A Multicenter, Randomized, Open-Label Study to Compare the Effects of Gemigliptin Add-on or Escalation of Metformin Dose on Glycemic Control and Safety in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Treated with Metformin and SGLT-2 Inhibitors (SO GOOD Study).

Background: We aimed to compare efficacy and safety between gemigliptin add-on and escalation of the metformin dose in patients with inadequately controlled type 2 diabetes mellitus (T2DM) despite treatment with metformin and SGLT2 inhibitors. Methods: This study was a multicenter, randomized, open-label, active-controlled, parallel-group comparative study. Patients with T2DM uncontrolled on metformin and SGLT2 inhibitors were randomized to receive gemigliptin 50 mg as an add-on (GEM group, n = 37) or escalation of the metformin dose (500 mg, MET group, n = 38) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) from baseline to week 24. Results: At weeks 12 and 24, the reduction in HbA1c levels was significantly greater in the GEM group than in the MET group (GEM vs. MET = -0.64% ± 0.34% vs. -0.36% ± 0.50%, p = 0.009 at week 12; -0.61% ± 0.35% vs. -0.33% ± 0.70%, p = 0.045 at week 24). The proportions of patients who achieved target HbA1c levels of <7.0% at weeks 12 and 24 and <6.5% at week 12 were greater in the GEM group than in the MET group. An index of ß-cell function was also significantly improved in the GEM group. The safety profiles were similar between the two groups. Conclusions: Gemigliptin add-on therapy may be more effective than metformin dose escalation in patients with T2DM insufficiently controlled using metformin and SGLT2 inhibitors, without safety concerns. This trial is registered with CRIS_number: KCT0003520.

Preparation and evaluation of injectable microsphere formulation for longer sustained release of donepezil.

In this study, donepezil-loaded PLGA and PLA microspheres (Dp-PLGA-M/Dp-PLA-M) and Dp-PLA-M wrapped in a polyethylene glycol-b-polycaprolactone (PC) hydrogel (Dp-PLA-M/PC) were prepared to reduce the dosing frequency of injections to treat Alzheimer's disease patients. Dp-PLGA-M and Dp-PLA-M with a uniform particle size distribution were repeatably fabricated in nearly quantitative yield and with high encapsulated Dp yields using an ultrasonic atomizer. The injectability and in vitro and in vivo Dp release, biodegradation, and inflammatory response elicited by the Dp-PLGA-M, Dp-PLA-M, and Dp-PLA-M/PC formulations were then compared. All injectable formulations showed good injectability with ease of injection, even flow, and no clogging using a syringe needle under 21-G. The injections required a force of <1 N. According to the biodegradation rate of micro-CT, GPC and NMR analyses, the biodegradation of Dp-PLA-M was slower than that of Dp-PLGA-M, and the biodegradation rate of Dp-PLA-M/PC was also slower. In the Dp release experiment, Dp-PLA-M sustained Dp for longer compared with Dp-PLGA-M. Dp-PLA-M/PC exhibited a longer sustained release pattern of two months. In vivo bioavailability of Dp-PLA-M/PC was almost 1.4 times higher than that of Dp-PLA-M and 1.9 times higher than that of Dp-PLGA-M. The variations in the Dp release patterns of Dp-PLGA-M and Dp-PLA-M were explained by differences in the degradation rates of PLGA and PLA. The sustained release of Dp by Dp-PLA-M/PC was attributed to the fact that the PC hydrogel served as a wrapping matrix for Dp-PLA-M, which could slow down the biodegradation of PLA-M, thus delaying the release of Dp from Dp-PLA-M. Dp-PLGA-M induced a higher inflammatory response compared to Dp-PLA-M/PC, suggesting that the rapid degradation of PLGA triggered a strong inflammatory response. In conclusion, Dp-PLA-M/PC is a promising injectable Dp formulation that could be used to reduce the dosing frequency of Dp injections.

Comparison of Efficacy of Glimepiride, Alogliptin, and Alogliptin-Pioglitazone as the Initial Periods of Therapy in Patients with Poorly Controlled Type 2 Diabetes Mellitus: An Open-Label, Multicenter, Randomized, Controlled Study.

BACKGROUND: The choice of an optimal oral hypoglycemic agent in the initial treatment periods for type 2 diabetes mellitus (T2DM) patients remains difficult and deliberate. We compared the efficacy and safety of glimepiride (GLIM), alogliptin (ALO), and alogliptin-pioglitazone (ALO-PIO) in poorly controlled T2DM patients with drug-naïve or metformin failure. METHODS: In this three-arm, multicenter, open-label, randomized, controlled trial, poorly controlled T2DM patients were randomized to receive GLIM (n=35), ALO (n=31), or ALO-PIO (n=33) therapy for 24 weeks. The primary endpoint was change in the mean glycosylated hemoglobin (HbA1c) levels at week 24 from baseline. Secondary endpoints were changes in HbA1c level at week 12 from baseline, fasting plasma glucose (FPG) levels, lipid profiles at weeks 12 and 24, and parameters of glycemic variability, assessed by continuous glucose monitoring for 24 weeks. RESULTS: At weeks 12 and 24, the ALO-PIO group showed significant reduction in HbA1c levels compared to the ALO group (-0.96%±0.17% vs. -0.37%±0.17% at week 12; -1.13%±0.19% vs. -0.18%±0.2% at week 24). The ALO-PIO therapy caused greater reduction in FPG levels and significant increase in high-density lipoprotein cholesterol levels at weeks 12 and 24 than the ALO therapy. Compared to low-dose GLIM therapy, ALO-PIO therapy showed greater improvement in glycemic variability. The adverse events were similar among the three arms. CONCLUSION: ALO-PIO combination therapy during the early period exerts better glycemic control than ALO monotherapy and excellency in glycemic variability than low-dose sulfonylurea therapy in uncontrolled, drug-naïve or metformin failed T2DM patients.

A Real-World Study of Long-Term Safety and Efficacy of Lobeglitazone in Korean Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Thiazolidinediones (TZDs) have been associated with various safety concerns including weight gain, bladder cancer, and congestive heart failure (CHF). This study evaluated the efficacy and safety of lobeglitazone, a novel TZD in patients with type 2 diabetes mellitus (T2DM) in real practice. METHODS: In this non-interventional, multi-center, retrospective, and observational study conducted at 15 tertiary or secondary referral hospitals in Korea, a total of 2,228 patients with T2DM who received lobeglitazone 0.5 mg for more than 1 year were enrolled. RESULTS: Overall adverse events (AEs) occurred in 381 patients (17.10%) including edema in 1.97% (n=44). Cerebrovascular and cardiovascular diseases were identified in 0.81% (n=18) and 0.81% (n=18), respectively. One case of CHF was reported as an AE. Edema occurred in 1.97% (n=44) of patients. Hypoglycemia occurred in 2.47% (n=55) of patients. Fracture occurred in 1.17% (n=26) of all patients. Lobeglitazone significantly decreased HbA1c level, resulting in a mean treatment difference of -1.05%± 1.35% (P<0.001), and decreased total cholesterol, triglyceride, and low-density lipoprotein cholesterol. However, it increased high-density lipoprotein cholesterol, regardless of statin administration. The patients who received lobeglitazone 0.5 mg showed an apparent reduction in glycosylated hemoglobin (HbA1c) from baseline during the first 6 months of treatment. The HbA1c levels remained stable between months 6 and 42. CONCLUSION: Lobeglitazone has long-term safety profile, good glycemic-lowering effect and long-term durability of glycemic control in real-world clinical settings.

Prevalence and clinical characteristics of fulminant type 1 diabetes mellitus in Korean adults: A multi-institutional joint research.

AIMS/INTRODUCTION: We aimed to determine the hospital-based prevalence and clinical features of fulminant type 1 diabetes mellitus in Korea. MATERIALS AND METHODS: We identified all patients with diabetes who regularly visited the Endocrinology outpatient clinics at eight centers for a period >1 year between January 2012 and June 2017. We investigated their medical records retrospectively. RESULTS: During this period, 76,309 patients with diabetes had been regularly followed up. Among them, 913 (1.2%) patients had type 1 diabetes mellitus . There were 462 patients with type 1 diabetes mellitus whose data at the time of the first diagnosis could be identified (359 and 103 with non-ketosis and ketosis onset, respectively). Of these, 15 (3.2% of type 1 diabetes mellitus, 14.6% of ketosis onset diabetes) patients had fulminant type 1 diabetes mellitus. The median ages at diagnosis were 40 and 27 years in the fulminant type 1 diabetes mellitus and non-fulminant type 1 diabetes mellitus groups, respectively. The patients with fulminant type 1 diabetes mellitus had higher body mass index, lower glycated hemoglobin and fasting/peak C-peptide, and lower frequent glutamic acid decarboxylase antibody-positive rate (P =0.0010) at diagnosis. Furthermore, they had lower glycated hemoglobin at the last follow-up examination than those with non-fulminant type 1 diabetes mellitus. CONCLUSIONS: In this study, the prevalence of type 1 diabetes mellitus was 1.2% among all patients with diabetes, and that of fulminant type 1 diabetes mellitus was 3.2% among those newly diagnosed with type 1 diabetes mellitus. The glycated hemoglobin levels were lower in patients with fulminant type 1 diabetes mellitus than in those with non-fulminant type 1 diabetes mellitus at diagnosis and at the last follow-up examination.

The Association Between Second-Line Oral Antihyperglycemic Medication on Types of Dementia in Type 2 Diabetes: A Nationwide Real-World Longitudinal Study.

BACKGROUND: There are few reports that evaluated the association between various types of dementia and dual oral therapy with antihyperglycemic medication. OBJECTIVE: The goal of this study was to investigate the association between treatment of dual antihyperglycemic medication and dementia subclass in type 2 diabetes mellitus using the Korean National Health Insurance System. METHODS: This study included 701,193 individuals with diabetes prescribed dual oral therapy between 2009 and 2012 from the Korean National Health Insurance Service Database, which were tracked until 2017. All-cause, Alzheimer's (AD) and vascular dementia (VaD) were investigated by dual oral therapy. Adjustments were made for age, sex, income, diabetes duration, hypertension, dyslipidemia, smoking, drinking, exercise, body mass index, glucose level, and estimated glomerular filtration rate. RESULTS: Dual therapy with metformin (Met) + dipeptidyl peptidase-4 inhibitor (DPP-4i), Met + thiazolidinedione (TZD), and sulfonylurea (SU) + thiazolidinediones (TZD) were significantly associated with all-cause dementia (HR = 0.904, 0.804, and 0.962, respectively) and VaD (HR = 0.865, 0.725, and 0.911, respectively), compared with Met + SU. Met + DPP-4i and Met + TZD were associated with significantly lower risk of AD (HR = 0.922 and 0.812), compared with Met + SU. Dual therapy with TZD was associated with a significantly lower risk of all-cause dementia, AD, and VaD than nonusers of TZD (HR = 0.918, 0.925 and 0.859, respectively). CONCLUSION: Adding TZD or DPP-4i instead of SU as second-line anti-diabetic treatment may be considered for delaying or preventing dementia. Also, TZD users relative to TZD non-users on dual oral therapy were significantly associated with lower risk of various types of dementia.

The prevalence of and factors associated with depressive symptoms in the Korean adults: the 2014 and 2016 Korea National Health and Nutrition Examination Survey.

PURPOSE: This study was performed to investigate the prevalence of and factors associated with depressive symptoms in the Korean adult population. METHODS: 10,710 participants in the 2014 and 2016 Korea National Health and Nutrition Examination Survey (KNHANES) were analyzed in this study. Assessment of depressive symptoms was performed using the self-administered nine-item Patient Health Questionnaire (PHQ-9). RESULTS: The weighted prevalence of clinically relevant depression (PHQ-9 score ≥ 10) in the Korean adult population was 6.1% [5.5-6.8%]. Female sex, adults aged 19-29 years, elementary school graduation, living alone were significantly associated with clinically relevant depression. Having a household income ≤ 24th percentile was associated with a 2.26 (CI 1.49-3.45, p < 0.001)-fold higher prevalence of clinically relevant depression compared to having a household income ≥ 75th percentile. Regarding occupation, treating managers and professionals as controls, we found that unemployed individuals (OR 2.36, 95% CI 1.52-3.65, p < 0.001) had an increased risk of clinically relevant depression. Alcohol consumption < 30 g/day was reversely associated with clinically relevant depression (OR 0.75, 95% CI 0.62-0.93, p = 0.007), when abstain from alcohol was treated as control. Current smokers (OR 3.42, 95% CI 2.54-4.60, p < 0.001) and ex-smokers (OR 1.73, 95% CI 1.24-2.42, p = 0.001) had a higher risk of clinically relevant depression than never-smokers. CONCLUSIONS: The estimated prevalence of depressive symptoms in a representative sample of the Korean adult population was 6.1%. This study suggests that younger age, female sex, elementary school graduation, living alone, low household income, current smoking, and being unemployed are associated with depressive symptoms.

Radiologic findings and the molecular expression profile of diffuse midline glioma H3 K27M mutant.

BACKGROUND: Diffuse midline glioma H3 K27M-mutant (DMG) are reported to show heterogeneous radiologic imaging features in children. We hypothesized that other genetic mutations may contribute to this heterogeneity. PURPOSE: To describe the magnetic resonance imaging (MRI) findings of DMG in adult patients and to correlate the imaging findings with the molecular expression profile. MATERIAL AND METHODS: Eighteen patients with pathologically proven DMG were enrolled. On preoperative MRI, the following were evaluated: location; size of the lesion; ratio of non-enhancing (NE) and contrast-enhancing (CE) area; presence of cortical invasion and necrotic component; maximum relative cerebral blood volume ratio (rCBV ratio) of NE and CE portions; and minimum apparent diffusion coefficient (ADC) of NE and CE portions, among others. Molecular profiles including ATRX expression and p53 mutation were reviewed to find correlation with imaging features. RESULTS: Thalamus was the most commonly involved location, followed by pons and tectum. Five patients showed loss of normal ATRX expression. p53 mutation was positive in 12 patients. 40% of normal ATRX expression patients had cortical involvement and 20% had leptomeningeal seeding; none of the patients with ATRX loss had cortical involvement or leptomeningeal seeding. Patients with normal ATRX expression showed significantly higher rCBV ratio and lower ADC value in the NE area than patients with ATRX loss (P=0.04, 0.016). p53 mutation status did not correlate with any imaging finding. CONCLUSION: Cortical invasion, leptomeningeal tumor spread, lower ADC value and higher rCBV ratio in NE areas of DMG may be related to normal expression of ATRX.

Association between serum uric acid and spirometric pulmonary function in Korean adults: The 2016 Korea National Health and Nutrition Examination Survey.

BACKGROUND: A limited number of epidemiological studies have investigated the association between serum uric acid and pulmonary function in the general population. However, the results have been inconclusive. OBJECTIVES: This study was performed to investigate the association between serum uric acid and spirometric pulmonary function in general population. METHODS: Among the 8,150 participants who participated in the 2016 Korea National Health and Nutrition Examination Survey, 2,901 participants were analyzed in this study. Subjects were divided into four groups according to forced vital capacity (FVC)% predicted or forced expiratory volume in 1 second (FEV1) % predicted quartiles. Participants in the lowest quartile of FVC % predicted and FEV1% predicted were compared to those in the remaining quartiles according to age, education level, household income, smoking status, alcohol consumption, aerobic exercise, obesity, hypertension, diabetes, renal impairment, serum uric acid, and hyperuricemia. Multivariable logistic regression analyses were used to calculate the odds ratio (OR) of hyperuricemia for participants in the lowest quartile of FVC% and FEV1 predicted, with above covariates. RESULTS: In women, hyperuricemia was associated with lowest quartile of FVC% predicted (OR 1.71, 95% CI 1.06-2.75, p = 0.027) and FEV1 predicted (OR 1.70, 95% CI 1.06-2.74, p = 0.028) respectively, serving as above confounding variables. In men, hyperuricemia (OR 1.54, 95% CI 1.07-2.22, p = 0.021) was associated with the lowest quartile of FEV1% predicted, not FVC% predicted. According to median age, in women, age ≥ 56 years old with hyperuricemia was associated with lowest quartile of FVC% predicted (OR 1.85, 95% CI 1.04-3.28, p = 0.037) and FEV1% predicted (OR 1.99, 95% CI 1.11-3.75, p = 0.021), respectively. In men, age ≥ 56 years old with hyperuricemia was associated with lowest quartile of FEV1% predicted (OR 1.75, 95% CI 1.05-2.94, p = 0.033), not FCV% predicted. CONCLUSIONS: Hyperuricemia was associated with lowest quartile of FEV1% or FVC% predicted in Korean general population. This correlation between hyperuricemia and low pulmonary function was more pronounced in women and older age.

The prevalence of and demographic factors associated with radiographic knee osteoarthritis in Korean adults aged ≥ 50 years: The 2010-2013 Korea National Health and Nutrition Examination Survey.

BACKGROUND: To reduce the social burden of knee osteoarthritis (OA) by addressing it in the early stages in the population at greatest risk, the epidemiology of knee OA needs to be understood and associated demographic factors need to be identified. OBJECTIVES: We evaluated the weighted prevalence of and demographic factors associated with radiographic knee OA in Korean adults. METHODS: We analyzed data from 12,287 individuals aged ≥ 50 years who had radiographs of the knee taken in the 2010-2013 Korea National Health and Nutrition Examination Survey (KNHANES). Radiographic knee OA was defined based on the Kellgren-Lawrence grade, as follows: 0: No abnormal finding 1: Mild degenerative changes, minute osteophytes 2: Mild knee OA, definite osteophytes 3: Moderate knee OA, moderate joint-space narrowing and definite osteophytes 4: Severe knee OA, severe joint-space narrowing with subchondral sclerosis. RESULTS: We found that the prevalence of radiographic knee OA in the Korean adult population was 35.1%. Logistic regression analyses were performed to identify factors associated independently with radiographic knee OA, with age, sex, area of residence, education level, household income, and obesity serving as covariates. Women were at greater risk than men of having knee OA (OR 2.12, 95% CI 1.90-2.37, p < 0.001). Compared with subjects aged 50-59 years, adults aged ≥ 80 years were at 8.87-fold (95% CI 7.12-11.06, p < 0.001) greater risk of having knee OA. Residence in a rural area was associated with a greater risk of having radiographic knee OA than was residence in an urban area (OR 1.26, 95% CI 1.08-1.48, p = 0.004), regardless of knee OA severity (Kellgren-Lawrence grades ≥2, ≥3, and 4). Elementary school graduates had 1.71-fold (p < 0.001) greater risks of having knee OA than did college graduates. Household incomes ≤24th percentile were associated with a greater risk of having knee OA compared with those ≥75th percentile (OR 1.28, 95% CI 1.08-1.52, p = 0.004). Obesity was associated with an approximately two-fold greater risk of knee OA, regardless of knee OA severity (Kellgren-Lawrence grades ≥2, ≥3, and 4). CONCLUSIONS: Using data from the 2010-2013 KNHANES and defining knee OA as Kellgren-Lawrence grade ≥ 2, we found that the prevalence of radiographic knee OA was 35.1% (24.4% in men, 44.3% in women) in a representative sample of Korean adults aged ≥ 50 years, with the highest prevalence (78.7%) observed in women aged ≥ 80 years. Low socioeconomic status and traditional factors, including age, female sex, and obesity, were associated with the risk of knee OA.

STING signaling is a potential immunotherapeutic target in colorectal cancer.

Background: Stimulator of Interferon Genes (STING) is an innate immune sensor for cytosolic DNA. STING signaling activation is indispensable for type I interferon response and the anti-cancer immune response by CD8+ T cells. The aim of this study was to characterize intratumoral STING expression pattern and its clinical implication in colorectal cancer (CRC). Methods: We analyzed STING and CD8 expression in 225 CRC patients who underwent surgical resection. Clinicopathological variables and survival outcomes were analyzed according to STING expression levels. Mice with syngeneic MC38 tumors were also treated with a STING agonist, and tumor microenvironments were analyzed using immunofluorescent staining and flow cytometry. Results: Distinct STING expression was observed in the CRC tumor specimens. Patients with higher STING expression had early stage cancer with increased intratumoral CD8+ T cell infiltration and less frequent lymphovascular invasion. Compared to CRC patients with lower STING expression, those with higher STING expression had longer overall and recurrence-free survival. Multivariate Cox regression model also revealed higher STING expression to be an independent prognostic factor for better overall survival. When MC38 colon tumors were treated with intratumoral injection of STING agonist, tumor growth was remarkably suppressed with increased intratumoral CD8+ T cell infiltration. Moreover, T-cell activation markers, ICOS and IFN-γ, were also upregulated in CD8+ T cells, indicating enhanced effector T cell function after STING treatment. Conclusion: We confirmed the distinct STING expression in CRC and demonstrated its independent prognostic value in survival outcomes. STING could be a potential therapeutic target that enhances anti-cancer immune response in CRC.

An Injectable Click-Crosslinked Hydrogel that Prolongs Dexamethasone Release from Dexamethasone-Loaded Microspheres.

Our purpose was to test whether a preparation of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepared using a monoaxial-nozzle ultrasonic atomizer with an 85% yield of the Dex-Ms preparation, encapsulation efficiency of 80%, and average particle size of 57 µm. Cx-HA was prepared via a click reaction between transcyclooctene (TCO)-modified HA (TCO-HA) and tetrazine (TET)-modified HA (TET-HA). The injectable formulations (Dex-Ms/PH and Dex-Ms/Cx-HA) were fabricated as suspensions and became a Dex-Ms-loaded hydrogel drug depot after injection into the subcutaneous tissue of Sprague Dawley rats. Dex-Ms alone also formed a drug depot after injection. The Cx-HA hydrogel persisted in vivo for 28 days, but the PH hydrogel disappeared within six days, as evidenced by in vivo near-infrared fluorescence imaging. The in vitro and in vivo cumulative release of Dex by Dex-Ms/Cx-HA was much slower in the early days, followed by sustained release for 28 days, compared with Dex-Ms alone and Dex-Ms/PH. The reason was that the Cx-HA hydrogel acted as an external gel matrix for Dex-Ms, resulting in the retarded release of Dex from Dex-Ms. Therefore, we achieved significantly extended duration of a Dex release from an in vivo Dex-Ms-loaded hydrogel drug depot formed by Dex-Ms wrapped in an injectable click-crosslinked HA hydrogel in a minimally invasive manner. In conclusion, the Dex-Ms/Cx-HA drug depot described in this work showed excellent performance on extended in vivo delivery of Dex.

Association between subclinical thyroid dysfunction and depressive symptoms in the Korean adult population: The 2014 Korea National Health and Nutrition Examination Survey.

BACKGROUND: Clinical hyper and hypothyroidism are associated with a risk for depression. OBJECTIVES: This study was performed to investigate the association between depressive symptoms and subclinical thyroid dysfunction. METHODS: Among the 7,550 subjects who participated in the 2014 Korea National Health and Nutrition Examination Survey, 1,763 participants without overt thyroid disease were included in this study. Serum thyroid stimulating hormone (TSH), serum free thyroxine (fT4), and depressive symptoms were analyzed based on the Patient Health Questionnaire (PHQ9). RESULTS: The percentages of subjects with subclinical hypothyroidism and subclinical hyperthyroidism were 3.3% and 2.6%, respectively. The percentages of subjects with moderate (10-14 points), moderately severe (15-19 points), and severe (≥20 points) depression according to the distribution of PHQ-9 scores were 4.7%, 1.1%, and 0.3%, respectively. TSH, fT4, and the percentage of patients with subclinical hypothyroidism were not significantly associated with PHQ-9 score. However, the percentage of patients with subclinical hyperthyroidism increased significantly with PHQ9 score (P = 0.002). Subjects with subclinical hyperthyroidism had higher PHQ-9 scores than those with normal thyroid function (mean ± standard error [SE], 4.2 ± 0.5 vs. 2.7 ± 0.1 points, P = 0.010). More subjects with subclinical hyperthyroidism had a PHQ9 score ≥ 10 than did those with normal thyroid function (mean ± SE, 17.1 ± 3.5 vs. 5.8 ± 0.6%, P = 0.005). We performed logistic regression analyses for the presence of depressive symptoms, using age, sex, education, household income, alcohol drinking, smoking, diabetes, cerebrovascular disease history, subclinical hypothyroidism, and subclinical hyperthyroidism as variables. Subclinical hyperthyroidism was associated with the presence of clinically relevant depression (PHQ9 score ≥ 10), (odds ratio [OR], 4.04; 95% confidence interval [CI], 1.75-9.31; P = 0.001), and clinically significant depression (PHQ9 score ≥ 15), (OR, 7.05; 95% CI, 1.67-29.67; P = 0.008), respectively. However, subclinical hypothyroidism was not associated with the presence of clinically relevant depression (OR, 1.15; 95% CI, 0.39-3.38; P = 0.800), or clinically significant depression (OR, 3.35; 95% CI, 0.71-15.79; P = 0.127). CONCLUSIONS: We demonstrated that subclinical hyperthyroidism was independently associated with depressive symptoms in the Korean general population using national cross-sectional data.

The Status and Distinct Characteristics of Endocrine Diseases in North Korean Articles Published between 2006 and 2015.

BACKGROUND: Past decades of division have led to substantial differences in medical environments between South and North Korea. However, little is known about North Korea's medical status and research field, especially regarding endocrinology. In this study, we report the characteristics of North Korea's articles regarding endocrine-related diseases. METHODS: Among the nine medical journals, articles published in Internal Medicine between 2006 and 2015 were reviewed. A total of 2,092 articles were included; among them, 96 articles were associated with endocrinology. We analyzed these articles according to the disease categories they focused on and evaluated their features. RESULTS: Articles related to diabetes mellitus accounted for 55.2% (n=53) and those to thyroid disease accounted for 28.1% (n=27). Other disease categories, including adrenal gland (n=1), pituitary gland (n=1), and osteoporosis (n=3), comprised minor portions. Regarding diabetes mellitus, more than half the articles (n=33) focused on treatment and complications. Experimental studies were conducted with old hypoglycemic drugs or natural substances for the treatment of hyperglycemia. Regarding thyroid disease, articles related to hyperthyroidism were the most common (51.9%, n=14), followed by thyroid nodule/cancer (18.5%, n=5). Unique article features were short length, no figures, and less than five references. CONCLUSION: North Korea's endocrinology articles mainly focused on diabetes mellitus and thyroid disease. Persistent studies have been carried out in North Korea with dedication despite the poor medical environment. We hope that this study will be the beginning of mutual medical exchange and collaboration between North and South Korea.

The prevalence of and factors associated with urinary cotinine-verified smoking in Korean adults: The 2008-2011 Korea National Health and Nutrition Examination Survey.

BACKGROUND: Smoking rate based on self-reporting questionnaire might be underestimated. Cotinine is the principal metabolite of nicotine and is considered an accurate biomarker of exposure to cigarette smoke. OBJECTIVES: This study evaluated the prevalence of and factors associated with urinary cotinine-verified smoking in Korean adults. METHODS: We analyzed data from 12,110 adults in the 2008-2011 Korea National Health and Nutrition Examination Survey (KNHANES), using three threshold levels of urinary cotinine ≥100ng/ml, ≥50ng/ml, and ≥30ng/ml. RESULTS: The weighted prevalence of urinary cotinine levels of ≥100, ≥50, and ≥30 ng/mL in the whole study population was 34.7%, 37.1%, and 41.1%, respectively. Male sex, younger age, elementary school graduation, household income in the ≤24th percentile, service and sales workers and assembly workers, and high-risk alcohol drinking were associated with a higher prevalence of urinary cotinine level of ≥ 50 or 30 ng/mL, after we adjusted for age, sex, education level, number of family members, household income, occupation, and alcohol drinking. Logistic regression analyses were performed using the aforementioned variables as covariates to identify factors independently associated with cotinine-verified smoking. Men had a higher risk than women of having a urinary cotinine level of ≥50 ng/mL (OR 4.67, 95% CI 4.09-5.32, p < 0.001). When subjects ages 19-29 years were used as controls, adults ages 30-39 years had a 1.19-fold (CI 1.02-1.39, p = 0.026) higher risk of having a urinary cotinine level of ≥50 ng/mL. College graduates had a 32% lower risk of having a urinary cotinine level of ≥50 ng/mL than elementary school graduates (p < 0.001). A household income in the 25-49th percentile (OR 0.82, 95% CI 0.69-0.98, p = 0.026), 50-74th percentile (OR 0.64, 95% CI 0.53-0.76, p < 0.001), or ≥75th percentile (OR 0.64, 95% CI 0.53-0.77, p < 0.001) was associated with a lower risk of having a urinary cotinine level of ≥50 ng/mL compared to a household income in the ≤24th percentile. High-risk (OR 2.75, 95% CI 2.37-3.18, p < 0.001) and intermediate-risk (OR 2.04, 95% CI 1.82-2.30, p < 0.001) alcohol drinking were associated with having a urinary cotinine level of ≥50 ng/mL compared to low-risk alcohol drinking. Similar to the results of the logistic regression analyses of urinary cotinine ≥50 ng/mL, male sex, younger age, elementary school education, household income in the ≤24th percentile, and high-risk alcohol drinking were significantly associated with having a urinary cotinine level of ≥30 ng/mL. Service and sales workers (OR 1.22, 95% CI 1.01-1.48, p = 0.041) had a significantly higher risk of having a urinary cotinine level of ≥30 ng/mL. CONCLUSIONS: Based on a threshold urinary cotinine level of 50 ng/mL, the prevalence of cotinine-verified smoking in a representative sample of Korean adults was 37.1% (men 52.7%, women 15.4%). Younger age, male sex, low education level, service and sales workers, low household income, and high-risk alcohol drinking were associated with the risk of smoking.

Author Correction: Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective.

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Association between White Blood Cell Counts within Normal Range and Hemoglobin A1c in a Korean Population.

BACKGROUND: We examined whether white blood cell (WBC) count levels within normal range, could be associated with hemoglobin A1c (HbA1c) levels. METHODS: Among the 11,472 people (≥19 years of age) who participated in the 2011 to 2012 Korea National Health and Nutrition Examination, subjects with chronic disease or illness, including 807 patients with diabetes currently taking anti-diabetic medications and/or 1,149 subjects with WBC levels <4,000 or >10,000/µL were excluded. RESULTS: Overall, adjusted HbA1c levels increased across the WBC quartiles (5.55%±0.01%, 5.58%±0.01%, 5.60%±0.01%, and 5.65%±0.01%, P<0.001) after adjusting for confounding factors, such as age, gender, fasting plasma glucose, college graduation, smoking history, waist circumference, presence of hypertension, serum total cholesterol, serum triglyceride, and presence of anemia. The adjusted proportions (%) of HbA1c levels of ≥5.7%, ≥6.1%, and ≥6.5% showed significant increases across WBC quartiles (P<0.001, P=0.002, and P=0.022, respectively). Logistic regression analyses of WBC quartiles for the risk of HbA1c levels of ≥5.7%, ≥6.1%, and ≥6.5%, using the variables above as covariates, showed that the odds ratios of the fourth quartile of WBCs were 1.59 (95% confidence interval [CI], 1.35 to 1.89; P<0.001), 1.78 (95% CI, 1.31 to 2.42; P<0.001), and 2.03 (95% CI, 1.13 to 3.64; P=0.018), using the first quartile of WBCs as the reference. CONCLUSION: HbA1c levels were positively associated with WBC levels within normal range in a general adult population.

Thermoresponsive and Biodegradable Amphiphilic Block Copolymers with Pendant Functional Groups.

BACKGROUND: To develop the biodegradability and thermoresponsive hydrogel, in this work we designed a pendant-functionalized, thermoresponsive, amphiphilic block copolymer. METHODS: Methoxy poly(ethylene glycol) (MPEG)-b-[poly(ε-caprolactone)-ran-poly(ε-caprolactone-3-one)-ran-polylactic acid] (MCL) and (MPEG-b-[PCL-ran-POD-ran-PLA]) [MCL-(CO)] block copolymers were prepared by ring-opening polymerization of ε-caprolactone, OD and lactide monomers. The subsequent derivatization of MCL-(CO) provided MPEG-b-[PCL-ran-poly(ε-caprolactone-3-COOH)-ran-PLA] [MCL-(COOH)] with COOH pendant groups and MPEG-b-[PCL-ran-poly(ε-caprolactone-3-NH2)-ran-PLA] [MCL-(NH2)] with NH2 pendant groups. RESULTS: The measured segment ratios of MCL-(CO), MCL-(COOH), and MCL-(NH2) agreed well with the target ratios. The abundances of the COOH and NH2 groups in the MCL-(COOH) and MCL-(NH2) copolymers were determined by 1H- and 13C-nuclear magnetic resonance spectroscopy, and agreed well with the target abundances. MCL-(CO), MCL-(COOH), and MCL-(NH2) formed homogeneous, white, opaque emulsions at room temperature. Rheological analysis of the block copolymer suspensions indicated a solution-to-hydrogel phase transition as a function of temperature. The solution-to-hydrogel phase transitions and the biodegradation of MCL-(CO), MCL-(COOH), and MCL-(NH2) were affected by varying the type (ketone, COOH, or NH2) and abundance of the pendant groups. CONCLUSION: MCL-(CO), MCL-(COOH), and MCL-(NH2) with ketone, COOH, and NH2 pendant groups showed solution-to-hydrogel phase transitions and biodegradation behaviors that depended on both the type and number of pendant groups.

Electrostatically Interactive Injectable Hydrogels for Drug Delivery.

BACKGROUND: Several injectable hydrogels have been developed extensively for a broad range of biomedical applications. Injectable hydrogels forming in situ through the change in external stimuli have the distinct properties of easy management and minimal invasiveness, and thus provide the advantage of bypassing surgical procedures for administration resulting in better patient compliance. METHODS: The injectable in situ-forming hydrogels can be formed irreversibly or reversibly under physiological stimuli. Among several external stimuli that induce formation of hydrogels in situ, in this review, we focused on the electrostatic interactions as the most simple and interesting stimulus. RESULTS: Currently, numerous polyelectrolytes have been reported as potential electrostatically interactive in situ-forming hydrogels. In this review, a comprehensive overview of the rapidly developing electrostatically interactive in situ-forming hydrogels, which are produced by various anionic and cationic polyelectrolytes such as chitosan, celluloses, and alginates, has been outlined and summarized. Further, their biomedical applications have also been discussed. CONCLUSION: The review concludes with perspectives on the future of electrostatically interactive in situ-forming hydrogels.

Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective.

The current in vitro or in vivo intestinal fibrosis models have many limitations. Recent advancements in the isolation and culturing of organoids has led to development of various three-dimensional (3D) intestinal disease models with in vivo physiology. In this study, we generated an organoid-based epithelial to mesenchymal transition (OEMT) model, which could be used as a novel intestinal fibrosis model. Intestinal epithelial organoids (IEOs) were isolated and cultured from the small intestines of normal mice. IEOs were treated with transforming growth factor- ß1 (TGF-ß1) or Tumor necrosis factor-α (TNF-α) to evaluate their phenotypic change. Raw 264.7 cells (macrophage) stimulated with lipopolysaccharide were co-cultured with IEOs in growth media with or without TGF-ß1. TGF-ß1 alone slightly induced epithelial to mesenchymal transition (EMT) in the IEOs but mainly disrupted them. Macrophage released cytokines synergistically induced mesenchymal phenotypic changes in TGF-ß1 stimulated intestinal organoids. TNF-α and TGF-ß1 synergistically induced proliferation of mesenchymal cells as well as EMT in the IEOs. We generated a novel OEMT model based on our finding that TNF-α and TGF-ß synergistically induce type 2 EMT in IEOs. This 3D EMT model with in vivo physiology could be used to study EMT associated intestinal fibrosis.