are many reports of subacute thyroiditis (SAT) that occurred after the coronavirus disease 2019 (COVID-19), but no such case has been reported in Korea. Moreover, the simultaneous occurrence of SAT and Graves' disease (GD) is rare. Here, we describe a patient who developed SAT and GD after the second episode of COVID-19. A 27-year-old woman with no known history of thyroid disease presented with fever, upper respiratory tract symptoms, and painful neck swelling. Thyroid function tests revealed thyrotoxicosis, and thyroid ultrasound showed heterogeneous echogenicity of enlarged thyroid glands. Her initial clinical presentation was consistent with SAT after viral infection, with typical neck tenderness and spontaneous improvement of thyrotoxicosis without antithyroid drug use. However, this case had some atypical features, such as an elevated thyroid-stimulating immunoglobulin level, relapse of thyrotoxicosis in short-term follow-up, and increased Tc-99m pertechnetate uptake, suggesting the coexistence of GD. About two months after methimazole (15 mg/day) was prescribed, she was lost to follow up again. We report the first case of unusual co-occurrence of SAT and GD following COVID-19.

Impact of diabetes on emergency care of acute myocardial infarction patients during the coronavirus disease 2019 pandemic: a nationwide population-based study.

Background: Although acute myocardial infarction (AMI) requires timely intervention, limited nationwide data is available regarding the association between disruption of emergency services and outcomes of patients with AMI during the coronavirus disease 2019 (COVID-19) pandemic. Moreover, whether diabetes mellitus (DM) adversely affects disease severity in these patients has not yet been investigated. Methods: This nationwide population-based study analyzed 45,648 patients with AMI, using data from the national registry of emergency departments (ED) in Korea. Frequency of ED visits and disease severity were compared between the COVID-19 outbreak period (year 2020) and the control period (the previous year 2019). Results: The number of ED visits by patients with AMI decreased during the first, second, and third waves of the outbreak period compared to the corresponding time period in the control period (all p-values < 0.05). A longer duration from symptom onset to ED visit (p = 0.001) and ED stay (p = 0.001) and higher rates of resuscitation, ventilation care, and extracorporeal membrane oxygen insertion were observed during the outbreak period than during the control period (all p-values < 0.05). These findings were exacerbated in patients with comorbid DM; Compared to patients without DM, patients with DM demonstrated delayed ED visits, longer ED stays, more intensive care unit admissions (p < 0.001), longer hospitalizations (p < 0.001), and higher rates of resuscitation, intubation, and hemodialysis (all p-values < 0.05) during the outbreak period. While in-hospital mortality was similar in AMI patients with and without comorbid DM during the two periods (4.3 vs. 4.4%; p = 0.671), patients with DM who had other comorbidities such as chronic kidney disease or heart failure or were aged ≥ 80 years had higher in-hospital mortality compared with those without any of the comorbidities (3.1 vs. 6.0%; p < 0.001). Conclusion: During the pandemic, the number of patients with AMI presenting to the ED decreased compared with that of the previous year, while the disease severity increased, particularly in patients with comorbid DM.

Association of plasma brain-derived neurotrophic factor levels and frailty in community-dwelling older adults.

Brain-derived neurotrophic factor (BDNF), an exercise-induced neurotrophin, is an important factor in memory consolidation and cognitive function. This study evaluates the association between plasma BDNF levels and frailty in community-dwelling older adults. Plasma BDNF levels were analyzed in a total of 302 individuals aged 70-84 years from the Korean Frailty and Aging Cohort Study. There were 30 (9.9%) participants with frailty. They were older and had a higher prevalence of dementia and depression than those without frailty. There were no differences in the proportion of male sex between the frail and non-frail groups. Plasma BDNF levels were significantly lower in participants with frailty than in those without frailty. The presence of frailty was significantly associated with plasma BDNF levels (odds ratio 0.508, 95% confidence interval 0.304-0.849) as well as age, hemoglobin, and the presence of dementia, and depression. After adjustment for confounding factors, the significant association between plasma BDNF and frailty was maintained (0.495, 0.281-0.874). This association remained consistent after exclusion of individuals with dementia, depression, stroke, diabetes, and osteoporosis. Plasma BDNF levels were significantly associated with frailty in community-dwelling older adults. Our study may suggest the possible role of BDNF as a novel biomarker of frailty.

Impact of urinary iodine concentration on blood glucose levels and blood pressure: a nationwide population-based study.

PURPOSE: Iodine is a vital trace element for systemic metabolic control as well as thyroid hormone synthesis. Though iodine has significant antioxidant and anti-inflammatory effects, reports on its effects on metabolic disorders are limited and inconsistent. METHODS: Impact of urinary iodine concentrations (UICs) on fasting blood glucose (FBG) levels and blood pressure (BP) in the general Korean population was evaluated adjusting for covariates including thyrotropin level and presence of thyroid diseases. RESULTS: The median UIC was 302.3 µg/L in all participants and was significantly lower in those with dysglycemia (303.6 µg/L in normal participants, 285.1 µg/L in participants with FBG levels of 100-125 mg/dL, and 261.8 µg/L in participants with FBG levels ≥ 126 mg/dL; p = 0.002). Similarly, the UIC was lower in participants with higher BP (311.6 µg/L in normal participants, 288.7 µg/L in prehypertensive participants, and 265.8 µg/L in hypertensive participants; p < 0.001). The multiple linear regression model showed a negative correlation between the UIC and FBG levels (p = 0.002), and the UIC and systolic BP (p < 0.001). One standard deviation increase in the UIC showed odds ratios of 0.84 (95% confidence interval [CI] = 0.73-0.98) for elevated FBG levels (≥ 100 mg/dL) and 0.94 (95% CI = 0.88-0.99) for elevated SBP (≥ 120 mm Hg) after full adjustment. CONCLUSION: Higher UICs were associated with lower FBG and BP levels, independent of thyroid function and other confounding factors in Korea, an iodine-replete country.

Comparison of Laser and Conventional Lancing Devices for Blood Glucose Measurement Conformance and Patient Satisfaction in Diabetes Mellitus.

Self-monitoring of capillary blood glucose is important for controlling diabetes. Recently, a laser lancing device (LMT-1000) that can collect capillary blood without skin puncture was developed. We enrolled 150 patients with type 1 or 2 diabetes mellitus. Blood sampling was performed on the same finger on each hand using the LMT-1000 or a conventional lancet. The primary outcome was correlation between glucose values using the LMT-1000 and that using a lancet. And we compared the pain and satisfaction of the procedures. The capillary blood sampling success rates with the LMT-1000 and lancet were 99.3% and 100%, respectively. There was a positive correlation (r=0.974, P<0.001) between mean blood glucose levels in the LMT-1000 (175.8±63.0 mg/dL) and conventional lancet samples (172.5±63.6 mg/dL). LMT-1000 reduced puncture pain by 75.0% and increased satisfaction by 80.0% compared to a lancet. We demonstrated considerable consistency in blood glucose measurements between samples from the LMT-1000 and a lancet, but improved satisfaction and clinically significant pain reduction were observed with the LMT-1000 compared to those with a lancet.

Increased Risk of Type 2 Diabetes in Patients With Thyroid Cancer After Thyroidectomy: A Nationwide Cohort Study.

CONTEXT: Abnormal thyroid function after thyroidectomy and subsequent thyroid-stimulating hormone suppression can have detrimental effects on glucose homeostasis in patients with thyroid cancer. OBJECTIVE: To investigate whether thyroidectomy increases the risk of type 2 diabetes in patients with thyroid cancer and to explore the association between levothyroxine dosage and type 2 diabetes risk. METHODS: A retrospective population-based cohort study using the Korean National Health Insurance database. We included 36 377 thyroid cancer patients without known diabetes who underwent thyroidectomy between 2004 and 2013. Matched subjects with nonthyroid cancer were selected using 1:1 propensity score matching. The main outcome measure was newly developed type 2 diabetes mellitus. RESULTS: Patients with thyroid cancer who underwent thyroidectomy had a higher risk of developing type 2 diabetes mellitus than the matched controls (hazard ratio [HR] 1.43, 95% CI 1.39-1.47). Among patients with thyroid cancer, when the second quartile group (in terms of the mean levothyroxine dosage; 101-127 µg/day) was considered the reference group, the risk of type 2 diabetes mellitus increased in the first quartile (<101 µg/day; HR 1.45, 95% CI 1.36-1.54) and fourth quartile groups (≥150 µg/day; HR 1.37, 95% CI 1.29-1.45); meanwhile, the risk decreased in the third quartile group (128-149 µg/day; HR 0.91, 95% CI 0.85-0.97). CONCLUSION: Patients with thyroid cancer who underwent thyroidectomy were more likely to develop type 2 diabetes mellitus than the matched controls. There was a U-shaped dose-dependent relationship between the levothyroxine dosage and type 2 diabetes mellitus risk.

Risk of Diabetes in Patients with Long-Standing Graves' Disease: A Longitudinal Study.

BACKGROUND: The detrimental effects of excessive thyroid hormone on glucose metabolism have been widely investigated. However, the risk of diabetes in patients with long-standing hyperthyroidism, especially according to treatment modality, remains uncertain, with few longitudinal studies. METHODS: The risk of diabetes in patients with Graves' disease treated with antithyroid drugs (ATDs) for longer than the conventional duration (≥2 years) was compared with that in age-and sex-matched controls. The risk was further compared according to subsequent treatment modalities after a 24-month course of ATD: continuation of ATD (ATD group) vs. radioactive iodine ablation (RIA) group. RESULTS: A total of 4,593 patients were included. Diabetes was diagnosed in 751 (16.3%) patients over a follow-up of 7.3 years. The hazard ratio (HR) for diabetes, after adjusting for various known risk factors, was 1.18 (95% confidence interval [CI], 1.10 to 1.28) in patients with hyperthyroidism. Among the treatment modality groups, the RIA group (n=102) had a higher risk of diabetes than the ATD group (n=4,491) with HR of 1.56 (95% CI, 1.01 to 2.42). Further, the risk of diabetes increased with an increase in the ATD treatment duration (P for trend=0.019). CONCLUSION: The risk of diabetes was significantly higher in patients with long-standing Graves' disease than in the general population, especially in patients who underwent RIA and prolonged ATD treatment. Special attention to hyperglycemia during follow-up along with effective control of hyperthyroidism may be necessary to reduce the risk of diabetes in these patients.

Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma.

The prognosis of BRAFV600E-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAFV600E-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAFV600E-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAFV600E-mutation (group 1), 22 had BRAFV600E and mutation other than FGs (group 2), and 13 had BRAFV600E and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39-97.58, p = 0.024). Coexistence of mutations in BRAFV600E and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAFV600E-mutant PTCs may be valuable in risk stratifying this subtype.

Implication of thyroid function in periodontitis: a nationwide population-based study.

Possible links between periodontitis and various cardiometabolic and autoimmune diseases have been advocated on the basis of chronic inflammation or oxidative stress. However, the association between periodontitis and thyroid dysfunction is under-researched. Participants without previous thyroid disease or ongoing thyroid-related medication were included from a nationwide population-level survey. Participants were categorized into tertiles of thyroid stimulating hormone (TSH) levels (first tertile < 1.76 mIU/L; second tertile 1.76-2.83 mIU/L; third tertile > 2.83 mIU/L), and periodontal condition was assessed using the Community Periodontal Index. Of the total of 5468 participants, 1423 had periodontitis (26%). A significant difference in the weighted prevalence of periodontitis according to TSH tertiles was observed, with the highest prevalence in the first tertile (26.5%) and the lowest prevalence in the third tertile (20.9%, p = 0.003). Subjects in the first TSH tertile had higher odds for periodontitis than those in the third tertile (OR 1.36, 95% CI 1.10-1.68; p for trend = 0.005) after adjusting for covariates. This association was consistent across subgroups and within sensitivity analyses among subjects without specific factors affecting thyroid function or diseases reported to be related to periodontitis. The present study demonstrated that low TSH levels were associated with significantly higher odds for periodontitis.

Treatment Modality and Risk of Heart Failure in Patients With Long-Standing Graves' Disease: A Nationwide Population-Based Cohort Study.

Background: Optimal treatment for persistent Graves' disease following 12-18 months of treatment with anti-thyroid drugs (ATDs) is unclear. Given the increased risk of cardiovascular morbidity and mortality with hyperthyroidism, assessing the risk of cardiovascular events associated with different treatment modalities after the conventional ATD course would be valuable in determining the appropriate next-line therapy. Methods: This retrospective cohort study included data from the Korean National Health Insurance database of 16,882 patients with newly diagnosed hyperthyroidism who received primary ATD treatment for 24 months. Patients were categorized based on the treatment they received after receiving ATD for 24 months: continued ATD for at least 12 more months (ATD group), radioiodine ablation (RIA) with remission (RIA group 1), and RIA without remission (RIA group 2). The incidence and risk of heart failure (HF), the leading cause of cardiovascular mortality in hyperthyroidism, were compared between patients and age-and sex-matched controls. Results: There were 16,516 (97.8%) patients in the ATD group, 230 (1.4%) in RIA group 1, and 136 (0.8%) in RIA group 2. Compared to that of controls, a significant difference in the cumulative incidence of HF was observed according to second-line treatment modality after adjusting for covariates; the risk was highest in patients in RIA group 2, with a hazard ratio (HR) of 2.54 (95% confidence interval (CI) 1.60-4.03), followed by those in the ATD group, with an HR of 1.23 (95% CI 1.20-1.36). Patients in RIA group 1 were not at an increased risk of HF compared to their matched controls (HR 0.77; 95% CI 0.38-1.54). When patients in the ATD group were further classified by the duration of ATD treatment at one-year intervals, the risk of HF was higher in patients with longer ATD use (p for linear trend < 0.001). Conclusions: In patients with long-standing hyperthyroidism treated with conventional duration of ATD therapy, the risk of HF was attenuated by RIA with remission of hyperthyroidism and increased as ATD was required for longer duration. To reduce the risk of HF, resolution of hyperthyroidism with RIA should be considered in patients with long-standing Graves' disease.

Long Working Hours and Risk of Nonalcoholic Fatty Liver Disease: Korea National Health and Nutrition Examination Survey VII.

Background: The global incidence of NAFLD is rising sharply due to various risk factors. As previous studies reported adverse health impact of long working hours on metabolic diseases, such as diabetes mellitus and obesity, it is plausible that NAFLD is also associated with working excessive hours. However, data regarding this issue is limited. Methods: In this cross-sectional study based on Korea National Health and Nutrition Examination Survey VII, 5,661 working adults without previous liver disease or heavy alcohol drinking habits were included. The subjects were categorized into three groups according to working hours: 36-42, 43-52, and 53-83 hours/week. NAFLD was defined using the hepatic steatosis index (HSI), which is a validated prediction model for determining NAFLD. Results: The prevalence of NAFLD (HSI ≥36) increased with longer working hours: 23.0%, 25.6%, and 30.6% in the 36-42, 43-52, and 53-83 hours/week group, respectively (p <0.001). Subjects who worked 53-83 hours/week had higher odds for NAFLD than those who worked the standard 36-42 hours/week (OR 1.23, 95% CI 1.02-1.50, p = 0.033) after adjusting for age, sex, body mass index, smoking, alcohol, exercise, diabetes mellitus, hypertension, serum triglyceride, and total cholesterol. This association was consistent across subgroups according to working schedule (daytime vs. shift workers) or occupation type (office vs. manual workers). In particular, the relationship between long working hours and NAFLD was pronounced in workers aged <60 years and in female workers. Conclusions: Long working hours was significantly associated with NAFLD. Further prospective studies are required to validate this finding with causal relationship.

Association Between Visit-to-Visit Fasting Plasma Glucose Variability and Osteoporotic Fractures in Nondiabetic Subjects.

CONTEXT: Although long-term glucose variability has been reported to be a risk factor associated with osteoporosis, there have been no previous studies between the relationship of glucose variability and fractures in people without diabetes. OBJECTIVE: We assessed visit-to-visit variations in fasting plasma glucose (FPG) as a prognostic factor in predicting osteoporotic fractures in individuals without diabetes. METHODS: Using a nationwide cohort database, we examined the impact of FPG on the development of osteoporotic fractures in men and women (aged ≥50 years). The primary outcomes were the number of total fractures and vertebral fractures. FPG variability was measured using standard deviation (FPG-SD), coefficient of variation (FPG-CV), and variability independent of the mean (FPG-VIM). RESULTS: Of the 92 929 participants, 5262 (5.7%) developed osteoporotic fractures during the mean follow-up of 8.4 years. Individuals in the highest quartile of FPG-SD showed an 11% and 16% increase in risk of total and vertebral fractures, respectively, compared with those in the lowest quartile after adjustment for mean FPG and other risk factors. Analyses using FPG-CV and FPG-VIM demonstrated similar results. Subgroup analyses and sensitivity analyses to explore potential heterogeneity showed consistent results. CONCLUSION: FPG variability may be a novel risk factor for osteoporotic fractures independent of risk factors in the general population without diabetes.

Gender-Dependent Reference Range of Serum Calcitonin Levels in Healthy Korean Adults.

BACKGROUND: Serum calcitonin measurement contains various clinical and methodological aspects. Its reference level is wide and unclear despite sensitive calcitonin kits are available. This study aimed to identify the specific reference range in the healthy Korean adults. METHODS: Subjects were ≥20 years with available calcitonin (measured by a two-site immunoradiometric assay) data by a routine health checkup. Three groups were defined as all eligible subjects (group 1, n=10,566); subjects without self or family history of thyroid disease (group 2, n=5,152); and subjects without chronic kidney disease, autoimmune thyroid disease, medication of proton pump inhibitor/H2 blocker/steroid, or other malignancies (group 3, n=4,638). RESULTS: This study included 6,341 male and 4,225 female subjects. Males had higher mean calcitonin than females (2.3 pg/mL vs. 1.9 pg/mL, P<0.001) in group 1. This gender difference remained similar in groups 2 and 3. Calcitonin according to age or body mass index was not significant in both genders. Higher calcitonin in smoking than nonsmoking men was observed but not in women. Sixty-nine subjects had calcitonin higher than the upper reference limit (10 pg/mL) and 64 of them had factors associated with hypercalcitoninemia besides medullary thyroid cancer. Our study suggests the reference intervals for men who were non, ex-, current smokers, and women (irrespective of smoking status) as <5.7, <7.1, <7.9, and <3.6 pg/mL, respectively. CONCLUSION: Specific calcitonin reference range should be provided considering for sex and smoking status. Taking account for several factors known to induce hypercalcitoninemia can help interpret the gray zone of moderately elevated calcitonin.

Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas.

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.

Immune Profiling of Advanced Thyroid Cancers Using Fluorescent Multiplex Immunohistochemistry.

Background: Advanced thyroid cancers, including differentiated thyroid carcinoma (DTC) with distant metastasis, and anaplastic thyroid carcinoma (ATC), are associated with poor clinical outcomes and limited treatment options. This study aimed to determine the immune profiles of advanced thyroid cancers using fluorescent multiplex immunohistochemistry (F-MIHC) and multispectral imaging (MSI). Methods: Twenty-eight tissue samples were collected from 12 patients who had DTC with distant metastasis and from 16 with ATC. The samples were assessed using F-MIHC and MSI with antibodies against the cell surface molecules, cluster of differentiation (CD)4, CD8, programmed cell death-1 (PD-1), PD ligand 1 (PD-L1), forkhead box protein 3, and cytokeratin (CK). The expression of PD-L1 was evaluated using tumor proportion score (TPS) and combined positive score (CPS). Results: Significantly, more PD-L1-positive tumor cells (CK+PD-L1+) per mm2 were found in ATC samples than in DTC samples (183.5 vs. 0.03, p < 0.001). Lymphocyte infiltration was significantly increased in ATC compared with DTC, with significantly more PD-L1- or PD-1-positive lymphocytes in ATC samples than in DTC samples. The TPS and CPS for PD-L1 expression were negative in all DTC samples but positive in 81% and 94% of ATC samples, respectively. Conclusions: Immune profiling revealed significant differences between advanced DTC and ATC, particularly in terms of PD-L1 expression and lymphocyte infiltration. Therefore, immune profiling using F-MIHC and MSI can provide invaluable information regarding tumor microenvironments, which could help select candidates for immunotherapy.