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Purpose: Infants in the neonatal intensive care unit (NICU) often show cardiorespiratory deterioration during gavage feeding. We aimed to determine whether slow infusion intermittent feeding (SIIF) can reduce respiratory deterioration during gavage feeding in preterm infants in the NICU.Methods: Data on preterm infants whose gavage feeding method was changed to SIIF (1-­­hour infusion with an infusion pump and 2-­hour rest within a 3­-hour interval) from bolus gravity feeding (2-­ or 3-­hour interval) due to feeding­-associated cardiorespiratory deterioration were retrospectively reviewed. A significant cardiorespiratory event was defined as a saturation level below 80% or heart rate below 80 bpm. We compared the frequency of cardiorespiratory events and the level of respiratory support 24 hours before and after the application of SIIF.Results: A total of 34 infants were enrolled and analyzed. The total frequency of desaturation or bradycardia significantly decreased after SIIF application (8.94 vs. 5.03, P=0.001). The frequency of feeding­related bradycardia and desaturation also significantly decreased (4.15 vs. 1.68, P=0.008). Out of 34 patients, 11 (32.4%) had a decreased level of ventilator support within 1 day after SIIF. The respiratory severity scores of the 10 patients who received invasive ventilator support decreased significantly after SIIF (5.24 vs. 4.59, P=0.032).Conclusion: SIIF significantly decreased gavage feeding­associated cardiorespiratory events and reduced respiratory support in approximately one­third of subjects. Therefore, SIIF may be a therapeutic option for gavage feed­associated respiratory deterioration in preterm infants in the NICU.

BackgroundAutonomic neuropathy commonly occurs as a long-term complication of diabetes mellitus (DM) and can be diagnosed based on heart rate variability (HRV), calculated from electrocardiogram (ECG) recordings. There are limited data on HRV using real-time ECG and ambulatory glucose monitoring in patients with DM.Methods and ResultsA total of 43 patients (66.3±7.5 years) with DM underwent continuous real-time ECG monitoring (225.7±107.3 hours) for HRV and ambulatory glucose monitoring using a remote monitoring system. We compared the HRV according to the ambulatory glucose profile. Data were analyzed according to the target in glucose range (TIR). There were no significant differences in the baseline characteristics of the patients according to the TIR. During monitoring, we checked ECG and ambulatory glucose levels (a total of 15,090 times) simultaneously for all patients. Both time- and frequency-domain HRVs were lower when the patients had poorly controlled glucose levels (>200 mg/dL) and TIR70%. In addition, heart and respiratory rates increased with real-time glucose levels (PConclusionsPoorly controlled glucose levels were independently associated with lower HRV in patients with DM. This was further substantiated by the independent continuous association between real-time measurements of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is caused by elevated blood sugar levels.

This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (1–3) responsible for cathepsin D (CTSD) inhibition. Structurally modified izenamides were synthesized and biologically evaluated, and their biologically important core structures were identified. We confirmed that the natural statine (Sta) unit (3S,4S)-γ-amino-β-hydroxy acid is a requisite core structure of izenamides for inhibition of CTSD, which is closely related to the pathophysiological roles in numerous human diseases. Interestingly, the statine-incorporated izenamide C variant (7) and 18-epi-izenamide B variant (8) exhibited more potent CTSD-inhibitory activities than natural izenamides.

Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary gland. Although characterized as an indolent tumor, ACC often leads to incurable metastatic disease. Patients with ACC respond poorly to currently available therapeutic drugs and factors contributing to the limited response remain unknown. Determining the role of molecular alterations frequently occurring in ACC may clarify ACC tumorigenesis and advance the development of effective treatment strategies. Applying Splice Expression Variant Analysis and outlier statistics on RNA sequencing of primary ACC tumors and matched normal salivary gland tissues, we identified multiple alternative splicing events (ASE) of genes specific to ACC. In ACC cells and patient-derived xenografts, FGFR1 was a uniquely expressed ASE. Detailed PCR analysis identified three novel, truncated, intracellular domain-lacking FGFR1 variants (FGFR1v). Cloning and expression analysis suggest that the three FGFR1v are cell surface proteins, that expression of FGFR1v augmented pAKT activity, and that cells became more resistant to pharmacologic FGFR1 inhibitor. FGFR1v-induced AKT activation was associated with AXL function, and inhibition of AXL activity in FGFR1v knockdown cells led to enhanced cytotoxicity in ACC. Moreover, cell killing effect was increased by dual inhibition of AXL and FGFR1 in ACC cells. This study demonstrates that these previously undescribed FGFR1v cooperate with AXL and desensitize cells to FGFR1 inhibitor, which supports further investigation into combined FGFR1 and AXL inhibition as an effective ACC therapy.This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor suggestive of a potential resistance mechanism in ACC.Significance:This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor, suggestive of a potential resistance mechanism in ACC.

Supplemental Data S1 provides description on the ACC-01-XP xenograft development using ACC-01 cell line and shows list of PCR primers and other reagents used in the study. Supplemental Data S2 shows list of alternative splicing events identified in ACC compared to normal salivary gland tissue. Supplemental Data S3 shows nucleotides and corresponding amino acid composition of the three novel FGFR1 splice variants. Figure S1 shows ASE genes in PI3K-AKT signaling pathway enrichment using the Enrichr web tool. Figure S2 shows characterization of FGFR1v and impact on cell growth following siRNA-mediated knockdown. Figure S3 shows FGFR1v stability analysis and its effect on signaling and resistance to FGFR1 inhibitor. Figure S4 shows FGFR1v-mediated AKT signaling is independent on EGFR but supports the involvement of AXL. Figure S5 shows supportive expression and activities of FGFR1v in HACC-2A cells.

INTRODUCTION We aimed to identify imaging-based findings that can differentiate between spinal subchondral bone metastasis with focal pathologic endplate fracture and oedematous Schmorl's nodes that have been histopathologically confirmed. METHODS Between March 2010 and April 2016, 11 patients who had undergone spinal magnetic resonance (MR) imaging or computed tomography (CT) with final radiologic reports that included 'subchondral bone metastasis with focal pathologic endplate fracture' or 'edematous Schmorl's node' and had also undergone percutaneous imaging-guided spinal biopsies were included. Two radiologists retrospectively evaluated the following imaging features in consensus: size, location, presence of sclerotic margin, presence of intralesional or perilesional enhancement and opposite endplate enhancement of the involved disc, presence of disc height loss and presence of metabolic uptake at a corresponding lesion on nuclear medicine imaging. RESULTS A total of 11 patients, including six patients with spinal subchondral bone metastasis with focal pathologic endplate fracture and five patients with oedematous Schmorl's nodes, were included in this study (median age, 58 years; range, 50-63 years; six men). Sclerotic margin (P = 0.002) and enhancement on the opposite endplate of the involved disc (P = 0.047) were significantly different between oedematous Schmorl's node and subchondral bone metastasis with focal pathologic endplate fracture. CONCLUSION Sclerotic margin and enhancement on the opposite endplate of the involved disc suggest oedematous Schmorl's node rather than subchondral bone metastasis with focal pathologic endplate fracture. Decreased disc height is likely to be an oedematous Schmorl's node rather than subchondral bone metastasis with focal pathologic endplate fracture.

Charcot-Marie-Tooth disease (CMT) and related diseases are a genetically and clinically heterogeneous group of peripheral neuropathies. Particularly, mutations in several aminoacyl-tRNA synthetase (ARS) genes have been reported to cause axonal CMT (CMT2) or distal hereditary motor neuropathy (dHMN). However, the common pathogenesis among CMT subtypes by different ARS gene defects is not well understood. This study was performed to investigate ARS gene mutations in a CMT cohort of 710 Korean families. Whole-exome sequencing was applied to 710 CMT patients who were negative for PMP22 duplication. We identified 12 disease-causing variants (from 13 families) in GARS1, AARS1, HARS1, WARS1, and YARS1 genes. Seven variants were determined to be novel. The frequency of overall ARS gene mutations was 1.22% among all independent patients diagnosed with CMT and 1.83% in patients negative for PMP22 duplication. WARS1 mutations have been reported to cause dHMN; however, in our patients with WARS1 variants, CMT was associated with sensory involvement. We analyzed genotype-phenotype correlations and expanded the phenotypic spectrum of patients with CMT possessing ARS gene variants. We also characterized clinical phenotypes according to ARS genes. This study will be useful for performing exact molecular and clinical diagnoses and providing reference data for other population studies.

To assess the diagnostic accuracy of conventional MRI for detecting and grading subscapularis (SSC) tears by applying the Yoo and Rhee classification. A total of 179 patients who underwent MRI followed by arthroscopic rotator cuff surgery were enrolled. Two musculoskeletal radiologists evaluated the SSC using axial, oblique sagittal, and oblique coronal MRI according to the Yoo and Rhee classification. Using arthroscopic findings as the reference standard, the sensitivity, specificity, accuracy, and interobserver agreement of SSC tears were analyzed. Arthroscopy confirmed that the numbers of type I, IIA, IIB, III, IV, and V tears were 35, 70, 35, 9, 9, and 0, respectively. The sensitivity, specificity, and accuracy of readers 1 and 2 for the detection of tears (type IIA or higher) were 85%, 75%, and 82%, and 89%, 70%, and 83%, respectively, while those for the detection of surgical candidates (type IIB or higher) were 77%, 75%, and 75%, and 77%, 83%, and 82%, respectively. The interobserver agreement for detecting SSC tear presence was substantial (κ = 0.70) for reader 1 vs. reader 2, and those for detecting the surgical candidate group was substantial (κ = 0.68) for reader 1 vs. reader 2. The interobserver agreement for grading SSC tears was excellent (κ = 0.86) for reader 1 vs. reader 2. Conventional MRI showed 82.5% and 78.5% average accuracy in detecting IIA and IIB or higher tears by applying the Yoo and Rhee classification for the diagnosis of SSC tears with an excellent interobserver agreement in tear grading.

We aimed to derive comprehensive MRI parameters that reflect intramuscular fat infiltration severity for designated lower extremity levels, based on semiquantitative analyses in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. We reviewed lower extremity MRIs of 116 CMT1A patients. Intramuscular fat infiltration grading using the Mercuri scale was performed for the non-dominant lower extremity at three levels (proximal, mid, and distal) for the thigh and at two levels (proximal and distal) for the lower leg. Based on MRI results, the following parameters were calculated for each level and for entire muscles: fat infiltration proportion (FIP), significant fat infiltration proportion (SigFIP), and severe fat infiltration proportion (SevFIP). The relationships between the MRI parameters and clinical data were evaluated using Spearman’s correlation analysis. FIP, SigFIP, and SevFIP measured for entire muscles significantly correlated with Charcot-Marie-Tooth Neuropathy Score (p p p = 0.0003, 0.0010, and 0.0011), and disease duration (p

Objective: To describe the ultrasound, CT findings, and clinical manifestations of pathologically confirmed skeletal muscle metastases involving trunk and pelvis. Methods: 71 patients with 71 skeletal muscle metastases of the trunk and pelvis, pathologically proven by ultrasound-guided biopsy, were included in the study, and ultrasound findings were reviewed. CT findings were reviewed for 60 patients who underwent post-contrast CT obtained prior to biopsy, which included skeletal muscle metastases. Medical records, including the type of primary malignancy, presence of coexisting distant metastasis, and method of detection that led to referral for biopsy, were reviewed. Results: Most skeletal muscle metastases were hypoechoic (98.6%) with well-defined margins (85.9%), round-to-oval (47.9%), or lobulated (42.2%) with intralesional vascularity (64.8%). Typical CT findings included abscess-like lesions with rim enhancement (53.3%) or round-to-oval lesions with homogeneous enhancement (40.0%). The most common primary malignancy was lung cancer (49.3%), followed by gastrointestinal cancer (7.0%). Distant metastases other than muscle metastases were found in 84.5% of patients, and coexisting skeletal muscle metastases were found in 47.9%. CT was the most common detection method for metastases (57.8%), being more common than positron emission tomography-CT (22.5%). Conclusion: The current study describes the typical imaging findings of skeletal muscle metastases of the trunk and pelvis in patients with advanced cancer. CT may play an important role in the early detection of skeletal muscle metastases, and our results may aid radiologists in their diagnosis. Advances in knowledge: 1. Skeletal muscle metastases of the trunk and pelvis demonstrate typical imaging findings on ultrasound and CT. 2. CT may aid in the early detection of skeletal muscle metastases, which are among the rarest, and our results may aid radiologists in their diagnosis.

Landmark structures are commonly constructed as tall buildings with complex shapes, such as twisted, tilted, and tapered towers. Although the appearances of these buildings are attractive, their structural safety must be investigated more carefully in comparison with conventional high-rise buildings. Especially in the case of a tilted high-rise building, lateral displacement even occurs from its own weight. Therefore, seismic response reduction is a very important issue for a tilted-form tower to secure structural safety. In this study, a semi-active tuned mass damper (SATMD) was employed for a tilted high-rise building subjected to seismic excitations, and its dynamic-response reduction capacity was evaluated. Two 300-kN magnetorheological (MR) dampers were employed to make a SATMD, which was installed on the top of a 100-story tilted example building. A fuzzy inference system controller (FISC) was used to make appropriate command voltages to control the SATMD. The various design parameters of the FISC were optimized by an evolutionary multiobjective optimization technique. A conventional semi-active groundhook controller was also used for comparison. The control performance of the proposed SATMD was compared to that of a conventional optimal passive TMD. The numerical results show that the fuzzy-controlled SATMD provided the best control performance. The proposed SATMD provided similar control performance while using only less than 30% of the mass quantity compared to passive TMD.

The objectives of this study were to assess changes in apparent diffusion coefficient (ADC) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters after radiation therapy (RT) for bone metastases from hepatocellular carcinoma (HCC) and to evaluate their prognostic value. This prospective study was approved by the Institutional Review Board. Fourteen patients with HCC underwent RT (30 Gy in 10 fractions once daily) for bone metastases. The ADC and DCE-MRI parameters and the volume of the target lesions were measured before (baseline) and one month after RT (post-RT). The Wilcoxon signed-rank test was used to compare the parameters between the baseline and post-RT MRI. The parameters were compared between patients with or without disease progression in RT fields using the Mann–Whitney test. Intraclass correlation coefficients were used to evaluate the interobserver agreement. The medians of the ADC, rate constant [kep], and volume fraction of the extravascular extracellular matrix [ve] in the baseline and post-RT MRI were 0.67 (range 0.61–0.72) and 0.75 (range 0.63–1.43) (× 10–3 mm2/s) (P = 0.027), 836.33 (range 301.41–1082.32) and 335.80 (range 21.86–741.87) (× 10–3/min) (P = 0.002), and 161.54 (range 128.38–410.13) and 273.99 (range 181.39–1216.95) (× 10–3) (P = 0.027), respectively. The medians of the percent change in the ADC of post-RT MRI in patients with progressive disease and patients without progressive disease were − 1.35 (range − 6.16 to 6.79) and + 46.71 (range 7.71–112.81) (%) (P = 0.011), respectively. The interobserver agreements for all MRI parameters were excellent (intraclass correlation coefficients > 0.8). In conclusion, the ADC, kep, and ve of bone metastases changed significantly after RT. The percentage change in the ADC was closely related to local tumor progression.

Olive flounder (Paralichthys olivaceus) is one of the major cultured fish species in Asia including Korea. However, the mass mortality of olive flounder caused by various pathogens leads to huge economic loss. The pathogens that lead to fish mortality include parasites, bacteria, and viruses that can cause various kinds of diseases. The purpose of this study was to investigate the protein expression patterns in the gills and spleens of olive flounder after artificial infection. We hypothesized that proteomics levels in gills and spleen may be differentially expressed depending on infectious agents. To investigate the expression pattern of proteins in gills and spleens, olive flounders were experimentally infected with VHSV (virus), S. parauberis (bacteria), or M. avidus (pathogenic ciliate). Proteins were extracted from the gills and spleens of infected olive flounder. We used 2-DE analysis with LC–MS/MS to investigate proteome changes in infected olive flounders. The results of the LC–MS/MS analyses showed different protein expression profiles depending on pathogenic sources and target organs. Proteins related to cytoskeletal structure like keratin, calmodulin and actin were mostly expressed in the infected gills. Proteins involved in the metabolism pathway like glycolysis were expressed mainly in the spleens. The protein profiles of S. parauberis and VHSV infection groups had many similarities, but the profile of the M. avidus infection group was greatly different in the gill and spleen. Our results indicate that measures according to the characteristics of each pathogen are necessary for disease prevention and treatment of farmed fish.

Three-dimensional NAND flash memory featuring dozens of vertically stacked memory cells is the state-of-the-art technology for most storage platforms. To fabricate three-dimensional (3D) NAND memory, lateral etching of the Si₃N₄ layer over SiO₂ is an essential step that is conducted through a wet etching process using a phosphoric acid-based etchant. Silyl-phosphate or highly selective nitride serves as an etching solution additive to control the SiO₂ layer dissolution rate. However, silyl-phosphate is prepared with an expensive monomeric silica precursor and at high reaction temperatures and generates environmentally harmful byproduct gases, such as HCl, HF, and CH₃OH. This study demonstrates that silyl-phosphate can be prepared using low-cost polymeric silica under a mild reaction temperature by changing the characteristic acidity of phosphoric acid. The possibility of tuning the phosphoric acid acidity was first studied by molecular dynamics simulations, and phosphoric acids with stronger acidity were prepared by the evaporation of water from H₃PO₄ (85%). The concentrated phosphoric acid enabled a fast reaction of polymeric silica and phosphate at a low reaction temperature (80 °C). The obtained silyl-phosphate lowered the SiO₂ layer dissolution rate, thereby yielding a Si₃N₄/SiO₂ layer etching ratio of up to 940. The proposed method offers an environmentally friendly production process for special chemicals used in 3D NAND flash memory fabrication.

Recently, to reduce seismic responses, dozens of high-rise buildings in Japan and Korea have adopted the intermediate isolation system (IIS). These applications have shown successful response reduction performance for tall buildings. The important dynamic responses of building structures with the IIS are the peak intermediate isolator drift (IID), and the peak inter-story drift (ISD). The semi-active intermediate isolation system (SAIIS) was developed to more effectively reduce these seismic responses. In previous study, the authors showed that the SAIIS using magnetorheological dampers successfully reduced both the IID and the ISD. However, the optimal design of the SAIIS only was conducted, without considering the building structure. If both the SAIIS and the building structure properties are considered in the optimal design procedure, more effective optimal design for both the SAIIS and the building structure can be achieved. In this research, a simultaneous multi-objective optimization (MOO) method of the SAIIS and the building structure is proposed to achieve this. Genetic algorithm was selected for simultaneous MOO of the SAIIS and the building structure. The fuzzy inference controller was selected as a control algorithm. The authors show that in comparison to the sequential optimization procedure that practical applications generally use, the simultaneous MOO method can provide much better control capacity and structural design process.