Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. −0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (−55.20% vs. −7.69%, P<0.001) without previously unknown adverse drug events. Conclusion The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin’s preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Background: Coronary artery disease patients undergoing percutaneous coronary intervention (PCI) often exhibit reduced left ventricular ejection fraction (LVEF). However, the impact of LV dysfunction status in conjunction with platelet reactivity on clinical outcomes has not been previously investigated. Methods: From the multicenter PTRG-DES (Platelet function and genoType-Related long-term prognosis in DES-treated patients) consortium, the patients were classified as preserved-EF (PEF: LVEF ≥ 50%) and reduced-EF (REF: LVEF< 5 0%) group by echocardiography. Platelet reactivity was measured using VerifyNow P2Y 12 assay and high platelet reactivity (HPR) was defined as PRU ≥ 252. The major adverse cardiac and cerebrovascular events (MACCEs) were a composite of death, myocardial infarction, stent thrombosis and stroke at 5 years after PCI. Major bleeding was defined as Bleeding Academic Research Consortium bleeding types 3–5. Results: A total of 13,160 patients from PTRG-DES, 9,319 (79.6%) patients with the results of both PRU and LVEF were analyzed. The incidence of MACCE and major bleeding was higher in REF group as compared with PEF group (MACCEs: hazard ratio [HR] 2.17, P < 0.001, 95% confidence interval [CI] 1.85–2.55; major bleeding: HR 1.78, P < 0.001, 95% CI 1.39–2.78).The highest rate of MACCEs was found in patients with REF and HPR, and the difference between the groups was statistically significant (HR 3.14 in REF(+)/HPR(+) vs. PEF(+)/HPR(-) group,P <0.01, 95% CI 2.51–3.91). The frequency of major bleeding was not associated with the HPR in either group. Conclusion LV dysfunction was associated with an increased incidence of MACCEs and major bleeding in patients who underwent PCI. The HPR status further exhibited significant increase of MACCEs in patients with LV dysfunction in a large, real-world registry.Trial Registration: ClinicalTrials.gov Identifier: NCT04734028

Objective: To assess the influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida. Methods: A retrospective study was conducted using the Korean National Health Insurance Service database spanning from January 2005 to December 2019. All live-born offspring of nulligravida (n=3,685,817) were included. The maternal age was subdivided into the following subgroups: <25 years (n=153,818), 25-29 years (n=845,355), 30-34 years (n=1,738,299), 35-39 years (n=787,530), 40-44 years (n=151,519), and >44 years (n=9,296). Outcomes were assessed based on International Classification of Diseases-10 codes. Adjusted odds ratios (aOR) were calculated with the group of 25-29 years as a reference.Result Most congenital malformations showed an age dependent increase, but cleft lip and abdominal wall defect exhibited a U-shape curve, indicating an increase even in those <25 years old. Similarly, various disorders included in the neonatal composite outcomes from short-term outcomes showed aged dependent escalation. However, the preterm birth from the short-term outcome and most of the long-term developmental outcomes, except for motor developmental delay and Tics, showed a U-shaped pattern. The aOR of autism and cerebral palsy, showing the most obvious U-shaped curved in the long-term outcomes, was 1.50 (95% confidence interval [CI], 1.24-1.82) and 1.54 (95% CI, 1.17-2.03), respectively in the group >44 years old and 1.18 (95% CI, 1.11-1.25) and 1.19 (95% CI, 1.09-1.30) in <25 years old group. Conclusion Overall, an advanced maternal age has an age-dependent correlation with most congenital malformations and shortand long-term outcomes of neonates.

Background: Preeclampsia (PE) is known to arise from insufficient trophoblast invasion as uterine spiral arteries lack remodeling. A significant reduction in placental perfusion induces an ischemic placental microenvironment due to reduced oxygen delivery to the placenta and fetus, leading to oxidative stress. Mitochondria are involved in the regulation of cellular metabolism and the production of reactive oxygen species (ROS). NME/NM23 nuceloside diphosphate kinase 4 (NME4) gene is known to have the ability to supply nucleotide triphosphate and deoxynucleotide triphosphate for replication and transcription of mitochondria. Our study aimed to investigate changes in NME4 expression in PE using trophoblast stem-like cells (TSLCs) from induced pluripotent stem cells (iPSCs) as a model of early pregnancy and peripheral blood mononuclear cells (PBMNCs) as a model of late preterm pregnancy. Methods: Transcriptome analysis using TSLCs was performed to identify the candidate gene associated with the possible pathophysiology of PE. Then, the expression of NME4 associated with mitochondrial function, p53 associated with cell death, and thioredoxin (TRX) linked to ROS were investigated through qRT-PCR, western blotting and deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) assay. Results: In patients with PE, NME4 was significantly downregulated in TSLCs but upregulated in PBMNCs. p53 was shown to be upregulated in TSLCs and PBMNCs of PE. In addition, western blot analysis confirmed that TRX expression had the tendency to increase in TSLCs of PE. Similarly, TUNEL analysis confirmed that the dead cells were higher in PE than in normal pregnancy. Conclusion Our study showed that the expression of the NME4 differed between models of early and late preterm pregnancy of PE, and suggests that this expression pattern may be a potential biomarker for early diagnosis of PE.

Purpose: Data are limited on the long-term efficacy and safety of drug-coated balloon (DCB) treatment in comparison to drugeluting stent (DES) for de novo coronary lesions. We investigated the long-term clinical outcomes of DCB treatment in percutaneous coronary intervention (PCI) for de novo coronary lesions. Materials and Methods: A total of 103 patients scheduled for elective PCI for de novo non-small coronary lesions (≥2.5 mm) who were successfully treated with DCB alone were retrospectively compared with 103 propensity-matched patients treated with second-generation DES from the PTRG-DES registry (n=13160). All patients were followed for 5 years. The primary endpoint was major adverse cardiac events [MACE; cardiac death, myocardial infarction, stroke, target lesion thrombosis, target vessel revascularization (TVR), and major bleeding] at 5 years. Results: At 5-year clinical follow-up, Kaplan-Meier estimates of the rate of MACE were significantly lower in the DCB group [2.9% vs. 10.7%; hazard ratio (HR): 0.26; 95% confidence interval (CI): 0.07–0.96; log-rank p=0.027]. There was a significantly lower incidence of TVR in the DCB group (1.0% vs. 7.8%; HR: 0.12; 95% CI: 0.01–0.98; long-rank p=0.015), and there was major bleeding only in the DES group (0.0% vs. 1.9%; log-rank p=0.156). Conclusion At 5-year follow-up, DCB treatment was significantly associated with reduced incidences of MACE and TVR, compared with DES implantation, for de novo coronary lesions.

Background: Coronary artery calcium score (CACS) has become an important tool for evaluating cardiovascular disease (CVD). This study evaluated the significance of CACS for future CVD through more than 10 years of follow-up in asymptomatic Korean populations with type 2 diabetes mellitus (T2DM) known to have a relatively low CACS burden. Methods: We enrolled 981 asymptomatic T2DM patients without CVD at baseline who underwent CACS evaluation using multidetector computed tomography between January 2008 and December 2014. They were grouped into five predefined CACS categories based on Agatston scores and followed up by August 2020. The primary endpoint was incident CVD events, including coronary, cerebrovascular, and peripheral arterial disease. Results: The relative risk of CVD was significantly higher in patients with CACS ≥10, and the significance persisted after adjustment for known confounders. A higher CACS category indicated a higher incidence of future CVD: hazard ratio (95% confidence interval) 4.09 (1.79 to 9.36), 12.00 (5.61 to 25.69), and 38.79 (16.43 to 91.59) for 10≤ CACS <100, 100≤ CACS <400, and CACS ≥400, respectively. During the 12-year follow-up period, the difference in event-free survival more than doubled as the category increased. Patients with CACS below 10 had very low CVD incidence throughout the follow-up. The receiver operating characteristic analysis showed better area under curve when the CACS cutoff was 10 than 100. Conclusion CACS can be a sensitive marker of CVD risk. Specifically, CACS above 10 is an indicator of CVD high-risk requiring more intensive medical treatment in Koreans with T2DM.

Background/Aims: Acute pancreatitis (AP) is a common gastrointestinal disease associated with hospitalization. With the increase in its incidence, AP has become a greater burden on healthcare resources. Early identification of patients with mild AP can facilitate the appropriate use of resources. We aimed to investigate the ability of inflammatory markers, including interleukin-6 (IL-6), procalcitonin, and C-reactive protein (CRP), as well as various scoring systems to differentiate mild AP from more severe diseases. Methods: We retrospectively investigated patients hospitalized with AP, for whom severity assessment and clinical course confirmation were possible. Inflammatory markers were measured at admission, and CRP levels were measured 24 hours after admission (CRP2). Predictive values were calculated using the area under the receiver operating characteristic curve (AUROC) and logistic regression model analysis. Results: Of 103 patients with AP, 42 (40.8%) were diagnosed with mild AP according to the revised Atlanta classification. Based on the AUROC, IL-6 (0.755, p<0.001), CRP2 (0.787, p<0.001), and computed tomography severity index (CTSI) (0.851, p<0.001) were useful predictors of mild AP. With standard cutoff values, the diagnostic sensitivity, specificity, and accuracy were 83.3%, 62.3%, and 70.9% for IL-6 (<50 pg/mL), and 78.6%, 63.9%, and 69.9% for CRP2 (<50 mg/L), respectively. The AUROC of IL-6 and CRP2 were significantly higher than those of other inflammatory markers and were not significantly different from that of CTSI. Conclusions IL-6, CRP2, and CTSI are helpful for early differentiation of AP severity. Among inflammatory markers, IL-6 has the advantage of early prediction of mild pancreatitis at the time of admission.

Background: The purpose of this study was to evaluate the effect of vanishing twin (VT) on maternal serum marker concentrations and nuchal translucency (NT). Methods: This is a secondary analysis of a multicenter prospective cohort study in 12 institutions. Serum concentrations of pregnancy-associated plasma protein-A in the first trimester and alpha-fetoprotein (AFP), total human chorionic gonadotrophin, unconjugated estriol, and inhibin A in the second trimester were measured, and NT was measured between 10 and 14 weeks of gestation. Results: Among 6,793 pregnant women, 5,381 women were measured for serum markers in the first or second trimester, including 65 cases in the VT group and 5,316 cases in the normal singleton group. The cases in the VT group had a higher median multiple of the median value of AFP and inhibin A than the normal singleton group. The values of other serum markers and NT were not different between the two groups. After the permutation test with adjustment,AFP and inhibin A remained significant differences. The frequency of abnormally increased AFP was also higher in the VT group than in the normal singleton group. Conclusion VT can be considered as an adjustment factor for risk assessment in the secondtrimester serum screening test.

Objective: We aimed to present the study design and baseline cross-sectional participant characteristics of biobank innovations for chronic cerebrovascular disease with Alzheimer’s disease study (BICWALZS) participants. Methods: A total of 1,013 participants were enrolled in BICWALZS from October 2016 to December 2020. All participants underwent clinical assessments, basic blood tests, and standardized neuropsychological tests (n=1,013). We performed brain magnetic resonance imaging (MRI, n=817), brain amyloid positron emission tomography (PET, n=713), single nucleotide polymorphism microarray chip (K-Chip, n=949), locomotor activity assessment (actigraphy, n=200), and patient-derived dermal fibroblast sampling (n=175) on a subset of participants. Results: The mean age was 72.8 years, and 658 (65.0%) were females. Based on clinical assessments, total of 168, 534, 211, 80, and 20 had subjective cognitive decline, mild cognitive impairment (MCI), Alzheimer’s dementia, vascular dementia, and other types of dementia or not otherwise specified, respectively. Based on neuroimaging biomarkers and cognition, 199, 159, 78, and 204 were cognitively normal (CN), Alzheimer’s disease (AD)-related cognitive impairment, vascular cognitive impairment, and not otherwise specified due to mixed pathology (NOS). Each group exhibited many differences in various clinical, neuropsychological, and neuroimaging results at baseline. Baseline characteristics of BICWALZS participants in the MCI, AD, and vascular dementia groups were generally acceptable and consistent with 26 worldwide dementia cohorts and another independent AD cohort in Korea. Conclusion The BICWALZS is a prospective and longitudinal study assessing various clinical and biomarker characteristics in older adults with cognitive complaints. Details of the recruitment process, methodology, and baseline assessment results are described in this paper.

Purpose: Platelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel. Materials and Methods: Searching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them. Results: Nine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRGGenotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (*2 or *3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively. Conclusion The PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.