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Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.

To assess the performance of deep convolutional neural network (CNN) to discriminate malignant and benign thyroid nodules

To compare the diagnostic performances of physicians and a deep convolutional neural network (CNN) predicting malignancy with ultrasonography images of thyroid nodules with atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) results on fine-needle aspiration (FNA). This study included 202 patients with 202 nodules ≥ 1 cm AUS/FLUS on FNA, and underwent surgery in one of 3 different institutions. Diagnostic performances were compared between 8 physicians (4 radiologists, 4 endocrinologists) with varying experience levels and CNN, and AUS/FLUS subgroups were analyzed. Interobserver variability was assessed among the 8 physicians. Of the 202 nodules, 158 were AUS, and 44 were FLUS; 86 were benign, and 116 were malignant. The area under the curves (AUCs) of the 8 physicians and CNN were 0.680–0.722 and 0.666, without significant differences (P > 0.05). In the subgroup analysis, the AUCs for the 8 physicians and CNN were 0.657–0.768 and 0.652 for AUS, 0.469–0.674 and 0.622 for FLUS. Interobserver agreements were moderate (k = 0.543), substantial (k = 0.652), and moderate (k = 0.455) among the 8 physicians, 4 radiologists, and 4 endocrinologists. For thyroid nodules with AUS/FLUS cytology, the diagnostic performance of CNN to differentiate malignancy with US images was comparable to that of physicians with variable experience levels.

Immune checkpoint inhibitors (ICI) have demonstrated efficacy in the treatment of solid cancers. However, there is no unified predictive biomarker available for ICIs. We aimed to compare the prognostic impact of using three PD-L1 antibodies (SP142, SP263, and 22C3) for immunohistochemical (IHC) analysis. We retrospectively investigated tumor tissues derived from 316 breast cancer cases, by constructing tissue microarrays and by performing IHC staining. The immune-cell expression rate (for SP142 and SP263) and combined proportional score (for 22C3) were evaluated, and survival outcomes were analyzed. Prediction models were developed, and values of Harrel’s c-index and areas under curves were calculated to compare the discriminatory power. Negative PD-L1 expression based on the 22C3-IHC assay was determined to be an independent prognostic marker for recurrence-free survival (RFS, P = 0.0337) and distant metastasis-free survival (DMFS, P = 0.0131). However, PD-L1 expression based on SP142- and SP263-IHC assays did not reveal a prognostic impact. Among the three antibodies, adding PD-L1 expression data obtained via 22C3-IHC assay to the null model led to a significant improvement in the discriminatory power of RFS and DMFS. We suggest that PD-L1 expression based on the 22C3-IHC assay is a superior prognostic marker than that based on SP142- and SP263-IHC assays.

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676–0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724–0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL: RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL: RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500–600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin’s equation may be optimal for LDL-C and ASCVD risk estimation.

Diagnosing osteosarcoma (OS) is very challenging and OS is often misdiagnosed as osteomyelitis (OM) due to the nonspecificity of its symptoms upon initial presentation. This study investigated the possibility of detecting OS-induced trabecular bone changes on panoramic radiographs and differentiating OS from OM by analyzing fractal dimensions (FDs) and degrees of anisotropy (DAs). Panoramic radiographs of patients with histopathologically proven OS and OM of the jaw were obtained. A total of 23 patients with OS and 40 patients with OM were enrolled. To investigate whether there was a microarchitectural difference between OS lesions and normal trabecular areas in each patient, two regions of interest (ROIs) were located on the CT images. Three microarchitectural parameters (box-counting FD, fast Fourier transform-based FD, and DA) were calculated. For both OS and OM, significant differences were found for all three microarchitectural parameters. Compared to normal trabecular bone, trabecular bone affected by OS and OM became isotropic and more complex. When comparing OS and OM, a statistically significant difference was found only in DA. Trabecular bones affected by OS became more isotropic than those affected by OM. Microarchitectural analysis, especially DA, could be useful for detecting OS-induced trabecular alterations and differentiating OS from OM.

We evaluated the risk of osteoporosis and fractures associated with androgen deprivation therapy (ADT) use and duration in men with prostate cancer. From the nationwide claims database in South Korea, a total of 218,203 men with prostate cancer were identified between 2008 and 2017. After applying the inclusion and exclusion criteria, a total of 144,670 patients were included in the analysis. To adjust for comorbidities between cohorts, 1:1 propensity score matching was used. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events associated with ADT, after controlling for potential confounding factors. In the matched cohort, there were differences in the incidence of newly developed osteoporosis (8.79% in the ADT group vs. 7.08% in the non-ADT group, p

The purpose of this study was to propose a continuity-aware contextual network (Canal-Net) for the automatic and robust 3D segmentation of the mandibular canal (MC) with high consistent accuracy throughout the entire MC volume in cone-beam CT (CBCT) images. The Canal-Net was designed based on a 3D U-Net with bidirectional convolutional long short-term memory (ConvLSTM) under a multi-task learning framework. Specifically, the Canal-Net learned the 3D anatomical context information of the MC by incorporating spatio-temporal features from ConvLSTM, and also the structural continuity of the overall MC volume under a multi-task learning framework using multi-planar projection losses complementally. The Canal-Net showed higher segmentation accuracies in 2D and 3D performance metrics (p

Synbiotics are feed supplements with the potential to promote health and productivity in pigs partly, through modulation of the intestinal microbiome. Our study used shotgun sequencing and 16S rRNA gene sequencing techniques to characterize the effect of a synbiotic containing three Lactobacillus species and a fructo-oligosaccharide on the proximal colonic microbiome of 4- to 7-month-old Korean native black gilts. With shotgun sequencing we constructed unique metagenome-assembled genomes of gut microbiota in Native Black Pig for the first time, which we then used for downstream analysis. Results showed that synbiotic treatment did not alter microbial diversity and evenness within the proximal colons, but altered composition of some members of the Lactobacillaceae, Enterococcaceae and Streptococcaceae families. Functional analysis of the shotgun sequence data revealed 8 clusters of orthologous groups (COGs) that were differentially represented in the proximal colonic microbiomes of synbiotic-treated Jeju black pigs relative to controls. In conclusion, our results show that administering this synbiotic causes changes in the functional capacity of the proximal colonic microbiome of the Korean native black pig. This study improves our understanding of the potential impact of synbiotics on the colonic microbiome of Korean native black pigs.

This study investigated the effect of image quality fluctuations on the repeatability of thickness measurements of the peripapillary retinal nerve fibre (PP-RNFL) and ganglion cell-inner plexiform (GC-IPL) layers using swept-source optical coherence tomography (SS-OCT). Three consecutive OCT scans each were performed on 56 healthy subject. Finally, 168 SS-OCT results were analysed. Based on the tertile values of the mean absolute difference of image quality score, all subjects were divided into the following three groups—low-(LIQD), moderate-(MIQD), and high-(HIQD) image quality score difference groups. A linear mixed model and intraclass correlation coefficients (ICCs) were used for analyses. Despite high ICC values (> 0.9), several sectors showed significant differences in the ICC values in intergroup comparisons. For LIQD-HIQD and MIQD-HIQD, most PP-RNFL sectors showed significant differences. For GC-IPL sectors, the LIQD-HIQD comparison showed significant differences in the temporosuperior (p = 0.012), inferior (p p = 0.042) sectors. Significant differences existed in the average GC-IPL (p = 0.009), nasoinferior (p = 0.035), and inferior GC-IPL sectors (p

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is essential for human development, and DYRK1A haploinsufficiency is associated with a recognizable developmental syndrome and variable clinical features. Here, we present a patient with DYRK1A haploinsufficiency syndrome, including facial dysmorphism, delayed motor development, cardiovascular system defects, and brain atrophy. Exome sequencing identified a novel de novo heterozygous mutation of the human DYRK1A gene (c.1185dup), which generated a translational termination codon and resulted in a C-terminally truncated protein (DYRK1A-E396ter). To study the molecular effect of this truncation, we generated mammalian cell and Drosophila models that recapitulated the DYRK1A protein truncation. Analysis of the structure and deformation energy of the mutant protein predicted a reduction in protein stability. Experimentally, the mutant protein was efficiently degraded by the ubiquitin-dependent proteasome pathway and was barely detectable in mammalian cells. More importantly, the mutant kinase was intrinsically inactive and had little negative impact on the wild-type protein. Similarly, the mutant protein had a minimal effect on Drosophila phenotypes, confirming its loss-of-function in vivo. Together, our results suggest that the novel heterozygous mutation of DYRK1A resulted in loss-of-function of the kinase activity of DYRK1A and may contribute to the developmental delay observed in the patient.

We developed an automatic method for staging periodontitis on dental panoramic radiographs using the deep learning hybrid method. A novel hybrid framework was proposed to automatically detect and classify the periodontal bone loss of each individual tooth. The framework is a hybrid of deep learning architecture for detection and conventional CAD processing for classification. Deep learning was used to detect the radiographic bone level (or the CEJ level) as a simple structure for the whole jaw on panoramic radiographs. Next, the percentage rate analysis of the radiographic bone loss combined the tooth long-axis with the periodontal bone and CEJ levels. Using the percentage rate, we could automatically classify the periodontal bone loss. This classification was used for periodontitis staging according to the new criteria proposed at the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. The Pearson correlation coefficient of the automatic method with the diagnoses by radiologists was 0.73 overall for the whole jaw (p 0.91 overall for the whole jaw (p

Non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome and is associated with cardiovascular outcomes. We investigated whether NAFLD was associated with coronary artery calcification (CAC) in participants without a previous history of cardiovascular disease and whether this association differed according to sex and obesity status after adjustment for other atherosclerosis risk factors, alcohol intake, and liver enzyme levels. Among 67,441 participants, data from 8,705 participants who underwent a fatty liver status and CAC assessment during routine health screening were analysed. CAC scores were calculated using computed tomography. NAFLD was diagnosed in patients with evidence of liver steatosis on ultrasonography. Obesity was defined as a body mass index of ≥25 kg/m2. Multivariate analysis showed a significant association between NAFLD and CAC in non-obese participants (odds ratio, 1.24 [95% confidence interval, 1.01–1.53]), whereas NAFLD and CAC were not associated in obese participants. Interaction analysis showed that the association between NAFLD and CAC was influenced by sex and obesity. Subgroup analysis revealed a significant association between NAFLD and CAC in non-obese male participants (odds ratio, 1.36 [1.07–1.75]), but not in female participants. Our study indicates that non-obese men with NAFLD are prone to CAC.

Angle measurement methods for measuring pes planus may lose consistency by errors between observers. If the feature points for angle measurement can be provided in advance with the algorithm developed through the deep learning method, it is thought that the error between the observers can be reduced. A total of 300 weightbearing lateral radiographs were used for the development of the deep learning-based algorithm, and a total of 95 radiographs were collected for the clinical validation test set. Meary angle (MA) and calcaneal pitch (CP) were selected as measurement methods and measured twice by three less-experienced physicians with the algorithm-based tool and twice without. The intra- and inter-observer agreements of MA and CP measures were assessed via intra-class correlation coefficient. In addition, verification of the improvement of measurement performance by the algorithm was performed. Interobserver agreements for MA and CP measurements with algorithm were more improved than without algorithm. As for agreement with reference standard, combining the results of all readers, both MA and CP with algorithm were greater than those without algorithm. The deep learning algorithm tool is expected to improve the reproducibility of radiographic measurements for pes planus, especially by improving inter-observer agreement.

Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. Dihydrotestosterone (DHT) and androgen receptor (AR) levels are increased in patients with AGA, and DHT-AR signaling correlates strongly with AGA pathogenesis. In this study, treatment with self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticle-type siRNA selectively suppressed AR expression in vitro. Clinical studies with application of SAMiRNA to the scalp and massaging to deliver it to the hair follicle confirmed its efficacy in AGA. For identification of a potent SAMiRNA for AR silencing, 547 SAMiRNA candidates were synthesized and screened. SAMiRNA-AR68 (AR68) was the most potent and could be efficiently delivered to human follicle dermal papilla cells (HFDPCs) and hair follicles, and this treatment decreased the AR mRNA and protein levels. We confirmed that 10 µM AR68 elicits no innate immune response in human PBMCs and no cytotoxicity up to 20 µM with HFDP and HaCaT cells. Clinical studies were performed in a randomized and double-blind manner with two different doses and frequencies. In the low-dose (0.5 mg/ml) clinical study, AR68 was applied three times per week for 24 weeks, and through quantitative analysis using a phototrichogram, we confirmed increases in total hair counts. In the 24-week long high-dose (5 mg/ml) clinical study, AR68 showed average additional hair growth of 1.3-1.9 hairs/cm2 per month, which is comparable to finasteride. No side effects were observed. Therefore, SAMiRNA targeting AR mRNA is a potential novel topical treatment for AGA.

This study aimed to develop quantitative assessments of spontaneous movements in high-risk preterm infants based on a deep learning algorithm. Video images of spontaneous movements were recorded in very preterm infants at the term-equivalent age. The Hammersmith Infant Neurological Examination (HINE) was performed in infants at 4 months of corrected age. Joint positional data were extracted using a pretrained pose-estimation model. Complexity and similarity indices of joint angle and angular velocity in terms of sample entropy and Pearson correlation coefficient were compared between the infants with HINE p

The purpose of this study was to directly and quantitatively measure BMD from Cone-beam CT (CBCT) images by enhancing the linearity and uniformity of the bone intensities based on a hybrid deep-learning model (QCBCT-NET) of combining the generative adversarial network (Cycle-GAN) and U-Net, and to compare the bone images enhanced by the QCBCT-NET with those by Cycle-GAN and U-Net. We used two phantoms of human skulls encased in acrylic, one for the training and validation datasets, and the other for the test dataset. We proposed the QCBCT-NET consisting of Cycle-GAN with residual blocks and a multi-channel U-Net using paired training data of quantitative CT (QCT) and CBCT images. The BMD images produced by QCBCT-NET significantly outperformed the images produced by the Cycle-GAN or the U-Net in mean absolute difference (MAD), peak signal to noise ratio (PSNR), normalized cross-correlation (NCC), structural similarity (SSIM), and linearity when compared to the original QCT image. The QCBCT-NET improved the contrast of the bone images by reflecting the original BMD distribution of the QCT image locally using the Cycle-GAN, and also spatial uniformity of the bone images by globally suppressing image artifacts and noise using the two-channel U-Net. The QCBCT-NET substantially enhanced the linearity, uniformity, and contrast as well as the anatomical and quantitative accuracy of the bone images, and demonstrated more accuracy than the Cycle-GAN and the U-Net for quantitatively measuring BMD in CBCT.

Serum inflammatory markers are used in the prognostication of colorectal cancer (CRC); however, the corresponding role of positron emission tomography (PET)-derived inflammatory markers remains unclear. This study aimed to investigate the prognostic value of 18F-fluorodeoxyglucose (FDG) uptake in the bone marrow and spleen of patients with CRC and evaluate the relationship between FDG uptake estimates in these organs and serum inflammatory markers. In total, 411 patients who underwent preoperative FDG PET/computed tomography (CT) within 1 month of surgery were enrolled. The mean standardized uptake values of the bone marrow and spleen were normalized to the value of the liver, thereby generating bone marrow-to-liver uptake ratio (BLR) and spleen-to-liver uptake ratio (SLR) estimates. The value of BLR and SLR in predicting overall survival (OS) was assessed using the Cox proportional hazards model. The correlation between BLR or SLR and neutrophil-to-lymphocyte ratio (NLR) was evaluated. The predictive accuracy of BLR alone and in combination with SLR was compared using the integrated area under the receiver operating characteristic curves (iAUC). In the univariate analysis, BLR (> 1.06) and SLR (> 0.93) were significant predictors of OS. In the multivariate analysis, BLR was an independent predictor of OS (hazard ratio = 5.279; p p

A ketogenic diet is a potential adjuvant cancer therapy that limits glucose availability to tumours while fuelling normal tissues with ketone bodies. We examined the effect of a low carbohydrate ketogenic diet (LCKD) (80% kcal from fat, ketogenic ratio 1.75:1, w/w) compared to a general hospital diet (GD) on serum metabolic profiles in patients (n = 18, ≥ 19 years old) who underwent pancreatectomy for pancreatobiliary cancer. Serum samples collected preoperatively (week 0) and after the dietary intervention (week 2) were analysed with a nontargeted metabolomics approach using liquid chromatography–tandem mass spectrometry. Serum β-hydroxybutyrate and total ketone levels significantly increased after 2 weeks of LCKD compared to GD (p

Prompt diagnosis and timely treatment are important for reducing morbidity and mortality from pyogenic liver abscess (PLA). The purpose of this study was to investigate the importance of the delta neutrophil index (DNI) reflecting the fraction of immature granulocytes as a predictor of the development of in-hospital hypotension in initially stable patients with PLA. We retrospectively identified 308 consecutive patients (>18 years) who were hemodynamically stable at presentation and diagnosed with PLA in the emergency department (ED) between January 2011 and September 2017. The outcome of interest was in-hospital hypotension 1–24 hours after admission to the ED. A high DNI at ED admission was an independent predictor of the development of in-hospital hypotension in initially stable patients with PLA (odds ratio [OR]: 1.44, 95.0% confidence interval [CI]: 1.06–1.95; P = 0.02). A DNI > 3.3% was associated with in-hospital hypotension at ED admission (OR: 5.37, 95.0% CI: 2.91–9.92; P P

Monte Carlo (MC) simulation is a simpler radiation dose assessment method than the conventional method, thermoluminescent dosimetry (TLD). MC simulation and TLD were compared as tools to evaluate the effective dose from paediatric panoramic radiography. Various exposure conditions and machine geometries were simulated using the MC method to investigate factors resulting in effective dose reduction. The effective dose of paediatric panoramic radiography was obtained using an MC simulation and its reliability was verified by a comparison with the value obtained using TLD. Next, 7 factors determining the effective dose in the MC simulation were input with 6 equally-spaced values, and a total of 36 simulations were performed to obtain effective dose values. The correlations between each dose-determining factor and the resulting effective dose were evaluated using linear regression analysis. The TLD-measured dose was 3.850 µSv, while the MC simulation yielded a dose of 3.474 µSv. Beam height was the factor that most strongly influenced the effective dose, while rotation angle and focus-to-patient distance were the least influential factors. MC simulation is comparable to TLD for obtaining effective dose values in paediatric panoramic radiography. Obtaining panoramic radiography with a short beam height can effectively reduce the dose in paediatric patients.

This study analysed the trabecular meshwork (TM) length in open and closed angle patients and presented a better method for locating the scleral spur using Schwalbe’s line method in anterior segment optical coherence tomography (AS-OCT). Patients who underwent AS-OCT at Yonsei University Gangnam Severance Hospital we enrolled; 58 and 57 open and closed angle eyes, respectively. We measured the distance from the scleral spur to Schwalbe’s line as the TM length and compared it between open and closed angle patients, and to previous studies. TM length was applied to locate the scleral spur using Schwalbe’s line method. Mean TM lengths were 811 ± 83 μm and 575 ± 96 μm in the open and closed angle groups, respectively (p

Specific protein 1 (SP1) is associated with aggressive behavior, invasive clinical phenotype and poor clinical outcomes in various cancers. We studied whether SP1 exerts its effect on invasiveness and promotion of the epithelial-mesenchymal transition (EMT) by regulating lysyl oxidase-like 2 (LOXL2) in pancreatic ductal adenocarcinoma (PDAC) cell lines. We showed that silencing of SP1 in MIA Paca-2 cell significantly decreased cell invasion and migration. In MIA Paca-2 cells, silencing of SP1 induced a reduction of LOXL2 expression, whereas LOXL2 silencing did not lead to a decrease in the expression of SP1. Chromatin immunoprecipitation assay demonstrated the binding of SP1 to LOXL2 promoter. Wound healing and transmigration assays also showed that transfection of both SP1 and LOXL2 siRNA induced most significant decrease of cell invasion and migration compared to either SP1 or LOXL2-only silenced cells. Finally, we investigated the prognostic value of SP1 in patients with PDAC and SP1/LOX2 expression was examined by immunochemistry. Univariate and multivariate analyses showed that tumor differentiation and co-expression of SP1 and LOXL2 were independent factors for disease-free survival. In summary, our study demonstrates that SP1 modulates EMT and is involved in tumor invasion and migration of PDAC cells through the regulation of LOXL2.

Breast cancer is a heterogeneous disease that among Korean women has a peak incidence in the perimenopausal period. The full epidemiological characteristics of breast cancer in Korean women are not yet properly understood. We investigated whether white blood cell (WBC) is related to breast cancer burden according to estrogen receptor (ER) and progesterone receptor (PR) status in the context of body mass index and menopausal status. We conducted a large case-control study and compared WBC counts between patients with breast cancer (N = 4,402) and propensity score-matched controls (N = 4,402) selected from the Korean National Health and Nutrition Examination Survey (KNHANES). We stratified the study sample by ER/PR status, menopausal status, and body mass index and assessed the association between WBC count and breast cancer burden using multinomial logistic regression. Compared with controls, non-obese patients with ER+/PR+ breast cancer had significantly higher WBC counts regardless of menopausal status (OR 1.293 95% CI 1.139–1.363, p p = 0.023 in postmenopausal). There was no relationship between WBC count and ER+/PR+ breast cancer among premenopausal obese women. Furthermore, premenopausal non-obese women and postmenopausal obese women with ER+/PR+ breast cancer had higher WBC counts than those with ER−/PR− breast cancer. Further larger-scale prospective cohort studies are warranted to determine these associations in the future.

Low serum bilirubin levels have been associated with increased risk of cardiovascular disease (CVD) and metabolic syndrome. Testosterone deficiency could also contribute to increased risk of CVD and metabolic syndrome. Therefore, this study aimed to examine the relationship between serum bilirubin level and testosterone deficiency in 1284 Korean men aged 45 to 70 years. Serum bilirubin level was categorized into quartiles: Q1 ≤ 0.7, Q2 0.8–0.9, Q3 1.0–1.1, and Q4 ≥ 1.2 mg/dL. Testosterone deficiency was defined as level less than 8.0 nmol/L, as suggested by the position statement of International Society of Andrology. The overall prevalence of testosterone deficiency was 5.8% and significantly decreased with the quartiles from Q1 to Q4. Compared with the referent fourth quartile (serum bilirubin ≥ 1.2 mg/dL), the ORs (95% CIs) for testosterone deficiency was 2.29 (1.04–4.94) for the first quartile after adjusting for age, fasting glucose, triglyceride, HDL-cholesterol, leukocyte count, hemoglobin, smoking status, and alcohol intake. We found inversely graded associations of serum bilirubin level with testosterone deficiency. These findings suggest that low bilirubin level may be interpreted as a state of testosterone deficiency in middle-aged and older men.

Prematurity, size at birth, and postnatal growth are important factors that determine cardiometabolic and neurodevelopmental outcomes later in life. In the present study, we aimed to investigate the associations between the size at birth and growth velocity after birth with cardiometabolic and neurodevelopmental outcomes in preterm infants. Fifty-six preterm infants born at p = 0.036) and perceptional reasoning index (β = 0.456, p = 0.003) of K-WISC-IV were positively correlated with postnatal weight gain in the neonatal intensive care unit. Although cardiometabolic outcomes were comparable in preterm SGA and AGA infants, the growth velocity at different time periods resulted in different cardiometabolic and neurocognitive outcomes. Thus, ensuring an optimal growth velocity at early neonatal period could promote good neurocognitive outcomes, while adequate growth after 1 year could prevent adverse cardiometabolic outcomes in preterm infants.

To investigate the epidemiology of congenital scoliosis (CS) and treatment trends. An age-matched, nationwide, population-based study was conducted using the National Health Insurance and Health Insurance Review and Assessment databases from 2010 to 2015. Data regarding the diagnosis and treatment of scoliosis were extracted using International Classifications of Diseases, 10th revision codes. The age-matched normal population was determined from the Korean Statistical Information Service database. We analyzed the incidence rate of CS according to age and sex, as well as the proportion of surgically treated patients. A total of 1664 patients (aged 0–19 years) were diagnosed with CS. The overall average incidence rate of CS over the 5-year period was 3.08 per 100,000 persons, with the highest and second highest rates at 0 years and 12–16 years of age, respectively. The incidence rate stratified by age ranged from 1.5 to 20.1 per 100,000 persons among the age-matched normal population, with peaks at 0 years of age and the second growth spurt in adolescence (12–16 years for males; 10–14 years for females). Anterior surgery was rarely performed; posterior surgery was performed in 92 patients (5.5% of all patients), with the highest prevalence (56.5%) in patients diagnosed at 10–14 years of age. The overall average incidence rate of CS over a 5-year period was 3.08 per 100,000 persons. Only 5.5% of patients underwent surgery within 5 years after the initial diagnosis.

The relationship between changes in body components and the risk of nonalcoholic fatty liver disease (NAFLD) is not fully understood. We investigated the effects of body components and subsequent changes on incident NAFLD at follow-up ultrasound scanning in a longitudinal cohort. We included 9967 participants without NAFLD at baseline who underwent serial health examinations. Sex-specific, weight-adjusted skeletal muscle index (SMI_Wt) was used. Mean follow-up duration was 48.5 ± 33.5 months. NAFLD developed in 2395 participants (24.0%). Body composition was measured using bioelectrical impedance analysis. The following baseline body components were significantly associated with incident NAFLD: the lowest and middle SMI_Wt tertiles in the normal-weight group (adjusted hazard ratio [aHR] = 2.20 and 1.54, respectively), and fat percentage in the normal-weight (aHR = 1.12), overweight (aHR = 1.05), and obese groups (aHR = 1.03) (all P _Wt increase between the first and second examinations was an independent protective factor against incident NAFLD in non-obese groups (P P

Panoramic radiography is the most commonly used equipment in the dental field, but there is no comprehensive standard about how to evaluate the spatial resolution of panoramic radiography. In this study, panorama resolution phantoms were developed for evaluation of horizontal and vertical resolution reflecting unique characteristics of panoramic radiography. Four horizontal resolution phantoms of staircase shape were designed to obtain images of horizontal lead line pairs in a 52 mm width. Four vertical resolution phantoms with vertical lead line pairs placed at an oblique angle were also designed. A phantom stand was made. Three machines were evaluated twice by two oromaxillofacial radiologists. The horizontal lead line pairs were readable over the entire measured area at the values of 1.88, 2.32, and 2.58 lp/mm for all machines. A readable area of horizontal 3.19 lp/mm was observed in the lingual side. In the vertical resolution phantoms, it was possible to read a narrower range. By using the panorama resolution phantoms and phantom stand, it was possible to evaluate the resolution of a wide buccolingual width in four significant areas. By evaluating the resolution of the vertical and horizontal compartments separately, it was possible to gain a better understanding of the obtained images.

Human pluripotent stem cells (hPSCs) have promising therapeutic applications due to their infinite capacity for self-renewal and pluripotency. Genomic stability is imperative for the clinical use of hPSCs; however, copy number variation (CNV), especially recurrent CNV at 20q11.21, may contribute genomic instability of hPSCs. Furthermore, the effects of CNVs in hPSCs at the whole-transcriptome scale are poorly understood. This study aimed to examine the functional in vivo and in vitro effects of frequently detected CNVs at 20q11.21 during early-stage differentiation of hPSCs. Comprehensive transcriptome profiling of abnormal hPSCs revealed that the differential gene expression patterns had a negative effect on differentiation potential. Transcriptional heterogeneity identified by single-cell RNA sequencing (scRNA-seq) of embryoid bodies from two different isogenic lines of hPSCs revealed alterations in differentiated cell distributions compared with that of normal cells. RNA-seq analysis of 22 teratomas identified several differentially expressed lineage-specific markers in hPSCs with CNVs, consistent with the histological results of the altered ecto/meso/endodermal ratio due to CNVs. Our results suggest that CNV amplification contributes to cell proliferation, apoptosis, and cell fate specification. This work shows the functional consequences of recurrent genetic abnormalities and thereby provides evidence to support the development of cell-based applications.

The eligibility of reperfusion therapy has been expanded to increase the number of patients. However, it remains unclear the reperfusion therapy will be beneficial in stroke patients with various comorbidities. We developed a reperfusion comorbidity index for predicting 6-month mortality in patients with acute stroke receiving reperfusion therapy. The 19 comorbidities included in the Charlson comorbidity index were adopted and modified. We developed a statistical model and it was validated using data from a prospective cohort. Among 1026 patients in the retrospective nationwide reperfusion therapy registry, 845 (82.3%) had at least one comorbidity. As the number of comorbidities increased, the likelihood of mortality within 6 months also increased (p

Odor identification ability may serve as an important diagnostic biomarker in Alzheimer’s disease (AD). The aim of the study is to investigate the contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer’s disease spectrum. In 127 participants, we compared A/T/N neuroimaging biomarkers between normosmia and hyposmia groups, and performed correlation analysis between the biomarkers and Cross-Cultural Smell Identification Test (CCSIT) scores. Additionally, path analysis for odor identification ability was performed using cognitive function as a mediator. In between-group comparison, individuals with hyposmia showed higher frequency of amyloid-β (Aβ) positivity, and lower neuropsychological test performance than those with normosmia. After correction for covariates including total cognition scores, there was no difference in the Aβ or tau burden between the normosmia and hyposmia groups, and no correlation between CCSIT scores and Aβ or tau burden. Meanwhile, cortical volumes in the lateral and medial temporal cortices were smaller in the hyposmia group and decreased with the worsening of CCSIT scores. Path analysis showed that only neurodegeneration had a direct effect on odor identification, while Aβ and tau burden contributed to odor identification with the mediation of cognition. In the Alzheimer’s disease spectrum, impaired odor identification ability may be attributable to neurodegeneration rather than the direct effect of Aβ or tau burden.

The prognosis for patients with pancreatic cancer is extremely poor, as they are resistant to first line chemotherapy. The long-term goal of this study was to identify effective combination chemotherapy for pancreatic cancer using pancreatic cancer surgical specimens in the histoculture drug response assay (HDRA) based on three-dimensional culture of tumour fragments, which maintains nature tumour histology in vitro. From 2015 to 2017, the HDRA was performed with tumour specimens from 52 pancreatic cancer patients from Asan Medical Hospital. First, combination drug regimens showed higher drug efficacy and less patient variation than single drugs. Initially, 5-Fluorouracil(5-FU)/Belotecan/Oxaliplatinum and Tegafur/Gimeracil (TS-1)/Oxaliplatinum/Irinotecan were found to be effective. Second, we were able to correlate the efficacy of some drugs with tumour stage. Third, when designing new combination regimens containing 5-FU or gemcitabine, we could identify more effective drug combinations. This is the first study to demonstrate usefulness of the HDRA for pancreatic cancer. Using this technique, we could identify novel candidate combination drug regimens that should be effective in treating pancreatic cancer.

We compared the diagnostic performances and unnecessary FNA rates of several guidelines and modified versions using the size threshold of the ACR TIRADS. Our Institutional Review Board approved this retrospective study and waived the requirement for informed consent and all methods were performed in accordance with the Declaration of Helsinki. A total of 1,384 thyroid nodules in 1,301 patients with definitive cytopathologic findings were included. US categories were assigned according to each guideline. We applied the size threshold suggested by the ACR TIRADS for FNA to the Kwak, ATA and EU guidelines and defined these modified guidelines as the modified Kwak (mKwak), modified ATA (mATA) and modified EU (mEU) guidelines. Diagnostic performances and unnecessary FNA rates of all guidelines were evaluated. Of 1,384 thyroid nodules, 291 (21%) were malignant. Among the original guidelines, the ACR TIRADS had the highest specificity, accuracy, LR and AUC (62.2%, 66%, 2.128 and 0.713). The mKwak, mATA and mEU guidelines had higher specificity, accuracy, LR and AUC (P

The spatial distributions of diverse facilities are often understood in terms of the optimization of the commute distance or the economic profit. Incorporating more general objective functions into such optimization framework may be useful, helping the policy decisions to meet various social and economic demands. As an example, we consider how hospitals should be distributed to minimize the total fatalities of tuberculosis (TB). The empirical data of Korea shows that the fatality rate of TB in a district decreases with the areal density of hospitals, implying their correlation and the possibility of reducing the nationwide fatalities by adjusting the hospital distribution across districts. Approximating the fatality rate by the probability of a patient not to visit a hospital in her/his residential district for the duration period of TB and evaluating the latter probability in the random-walk framework, we obtain the fatality rate as an exponential function of the hospital density with a characteristic constant related to each district’s effective lattice constant estimable empirically. This leads us to the optimal hospital distribution which finds the hospital density in a district to be a logarithmic function of the rescaled patient density. The total fatalities is reduced by 13% with this optimum. The current hospital density deviates from the optimized one in different manners from district to district, which is analyzed in the proposed model framework. The assumptions and limitations of our study are also discussed.

Non-alcoholic steatohepatitis (NASH) is a complex disease consisting of various components including steatosis, lobular inflammation, and ballooning degeneration, with or without fibrosis. Therefore, it is difficult to diagnose NASH with only one imaging modality. This study was aimed to evaluate the feasibility of magnetic resonance imaging (MRI) for predicting NASH and to develop a non-invasive multiparametric MR index for the detection of NASH in non-alcoholic fatty liver disease (NAFLD) patients. This prospective study included 47 NAFLD patients who were scheduled to undergo or underwent ultrasound-guided liver biopsy within 2 months. Biopsy specimens were graded as NASH or non-NASH. All patients underwent non-enhanced MRI including MR spectroscopy (MRS), MR elastography (MRE), and T1 mapping. Diagnostic performances of MRS, MRE, and T1 mapping for grading steatosis, activity, and fibrosis were evaluated. A multiparametric MR index combining fat fraction (FF), liver stiffness (LS) value, and T1 relaxation time was developed using linear regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of the newly devised MR index. Twenty NASH patients and 27 non-NASH patients were included. Using MRS, MRE, and T1 mapping, the mean areas under the curve (AUCs) for grading steatosis, fibrosis, and activity were 0.870, 0.951, and 0.664, respectively. The multiparametric MR index was determined as 0.037 × FF (%) + 1.4 × LS value (kPa) + 0.004 × T1 relaxation time (msec) −3.819. ROC curve analysis of the MR index revealed an AUC of 0.883. The cut-off value of 6 had a sensitivity of 80.0% and specificity of 85.2%. The multiparametric MR index combining FF, LS value, and T1 relaxation time showed high diagnostic performance for detecting NASH in NAFLD patients.

Megakaryocytes (MKs) play key roles in regulating bone metabolism. To test the roles of MK-secreted factors, we investigated whether MK and promegakaryocyte (pro-MK) conditioned media (CM) may affect bone formation and resorption. K562 cell lines were differentiated into mature MKs. Mouse bone marrow macrophages were differentiated into mature osteoclasts, and MC3T3-E1 cells were used for osteoblastic experiments. Bone formation was determined by a calvaria bone formation assay in vivo. Micro-CT analyses were performed in the femurs of ovariectomized female C57B/L6 and Balb/c nude mice after intravenous injections of MK or pro-MK CM. MK CM significantly reduced in vitro bone resorption, largely due to suppressed osteoclastic resorption activity. Compared with pro-MK CM, MK CM suppressed osteoblastic differentiation, but stimulated its proliferation, resulting in stimulation of calvaria bone formation. In ovariectomized mice, treatment with MK CM for 4 weeks significantly increased trabecular bone mass parameters, such as bone volume fraction and trabecular thickness, in nude mice, but not in C57B/L6 mice. In conclusion, MKs may secrete anti-resorptive and anabolic factors that affect bone tissue, providing a novel insight linking MKs and bone cells in a paracrine manner. New therapeutic agents against metabolic bone diseases may be developed from MK-secreted factors.

Translationally controlled tumor protein (TCTP), also called histamine releasing factor, is an evolutionarily conserved multifunctional protein in eukaryotes. We previously reported that extracellular TCTP acquires its cytokine-like function following dimerization. This study aims to identify the functional domain involved in the cytokine-like function of dimerized TCTP (dTCTP). We performed X-ray crystallographic studies and a deletion mutant of dTCTP which lacks the flexible loop domain. Synthetic peptides corresponding to TCTP domains and antibodies developed against them were examined for the anti-allergic effect. In an OVA-induced airway inflammation mouse model, inhibitory effect of synthetic peptides was evaluated. dTCTP was mediated by dimers between Cys172s of TCTP monomers. Synthetic peptides corresponding to the flexible loop and helix 2 domain of TCTP, and antibodies against them inhibited dTCTP-induced IL-8 release. In particular, the TCTP mutant lacking the flexible loop domain decreased the inflammatory cytokine activity of dTCTP. We conclude that the flexible loop and helix 2 domain of TCTP are the functional domains of dTCTP. They may have the potential to be therapeutic targets in the suppression of allergic reactions induced by dTCTP.

Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. The molecular chaperone heat shock protein 90 (Hsp90) plays important roles in the maturation of oncogenic proteins and thus has been considered as an anticancer therapeutic target. Here we show the efficacy and biological mechanism of a Hsp90 inhibitor NCT-50, a novobiocin-deguelin analog hybridizing the pharmacophores of these known Hsp90 inhibitors. NCT-50 exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy. In contrast, NCT-50 showed minimal effects on the viability of normal cells. NCT-50 induced apoptosis in NSCLC cells, inhibited the expression and activity of several Hsp90 clients including hypoxia-inducible factor (HIF)-1α, and suppressed pro-angiogenic effects of NSCLC cells. Further biochemical and in silico studies revealed that NCT-50 downregulated Hsp90 function by interacting with the C-terminal ATP-binding pocket of Hsp90, leading to decrease in the interaction with Hsp90 client proteins. These results suggest the potential of NCT-50 as an anticancer Hsp90 inhibitor.

Development of plant tissues is dependent on numerous factors, including hormone activity, signaling, cell division, and elongation. In plants, Defective Entry into Mitosis 1 (Dim1) homologs are recognized as pivotal in leaf senescence and progress of normal growth, but their role in rice has not been functionally characterized. The findings presented in this paper suggest that OsDim1 is important in early seedling development, pollen tube elongation, and impacts rice yield components. The gene is expressed in the scutellum, endosperm, embryonic root, shoot, pollen grains and tubes, as well as in several organs of the rice flower. According to the present study findings, RNAi mediated knockdown of OsDim1 resulted in phytohormonal imbalance, reduced amylase activity, affected differentiation of embryonic root elongation zone tissues, suppressed embryonic root and shoot growth, and impaired pollen tube elongation. In contrast, overexpression of OsDim1 showed significant growth in embryonic roots and shoots, while it increased culm length, total number of tillers per plant, seed setting rate, and total number of grains per panicle compared to its wild type line. In summary, we propose OsDim1 plays an important role in seedling growth and pollen tube elongation, and has pleiotropic effects on reproductive tissues.

To identify novel loci for susceptibility to MetS, we conducted genome-wide association and exome wide association studies consisting of a discovery stage cohort (KARE, 1946 cases and 6427 controls), and a replication stage cohort (HEXA, 430 cases and 3,264 controls). For finding genetic variants for MetS, with its components, we performed multivariate analysis for common and rare associations, using a standard logistic regression analysis for MetS. From the discovery and replication GWA studies, we confirmed 21 genome-wide signals significantly associated with MetS. Of these 21, four were previously unreported to associate with any MetS components: rs765547 near LPL; rs3782889 in MYL2; and rs11065756 and rs10849915 in CCDC63. Using exome chip variants, gene-based analysis of rare variants revealed three genes, CETP, SH2B1, and ZFP2, in the discovery stage, among which only CETP was confirmed in the replication stage. Finally, CETP D442G (rs2303790) associated, as a less common variant, with decreased risk of MetS. In conclusion, we discovered a total of five new MetS-associated loci, and their overlap with other disease-related components, suggest roles in the various etiologies of MetS, and its possible preventive strategies.

This study aimed to evaluate the association between the delta neutrophil index (DNI), which reflects immature granulocytes, and the severity of ST-elevation myocardial infarction (STEMI), as well as to determine the significance of the DNI as a prognostic marker for early mortality and other clinical outcomes in patients with STEMI who underwent reperfusion. This retrospective, observational cohort study was conducted using patients prospectively integrated in a critical pathway program for STEMI. We included 842 patients diagnosed with STEMI who underwent primary percutaneous coronary intervention (pPCI). Higher DNI values at time-I (within 2 h of pPCI; hazard ratio [HR], 1.075; 95% confidence interval [CI]: 1.046–1.108; p 2.5% at time-I (HR, 13.643; 95% CI: 8.13–22.897; p 2.9% at time-24 (HR, 12.752; 95% CI: 7.308–22.252; p

During laser treatment for tattoo removal, pigment chromophores absorb laser energy, resulting in fragmentation of the ink particles via selective photothermolysis. The present study aimed to outline macroscopic laser-tattoo interactions in tissue-mimicking (TM) phantoms treated with picosecond- and nanosecond-domain lasers. Additionally, high-speed cinematographs were captured to visualize time-dependent tattoo-tissue interactions, from laser irradiation to the formation of photothermal and photoacoustic injury zones (PIZs). In all experimental settings using the nanosecond or picosecond laser, tattoo pigments fragmented into coarse particles after a single laser pulse, and further disintegrated into smaller particles that dispersed toward the boundaries of PIZs after repetitive delivery of laser energy. Particles fractured by picosecond treatment were more evenly dispersed throughout PIZs than those fractured by nanosecond treatment. Additionally, picosecond-then-picosecond laser treatment (5-pass-picosecond treatment + 5-pass-picosecond treatment) induced greater disintegration of tattoo particles within PIZs than picosecond-then-nanosecond laser treatment (5-pass-picosecond treatment + 5-pass-nanosecond treatment). High-speed cinematography recorded the formation of PIZs after repeated reflection and propagation of acoustic waves over hundreds of microseconds to a few milliseconds. The present data may be of use in predicting three-dimensional laser-tattoo interactions and associated reactions in surrounding tissue.

Different shares of distinct commodity sectors in production, trade, and consumption illustrate how resources and capital are allocated and invested. Economic progress has been claimed to change the share distribution in a universal manner as exemplified by the Engel's law for the household expenditure and the shift from primary to manufacturing and service sector in the three sector model. Searching for large-scale quantitative evidence of such correlation, we analyze the gross-domestic product (GDP) and international trade data based on the standard international trade classification (SITC) in the period 1962 to 2000. Three categories, among ten in the SITC, are found to have their export shares significantly correlated with the GDP over countries and time; The machinery category has positive and food and crude materials have negative correlations. The export shares of commodity categories of a country are related to its GDP by a power-law with the exponents characterizing the GDP-elasticity of their export shares. The distance between two countries in terms of their export portfolios is measured to identify several clusters of countries sharing similar portfolios in 1962 and 2000. We show that the countries whose GDP is increased significantly in the period are likely to transit to the clusters displaying large share of the machinery category., Comment: 7 figures, 4 tables

Personalized dosimetry with high accuracy is crucial owing to the growing interests in personalized medicine. The direct Monte Carlo simulation is considered as a state-of-art voxel-based dosimetry technique; however, it incurs an excessive computational cost and time. To overcome the limitations of the direct Monte Carlo approach, we propose using a deep convolutional neural network (CNN) for the voxel dose prediction. PET and CT image patches were used as inputs for the CNN with the given ground truth from direct Monte Carlo. The predicted voxel dose rate maps from the CNN were compared with the ground truth and dose rate maps generated voxel S-value (VSV) kernel convolution method, which is one of the common voxel-based dosimetry techniques. The CNN-based dose rate map agreed well with the ground truth with voxel dose rate errors of 2.54% ± 2.09%. The VSV kernel approach showed a voxel error of 9.97% ± 1.79%. In the whole-body dosimetry study, the average organ absorbed dose errors were 1.07%, 9.43%, and 34.22% for the CNN, VSV, and OLINDA/EXM dosimetry software, respectively. The proposed CNN-based dosimetry method showed improvements compared to the conventional dosimetry approaches and showed results comparable with that of the direct Monte Carlo simulation with significantly lower calculation time.