Search

Abstract Cytomegalovirus (CMV) commonly infects immunocompromised individuals, such as cancer patients. We present a case involving a 60‐year‐old male with Stage 3A lung adenocarcinoma and chronic obstructive pulmonary disease (COPD) diagnosed with CMV tracheobronchitis, initially suspected as cancer progression. Treatment with ganciclovir led to partial improvement in symptoms of shortness of breath and cough, as well as bronchoscopic findings. However, due to ganciclovir‐induced neutropenia, the therapy was switched to foscarnet. Distinguishing between cancer progression and infectious tracheobronchitis through physical examination and chest CT scans remains challenging. In lung cancer patients presenting with airway and bronchial narrowing along with ulcerative mucosal lesions, CMV infection should be considered. A bronchoscopic biopsy is crucial for accurate diagnosis and determining the appropriate treatment in these patients.

Background/Aims Metabolic syndrome (MetS) raises the risk of cardiovascular disease and type 2 diabetes. An awareness of MetS is vital for early detection and proactive management, which can mitigate the risks associated with MetS. Therefore, our study aimed to investigate the level of awareness of MetS among the Korean population. Methods We conducted a nationwide survey between January and February 2023 among a representative sample of the Korean population using an online survey. Information regarding the awareness of MetS and its risk, the importance of lifestyle modification, and health behavior were collected. The question about the awareness of MetS was “How much do you think you know about MetS?” and there were five answers: 1) I know very well, 2) I know well, 3) I know a little, 4) I do not know, and 5) I have no idea. The high-awareness group was defined as those who answered that they knew very well or well. Results Among 1,000 participants (mean age, 45.7 ± 13.2 yr), 29% were unaware of MetS, and only 20.8% had high awareness. The high-awareness group was significantly more knowledgeable about lifestyle modifications and demonstrated better health behaviors. After adjustment for possible confounding factors, younger age, low household income, and absence of comorbidity were independently associated with a lack of awareness regarding MetS. Conclusions The high-awareness group showed greater knowledge of the importance of lifestyle modifications and better health behaviors regarding MetS. The findings highlight the need for improved public education and awareness programs regarding MetS.

BackgroundThe alpha-protein kinase 3 (ALPK3) gene (OMIM: 617608) is associated with autosomal recessive familial hypertrophic cardiomyopathy-27 (CMH27, OMIM: 618052). Recently, several studies have shown that monoallelic premature terminating variants (PTVs) in ALPK3 are associated with adult-onset autosomal dominant hypertrophic cardiomyopathy (HCMP). However, these studies were performed on patient cohorts mainly from European Caucasian backgrounds.MethodsTo determine if this finding is replicated in the Korean HCMP cohort, we evaluated 2,366 Korean patients with non-syndromic HCMP using exome sequencing and compared the cohort dataset with three independent population databases.ResultsWe observed that monoallelic PTVs in ALPK3 were also significantly enriched in Korean patients with HCMP with an odds ratio score of 10–21.ConclusionsWe suggest that ALPK3 PTV carriers be considered a risk group for developing HCMP and be monitored for cardiomyopathies.

Abstract Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep binding pockets for specific small molecule inhibitors. Here, we demonstrated that the mRNA and protein levels of the class III histone deacetylase SIRT1 were upregulated by the KRASMut-Raf-MEK-c-Myc axis in KRASMut lung cancer cells and in lung tumors of a mouse model with spontaneous KrasG12D expression. KRASMut-induced SIRT1 bound to KRASMut and stably deacetylated KRASMut at lysine 104, which increased KRASMut activity. SIRT1 knockdown (K/D) or the SIRT1H363Y mutation increased KRASMut acetylation, which decreased KRASMut activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in KrasG12D/+;Sirt1co/co mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-KrasG12D/+;Sirt1+/+ mice and mice in each single-drug treatment group. Then, we identified p300 as a KRASMut acetyltransferase that reinforced KRASMut lysine 104 acetylation and robustly decreased KRASMut activity. KRASMut lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC‒MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRASMut activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRASMut mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRASMut lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRASMut lung cancer patients.

Hereditary transthyretin (ATTRv) amyloidosis is a rare and complex genetic disorder that can lead to life-threatening cardiac amyloidosis and rapid disease progression. Early diagnosis and treatment with disease-modifying drugs can improve patient outcomes; however, heart transplantation may be necessary in some patients. We present the unique case of a 65-year-old Korean woman diagnosed with ATTRv amyloidosis after experiencing progressive neurological symptoms, followed by heart failure. Despite the absence of significant symptoms of heart failure, subsequent screening revealed cardiac amyloid infiltration, which caused left ventricular hypertrophy and rapid disease progression. The patient underwent successful heart transplantation, and subsequent genetic testing revealed a pathogenic variant, NM_000371.3:c.425T>C (p.Val142Ala), which affects both the nerves and heart and has not been previously reported in Korea. Our report underscores the potential benefits of heart transplantation in managing advanced ATTRv amyloidosis and emphasizes the need for continued research on the genetic heterogeneity of the disease. Clinicians should consider ATTRv amyloidosis in the differential diagnosis of patients presenting with neurological symptoms and heart failure, particularly in those with a family history of the disease.

Hemolymphangioma or hemangiolymphangioma is a rare venolymphatic vascular malformation composed of proliferations or networks of vascular spaces including the lymphatics, capillaries, veins, or arteries. The small bowel is a rare location for hemolymphangioma, and the small bowel mesentery is an even rarer site. Herein, we report a surgically confirmed large complex hemolymphangioma in the small bowel mesentery in a 55-year-old male.

Background: Previous cohort studies focused on relative risk stratification among patients diagnosed with vasospastic angina, and it is unknown how much vasospasm accounts for the cause of out-of-hospital cardiac arrest, and whether prognosis differs. Methods: From a registry data collected from 65 hospitals in Korea, 863 subjects who survived hospital cardiac arrest were evaluated. The patients with insignificant coro-nary lesion, vasospasm, and obstructive lesion were each grouped as group I, group II, and group III, respectively. The primary and secondary outcomes were survival to hospital discharge and good neurological function at discharge defined as cerebral performance index 1. Results: At hospital discharge, 529 subjects (61.3%) survived. There was no significant difference in survival according to coronary angiographic findings (P =.133 and P =.357, group II and group III compared to group I), but the neurological outcome was significantly better in groups II and III (P =.046 and P =.022, groups II and III compared to group I). Two multivariate models were evaluated to adjust traditional risk factors and cardiac biomarkers. The presence of coronary artery vasospasm did not affect survival to hospital discharge (P = 0.060 and P =.162 for both models), but neurological function was significantly better (OR: 1.965, 95% CI: 1.048-3.684, P =.035, and OR: 1.706, 95% CI: 1.012-2.878, P =.045 for vasospasm, models I and II, respectively). Conclusions: Coronary vasospasm does not show better survival to hospital discharge, but shows better neurological outcomes. Aggressive coronary angiography and intensive medical treatment for adequate control of vasospasm should be emphasized to prevent and manage fatal events.

Abstract This Korean nationwide, multicenter, noninterventional, prospective cohort study aimed to analyze physician adherence to guideline-recommended therapy for heart failure (HF) with reduced ejection fraction (HFrEF) and its effect on patient-reported outcomes (PROs). Patients diagnosed with or hospitalized for HFrEF within the previous year were enrolled. Treatment adherence was considered optimal when all 3 categories of guideline-recommended medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor-neprilysin inhibitors; beta-blockers; and mineralocorticoid receptor antagonists) were prescribed and suboptimal when ≤ 2 categories were prescribed. The 36-Item Short Form Survey (SF-36) scores were compared at baseline and 6 months between the 2 groups. Overall, 854 patients from 30 hospitals were included. At baseline, the optimal adherence group comprised 527 patients (61.7%), whereas during follow-up, the optimal and suboptimal adherence groups comprised 462 (54.1%) and 281 (32.9%) patients, respectively. Patients in the suboptimal adherence group were older, with a lower body mass index, and increased comorbidities, including renal dysfunction. SF-36 scores were significantly higher in the optimal adherence group for most domains (P

Climate change is affecting all regions of the world with different climates, and the scale of damage is increasing due to the occurrence of various natural disasters. In particular, maize production is highly affected by abnormal climate events such as heat waves and droughts. Increasing temperatures can accelerate growth and shorten the growing season, potentially reducing productivity. Additionally, enhanced temperatures during the ripening period can accelerate the process, reducing crop yields. In addition, drought stress due to water deficit can greatly affect seedling formation, early plant growth, photosynthesis, reproductive growth, and yield, so proper water management is critical to maize growth. Maize, in particular, is tall and broad-leaved, so extreme drought stress at planting can cause leaves to curl and stunt growth. It is important to understand that severe drought can have a detrimental effect on the growth and reproduction of maize. In addition, high temperatures caused by drought stress can inhibit the induction of flowering in male flowers and cause factors that interfere with pollen development. It is therefore important to increase the productivity of all food crops, including maize, while maintaining them in the face of persistent drought caused by climate change. This requires a strategy to develop genetically modified crops and drought-tolerant maize that can effectively respond to climate change. The aim of this paper is to investigate the effects of climate change and drought tolerance on maize growth. We also reviewed molecular breeding techniques to develop drought-tolerant maize varieties in response to climate change.

Abstract Aims We sought to determine whether the Diamond–Forrester classification using non‐invasive haemodynamic measurements by 2‐D and Doppler echocardiography would predict hospital mortality in cardiac intensive care unit (CICU) patients. Methods and results We retrospectively analysed unique patients admitted to the CICU at Mayo Clinic Rochester from 2007 to 2018. Doppler‐derived cardiac index (CI) and ratio of mitral valve E velocity to medial mitral annulus e′ velocity (E/e′ ratio) were used to classify patients into four profiles: Profile I (warm/dry), Profile II (warm/wet), Profile III (cold/dry), and Profile IV (cold/wet). Logistic regression was used to determine predictors of hospital mortality, and Cox proportional‐hazards analysis was used to determine predictors of mortality during one year of follow‐up. We included 4563 patients with a mean age of 68.3 ± 14.3 years, including 36.2% female patients. The distribution of each profile was as follows: I, 47.4%; II, 36.2%; III, 7.9%; IV, 8.5%. A total of 5.8% patients died during hospitalization, and 18.1% died by 1 year. Patients with either low CI or elevated E/e′ ratio had higher in‐hospital and 1 year mortality. Patients with elevated E/e′ ratio (i.e. Profiles II and IV) had an increased risk of death during hospitalization and at 1 year after multivariate adjustment (adjusted hazard ratio 1.72 and 2.17 for 1 year mortality, respectively, compared with Profile I, P

BackgroundExtreme weight conditions in young women are associated with adverse health outcomes. Closely linked with extreme weight status, eating disorders (EDs) are associated with several medical complications and high mortality rates.ObjectiveThe study aimed to investigate the biochemical, hematologic, and skeletal features of young Korean women with underweight (UW) and overweight/obesity (OW) conditions, and patients with anorexia nervosa (AN) and bulimia nervosa (BN) compared to women with normal-weight (NW).MethodA total of 808 women (mean age 22.3 ± 3.4 years) were recruited for the study, including 144 with UW status [body mass index (BMI) < 18.5 kg/m2], 364 with NW, 137 with OW or obesity (27 with obesity; BMI ≥ 25 kg/m2), 63 patients with anorexia nervosa (AN), and 100 with bulimia nervosa (BN). We measured blood pressure and performed biochemical, hematologic and bone mineral density (BMD) evaluations at the lumbar and femoral neck.ResultsBlood pressure and triiodothyronine levels were found to be lower in both ED groups and higher in the OW group, but no difference in the UW group, compared to the NW group. The aminotransferases and total cholesterol levels were higher in the ED and OW groups, compared to the NW group. Blood cell counts were decreased in the AN group, while increased in the OW group, compared to the NW group. Blood urea nitrogen was elevated in both ED groups. The UW and AN groups had lower BMD, whereas the OW group had higher BMD, compared to the NW group.ConclusionOur findings suggested that both ED groups were associated with decreases in the resting energy expenditure. OW status was associated with a risk of metabolic syndrome, and UW status with lower BMD in young women. Overall, the medical parameters in Korean patients with ED were similar to the patterns reported in Western samples in previous studies, with few exceptions such as potassium level in BN.

Abstract Background Sepsis is a life-threatening organ dysfunction and a major healthcare burden worldwide. Although sepsis is a medical emergency that requires immediate management, screening for the occurrence of sepsis is difficult. Herein, we propose a deep learning-based model (DLM) for screening sepsis using electrocardiography (ECG). Methods This retrospective cohort study included 46,017 patients who were admitted to two hospitals. A total of 1,548 and 639 patients had sepsis and septic shock, respectively. The DLM was developed using 73,727 ECGs from 18,142 patients, and internal validation was conducted using 7774 ECGs from 7,774 patients. Furthermore, we conducted an external validation with 20,101 ECGs from 20,101 patients from another hospital to verify the applicability of the DLM across centers. Results During the internal and external validations, the area under the receiver operating characteristic curve (AUC) of the DLM using 12-lead ECG was 0.901 (95% confidence interval, 0.882–0.920) and 0.863 (0.846–0.879), respectively, for screening sepsis and 0.906 (95% confidence interval (CI), 0.877–0.936) and 0.899 (95% CI, 0.872–0.925), respectively, for detecting septic shock. The AUC of the DLM for detecting sepsis using 6-lead and single-lead ECGs was 0.845–0.882. A sensitivity map revealed that the QRS complex and T waves were associated with sepsis. Subgroup analysis was conducted using ECGs from 4,609 patients who were admitted with an infectious disease, and the AUC of the DLM for predicting in-hospital mortality was 0.817 (0.793–0.840). There was a significant difference in the prediction score of DLM using ECG according to the presence of infection in the validation dataset (0.277 vs. 0.574, p

Abstract Background Patients with acute myocardial infarction (AMI) are usually treated with angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) if ACEIs are not tolerated. However, there is no data regarding the impact of switching from ACEIs to ARBs on long-term clinical outcomes in AMI patients with preserved left ventricular (LV) systolic function especially beyond 1 year. To investigate the effectiveness of treatment with ACEIs or ARBs on clinical outcomes over 3 years in AMI patients with preserved LV systolic function following percutaneous coronary intervention. Method It is a prospective cohort study using data from a nationwide large scale registry with 53 hospitals involved in treatment of acute myocardial infarction (AMI) in Korea. Between March 2011 and September 2015, we enrolled 6236 patients with AMI who underwent primary percutaneous coronary intervention and had a left ventricular ejection fraction ≥ 50%. Main outcome measures composite of total death or recurrent AMI over 3 years after AMI. Patients were divided into an ACEI group (n = 2945), ARB group (n = 2197), or no renin-angiotensin system inhibitor (RASI) treatment (n = 1094). We analyzed patients who changed treatment. Inverse probability of treatment weighting (IPTW) analysis was also performed. Results After the adjustment with inverse probability weighting, the primary endpoints at 1 year, AMI patients receiving ACEIs showed overall better outcomes than ARBs [ARBs hazard ratio (HR) compared with ACEIs 1.384, 95% confidence interval (CI) 1.15–1.71; P = 0.003]. However, 33% of patients receiving ACEIs switched to ARBs during the first year, while only about 1.5% switched from ARBs to ACEIs. When landmark analysis was performed from 1 year to the end of the study, RASI group showed a 31% adjusted reduction in primary endpoint compared to patients with no RASI group (HR, 0.74; 95% CI 0.56–0.97; P = 0.012). Conclusions This result suggests that certain patients got benefit from treatment with ACEIs in the first year if tolerated, but switching to ARBs beyond the first year produced similar outcomes. RASI beyond the first year reduced death or recurrent AMI in AMI patients with preserved LV systolic function. CRIS Registration number: KCT0004990.

Cholangiocarcinoma is a malignant epithelial tumor arising from bile ducts that is frequently fatal. Diagnosis is difficult due to tumor location in the biliary tract. Earlier diagnosis requires less invasive methods of identifying effective biomarkers for cholangiocarcinoma. The present study investigated the genomic profiles of cell-free DNA (cfDNA) and DNA from corresponding primary cholangiocarcinomas using a targeted sequencing panel. Somatic mutations in primary tumor DNA and circulating tumor DNA (ctDNA) were compared and clinical applications of ctDNA validated in patients with cholangiocarcinoma. A comparison of primary tumor DNA and ctDNA identified somatic mutations in patients with early cholangiocarcinomas that showed clinical feasibility for early screening. The predictive value of single-nucleotide variants (SNVs) of preoperative plasma cfDNA positive for somatic mutations of the primary tumor was 42%. The sensitivity and specificity of postoperative plasma SNVs in detecting clinical recurrence were 44% and 45%, respectively. Targetable fibroblast growth factor receptor 2 (FGFR2) and Kirsten rat sarcoma virus (KRAS) mutations were detected in 5% of ctDNA samples from patients with cholangiocarcinoma. These findings showed that genomic profiling of cfDNA was useful in clinical evaluation, although ctDNA had limited ability to detect mutations in cholangiocarcinoma patients. Serial monitoring of ctDNA is important clinically and in assessing real-time molecular aberrations in cholangiocarcinoma patients.

Context Sauropus brevipes Müll. Arg. (Phyllanthaceae) has been used as an effective ingredient in a decoction for the treatment of diarrhoea. However, there was no report on its modulatory role in inflammation. Objective This study investigates anti-inflammatory effect of S. brevipes in various inflammation models. Materials and methods The aerial part of S. brevipes was extracted with 95% ethanol to produce Sb-EE. RAW264.7 cells pre-treated with Sb-EE were stimulated by lipopolysaccharide (LPS), and Griess assay and PCR were performed. High-performance liquid chromatography (HPLC) analysis, luciferase assay, Western blotting and kinase assay were employed. C57BL/6 mice (10 mice/group) were orally administered with Sb-EE (200 mg/kg) once a day for five days, and peritonitis was induced by an intraperitoneal injection of LPS (10 mg/kg). ICR mice (four mice/group) were orally administered with Sb-EE (20 or 200 mg/kg) or ranitidine (positive control) twice a day for two days, and EtOH/HCl was orally injected to induce gastritis. Results Sb-EE suppressed nitric oxide (NO) release (IC50=34 µg/mL) without cytotoxicity and contained flavonoids (quercetin, luteolin and kaempferol). Sb-EE (200 µg/mL) reduced the mRNA expression of inducible NO synthase (iNOS). Sb-EE blocked the activities of Syk and Src, while inhibiting interleukin-1 receptor associated kinases (IRAK1) by 68%. Similarly, orally administered Sb-EE (200 mg/kg) suppressed NO production by 78% and phosphorylation of Src and Syk in peritonitis mice. Sb-EE also decreased inflammatory lesions in gastritis mice. Discussion and conclusions This study demonstrates the inhibitory effect of Sb-EE on the inflammatory response, suggesting that Sb-EE can be developed as a potential anti-inflammatory agent.

Context Among the plants in the genus Barringtonia (Lecythidaceae) used as traditional medicines to treat arthralgia, chest pain, and haemorrhoids in Indonesia, Barringtonia racemosa L. and Barringtonia acutangula (L.) Gaertn. have demonstrated anti-inflammatory activity in systemic inflammatory models. Objective The anti-inflammatory activity of Barringtonia angusta Kurz has not been investigated. We prepared a methanol extract of the leaves and stems of B. angusta (Ba-ME) and systemically evaluated its anti-inflammatory effects in vitro and in vivo. Materials and methods RAW264.7 cells stimulated with LPS or Pam3CSK4 for 24 h were treated with Ba-ME (12.5, 25, 50, 100, and 150 µg/mL), and NO production and mRNA levels of inflammatory genes were evaluated. Luciferase reporter gene assay, western blot analysis, overexpression experiments, and cellular thermal shift assay were conducted to explore the mechanism of Ba-ME. In addition, the anti-gastritis activity of Ba-ME (50 and 100 mg/kg, administered twice per day for two days) was evaluated using an HCl/EtOH-induced gastritis mouse model. Results Ba-ME dose-dependently suppressed NO production [IC50 = 123.33 µg/mL (LPS) and 46.89 µg/mL (Pam3CSK4)] without affecting cell viability. Transcriptional expression of iNOS, IL-1β, COX-2, IL-6, and TNF-α and phosphorylation of Src, IκBα, p50/105, and p65 were inhibited by Ba-ME. The extract specifically targeted the Src protein by binding to its SH2 domain. Moreover, Ba-ME significantly ameliorated inflammatory lesions in the HCl/EtOH-induced gastritis model. Discussion and Conclusions The anti-inflammatory activity of Ba-ME is mediated by targeting of the Src/NF-κB signalling pathway, and B. angusta has potential as an anti-inflammatory drug.

Abstract Rapid diagnosis of myocardial infarction (MI) using electrocardiography (ECG) is the cornerstone of effective treatment and prevention of mortality; however, conventional interpretation methods has low reliability for detecting MI and is difficulty to apply to limb 6-lead ECG based life type or wearable devices. We developed and validated a deep learning-based artificial intelligence algorithm (DLA) for detecting MI using 6-lead ECG. A total of 412,461 ECGs were used to develop a variational autoencoder (VAE) that reconstructed precordial 6-lead ECG using limb 6-lead ECG. Data from 9536, 1301, and 1768 ECGs of adult patients who underwent coronary angiography within 24 h from each ECG were used for development, internal and external validation, respectively. During internal and external validation, the area under the receiver operating characteristic curves of the DLA with VAE using a 6-lead ECG were 0.880 and 0.854, respectively, and the performances were preserved by the territory of the coronary lesion. Our DLA successfully detected MI using a 12-lead ECG or a 6-lead ECG. The results indicate that MI could be detected not only with a conventional 12 lead ECG but also with a life type 6-lead ECG device that employs our DLA.

Abstract Background In-hospital cardiac arrest is a major burden in health care. Although several track-and-trigger systems are used to predict cardiac arrest, they often have unsatisfactory performances. We hypothesized that a deep-learning-based artificial intelligence algorithm (DLA) could effectively predict cardiac arrest using electrocardiography (ECG). We developed and validated a DLA for predicting cardiac arrest using ECG. Methods We conducted a retrospective study that included 47,505 ECGs of 25,672 adult patients admitted to two hospitals, who underwent at least one ECG from October 2016 to September 2019. The endpoint was occurrence of cardiac arrest within 24 h from ECG. Using subgroup analyses in patients who were initially classified as non-event, we confirmed the delayed occurrence of cardiac arrest and unexpected intensive care unit transfer over 14 days. Results We used 32,294 ECGs of 10,461 patients and 4483 ECGs of 4483 patients from a hospital were used as development and internal validation data, respectively. Additionally, 10,728 ECGs of 10,728 patients from another hospital were used as external validation data, which confirmed the robustness of the developed DLA. During internal and external validation, the areas under the receiver operating characteristic curves of the DLA in predicting cardiac arrest within 24 h were 0.913 and 0.948, respectively. The high risk group of the DLA showed a significantly higher hazard for delayed cardiac arrest (5.74% vs. 0.33%, P

Background Since 1995, the Korean Society for Cytopathology has overseen the Continuous Quality Improvement program for cytopathology laboratories. The Committee of Quality Improvement has carried out an annual survey of cytology data for each laboratory and set standards for proficiency tests. Methods Evaluations were conducted four times per year from 2008 to 2018 and comprised statistics regarding cytology diagnoses of previous years, proficiency tests using cytology slides provided by the committee, assessment of adequacy of gynecology (GYN) cytology slides, and submission of cytology slides for proficiency tests. Results A total of 206 institutes participated in 2017, and the results were as follows. The number of cytology tests increased from year to year. The ratio of liquid-based cytology in GYN gradually decreased, as most of the GYN cytology had been performed at commercial laboratories. The distribution of GYN diagnoses demonstrated nearly 3.0% as atypical squamous cells. The rate for squamous cell carcinoma was less than 0.02%. The atypical squamous cell/squamous intraepithelial lesion ratio was about 3:1 and showed an upward trend. The major discordant rate of cytology-histology in GYN cytology was less than 1%. The proficiency test maintained a major discordant rate less than 2%. The rate of inappropriate specimens for GYN cytology slides gradually decreased. Conclusions The Continuous Quality Improvement program should be included in quality assurance programs. Moreover, these data can contribute to development of national cancer examination guidelines and facilitate cancer prevention and treatment.

Abstract Aims We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Methods and results The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A 1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke. Conclusions Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

Food-related content varies widely and is increasingly popular. Using various media, teenagers can easily access food content, which could affect they eating habits. This study was conducted to confirm the effects of watching motivation on the relationship between food content watching time and eating habits among adolescents in Seoul, Korea. Exactly 806 participants were surveyed about their food content watching status, including watching time and watching motivation. The Nutrition Quotient for adolescents (NQ-A) questionnaire was used to confirm eating habits. Exploratory factor analysis was conducted to classify watching motivation’s subfactors. A parallel multimedia model was used to analyze the effect of watching motivation on the relationship between food content watching time and eating habits. As a result of this study, following the factor analysis, watching motivation was classified into information acquisition, emotional satisfaction, and enjoyment. The influence of food content watching time on NQ-A scores through information acquisition motivation was positively significant, whereas that through emotional satisfaction motivation was negatively significant. Enjoyment motivation did not indirectly affect the relationship between food content watching time and NQ-A scores. Hence, attention should be paid to these mediating factors when analyzing the relationship between watching food-related content and eating habits. Developing and distributing content that meets viewing motivations should help improve adolescents’ eating habits.

Abstract Introduction The detection and monitoring of electrolyte imbalance is essential for appropriate management of many metabolic diseases; however, there is no tool that detects such imbalances reliably and noninvasively. In this study, we developed a deep learning model (DLM) using electrocardiography (ECG) for detecting electrolyte imbalance and validated its performance in a multicenter study. Methods and Results This retrospective cohort study included two hospitals: 92,140 patients who underwent a laboratory electrolyte examination and an ECG within 30 min were included in this study. A DLM was developed using 83,449 ECGs of 48,356 patients; the internal validation included 12,091 ECGs of 12,091 patients. We conducted an external validation with 31,693 ECGs of 31,693 patients from another hospital, and the result was electrolyte imbalance detection. During internal, the area under the receiving operating characteristic curve (AUC) of a DLM using a 12‐lead ECG for detecting hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hypercalcemia, and hypocalcemia were 0.945, 0.866, 0.944, 0.885, 0.905, and 0.901, respectively. The values during external validation of the AUC of hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hypercalcemia, and hypocalcemia were 0.873, 0.857, 0.839, 0.856, 0.831, and 0.813 respectively. The DLM helped to visualize the important ECG region for detecting each electrolyte imbalance, and it showed how the P wave, QRS complex, or T wave differs in importance in detecting each electrolyte imbalance. Conclusion The proposed DLM demonstrated high performance in detecting electrolyte imbalance. These results suggest that a DLM can be used for detecting and monitoring electrolyte imbalance using ECG on a daily basis.

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive, chronic disease without curative treatment. Large registry data of these patient populations have been published, although, phenotypic variants within each subtype of PAH have not been elucidated. As interest towards personalized medicine grows, the need for a PAH cohort with a comprehensive understanding of patient phenotypes through multiomics approaches, called deep phenotyping, is on the rise. The PAH Platform for Deep Phenotyping in Korean Subjects (PHOENIKS) cohort is designed to collect clinical data as well as biological specimens for deep phenotyping in patients with idiopathic PAH (IPAH) and heritable PAH (HPAH) in Korea. Methods A total of 17 regional hospitals are currently working on enrolling up to 100 consecutive IPAH/HPAH patients for obtaining clinical data and biological specimens across Korea. The diagnosis of PAH is based on right heart catheterization. All clinical data is stored in a government-based online database. Each participating hospitals collect a whole blood sample from each patient, through which DNA, RNA, serum, plasma, and peripheral blood mononuclear cells will be extracted from the buffy coat layer for further multiomics analysis. Results Not applicable. Conclusions The PHOENIKS cohort is enrolling IPAH and HPAH patients across Korea to determine the prognosis and drug response in different phenotypic variant. The data generated by this cohort are expected to open new doors for personalized medicine in PAH patients of South Korea. Trial registration ClinicalTrials.gov NCT03933579. Registered on May 1st, 2019.

Abstract Background Protein kinase C iota (PKCι) and protein kinase C zeta (PKCζ) are two atypical protein kinase (aPKC) enzymes that contribute to cell proliferation and cancer development. The Hippo/YAP pathway is commonly disrupted and upregulated in cancers. Herein, the expression patterns and clinical relevance of PKCι and PKCζ are evaluated in relation to YAP, a downstream effector of Hippo, in lung adenocarcinoma (LAC). The protein and mRNA expression levels of PKCι, PKCζ, YAP, and their phosphorylated forms, namely p-PKCι, p-PKCζ and p-YAP, are evaluated in relation to clinicopathological factors, including patient survival. Methods A total of 200 primary LAC tissue samples were examined by immunohistochemistry for PKCι, p-PKCι, PKCζ, p-PKCζ, YAP, and p-YAP protein expression. Sixty pairs of LAC and non-neoplastic lung tissue samples were assessed for PRKCI, PRKCZ, and YAP mRNA levels. PKCι, p-PKCι, PKCζ, and p-PKCζ protein expression were evaluated by Western blot analysis in the PC9 and PC9/GR LAC cell lines with YAP modulation. Results LAC demonstrated cytoplasmic PKCι, p-PKCι, PKCζ, and p-PKCζ immunostaining patterns. Positive aPKC protein expressions were related with poor patient survival. Especially, increased p-PKCι protein expression was significantly correlated with higher pathological stage and shortened overall survival. YAP overexpression contributes phosphorylation of PKCι and PKCζ protein expression in the LAC cell line. Conclusions PKCι and PKCζ are related to YAP in LAC. PKCι and PKCζ play distinct roles in LAC; specifically, p-PKCι overexpression is suggested to underlie factors that indicate a poor prognosis.

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major NADPH-producing enzyme which is essential for maintaining the mitochondrial redox balance in cells. We sought to determine whether IDH2 deficiency induces mitochondrial dysfunction and modulates auditory function, and investigated the protective potential of an antioxidant agent against reactive oxygen species (ROS)-induced cochlear damage in Idh2 knockout (Idh2−/−) mice. Idh2 deficiency leads to damages to hair cells and spiral ganglion neurons (SGNs) in the cochlea and ultimately to apoptotic cell death and progressive sensorineural hearing loss in Idh2−/− mice. Loss of IDH2 activity led to decreased levels of NADPH and glutathione causing abnormal ROS accumulation and oxidative damage, which might trigger apoptosis signal in hair cells and SGNs in Idh2−/− mice. We performed ex vivo experiments to determine whether administration of mitochondria-targeted antioxidants might protect or induce recovery of cells from ROS-induced apoptosis in Idh2-deficient mouse cochlea. MitoQ almost completely neutralized the H2O2-induced ototoxicity, as the survival rate of Idh2−/− hair cells were restored to normal levels. In addition, the lack of IDH2 led to the accumulation of mitochondrial ROS and the depolarization of ΔΨm, resulting in hair cell loss. In the present study, we identified that IDH2 is indispensable for the functional maintenance and survival of hair cells and SGNs. Moreover, the hair cell degeneration caused by IDH2 deficiency can be prevented by MitoQ, which suggests that Idh2−/− mice could be a valuable animal model for evaluating the therapeutic effects of various antioxidant candidates to overcome ROS-induced hearing loss. Keywords: Idh2, NADP+, ROS, Hearing loss, Antioxidant, MitoQ

Both underweight (UW) and overweight (OW) conditions are problematic in young women. The aim of this study was to examine the factors associated with extreme weight status and eating disorders (EDs) in young Korean women. A total of 808 women (mean age 22.3 ± 3.4 years) participated, including 144 with UW [Body Mass Index (BMI) < 18.5kg/m2], 364 with NW, and 137 with OW or obesity (BMI ≥ 25kg/m2), and 63 patients with anorexia nervosa (AN) and 100 with bulimia nervosa (BN). Participants completed questionnaires regarding nutrients consumed, eating behaviors, health behaviors, body image, and obsessive-compulsive symptoms with face to face interviews. The associations between the status of participants and the data were analyzed with NW group as a reference. OW status was associated with overeating and with frequent eating. UW status was associated with less frequent overeating and with longer sleep duration. AN status was associated with less frequent consumption of alcohol. BN status was associated with a larger discrepancy between the ideal and current body shape. Both OW status and BN were associated with more obsessive-compulsive symptoms. The results suggested that certain dietary, health, and psychological factors are associated with extreme weight conditions and EDs.

Background: We developed and validated an artificial intelligence (AI)-enabled smartwatch ECG to detect heart failure-reduced ejection fraction (HFrEF). Methods: This was a cohort study involving two hospitals (A and B). We developed the AI in two steps. First, we developed an AI model (ECGT2T) to synthesize ten-lead ECG from the asynchronized 2-lead ECG (Lead I and II). ECGT2T is a deep learning model based on a generative adversarial network, which translates source ECGs to reference ECGs by learning styles of the reference ECGs. For this, we included adult patients aged ≥18 years from hospital A with at least one digitally stored 12-lead ECG. Second, we developed an AI model to detect HFrEF using a 10 s 12-lead ECG. The AI model was based on convolutional neural network. For this, we included adult patients who underwent ECG and echocardiography within 14 days. To validate the AI, we included adult patients from hospital B who underwent two-lead smartwatch ECG and echocardiography on the same day. The AI model generates a 10 s 12-lead ECG from a two-lead smartwatch ECG using ECGT2T and detects HFrEF using the generated 12-lead ECG. Results: We included 137,673 patients with 458,745 ECGs and 38,643 patients with 88,900 ECGs from hospital A for developing the ECGT2T and HFrEF detection models, respectively. The area under the receiver operating characteristic curve of AI for detecting HFrEF using smartwatch ECG was 0.934 (95% confidence interval 0.913–0.955) with 755 patients from hospital B. The sensitivity, specificity, positive predictive value, and negative predictive value of AI were 0.897, 0.860, 0.258, and 0.994, respectively. Conclusions: An AI-enabled smartwatch 2-lead ECG could detect HFrEF with reasonable performance.

Chronic viral hepatitis is a major cause of chronic liver disease leading to liver fibrosis. This study aimed to assess the diagnostic performance of elastography point quantification (ElastPQ), transient elastography (TE), and aspartate aminotransferase-to-platelet count ratio index (APRI) for the staging of liver fibrosis in patients with chronic viral hepatitis using histopathological findings as a reference standard. For 122 patients with chronic viral hepatitis, diagnostic performance was evaluated using area under the receiver operating characteristic curve (AUROC) analysis and correlations were determined using Spearman’s correlation coefficient. The AUROC of ElastPQ for the diagnosis of the fibrosis stage ≥ F2 was 0.917 with a cut-off value of 3.935. There was a significant positive correlation between the different stages of histologic liver fibrosis and stiffness values obtained using ElastPQ, TE, and APRI (ρ = 0.556, ρ = 0.657, ρ = 0.375, respectively; p < 0.001). ElastPQ showed a higher diagnostic accuracy than APRI, resembling that of TE; AUROC values of ElastPQ, TE, and APRI were 0.917, 0.964, and 0.896, respectively, for a fibrosis stage ≥ F2. ElastPQ is a promising noninvasive technique with a diagnostic accuracy comparable with that of TE for the evaluation of liver fibrosis in patients with chronic viral hepatitis.

Background Severe, symptomatic aortic stenosis (AS) is associated with poor prognoses. However, early detection of AS is difficult because of the long asymptomatic period experienced by many patients, during which screening tools are ineffective. The aim of this study was to develop and validate a deep learning–based algorithm, combining a multilayer perceptron and convolutional neural network, for detecting significant AS using ECGs. Methods and Results This retrospective cohort study included adult patients who had undergone both ECG and echocardiography. A deep learning–based algorithm was developed using 39 371 ECGs. Internal validation of the algorithm was performed with 6453 ECGs from one hospital, and external validation was performed with 10 865 ECGs from another hospital. The end point was significant AS (beyond moderate). We used demographic information, features, and 500‐Hz, 12‐lead ECG raw data as predictive variables. In addition, we identified which region had the most significant effect on the decision‐making of the algorithm using a sensitivity map. During internal and external validation, the areas under the receiver operating characteristic curve of the deep learning–based algorithm using 12‐lead ECG for detecting significant AS were 0.884 (95% CI, 0.880–0.887) and 0.861 (95% CI, 0.858–0.863), respectively; those using a single‐lead ECG signal were 0.845 (95% CI, 0.841–0.848) and 0.821 (95% CI, 0.816–0.825), respectively. The sensitivity map showed the algorithm focused on the T wave of the precordial lead to determine the presence of significant AS. Conclusions The deep learning–based algorithm demonstrated high accuracy for significant AS detection using both 12‐lead and single‐lead ECGs.

BackgroundPulmonary arterial hypertension (PAH) is a progressive chronic disease with poor outcomes. One reason for poor prognosis is the lack of understanding regarding individual variability in response to treatment. Idiopathic PAH (IPAH) patients with bone morphogenetic protein receptor type 2 (BMPR2) mutations have distinct phenotypes that are crucial for individualized therapy but evidence regarding their prevalence and clinical features in the Korean population is lacking. Therefore, the present study aimed to screen Korean IPAH patients for BMPR2 mutations and analyze their clinical phenotypes.MethodsWe enrolled 73 unrelated IPAH patients for BMPR2 mutation screening between March 2010 to November 2015 from 11 hospitals in Korea. Thirty-three lineal family members from 6 families of BMPR2 mutation carriers were also screened.ResultsAmong 73 patients, 16 (22%) had BMPR2 mutations. Mutation carriers were younger (27 vs. 47 years; p = 0.02) and had a higher mean pulmonary arterial pressure (mPAP) than non-carriers (64 vs. 51 mmHg; pConclusionThe prevalence of BMPR2 mutations in Korean IPAH patients was 22%. Mutation carriers were younger and had a poorer hemodynamic profile compared with the non-carriers.Clinical trial registrationClinicaltrials.gov NCT01054105.

The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal LM, proved by MRI from 20 paired ventricular and lumbar CSF samples of LM patients, including 12 spinal LM (+) samples. In metabolome analysis, 9512 low-mass ions (LMIs) were identified—7 LMIs were abundant in all lumbar versus paired ventricular CSF samples, and 3 LMIs were significantly abundant in all ventricular CSF. In comparisons between spinal LM (+) CSF and LM (−) CSF, 105 LMIs were discriminative for spinal LM (+) CSF. In proteome analysis, a total of 1536 proteins were measured. A total of 18 proteins, including complement C3, were more highly expressed in all lumbar CSF, compared with paired ventricular CSF, while 82 proteins, including coagulation factor V, were higher in the ventricular CSF. Of 37 discriminative proteins, including uteroglobin and complement component C8 gamma chain, 4 were higher in all spinal LM (+) CSF versus spinal LM (−) CSF. We further evaluated metabolic pathways associated with these discriminative proteins using the Gene Ontology database. We found that 16/17 spinal LM (+) pathways, including complement activation, were associated with lumbar discriminative proteins, whereas only 2 pathways were associated with ventricular-discriminative proteins. In conclusion, we determined that metabolite and protein profiles differed between paired lumbar and ventricular CSF samples. The protein profiles of spinal LM (+) CSF showed more similarity with the lumbar CSF than the ventricular CSF. Thus, we suggest that CSF LMIs and proteins could reflect LM disease activity and that LM-associated differences in CSF are more likely to be present in the lumbar compartment.

Partitioning defective (Par) proteins regulate cell polarity and differentiation. Par3, Par6β, and protein kinase Cζ (PKCζ), which are PAR complex members, have been shown to be associated with oncogenesis and progression. Herein, we report the expression pattern and clinical relevance of Par3, Par6β, and PKCζ in colorectal adenocarcinoma (CRAC). A total of 393 primary CRACs, 41 primary-metastatic CRAC pairs, 41 adenomas with low-grade dysplasia, and 41 nontumor colorectal tissue samples were examined by immunohistochemistry and Western blot assays for Par3, Par6β, and PKCζ protein expressions. The association Par3, Par6β, and PKCζ expressions and clinicopathologic factors, including patient survival, was evaluated. Primary CRACs and adenomas demonstrated higher levels of Par3, Par6β, and PKCζ than in nontumor colorectal epithelia. The expressions of Par3, Par6β, and PKCζ were higher in primary CRACs as compared to adenomas or in metastatic CRACs. Among primary CRACs, decreased Par3 expression was found to correlate with a high proliferation rate and poor histologic differentiation, decreased PKCζ expression was correlated with pathologic TNM stage (I-II vs III-IV) and lymph node metastasis, and decreased Par6β and PKCζ expressions were correlated with shortened overall survivals. In metastatic CRACs, decreased PKCζ expression was correlated with a shortened metastasis-free survival. While increased Par3, Par6β, and PKCζ expressions were implicated in tumorigenesis, decreased expressions of Par3, Par6β, and PKCζ were found to be associated with worse clinicopathologic factors in CRAC. In particular, the results of our study suggest that PKCζ down-expression is an independent poor prognostic and metastatic factor for CRAC.

Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (−)/cytology (−). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (−)/cytology (−). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (−) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone.

Wheat starch is one of the most important components in wheat grain and is extensively used as the main source in bread, noodles, and cookies. The wheat endosperm is composed of about 70% starch, so differences in the quality and quantity of starch affect the flour processing characteristics. Investigations on starch composition, structure, morphology, molecular markers, and transformations are providing new and efficient techniques that can improve the quality of bread wheat. Additionally, wheat starch composition and quality are varied due to genetics and environmental factors. Starch is more sensitive to heat and drought stress compared to storage proteins. These stresses also have a great influence on the grain filling period and anthesis, and, consequently, a negative effect on starch synthesis. Sucrose metabolizing and starch synthesis enzymes are suppressed under heat and drought stress during the grain filling period. Therefore, it is important to illustrate starch and sucrose mechanisms during plant responses in the grain filling period. In recent years, most of these quality traits have been investigated through genetic modification studies. This is an attractive approach to improve functional properties in wheat starch. The new information collected from hybrid and transgenic plants is expected to help develop novel starch for understanding wheat starch biosynthesis and commercial use. Wheat transformation research using plant genetic engineering technology is the main purpose of continuously controlling and analyzing the properties of wheat starch. The aim of this paper is to review the structure, biosynthesis mechanism, quality, and response to heat and drought stress of wheat starch. Additionally, molecular markers and transformation studies are reviewed to elucidate starch quality in wheat.

Partially purified ginsenoside extract (PGE) and compound K enriched extract (CKE) were prepared from ginseng sprouts, and their antioxidant, anti-inflammatory and antithrombotic effects were investigated. Compared to the 6-year-old ginseng roots, ginseng sprouts were found to have a higher content of phenolic compounds, saponin and protopanaxadiol-type ginsenoside by about 56%, 36% and 43%, respectively. PGE was prepared using a macroporous adsorption resin, and compound K(CK) was converted and enriched from the PGE by enzymatic hydrolysis with a conversion rate of 75%. PGE showed higher effects than CKE on radical scavenging activity in antioxidant assays. On the other hand, CKE reduced nitric oxide levels more effectively than PGE in RAW 264.7 cells. CKE also reduced pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β and IL-6 than PGE. Tail bleeding time and volume were investigated after administration of CKE at 70–150 mg/kg/day to mice. CKE administered group showed a significant increase or increased tendency in bleeding time than the control group. Bleeding volume in the CKE group increased than the control group, but not as much as in the aspirin group. In conclusion, ginseng sprouts could be an efficient source of ginsenoside, and CKE converted from the ginsenosides showed antioxidant, anti-inflammatory and antithrombotic effects. However, it was estimated that the CKE might play an essential role in anti-inflammatory effects rather than antioxidant effects.

Few studies have reported on the flowering time mechanism of tropical maize under short-day conditions. Drought, another important factor that affects flowering time, has been reported to delay the silking date in tropical maize. However, due to the lack of genetic information related to flowering in maize, the mechanism by which drought delays flowering is unclear. To further understand this process, we analyzed drought-responsive genes using RNA sequencing and identified genes related to flowering time, including contigs from de novo assembly. The results revealed changes in the expression of flowering-time genes, including INDETERMINATE1 (ID1), Heading date 3a (Hd3a), CONSTANS-like genes, and ZEA MAYS CENTRORADIALES8 (ZCN8), which are known to be crucial factors in flowering. In particular, Hd3a, CONZ1, and ZCN8, which have been reported to accelerate flowering under short-day conditions, were downregulated by drought stress. Changes in gene expression appear to play an important role in changes in flowering time under drought. These expression profiles will help to further understand the flowering-time genes of tropical maize and the delayed flowering time resulting from drought.

OBJECTIVE:Conventional risk stratification models for mortality of acute myocardial infarction (AMI) have potential limitations. This study aimed to develop and validate deep-learning-based risk stratification for the mortality of patients with AMI (DAMI). METHODS:The data of 22,875 AMI patients from the Korean working group of the myocardial infarction (KorMI) registry were exclusively divided into 12,152 derivation data of 36 hospitals and 10,723 validation data of 23 hospitals. The predictor variables were the initial demographic and laboratory data. The endpoints were in-hospital mortality and 12-months mortality. We compared the DAMI performance with the global registry of acute coronary event (GRACE) score, acute coronary treatment and intervention outcomes network (ACTION) score, and the thrombolysis in myocardial infarction (TIMI) score using the validation data. RESULTS:In-hospital mortality for the study subjects was 4.4% and 6-month mortality after survival upon discharge was 2.2%. The areas under the receiver operating characteristic curves (AUCs) of the DAMI were 0.905 [95% confidence interval 0.902-0.909] and 0.870 [0.865-0.876] for the ST elevation myocardial infarction (STEMI) and non ST elevation myocardial infarction (NSTEMI) patients, respectively; these results significantly outperformed those of the GRACE (0.851 [0.846-0.856], 0.810 [0.803-0.819]), ACTION (0.852 [0.847-0.857], 0.806 [0.799-0.814] and TIMI score (0.781 [0.775-0.787], 0.593[0.585-0.603]). DAMI predicted 30.9% of patients more accurately than the GRACE score. As secondary outcome, during the 6-month follow-up, the high risk group, defined by the DAMI, has a significantly higher mortality rate than the low risk group (17.1% vs. 0.5%, p < 0.001). CONCLUSIONS:The DAMI predicted in-hospital mortality and 12-month mortality of AMI patients more accurately than the existing risk scores and other machine-learning methods.

AimsThis study aimed to develop and validate deep-learning-based artificial intelligence algorithm for predicting mortality of AHF (DAHF).Methods and results12,654 dataset from 2165 patients with AHF in two hospitals were used as train data for DAHF development, and 4759 dataset from 4759 patients with AHF in 10 hospitals enrolled to the Korean AHF registry were used as performance test data. The endpoints were in-hospital, 12-month, and 36-month mortality. We compared the DAHF performance with the Get with the Guidelines-Heart Failure (GWTG-HF) score, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score, and other machine-learning models by using the test data. Area under the receiver operating characteristic curve of the DAHF were 0.880 (95% confidence interval, 0.876-0.884) for predicting in-hospital mortality; these results significantly outperformed those of the GWTG-HF (0.728 [0.720-0.737]) and other machine-learning models. For predicting 12- and 36-month endpoints, DAHF (0.782 and 0.813) significantly outperformed MAGGIC score (0.718 and 0.729). During the 36-month follow-up, the high-risk group, defined by the DAHF, had a significantly higher mortality rate than the low-risk group(pConclusionDAHF predicted the in-hospital and long-term mortality of patients with AHF more accurately than the existing risk scores and other machine-learning models.

Background and Objectives: Evidence for effectiveness of early change from angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) to sacubitril/valsartan is lacking. We aimed to investigate whether early changes to sacubitril/valsartan could improve outcomes in patients with nonischemic dilated cardiomyopathy (DCM) in real-world practice. Materials and Methods: A total of 296 patients with nonischemic DCM who were treated with ARB or ACEI continuously (group A, n = 150) or had their medication switched to sacubitril/valsartan (group S, n = 146) were included. The sacubitril/valsartan group was divided into early change (within 60 days, group S/E, n = 59) and late change (group S/L, n = 87) groups. Changes in echocardiographic parameters from the time of initial diagnosis to the last follow-up were analyzed. Results: Patients in group S showed greater left ventricular (LV) end-diastolic dimension (EDD) (group A vs. S, 61.7 ± 7.4 vs. 66.5 ± 8.0, p < 0.001) and lower LV ejection fraction (LVEF) (28.9 ± 8.2% vs. 23.9 ± 7.5%, p < 0.001) than those in group A at initial diagnosis. During a median follow-up of 76 months, patients in group S/E, ∆ LVEF (%) and ∆ LVESD (mm) were significantly improved compared with those in patients in group A (group A vs. S/E, ∆ LVEF, p = 0.036; ∆ LVESD, p = 0.023) or S/L (group S/E vs. S/L, ∆ LVEF, p = 0.05; ∆ LVESD, p = 0.005). Among patients whose medications were switched to sacubitril/valsartan, those with an earlier change showed a significant correlation with greater LVEF improvement (r = −0.367, p < 0.001) and LV reverse remodeling (r = 0.277, p < 0.001). Conclusions: in patients with nonischemic DCM, an early switch to sacubitril/valsartan was associated with greater improvement in LV function. Patients might benefit in terms of LV function by early switching to sacubitril/valsartan.

The aim of this study was to form a scaffold-free coculture spheroid model of colonic adenocarcinoma cells (CACs) and normal colonic fibroblasts (NCFs) and to use the spheroids to investigate the role of NCFs in the tumorigenicity of CACs in nude mice. We analysed three-dimensional (3D) scaffold-free coculture spheroids of CACs and NCFs. CAC Matrigel invasion assays and tumorigenicity assays in nude mice were performed to examine the effect of NCFs on CAC invasive behaviour and tumorigenicity in 3D spheroids. We investigated the expression pattern of fibroblast activation protein-α (FAP-α) by immunohistochemical staining. CAC monocultures did not form densely-packed 3D spheroids, whereas cocultured CACs and NCFs formed 3D spheroids. The 3D coculture spheroids seeded on a Matrigel extracellular matrix showed higher CAC invasiveness compared to CACs alone or CACs and NCFs in suspension. 3D spheroids injected into nude mice generated more and faster-growing tumors compared to CACs alone or mixed suspensions consisting of CACs and NCFs. FAP-α was expressed in NCFs-CACs cocultures and xenograft tumors, whereas monocultures of NCFs or CACs were negative for FAP-α expression. Our findings provide evidence that the interaction between CACs and NCFs is essential for the tumorigenicity of cancer cells as well as for tumor propagation.

Inflammation is a complex protective response of body tissues to harmful stimuli. Acute inflammation can progress to chronic inflammation, which can lead to severe disease. Therefore, this research focuses on the development of anti-inflammatory drugs, and natural extracts have been explored as potential agents. No study has yet examined the inflammation-associated pharmacological activity of Potentilla glabra Var. mandshurica (Maxim.) Hand.-Mazz ethanol extract (Pg-EE). To examine the mechanisms by which Pg-EE exerts anti-inflammatory effects, we studied its activities in lipopolysaccharide (LPS)-treated murine macrophage RAW264.7 cells and an HCl/EtOH-induced gastritis model. LPS-triggered nitric oxide (NO) release and mRNA levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in RAW264.7 cells were suppressed by Pg-EE in a dose-dependent manner. Using a luciferase assay and western blot assay, we found that the NF-κB pathway was inhibited by Pg-EE, particularly by the decreased level of phosphorylated proteins of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunits (p65 and p50), inhibitor of kappa B alpha (IκBα), p85, and Src. Using an overexpression strategy, cellular thermal shift assay, and immunoprecipitation analysis, we determined that the anti-inflammatory effect of Pg-EE was mediated by the inhibition of Src. Pg-EE further showed anti-inflammatory effects in vivo in the HCl/EtOH-induced gastritis mouse model. In conclusion, Pg-EE exerts anti-inflammatory activities by targeting Src in the NF-κB pathway, and these results suggest that Pg-EE could be used as an anti-inflammatory herbal medicine.

Protein arginine methyltransferase 1 (PRMT1) is the most predominant PRMT and is type I, meaning it generates monomethylarginine and asymmetric dimethylarginine. PRMT1 has functions in oxidative stress, inflammation and cancers, and modulates diverse diseases; consequently, numerous trials to develop PRMT1 inhibitors have been attempted. One selective PRMT1 inhibitor is N,N′-(Sulfonyldi-4,1-phenylene)bis(2-chloroacetamide), also named TC-E 5003 (TC-E). In this study, we investigated whether TC-E regulated inflammatory responses. Nitric oxide (NO) production was evaluated by the Griess assay and the inflammatory gene expression was determined by conducting RT-PCR. Western blot analyzing was carried out for inflammatory signaling exploration. TC-E dramatically reduced lipopolysaccharide (LPS)-induced NO production and the expression of inflammatory genes (inducible NO synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α and interleukin (IL)-6) as determined using RT-PCR. TC-E downregulated the nuclear translocation of the nuclear factor (NF)-κB subunits p65 and p50 and the activator protein (AP)-1 transcriptional factor c-Jun. Additionally, TC-E directly regulated c-Jun gene expression following LPS treatment. In NF-κB signaling, the activation of IκBα and Src was attenuated by TC-E. Taken together, these data show that TC-E modulates the lipopolysaccharide (LPS)-induced AP-1 and NF-κB signaling pathways and could possibly be further developed as an anti-inflammatory compound.

Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2-21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.

Calgranulin B is known to be involved in tumor development, but the underlying molecular mechanism is not clear. To gain insight into possible roles of calgranulin B, we screened for calgranulin B-interacting molecules in the SNU-484 gastric cancer and the SNU-81 colon cancer cells. Calgranulin B-interacting partners were identified by yeast two-hybrid and functional information was obtained by computational analysis. Most of the calgranulin B-interacting partners were involved in metabolic and cellular processes, and found to have molecular function of binding and catalytic activities. Interestingly, 46 molecules in the network of the calgranulin B-interacting proteins are known to be associated with cancer and FKBP2 was found to interact with calgranulin B in both SNU-484 and SNU-81 cells. Polyubiquitin-C encoded by UBC, which exhibited an interaction with calgranulin B, has been associated with various molecules of the extracellular space and plasma membrane identified in our screening, including Na-K-Cl cotransporter 1 and dystonin in SNU-484 cells, and ATPase subunit beta-1 in SNU-81 cells. Our data provide novel insight into the roles of calgranulin B of gastrointestinal cancer cells, and offer new clues suggesting calgranulin B acts as an effector molecule through which the cell can communicate with the tumor microenvironment via polyubiquitin-C.

Pulmonary emphysema is characterized by a loss of alveolar integrity due to prolonged cigarette smoking and inhaled irritants. Dried yeast extracts (YE) are employed as food additives, savory flavorings, or creation of umami taste sensations. Despite being rich in nutrition, their application as nutraceuticals and functional foods is not investigated much and little is known about the inhibition of pulmonary emphysema. This study examined whether YE ameliorated pulmonary emphysema in mice is evoked by cigarette smoke (CS) and ovalbumin (OVA). Mice were orally administrated with 25–100 mg/kg YE for 8 weeks. Alveolar epithelial A549 cells exposed to lipopolysaccharide or CS extracts (CSE) were supplemented with 10–100 µg/mL YE. Oral YE administration reduced bronchoalveolar lavage fluid leukocytosis in CS-/OVA-exposed mice. YE reduced induction of inflammatory mediators and MMP-12, and diminished reactive oxygen species production and emphysematous alterations in CS-challenged airways. The YE treatment blunted bax/bcl-2 ratio and activation of p53 and caspases in CS-exposed lungs. Apoptotic death was dampened in CSE-loaded YE-supplemented A549 cells. YE curtailed tissue levels of MMP-12 in inflammatory OVA-exposed lungs. YE abrogated the secretion of TNF-α and MCP-1 through blocking NF-κB signaling in endotoxin-loaded A549 cells. Thus, the antioxidant YE may therapeutically ameliorate oxidative stress and inflammatory tissue destruction in emphysematous diseases.

Autophagy is a cellular process that disrupts and uses unnecessary or malfunctioning components for cellular homeostasis. Evidence has shown a role for autophagy in tumor cell survival, but the molecular determinants that define sensitivity against autophagic regulation in cancers are not clear. Importantly, we found that breast cancer cells with low expression levels of a zinc-finger protein, ZNF143 (MCF7 sh-ZNF143), showed better survival than control cells (MCF7 sh-Control) under starvation, which was compromised with chloroquine, an autophagy inhibitor. In addition, there were more autophagic vesicles in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells, and proteins related with the autophagic process, such as Beclin1, p62, and ATGs, were altered in cells with less ZNF143. ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor. Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability. Taken together, we showed that a subset of breast cancer cells with low expression of ZNF143 might exhibit better survival via an autophagic process by regulating the p53–Beclin1 axis, corroborating the necessity of blocking autophagy for the best therapy.

BackgroundThe aims of this study are to investigate the glycemic efficacy and predictive parameters of vildagliptin therapy in Korean subjects with type 2 diabetes.MethodsIn this retrospective study, we retrieved data for subjects who were on twice-daily 50 mg vildagliptin for at least 6 months, and classified the subjects into five treatment groups. In three of the groups, we added vildagliptin to their existing medication regimen; in the other two groups, we replaced one of their existing medications with vildagliptin. We then analyzed the changes in glucose parameters and clinical characteristics.ResultsUltimately, 327 subjects were analyzed in this study. Vildagliptin significantly improved hemoglobin A1c (HbA1c) levels over 6 months. The changes in HbA1c levels (ΔHbA1c) at month 6 were -2.24% (P=0.000), -0.77% (P=0.000), -0.80% (P=0.001), -0.61% (P=0.000), and -0.34% (P=0.025) for groups 1, 2, 3, 4, and 5, respectively, with significance. We also found significant decrements in fasting plasma glucose levels in groups 1, 2, 3, and 4 (P

Anthraquinone compounds are one of the abundant polyphenols found in fruits, vegetables, and herbs. However, the in vivo anti-inflammatory activity and molecular mechanisms of anthraquinones have not been fully elucidated. We investigated the activity of anthraquinones using acute inflammatory and nociceptive experimental conditions. Anthraquinone-2-carboxylic acid (9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, AQCA), one of the major anthraquinones identified from Brazilian taheebo, ameliorated various inflammatory and algesic symptoms in EtOH/HCl- and acetylsalicylic acid- (ASA-) induced gastritis, arachidonic acid-induced edema, and acetic acid-induced abdominal writhing without displaying toxic profiles in body and organ weight, gastric irritation, or serum parameters. In addition, AQCA suppressed the expression of inflammatory genes such as cyclooxygenase- (COX-) 2 in stomach tissues and lipopolysaccharide- (LPS-) treated RAW264.7 cells. According to reporter gene assay and immunoblotting analyses, AQCA inhibited activation of the nuclear factor- (NF-) κB and activator protein- (AP-) 1 pathways by suppression of upstream signaling involving interleukin-1 receptor-associated kinase 4 (IRAK1), p38, Src, and spleen tyrosine kinase (Syk). Our data strongly suggest that anthraquinones such as AQCA act as potent anti-inflammatory and antinociceptive components in vivo, thus contributing to the immune regulatory role of fruits and herbs.