Congenital heart disease (CHD) is now more common in adults than in children due to improvements in fetal echo, neonatal and pediatric care, and surgical techniques leading to dramatically increased survivability into adulthood. Adult patients with CHD, regardless of prior cardiac surgery, experience further cardiac problems or therapeutic challenges; therefore, a non-invasive, easily accessible echocardiographic examination is an essential follow-up tool. Among echocardiographic modalities, three-dimensional (3D) echocardiography provides better delineation of spatial relationships in complex cardiac geometries and more accurate volumetric information without geometric assumptions. For atrial septal defects, an en face view of the tissue defect allows better decisions on device closure. For tricuspid valve malformations, an en face view provides diagnostic information that is difficult to obtain from routine 2D tomography. In repaired tetralogy of fallot with pulmonary regurgitation, preoperative 3D echocardiography-based right ventricular volume may be used to determine the timing of a pulmonary valve replacement in conjunction with cardiovascular magnetic imaging. For optimal adult CHD care, 3D echocardiography is an important complement to routine 2D echocardiography.

A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors (HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through $HIF-1{\alpha}$ and $HIF-2{\alpha}$. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.

Interstitial lung disease (ILD) occurs in 15% of patients with collagen vascular disease (CVD), referred to as connective tissue disease (CTD). Despite advances in management strategies, ILD continues to be a significant cause of mortality in patients with CVD-associated ILD (CTD-ILD). There is a lack of randomized, clinical trials assessing pharmacological agents for CTD-ILD, except in cases of ILD-associated systemic sclerosis (SSc). This may be due to the lack of CTD cases available, the difficulty of histological confirmation of ILD, and the various types of CTD and ILD. As a result, evidence-based pharmacological treatment of CTD-ILD is not yet well established. CTD-ILD presents with varying degrees of histology, from inflammation to fibrosis, and a wide spectrum of clinical manifestations, from minimal symptoms to respiratory failure. This renders it difficult for clinicians to make decisions regarding treatment options, observational strategies, optimal timing for interventions, and the appropriateness of pharmacological agents for treatment. There is no specific treatment for reversing fibrosis-like idiopathic pulmonary fibrosis in a clinical setting. This review describes pharmacological interventions for SSc-ILD described in randomized control trials, and presents an overview of recent advances of CTD-ILD-dependent treatments based on the types of CTD.

Obesity is associated with a reduced life expectancy, largely because obese individuals are at an increased risk of type 2 diabetes, cardiovascular disease, and several types of cancer. Much interest has recently focused on the concept of "all obesity is not created equally." Obese individuals without the metabolic abnormalities that commonly accompany excess adiposity, a condition known as metabolically healthy obesity (MHO), account for a substantial proportion of the obese adult population. Numerous possible mechanisms underlying MHO have been suggested, including adipose tissue distribution and inflammation. However, the prognostic value of MHO is controversial and considerably challenging. The lack of a standard definition for metabolic health and obesity as well as the dynamic properties of MHO may have contributed to these inconsistent results. This review aimed to present several current issues regarding MHO including its definition, epidemiology, natural course, suggested mechanisms, and clinical implications in the context of patient prognosis.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease in Korea and worldwide, and is a risk factor for the development of cardiovascular complications. The conventional treatments for DKD are control of blood glucose and blood pressure levels by inhibiting the renin-angiotensin system. However, the prevalence of DKD continues to increase and additional therapies are required to prevent or ameliorate the condition. Many drugs have been, or are being, developed to target the molecular mechanisms in play in DKD. This review focuses on DVD treatment, considering current and emerging therapeutic targets and the clinical trial-based evidence.

Background/Aims: Entecavir is a potent nucleoside analogue with high efficacy and barrier for resistance. We aimed to investigate the long-term efficacy and viral resistance rate of entecavir and explore the factors associated with virologic response, including quantitative hepatitis B surface antigen (qHBsAg) levels. Methods: One thousand and nine treatment-naïve chronic hepatitis B (CHB) patients were evaluated for cumulative rates of virologic response, biochemical response, and entecavir mutations. The role of baseline qHBsAg for virologic response was assessed in 271 patients with qHBsAg prior to entecavir treatment. Results: The median duration of entecavir treatment was 26.5 months. The cumulative rate of virologic response at years 1, 3, and 5 were 79.0%, 95.6%, and 99.4%, respectively. The cumulative rate of entecavir resistance was 1.0% and 2.1% in years 3 and 5. Multivariate analysis identified baseline hepatitis B e antigen (HBeAg) negative status (p < 0.001) and lower hepatitis B virus (HBV) DNA (p < 0.001) as predictors of virologic response. Lower qHBsAg was an independent predictor of virologic response in patients with baseline qHBsAg. There were no serious adverse events during treatment. Conclusions: Long-term entecavir treatment of nucleos(t)ide-naïve CHB patients was associated with an excellent virologic response and a low rate of entecavir-resistant mutations at 5 years. Baseline HBV DNA load, qHBsAg levels, and HBeAg status were predictors of virologic response during entecavir treatment.

Background/Aims: Endoscopic resection (ER) is a well-established treatment modality for gastric epithelial neoplasm. However, there is a discrepancy between forceps biopsy and ER specimen pathology, including a negative pathologic diagnosis (NPD) after ER. It has been suggested that pit dysplasia (PD) is a subtype of gastric dysplasia, and the aim of this study was to assess the significance of PD in cases with NPD after ER for early gastric neoplasms. Methods: After ER, 29 NPD lesions that had an associated pretreatment forceps biopsy specimen, were correctly targeted during ER, and had no cautery artifact on the resected specimen were included in this study. Results: Sixteen lesions showed PD and 13 had no neoplastic pathology. The initial pretreatment forceps biopsy diagnoses of 29 NPD lesions were low-grade dysplasia (LGD) in 17 lesions, high-grade dysplasia (HGD) in seven lesions, and adenocarcinoma in five lesions, which after review were revised to PD in 19 lesions, LGD in four lesions, adenocarcinoma in two lesions, and no neoplastic pathology in four lesions. Overall, nine lesions (31%) were small enough to be removed by forceps biopsy, four NPD lesions (14%) were initially misinterpreted as neoplastic lesions, and 16 PD lesions (55%) were misinterpreted as NPD lesions on ER slides. Conclusions: Approximately half of the lesions initially diagnosed as LGD or HGD were subsequently classified as PD. Therefore, including PD as a subtype of gastric dysplasia could reduce the diagnostic discrepancy between initial forceps biopsy and ER specimens.

Background/Aims: We evaluated the efficacy and safety and influence on glucose tolerance by different doses of pitavastatins in acute myocardial infarction (AMI) patients. Methods: Consecutive 1,101 AMI patients who were enrolled in Livalo in Acute Myocardial Infarction Study (LAMIS)-II were randomly assigned to receive either 2 mg of pitavastatin or 4 mg of pitavastatin orally per day. Primary efficacy endpoint was composite of cardiac death, nonfatal myocardial infarction, target-lesion revascularization, and hospitalization for unstable angina, heart failure or arrhythmic events at 12-month. Results: There was no significant difference in primary efficacy endpoint between 2 mg and 4 mg groups (9.07% vs. 9.13%, p = 0.976). The degree of the reduction of low density lipoprotein cholesterol (LDL-C) was significantly greater in 4 mg group compared to 2 mg group from baseline to follow-up ($-42.05{\pm}32.73mg/dL$ vs. $-34.23{\pm}31.66mg/dL$, p = 0.002). Fasting plasma glucose level was reduced significantly in both groups ($-20.16{\pm}54.49mg/dL$ in 4 mg group and $-24.45{\pm}63.88mg/dL$ in 2 mg group, p < 0.001 and p < 0.001, respectively) and there was no significant change of glycated hemoglobin in two groups from baseline to follow-up ($-0.13%{\pm}1.21%$ in 4 mg group and $-0.04%{\pm}1.10%$ in 2 mg group, p = 0.256 and p = 0.671, respectively). Conclusions: Although LDL-C was reduced more significantly by using 4 mg of pitavastatin compared to 2 mg of pitavastatin, the event rate was comparable without adverse effects on glucose tolerance in both groups in AMI patients who were enrolled in LAMIS-II.

Background/Aims: Recent studies have shown an association of epicardial fat thickness with diabetes and hypertension (HTN) in asymptomatic populations. However, there is lack of information as to whether there is similar association between pericoronary adipose tissue (PAT) and HTN in the patients who have acute or chronic illness. Methods: This study included 214 nonobese patients hospitalized with acute or chronic noncardiogenic illness. PAT thicknesses were measured from fat tissues surrounding left and right coronary arteries in enhanced, chest computed tomography scans, yielding the maximal PAT value from left and right coronary arteries was used for analysis. Baseline data from hypertensive (n = 81) and normotensive (n = 133) patients were collected and compared. Results: PAT is positively correlated with age (r = 0.377, p <0.001), body mass index (BMI; r = 0.305, p < 0.001), systolic blood pressure (r = 0.216, p = 0.001), and total cholesterol (r = 0.200, p = 0.006). The hypertensive group was older ($69.58{\pm}11.69years$ vs. $60.29{\pm}14.98years$), and had higher PAT content ($16.30{\pm}5.37mm$ vs. $13.06{\pm}5.58mm$) and BMI ($23.14{\pm}3.32kg/m^2$ vs. $20.96{\pm}3.28kg/m^2$) than the normotensive group (all p < 0.001). Multivariate analysis showed that age (odds ratio [OR], 2.193; p = 0.016), PAT thickness (OR, 1.065; p = 0.041), and BMI ($25{\leq}BMI$ < $30kg/m^2$; OR, 6.077; p = 0.001) were independent risk factors for HTN. Conclusions: In nonobese patients with noncardiogenic acute or chronic illness, PAT thickness is independently correlated with HTN, age, and BMI.

Background/Aims: This study evaluated clinical characteristics and outcomes in very elderly (${\geq}80$ years of age) critical-ill patients admitted to a medical intensive care unit (MICU) in a regional single tertiary hospital. Methods: We retrospectively evaluated prospectively collected data in the MICU for the period of December 2011 to May 2014. Patients were divided into ${\geq}80$ and < 80 years of age and clinical characteristics and outcomes were compared among these patients. Results: A total of 468 patients were evaluated and 102 patients (21.7%) were ${\geq}80$ years of age. Overall mortality was 38.5% in the intensive care unit (ICU) and 44.7% in the hospital. There was no significant difference in ICU and in-hospital mortalities between those ${\geq}80years$ and those < 80 years (34.9% vs. 39.5% for ICU mortality; 40.6% vs. 45.9% for in-hospital mortality). Lengths of ICU and hospital stays were significantly longer in patients < 80 years compared to patients ${\geq}80years$ ($10.57{\pm}19.96days$ vs. $8.19{\pm}8.78days$ for ICU stay; $27.95{\pm}39.62days$ vs. $18.17{\pm}15.44days$ for hospital stay). The rate of withholding intensive care in hospital stay over 48 hours was significantly higher in patients ${\geq}80years$ compared to patients < 80 years (22.9% vs. 11.8%). In multivariate analysis, weaning failure and withdrawal or withholding of intensive care in ICU was significantly related to death in patients with age ${\geq}80$. Conclusions: Clinical outcomes were not significantly different for very elderly critical-ill patients compared to those of their younger counterparts in the MICU in this study.

Background/Aims: An association between reduced pulmonary function and diabetes has been observed. Our aim was to evaluate the prevalence and risk factors associated with reduced pulmonary function in diabetic patients. Methods: We analyzed data from the Korea National Health and Nutrition Examination Survey 2011 to 2013. The study population included data from 8,784 participants (including 1,431 diabetics) aged ${\geq}40years$. Reduced pulmonary function was defined as patients with restrictive (forced expiratory volume in 1 second/forced vital capacity $[FEV_1/FVC]{\geq}0.7$ and FVC < 80% of predicted value) or obstructive ($FEV_1/FVC$ < 0.7) patterns. Results: Subjects with diabetes had a higher prevalence of restrictive (18.4% vs. 9.4%, p < 0.001) and obstructive impairments (20% vs. 12.6%, p < 0.001) than those without diabetes. The adjusted odds ratios (aORs) (95% confidence interval [CI]) for obstructive and restrictive pulmonary impairment were 0.91 (0.75 to 1.11) and 1.57 (1.30 to 1.89), respectively. In the diabetes population, age (aOR, 1.04; 95% CI, 1.02 to 1.06), male sex (aOR, 1.40; 95% CI, 1.04 to 1.88), and body mass index (aOR, 1.15; 95% CI, 1.10 to 1.21) were independently associated with restrictive pulmonary impairment. Age (aOR, 1.12; 95% CI, 1.09 to 1.14), male sex (aOR, 4.24; 95% CI, 2.42 to 7.44), and smoking at any point (ever-smoker: aOR, 1.96; 95% CI, 1.16 to 3.33) were independent risk factors for obstructive pulmonary impairment in diabetics. Diabetes duration or glycated hemoglobin had no association with pulmonary impairment in diabetes. Conclusions: Subjects with diabetes had a higher risk of restrictive pulmonary impairment than those without diabetes after adjusting for confounding factors. Older age, male sex, body mass index, and smoking were associated with reduced lung function in diabetes.

Background/Aims: Although increased serum $anti-M{\ddot{u}}llerian$ hormone (AMH) level has been suggested to be a surrogate marker of polycystic ovarian morphology (PCOM), its association with polycystic ovary syndrome (PCOS) is controversial, and its diagnostic value has not been determined. We aimed to observe the relationship between the AMH level and PCOS phenotypes and to determine the optimal cutoff value of AMH for the diagnosis of PCOS in young Korean women. Methods: We recruited 207 women with PCOS (120 with PCOM and 87 without PCOM) and 220 regular cycling women with normoandrogenemia (100 with PCOM and 120 without PCOM). Subjects underwent testing at a single outpatient visit. Serum AMH level was measured. Results: Women with PCOS had higher serum AMH levels than did regular cycling women with normoandrogenemia (p < 0.05). Women with PCOM had higher serum AMH levels than women without PCOM, regardless of PCOS status (p < 0.05). The optimal AMH cutoff value for the diagnosis of PCOS was 10.0 ng/mL (71% sensitivity, 93% specificity). Serum AMH was an independent determinant of total testosterone after adjustment for age, body mass index, and the number of menses/year (${\beta}=0.31$, p < 0.01). An association between AMH and hyperandrogenism was only observed in women with PCOS, and it was independent of the presence of PCOM. Conclusion: The serum AMH level can be useful for the diagnosis of PCOS at any age less than 40 years, and the optimal cutoff value for the diagnosis of PCOS identified in this study of young Korean women was 10.0 ng/mL.

Background/Aims: Since comorbidities are major determinants of modality choice, and also interact with dialysis modality on mortality outcomes, we examined the pattern of modality choice according to comorbidities and then evaluated how such choices affected mortality in incident dialysis patients. Methods: We analyzed 32,280 incident dialysis patients in Korea. Patterns in initial dialysis choice were assessed by multivariate logistic regression analyses. Multivariate Poisson regression analyses were performed to evaluate the effects of interactions between comorbidities and dialysis modality on mortality and to quantify these interactions using the synergy factor. Results: Prior histories of myocardial infarction (p = 0.031), diabetes (p = 0.001), and congestive heart failure (p = 0.003) were independent factors favoring the initiation with peritoneal dialysis (PD), but were associated with increased mortality with PD. In contrast, a history of cerebrovascular disease and 1-year increase in age favored initiation with hemodialysis (HD) and were related to a survival benefit with HD (p < 0.001, both). While favoring initiation with HD, having Medical Aid (p = 0.001) and male gender (p = 0.047) were related to increased mortality with HD. Furthermore, although the severity of comorbidities did not inf luence dialysis modality choice, mortality in incident PD patients was significantly higher compared to that in HD patients as the severity of comorbidities increased (p for trend < 0.001). Conclusions: Some comorbidities exerted independent effects on initial choice of dialysis modality, but this choice did not always lead to the best results. Further analyses of the pattern of choosing dialysis modality according to baseline comorbid conditions and related consequent mortality outcomes are needed.

Background/Aims: The aims of this study were to identify the value of inflammatory markers as pretreatment prognostic factors for patients with multiple myeloma (MM) and to estimate the value of a prognostic index including these markers at diagnosis. Methods: A total of 273 newly diagnosed MM patients undergoing active treatment were analyzed in this study. The prognostic values for survival of the pretreatment inflammatory markers were investigated. A myeloma prognostic index (MPI) was derived using prognostic factors determined to be independently significant on multivariate analysis. Results: A high pretreatment neutrophil-lymphocyte ratio (NLR), low platelet count, and high C-reactive protein (CRP) level had independently unfavorable significance for overall survival (OS). The MPI was derived based on these factors. Per the MPI, 1 point each was assigned to high NLR, low platelet count, and high CRP. Risk categories were stratified into low- (score 0), intermediate- (score 1), and high-risk (score 2 or 3) groups. The MPI demonstrated independent statistical significance for OS on multivariate analysis ([intermediate: hazard ratio (HR), 1.91; 95% confidence interval (CI), 1.12 to 3.24] and [high: HR, 3.37; 95% CI, 2.00 to 5.69]; p < 0.001). Moreover, this significance could be observed regardless of age, renal function, and exposure to novel agents. In addition, the International Staging System risk group could be further significantly stratified using the MPI. Conclusions: The MPI, consisting of pretreatment inflammatory markers, NLR, platelet count, and CRP, might be effective in predicting the survival of newly diagnosed MM patients undergoing active treatment.

Background/Aims: Although multiple myeloma (MM) is typically a disease of the elderly, a certain subset of extremely young patients exists. It is necessary to establish clinicopathological characteristics for this population. Methods: We reviewed the medical records of MM patients whose age was 40 years or younger at diagnosis. Results: A total of 32 patients were analyzed (male to female ratio 19:13, median age 37 years). According to International Staging System, 29%, 48%, and 16% were in stage I, II, and III, respectively. Light chain myeloma accounted for 30%. Clinically significant anemia, hypercalcemia, azotemia, and hypoalbuminemia were present in 29%, 28%, 13%, and 28%, respectively. Three or more lytic bone lesions were detected in 45% of the patients, whereas 13% had no lytic bone lesions. Regarding treatment, 79% of patients received autologous hematopoietic stem cell transplantation. After a median follow-up duration of 64 months, the 1-, 3-, and 5-year overall survival (OS) rates were 84%, 62%, and 54%, respectively. The median OS was 61 months for the entire cohort. Conclusions: In our study, MM patients aged 40 years or younger at diagnosis showed no superior survival compared to those of the moderately elderly patients based on historical data.

Background/Aims: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV), a novel bunyavirus. As yet, there is no effective antiviral therapy for SFTS. Ribavirin is a broad-spectrum antiviral agent, which has been tried for treatment of SFTS. In this study, antiviral activity of ribavirin against SFTSV has been investigated. Methods: Vero cell-grown SFTSV strain Gangwon/Korea/2012 was treated with ribavirin at various concentrations. Antiviral activity of ribavirin was evaluated by inhibition of the SFTSV cytopathic effect in Vero cells and quantification of viral RNA load in culture supernatant using one-step real-time reverse transcription polymerase chain reaction. Cytotoxicity of ribavirin was determined by a tetrazolium-based colorimetric method. Results: Ribavirin reduced SFTSV titers in a dose-dependent manner, with a half-maximal inhibitory concentration ranged from 3.69 to $8.72{\mu}g/mL$. Cytopathic effects were reduced as ribavirin concentration increased. No significant cytotoxicity was detected at ribavirin concentrations of ${\leq}31.3{\mu}g/mL$. Conclusions: Ribavirin exhibited inhibitory activity against SFTSV replication in vitro, which suggests that ribavirin can be used as a potential antiviral agent for SFTS.

Background/Aims: To determine whether early diagnosis is beneficial for functional status of various disease durations in rheumatoid arthritis (RA) patients. Methods: A total of 4,540 RA patients were enrolled as part of the Korean Observational Study Network for Arthritis (KORONA). We defined early diagnosis as a lag time between symptom onset and RA diagnosis of ${\leq}12$ months, whereas patients with a longer lag time comprised the delayed diagnosis group. Demographic characteristics and outcomes were compared between early and delayed diagnosis groups. Logistic regression analyses were performed to identify the impact of early diagnosis on the development of functional disability in RA patients. Results: A total of 2,597 patients (57.2%) were included in the early diagnosis group. The average Health Assessment Questionnaire-Disability Index (HAQ-DI) score was higher in the delayed diagnosis group ($0.64{\pm}0.63$ vs. $0.70{\pm}0.66$, p < 0.01), and the proportion of patients with no functional disability (HAQ = 0) was higher in the early diagnosis group (22.9% vs. 20.0%, p = 0.02). In multivariable analyses, early diagnosis was independently associated with no functional disability (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.01 to 1.40). In a subgroup analysis according to disease duration, early diagnosis was associated with no functional disability in patients with disease duration < 5 years (OR, 1.37; 95% CI, 1.09 to 1.72) but not in patients with longer disease duration (for 5 to 10 years: OR, 1.07; 95% CI, 0.75 to 1.52; for ${\geq}10$ years: OR, 0.92; 95% CI, 0.65 to 1.28). Conclusions: Early diagnosis is associated with no functional disability, especially in patients with shorter disease duration.