Search

BackgroundRecently, we developed a chest compression device that can move the chest compression position without interruption during CPR and be remotely controlled to minimize rescuer exposure to infectious diseases. The purpose of this study was to compare its performance with conventional mechanical CPR device in a mannequin and a swine model of cardiac arrest.Materials and methodsA prototype of a remote-controlled automatic chest compression device (ROSCER) that can change the chest compression position without interruption during CPR was developed, and its performance was compared with LUCAS 3 in a mannequin and a swine model of cardiac arrest. In a swine model of cardiac arrest, 16 male pigs were randomly assigned into the two groups, ROSCER CPR (n = 8) and LUCAS 3 CPR (n = 8), respectively. During 5 minutes of CPR, hemodynamic parameters including aortic pressure, right atrial pressure, coronary perfusion pressure, common carotid blood flow, and end-tidal carbon dioxide partial pressure were measured.ResultsIn the compression performance test using a mannequin, compression depth, compression time, decompression time, and plateau time were almost equal between ROSCER and LUCAS 3. In a swine model of cardiac arrest, coronary perfusion pressure showed no difference between the two groups (p = 0.409). Systolic aortic pressure and carotid blood flow were higher in the LUCAS 3 group than in the ROSCER group during 5 minutes of CPR (p < 0.001, p = 0.008, respectively). End-tidal CO2 level of the ROSCER group was initially lower than that of the LUCAS 3 group, but was higher over time (p = 0.022). A Kaplan-Meier survival analysis for ROSC also showed no difference between the two groups (p = 0.46).ConclusionThe prototype of a remote-controlled automated chest compression device can move the chest compression position without interruption during CPR. In a mannequin and a swine model of cardiac arrest, the device showed no inferior performance to a conventional mechanical CPR device.

Background Granulosa cells play an important role in folliculogenesis, however, the role of RNA transcripts of granulosa cells in assessing embryo quality remains unclear. Therefore, we aims to investigate that RNA transcripts of granulosa cells be used to assess the probability of the embryonic developmental capacity. Methods This prospective cohort study was attempted to figure out the probability of the embryonic developmental capacity using RNA sequencing of granulosa cells. Granulosa cells were collected from 48 samples in good-quality embryo group and 79 in only poor- quality embryo group from women undergoing in vitro fertilization and embryo transfer treatment. Three samples from each group were used for RNA sequencing. Results 226 differentially expressed genes (DEGs) were related to high developmental competence of embryos. Gene Ontology enrichment analysis indicated that these DEGs were primarily involved in biological processes, molecular functions, and cellular components. Additionally, pathway analysis revealed that these DEGs were enriched in 13 Kyoto Encyclopedia of Genes and Genomes pathways. Reverse transcription quantitative polymerase chain reaction verified the differential expression of the 13 selected DEGs. Among them,10 genes were differently expressed in the poor-quality embryo group compared to good-quality embryo group, including CSF1R, CTSH, SERPINA1, CYP27A1, ITGB2, IL1β, TNF, TAB1, BCL2A1, and CCL4. Conclusions RNA sequencing data provide the support or confute granulosa expressed genes as non-invasive biomarkers for identifying the embryonic developmental capacity.

Whole-plant regeneration via plant tissue culture is a complex process regulated by several genetic and environmental conditions in plant cell cultures. Recently, epigenetic regulation has been reported to play an important role in plant cell differentiation and establishment of pluripotency. Herein, we tested the effects of chemicals, which interfere with epigenetic regulation, on the plant regeneration from mesophyll protoplasts of lettuce. The used chemicals were histone deacetylase inhibitors trichostatin A (TSA) and sodium butyrate (NaB), and the DNA methyltransferase inhibitor azacytidine (Aza). All three chemicals increased cell division, micro-callus formation and callus proliferation in lettuce protoplasts. Cell division increased by more than 20% with an optimal treatment of the three chemicals. In addition, substantial increase in the callus proliferation rates was observed. In addition, TSA enhances cell division and adventitious shoot formation in the protoplast culture of Nicotiana benthamiana. The regenerated tobacco plants from TSA-treated protoplasts did not show morphological changes similar to the control. TSA increased histone H3 acetylation levels and affected the expression of CDK, CYCD3-1, and WUS in tobacco protoplasts. Thus, we investigated the effect of TSA, NaB, and Aza on Lactuca sativa L. protoplasts and the effect of TSA on cell division and callus formation in Nicotiana benthamiana protoplasts, which facilitates plant regeneration from mesophyll protoplasts. Furthermore, these chemicals can be directly applied as media additives for efficient plant regeneration and crop improvement in various plant species.

Purpose To validate the diagnostic performance of commercially available, deep learning-based automatic white matter hyperintensity (WMH) segmentation algorithm for classifying the grades of the Fazekas scale and differentiating subcortical vascular dementia. Methods This retrospective, observational, single-institution study investigated the diagnostic performance of a deep learning-based automatic WMH volume segmentation to classify the grades of the Fazekas scale and differentiate subcortical vascular dementia. The VUNO Med-DeepBrain was used for the WMH segmentation system. The system for segmentation of WMH was designed with convolutional neural networks, in which the input image was comprised of a pre-processed axial FLAIR image, and the output was a segmented WMH mask and its volume. Patients presented with memory complaint between March 2017 and June 2018 were included and were split into training (March 2017–March 2018, n = 596) and internal validation test set (April 2018–June 2018, n = 204). Results Optimal cut-off values to categorize WMH volume as normal vs. mild/moderate/severe, normal/mild vs. moderate/severe, and normal/mild/moderate vs. severe were 3.4 mL, 9.6 mL, and 17.1 mL, respectively, and the AUC were 0.921, 0.956 and 0.960, respectively. When differentiating normal/mild vs. moderate/severe using WMH volume in the test set, sensitivity, specificity, and accuracy were 96.4%, 89.9%, and 91.7%, respectively. For distinguishing subcortical vascular dementia from others using WMH volume, sensitivity, specificity, and accuracy were 83.3%, 84.3%, and 84.3%, respectively. Conclusion Deep learning-based automatic WMH segmentation may be an accurate and promising method for classifying the grades of the Fazekas scale and differentiating subcortical vascular dementia.

Although balloon dilation has shown promising results in the treatment of dilatory Eustachian tube (ET) dysfunction, the histological effects of ET balloon dilation (ETBD) is unknown because histological examination of the whole human cartilaginous ET is impossible. Animal studies are needed to elucidate the effect of ETBD so we evaluated the histological changes after ETBD in a rat model. The left ET of 20 Wistar rats was dilated with a balloon catheter and the right ET was used as a control. Five rats were sacrificed immediately after ETBD, at 1, 4 and 12 weeks after the procedure for histological examination. The epithelial cells, presence of epithelial hyperplasia, and the proportion of the goblet cells in the epithelium; the vascular structures and dimensions of the submucosa; and presence of cartilage fracture and the area of the ET lumen were evaluated and compared between the groups. Desquamation of nearly all epithelial cells and the fracture of tubal cartilages were observed immediately after ETBD. At 1-week post-ETBD, the ciliated epithelial cells started to recover with epithelial hyperplasia. The goblet cells recovered by 4 weeks post-ETBD and epithelial hyperplasia decreased but was still present at 12 weeks post-ETBD. The depth of the submucosa increased and neovascularization in this region was observed at 1-week post-ETBD and persisted up to 12 weeks post-ETBD. The lumen of the cartilaginous ET increased immediately after ETBD but decreased at 1-week post-ETBD. The cartilaginous ET lumen recovered to the normal value at 4 weeks post-ETBD. This study is the first to describe the serial histological changes to the cartilaginous ET after ETBD and helps our understanding of the histological changes that occur after an ETBD intervention for intractable ET dysfunction.

BackgroundMeconium-related ileus in very low birth weight infants can lead to increased morbidity or mortality and prolonged hospitalization without prompt diagnosis and treatment. This study primarily aimed to identify the incidence of and factors associated with meconium-related ileus and secondarily sought to investigate clinical and growth outcomes after water-soluble contrast media (Gastrografin) enema.MethodsWe retrospectively reviewed medical records of very low birth weight infants born between February 2009 and March 2019 in the neonatal intensive care unit of a single medical center. Perinatal factors, clinical outcomes, and growth outcomes were compared between the group with meconium-related ileus that received Gastrografin enema and the control group.ResultsTwenty-four (6.9%) patients were diagnosed with meconium-related ileus among 347 very low birth weight infants. All achieved successful evacuation of meconium with an average of 2.8 (range: 1-8) Gastrografin enema attempts without procedure-related complications. Initiation of Gastrografin enema was performed at mean 7.0 days (range: 2-16) after birth. Incidences of moderate to severe bronchopulmonary dysplasia were higher and the duration of mechanical ventilation and need for oxygen were longer in the meconium-related ileus group (P = 0.039, 0.046, 0.048, respectively). Meconium-related ileus infants took more time to start enteral feeding and the nothing per oral time was longer (P = 0.001 and 0.018, respectively). However, time to achieve full enteral feeding and Z-scores for weight and height at 37 weeks and at 6 months corrected age did not differ between the two groups.ConclusionsGastrografin enema in very low birth weight infants with meconium-related ileus was an effective and safe medical management. Following Gastrografin enema, very low birth weight infants with meconium-related ileus achieved similar subsequent feeding progress and similar growth levels as the control groups without meconium-related ileus.

PurposeThe purpose of this study was to identify imaging risk factors on contrast-enhanced hip MRI after closed reduction of developmental dysplasia of the hip (DDH) that could predict future development of avascular necrosis (AVN) of the femoral head.Materials and methodsFifty-eight infants (F: M = 53: 5, aged 3-18 months) who underwent immediate postoperative contrast-enhanced hip MRI after closed reduction of DDH were included in this study. Quality of reduction (concentric vs eccentric reduction with or without obstacles), abduction angle of the hip, presence of ossific nucleus, and pattern of contrast enhancement of the femoral head were retrospectively evaluated on MRI. Interobserver agreement of contrast enhancement pattern on MRI were evaluated by two radiologists. Development of AVN was determined through radiographic findings at 1 year after reduction.ResultsAVN of the femoral head developed in 13 (22%) of 58 patients. Excessive abduction of the hip joint (OR 4.65, [95% CI 1.20, 18.06] and global decreased enhancement of the femoral head (OR 71.66, [95% CI 10.54, 487.31]) exhibited statistically significant differences between the AVN and non-AVN groups (P < 0.05). Eccentric reduction (P = 0.320) did not show statistically significant difference between two groups and invisible ossific nucleus (P = 0.05) showed borderline significance. Multi-variable logistic regression indicated that global decreased enhancement of the femoral head was a significant risk factor of AVN (OR 27.92, 95% CI [4.17, 350.18]) (P = 0.0031). Interobserver agreement of contrast enhancement pattern analysis and diagnosis of AVN were good (0.66, 95% CI [0.52, 0.80]).ConclusionContrast-enhanced hip MRI provides accurate anatomical assessment of the hip after closed reduction of DDH. Global decreased enhancement of the femoral head could be used as a good predictor for future development of AVN after closed reduction of DDH.

A helmet is critical for preventing head injuries during motorcycle accidents. However, South Korean motorcyclists have a lower prevalence of wearing a helmet, compared to developed countries. Therefore, we aimed to evaluate whether helmet wearing was associated with the clinical outcomes in Korean motorcycle accidents. Data were obtained from the Emergency Department-based Injury In-depth Surveillance database 2011-2015. We considered the patients had experienced a motorcycle accident and were only diagnosed with a craniocerebral trauma (CCT). The primary outcome was mortality and the secondary outcomes were the severity and hospitalization duration. The patients were separated whether they were wearing a helmet and the outcomes were compared using multivariate logistic regression after propensity score matching (PSM). Among 1,254,250 patients in the database, 2,549 patients were included. After PSM, 1,016 patients in each group were matched. The univariate analyses revealed that helmet wearing was associated with lesser severity (P < 0.001) and shorter hospitalization (P < 0.001). The regression analysis revealed that mortality was also lower in a helmet-wearing group (odds ratio: 0.34, 95% confidence interval: 0.21-0.56). In conclusion, wearing a helmet may reduce the mortality from a CCT after a motorcycle accident and associated with lesser severity and shorter hospitalization.

In patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with brain metastases, it remains controversial whether the use of EGFR-tyrosine kinase inhibitor (TKI) alone without radiotherapy (RT) is an optimal approach. Here, we investigated the clinical outcomes according to the use of upfront RT as well as the subsequent therapy following intracranial progression. This single-centre retrospective study included a total of 173 patients who were treated with EGFR-TKI alone (TKI alone group) or with upfront whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) followed by EGFR-TKI (RT plus TKI group). Clinical outcomes according to initial and subsequent therapies following intracranial progression were analysed. There was no significant difference in OS according to the use of upfront RT (TKI alone group, 24.5 months vs. WBRT group, 20.0 months vs. SRS group, 17.8 months; P = 0.186). Intracranial progression was found in 35 (32.7%) of 107 patients in the TKI alone group. Among them, 19 patients who received salvage RT had the better prognosis than others [median overall survival (OS); 28.6 vs. 11.2 months; P = 0.041]. In the RT plus TKI group, 12 (18.1%) of the 66 patients experienced intracranial progression and 3 of them received salvage RT (median OS; 37.4 vs. 20.0 months; P = 0.044). In multivariate analysis, upfront WBRT was associated with trends towards a lower probability of intracranial progression, whereas upfront SRS was found to be an independent risk factor for poor OS. In conclusion, using EGFR-TKI alone for brain metastasis in EGFR-mutant lung cancer patients showed outcomes comparable to those using upfront RT followed by EGFR-TKI. Patients who could not receive salvage RT following intracranial progression had the worst survival regardless of the type of initial treatment.

Recent advances in somatic cell nuclear transfer (SCNT) in canines facilitate the production of canine transgenic models. Owing to the importance of stable and strong promoter activity in transgenic animals, we tested human elongation factor 1α (hEF1α) and cytomegalovirus (CMV) promoter sequences in SCNT transgenic dogs. After transfection, transgenic donor fibroblasts with the hEF1α-enhanced green fluorescence protein (EGFP) transgene were successfully isolated using fluorescence-activated cell sorting (FACS). We obtained four puppies, after SCNT, and identified three puppies as being transgenic using PCR analysis. Unexpectedly, EGFP regulated by hEF1α promoter was not observed at the organismal and cellular levels in these transgenic dogs. EGFP expression was rescued by the inhibition of DNA methyltransferases, implying that the hEF1α promoter is silenced by DNA methylation. Next, donor cells with CMV-EGFP transgene were successfully established and SCNT was performed. Three puppies of six born puppies were confirmed to be transgenic. Unlike hEF1α-regulated EGFP, CMV-regulated EGFP was strongly detectable at both the organismal and cellular levels in all transgenic dogs, even after 19 months. In conclusion, our study suggests that the CMV promoter is more suitable, than the hEF1α promoter, for stable transgene expression in SCNT-derived transgenic canine model.

Silicone is used widely for tissue augmentation in humans. However, late complications, such as delayed inflammation and capsular contracture, remain uncharacterized, despite their importance. In the present study, we aimed to determine whether mechanical and thermal damage induce capsular inflammation around a foreign body, and elucidate the biological mechanism underlying this phenomenon. We injected silicone into the subcutaneous layer of the skin of New Zealand white rabbits. The rabbits were divided into two groups: the control group received no treatment; in the experimental group, external force was applied near the injection silicone using high-intensity focused ultrasound (HIFU). Tissues near the injected silicone were harvested from both groups on Days 4, 7, and 30 after HIFU treatment for comparative analysis. Visual and histological examinations showed clearly increased inflammation in the experimental group compared with that in the control group. Furthermore, capsular tissue from the experimental group displayed markedly increased collagen production. Immunofluorescence revealed marked activation of macrophages in the early stages of inflammation (Days 4 and 7 after HIFU treatment), which decreased on Day 30. Assessment of cytokine activation showed significantly increased expression of heat shock protein (HSP)27, HSP60, HSP70, toll-like receptor (TLR)2, TLR4, and interleukin-8 in the experimental group. The expression of transforming growth factor-β1 did not increase significantly in the experimental group. In conclusion, damage to tissues around the injected silicone induced capsular inflammation. Macrophages and damage-associated molecular pattern molecules were involved in the early stages of inflammation. HSP release activated TLRs, which subsequently activated innate immunity and induced the inflammatory response.

Lower back pain is a major public health problem. Despite claims that lumbar belts change spinal posture due to applied pressure on the trunk, no mechanical model has yet been published to prove this treatment. This paper describes a first model for belt design, based on the one hand on the mechanical properties of the fabrics and the belt geometry, and on the other hand on the trunk geometrical and mechanical description. The model provides the estimation of the pressure applied to the trunk, and a unique indicator of the belt mechanical efficiency is proposed: pressure is integrated into a bending moment characterizing the belt delordosing action on the spine. A first in-silico clinical study of belt efficiency for 15 patients with 2 different belts was conducted. Results are very dependent on the body shape: in the case of high BMI patients, the belt effect is significantly decreased, and can be even inverted, increasing the lordosis. The belt stiffness proportionally increases the pressure applied to the trunk, but the influence of the design itself on the bending moment is clearly outlined. Moreover, the belt/trunk interaction, modeled as sticking contact and the specific way patients lock their belts, dramatically modifies the belt action. Finally, even if further developments and tests are still necessary, the model presented in this paper seems suitable for in-silico pre-clinical trials on real body shapes at a design stage.

OBJECTIVE:To retrospectively evaluate the value of computerized 3D texture analysis for differentiating pulmonary metastases from non-metastatic lesions in pediatric patients with osteosarcoma. MATERIALS AND METHODS:This retrospective study was approved by the institutional review board. The study comprised 42 pathologically confirmed pulmonary nodules in 16 children with osteosarcoma who had undergone preoperative computed tomography between January 2009 and December 2014. Texture analysis was performed using an in-house program. Multivariate logistic regression analysis was performed to identify factors for differentiating metastatic nodules from non-metastases. A subgroup analysis was performed to identify differentiating parameters in small non-calcified pulmonary nodules. The receiver operator characteristic curve was created to evaluate the discriminating performance of the established model. RESULTS:There were 24 metastatic and 18 non-metastatic lesions. Multivariate analysis revealed that higher mean attenuation (adjusted odds ratio [OR], 1.014, P = 0.003) and larger effective diameter (OR, 1.745, P = 0.012) were significant differentiators. The analysis with small non-calcified pulmonary nodules (7 metastases and 18 non-metastases) revealed significant inter-group differences in various parameters. Logistic regression analysis revealed that higher mean attenuation (OR, 1.007, P = 0.008) was a significant predictor of non-calcified pulmonary metastases. The established logistic regression model of subgroups showed excellent discriminating performance in the ROC analysis (area under the curve, 0.865). CONCLUSION:Pulmonary metastases from osteosarcoma could be differentiated from non-metastases by using computerized texture analysis. Higher mean attenuation and larger diameter were significant predictors for pulmonary metastases, while higher mean attenuation was a significant predictor for small non-calcified pulmonary metastases.

The efficacy and safety of osimertinib were demonstrated in clinical trials; however, real-world clinical data, particularly the resistance profile, are limited. Here, we investigated the efficacy, safety, and resistance profile of osimertinib in real-world practice. We reviewed medical records of T790M mutation-positive lung cancer patients who started osimertinib between February 2016 and June 2017. Molecular pathologic data of biopsy samples obtained after acquisition of resistance to osimertinib were also analyzed. The study included 23 patients with a median age of 59 years. The median follow-up duration was 11.9 months (IQR, 4.7-15.8). Objective response was achieved in 17 (73.9%) patients, and the disease was controlled in 22 (95.7%) patients. Median progression-free survival (PFS) was 7.4 months (95% CI, 3.6-11.0). Adverse events were minimal except for one case of pneumonitis. Of 14 patients experiencing disease progression, 10 underwent re-biopsy. The T790M mutation disappeared in seven patients (70%), and one showed wild-type conversion. PFS was shorter in the T790M-loss group than in the T790M-persistent group (4.4 vs. 7.7 months). Two patients with small cell transformation responded well to subsequent chemotherapy. One patient developed a C797S mutation that became undetectable after two cycles of gemcitabine and cisplatin followed by six cycles of pembrolizumab, after which the patient responded well to osimertinib. In conclusion, osimertinib showed favorable efficacy and safety in real-world practice comparable to those observed in clinical trials. Repeat biopsy after the acquisition of resistance to osimertinib is helpful to direct further treatment strategies.

To enable selection of a safer suspension site to use in face and neck lifting procedures, the spatial relationship between the tympanoparotid fascia and the great auricular nerve should be clarified. In this study, we aimed to elucidate the position of the tympanoparotid fascia and the pathway of the lobular branch of the great auricular nerve traversing the tympanoparotid fascia. Twenty hemifaces from non-preserved bequeathed Korean cadavers (5 males, 7 females; mean age, 77.0 years) were dissected to determine the great auricular nerve distribution close to the tympanoparotid fascia of clinical significance for face and neck lift procedures. We observed the tympanoparotid fascia in all specimens (20 hemifaces). The tympanoparotid fascia was located anteriorly between the tragus and intertragic notch. Regarding the spatial relationship between the tympanoparotid fascia and the great auricular nerve, we found the sensory nerve entering the tympanoparotid fascia in all specimens (100%), and the depth from the skin was approximately 4.5 mm; in 65% of the specimens, the lobular branch was found to run close to the tympanoparotid fascia before going into the earlobe. Provided with relatively safer surface mapping to access the tympanoparotid fascia free of the lobular branch of the great auricular nerve, surgeons may better protect the lobular branch by anchoring the SMAS-platysma flap and thread to the deeper superior and anterior portions of the expected tympanoparotid fascia.

BackgroundRadiologic evaluation of children with Mycoplasma pneumoniae is important for diagnosis and management.ObjectiveTo investigate the correlation between chest radiographic findings and the clinical features in children with Mycoplasma pneumoniae pneumonia.Materials and methodsThis study included 393 hospitalized children diagnosed with M. pneumoniae pneumonia between January 2000 and August 2016. Their clinical features and chest radiographs were reviewed. Radiographic findings were categorized and grouped as consolidation group (lobar or segmental consolidation) and non-consolidation group (patchy infiltration, localized reticulonodular infiltration, or parahilar peribronchial infiltration).ResultsLobar or segmental consolidation (37%) was the most common finding, followed by parahilar or peribronchial infiltration (27%), localized reticulonodular infiltration (21%) and patchy infiltration (15%). The consolidation group was more frequently accompanied by pleural effusions (63%), compared to the non-consolidation group (16%). Compared with patients in the non-consolidation group, those in the consolidation group were associated with a significantly higher rate of hypoxia, tachypnea, tachycardia, extrapulmonary manifestations, prolonged fever, and longer periods of anti-mycoplasma therapy and hospitalization. Lobar or segmental consolidation was significantly more frequent in children ≥5 years old (44%) compared with children 2-5 years old (34%) and ConclusionThe chest radiographic findings of children with M. pneumoniae pneumonia correlate well with the clinical features. Consolidative lesions were frequently observed in older children and were associated with more severe clinical features.

BackgroundEvaluating allocation system effects on lung transplantation and determining systemic flaws is difficult. The purpose of this study was to assess the Korean urgency-based lung allocation system using the lung allocation score.MethodsWe reviewed transplantation patients retrospectively. Candidates were classified into groups based on urgency. Status 0 designated hospitalized patients requiring ventilator and/or extracorporeal life support. The lung allocation score was calculated based on the recipient's condition at transplantation.ResultsOne-hundred-twenty-three Status 0, 1, and 2/3 patients (40, 71, and 12, respectively) were enrolled. The median waiting time was 68 days. Nineteen Status 0 patients who received lung transplants deteriorated from non-Status 0 (median, 64 days). The lung allocation score showed a bimodal distribution (peaks around 45 and 90, corresponding with non-Status 0 and Status 0, respectively). Status 0 and the lung allocation score were independent risk factors for poor survival after adjustment for confounders (Status 0, hazard ratio, 2.788, p = 0.001; lung allocation score, hazard ratio, 1.025, p < 0.001). The lung allocation score cut-off for survival was 44. On dividing the non-Status 0 patients into 2 groups using the cut-off values and regrouping into Status 0, non-Status 0 with high lung allocation score (> 44), and non-Status 0 with low lung allocation score (< 44), we observed that non-Status 0 with high lung allocation score patients had better survival than Status 0 patients (p = 0.020) and poorer survival than non-Status 0 with low lung allocation score patients (p = 0.018).ConclusionsThe LAS demonstrated the characteristics of LTx recipients in Korea and the Korean allocation system needs to be revised to reduce the number of patients receiving LTx in Status 0. The LAS system could be used as a tool to evaluate lung allocation systems in countries that do not use the LAS system.

OBJECTIVE:To predict hospital admission at the time of ED triage using patient history in addition to information collected at triage. METHODS:This retrospective study included all adult ED visits between March 2014 and July 2017 from one academic and two community emergency rooms that resulted in either admission or discharge. A total of 972 variables were extracted per patient visit. Samples were randomly partitioned into training (80%), validation (10%), and test (10%) sets. We trained a series of nine binary classifiers using logistic regression (LR), gradient boosting (XGBoost), and deep neural networks (DNN) on three dataset types: one using only triage information, one using only patient history, and one using the full set of variables. Next, we tested the potential benefit of additional training samples by training models on increasing fractions of our data. Lastly, variables of importance were identified using information gain as a metric to create a low-dimensional model. RESULTS:A total of 560,486 patient visits were included in the study, with an overall admission risk of 29.7%. Models trained on triage information yielded a test AUC of 0.87 for LR (95% CI 0.86-0.87), 0.87 for XGBoost (95% CI 0.87-0.88) and 0.87 for DNN (95% CI 0.87-0.88). Models trained on patient history yielded an AUC of 0.86 for LR (95% CI 0.86-0.87), 0.87 for XGBoost (95% CI 0.87-0.87) and 0.87 for DNN (95% CI 0.87-0.88). Models trained on the full set of variables yielded an AUC of 0.91 for LR (95% CI 0.91-0.91), 0.92 for XGBoost (95% CI 0.92-0.93) and 0.92 for DNN (95% CI 0.92-0.92). All algorithms reached maximum performance at 50% of the training set or less. A low-dimensional XGBoost model built on ESI level, outpatient medication counts, demographics, and hospital usage statistics yielded an AUC of 0.91 (95% CI 0.91-0.91). CONCLUSION:Machine learning can robustly predict hospital admission using triage information and patient history. The addition of historical information improves predictive performance significantly compared to using triage information alone, highlighting the need to incorporate these variables into prediction models.

To evaluate the patients' morphologic factors affecting radiation dose in pediatric chest CT.From November 2013 to May 2015, 315 pediatric chest CT scans were obtained using a CT scanner, and classified into 5 groups according to the patients' age. For each age group, the chest CT scans were divided into two subgroups. A cut-off value used was the 75th percentile of size-specific dose estimates (SSDE), age-specific diagnostic reference level (DRL): less than the 75th percentile of SSDE (Group A, n = 238) and greater than the 75th percentile of SSDE (Group B, n = 77). All CT scans were performed with the same protocol using automatic tube voltage selection and current modulation techniques. The morphologic factors of the patients including body mass index (BMI), arm angles, presence of medical devices in the scan field, and degree of off-centering within the CT gantry were compared between groups A and B.Group B showed narrower arm angles on scout and coronal reformatted images, higher frequency of the presence of devices and higher BMI than group A (P < 0.001, P < 0.001; P = 0.018, and P < 0.001, respectively). In multivariate analysis, narrower arm angles, the presence of devices on the scout images and higher BMI were independently associated with higher SSDE (P = 0.001, P = 0.037, and P < 0.001, respectively).During acquisition of the scout images, arms-down position and the presence of medical devices were associated with a high radiation dose above age-specific DRLs in pediatric chest CT, regardless of repositioning before the actual scanning. In addition, off-centering had no clinical impact on radiation dose in the routine practice.

MicroRNAs (miRNAs) regulate gene expression during the peri-implantation period. The purpose of this study was to investigate whether genetic polymorphisms in the four miRNAs associated with fetal or placental development play roles in the development of idiopathic recurrent pregnancy loss (RPL) in Korean females.A case-control study involving 225 controls and 387 women with at least two consecutively recurrent pregnancy losses between 1999 and 2012 was performed. The genotypes of the four miRNA polymorphisms, including miR-27a rs895819, miR-423 rs6505162, miR-449b rs10061133, and miR-605 rs2043556, were analyzed by the polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals were estimated using multivariate analyses after maternal age adjustments. The relationships between each of the four microRNA genotypes and each of the six clinical parameters of the RPL patients (plasma homocysteine and folate levels, natural killer cell number, platelet count, prothrombin time, and, activated partial thromboplastin time) were analyzed using multiple linear regression analyses.Our results suggest that weak associations between decreased RPL risk and the genotypes of miR-27a (AG and AG+GG), combination genotype of miR-27a/miR-423 (AG/GC), and haplotypes of miR-27a/miR-423/miR-449b/miR-605 (G-C-A-G) and miR-27a/miR-449b/miR-605 (G-A-G), whereas weak associations between increased RPL risk and genotypes of miR-449b (GG and AG+GG), combination genotypes of miR-423/miR-449b (CC/GG and CA/AG), miR-449b/miR-605 (AG/AG), haplotypes of miR-27a/miR-423/miR-449b/miR-605 (A-C-G-A, A-A-A-G, and G-C-G-G), miR-27a/miR-423/miR-449b (A-C-G), miR-27a/miR-449b/miR-605 (A-A-G, A-G-A, and G-G-G), miR-423/miR-449b/miR-605 (C-G-G and A-A-G), and miR-423/miR-449b (C-G and A-A). The genotypes of miR-27a (AG and AG+GG) also showed significant contributions to the prediction of folate levels in RPL patients.The study showed associations between miRNA polymorphisms (miR-27a rs895819 and miR-449b rs10061133) and RPL development, and between the miRNA polymorphism (miR-27a rs895819) and plasma folate levels.

MicroRNAs post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to identify new target genes for microRNA polymorphisms (miR-146aC>G and miR-196a2T>C) in primary ovarian insufficiency (POI). We cloned and transfected miR-146aC>G and miR-196a2T>C into human granulosa cells and used microarrays and qPCR-arrays to examine the changes in the messenger RNA expression profile. We show miR-146aC>G and miR-196a2T>C change the mRNA expression patterns in granulosa cell. In each case, mRNAs were up or down-regulated after treatments with miR-146a C or G and miR-196a2 T or C. We found that miR-146a led to a significantly altered regulation of the mRNA levels of FOXO3, FOXL2 and CCND2 compared to controls. We also found that the polymorphisms of miR-146a led to a significantly altered regulation of CCND2 and FOXO3. Our results suggest that miR-146aC>G and miR-196a2T>C can regulate the levels of many of their target transcripts. In addition, specific target genes of miR-146aC>G polymorphisms may be involved in granulosa cell regulation.

To classify patients with orthotopic neobladder based on urodynamic parameters using cluster analysis and to characterize the voiding function of each group.From January 2012 to November 2015, 142 patients with bladder cancer underwent radical cystectomy and Studer neobladder reconstruction at our institute. Of the 142 patients, 103 with complete urodynamic data and information on urinary functional outcomes were included in this study. K-means clustering was performed with urodynamic parameters which included maximal cystometric capacity, residual volume, maximal flow rate, compliance, and detrusor pressure at maximum flow rate. Three groups emerged by cluster analysis. Urodynamic parameters and urinary function outcomes were compared between three groups.Group 1 (n = 44) had ideal urodynamic parameters with a mean maximal bladder capacity of 513.3 ml and mean residual urine volume of 33.1 ml. Group 2 (n = 42) was characterized by small bladder capacity with low compliance. Patients in group 2 had higher rates of daytime incontinence and nighttime incontinence than patients in group 1. Group 3 (n = 17) was characterized by large residual urine volume with high compliance. When we examined gender differences in urodynamics and functional outcomes, residual urine volume and the rate of daytime incontinence were only marginally significant. However, females were significantly more likely to belong to group 2 or 3 (P = 0.003). In multivariate analysis to identify factors associated with group 1 which has the most ideal urodynamic pattern, age (OR 0.95, P = 0.017) and male gender (OR 7.57, P = 0.003) were identified as significant factors.While patients with ileal neobladder present with various voiding symptoms, three urodynamic patterns were identified by cluster analysis. Approximately half of patients had ideal urodynamic parameters. The other two groups were characterized by large residual urine and small capacity bladder with low compliance. Young age and male gender appear to have a favorable impact on urodynamic and voiding outcomes in patients undergoing orthotopic neobladder reconstruction.

The SLC6A15 gene has been identified as a novel candidate gene for major depressive disorder (MDD). It is presumed to be involved in the pathophysiology of MDD through regulation of glutamate transmission in the brain. However, the involvement of this gene in microstructural changes in white matter (WM) tracts remains unclear. We aimed to investigate the influence of a polymorphism of this gene (rs1545853) on the structural integrity of WM tracts in the cortico-limbic network.Eighty-six patients with MDD and 64 healthy controls underwent T1-weighted structural magnetic resonance imaging, including diffusion tensor imaging (DTI), and genotype analysis. We selected the genu of the corpus callosum, the uncinate fasciculus, cingulum, and fornix as regions of interest, and extracted fractional anisotropy (FA) values using the FMRIB Diffusion Toolbox software.FA values for the left parahippocampal cingulum (PHC) was significantly reduced in the patients with MDD compared to healthy control participants (p = 0.004). We also found that MDD patients with the A allele showed reduced FA values for the left PHC than did healthy controls with the A allele (p = 0.012). There was no significant difference in the FA value of left PHC for the comparison between the G homozygotes of MDD and healthy control group.We observed an association between the risk allele of the SLC6A15 gene rs1545843 and the WM integrity of the PHC in MDD patients, which is known to play an important role in the neural circuit involved in emotion processing.

DNA damage response (DDR) molecules are protective against genotoxic stresses. DDR molecules are also involved in the survival of cancer cells in patients undergoing anti-cancer therapies. Therefore, DDR molecules are potential markers of cancer progression in addition to being potential therapeutic targets. In this study, we evaluated the immunohistochemical expression of PARP1, γH2AX, BRCA1, and BRCA2 and their prognostic significance in 112 cases of soft tissue sarcoma (STS). The expression of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with each other and were associated with higher tumor stage and presence of distant metastasis. The expression of PARP1, γH2AX, and BRCA2 were significantly associated with shorter disease-specific survival (DSS) and event-free survival (EFS) by univariate analysis. BRCA1 expression was associated with shorter DSS. Multivariate analysis revealed the expression of PARP1 and γH2AX to be independent indicators of poor prognosis of DSS and EFS. BRCA2 expression was an independent indicator of poor prognosis of DSS. In addition, the combined expressional patterns of PARP1, γH2AX, BRCA1, and BRCA2 (CSddrm) were independent prognostic predictors of DSS (P < 0.001) and EFS (P = 0.016). The ten-year DSS rate of the CSddrm-low, CSddrm-intermediate, and CSddrm-high subgroups were 81%, 26%, and 0%, respectively. In conclusion, this study demonstrates that the individual and combined expression patterns of the DDR molecules PARP1, γH2AX, BRCA1, and BRCA2 could be predictive of the prognosis of STS patients and suggests that controlling the activity of these DDR molecules could be employed in new therapeutic stratagems for the treatment of STS.

To investigate the serial changes of metabolic acidosis and identify associated risk factors in patients who underwent radical cystectomy and ileal neobladder.From January 2010 to August 2014, 123 patients who underwent radical cystectomy and ileal neobladder reconstruction for bladder cancer were included in this study. Metabolic acidosis was defined as a serum bicarbonate level less than 22 mEq/L and impaired renal function was defined as a GFR

The one-carbon metabolism pathway disorder was important role in successful pregnancy. The MTHFR and TS protein were crucial factor in one-carbon metabolism. To investigate the association between recurrent implantation failure (RIF) and enzymes in the one-carbon metabolism pathway. A total of 120 women diagnosed with RIF and 125 control subjects were genotyped for MTHFR 677C>T, 1298A>C, TSER 2R/3R and TS 1494del/ins by a polymerase chain reaction-restriction fragment length polymorphism assay. According to the gene-gene combination analysis, the MTHFR 677/MTHFR 1298 (TT/AA) and MTHFR 677/TS 1494 (TT/6bp6bp) genetic combinations were associated with relatively higher risks [adjusted odds ratio (AOR), 2.764; 95% CI, 1.065-7.174; P = 0.037 and AOR, 3.186; 95% CI, 1.241-8.178; P = 0.016] in RIF patients compared to the CC/AA (MTHFR 677/MTHFR 1298) and TT/6bp6bp (MTHFR 677/TS 1494) combinations, respectively. The results suggested that the combined MTHFR 677/MTHFR 1298 genotype might be associated with increased risk of RIF. To the best of our knowledge, this study is the first to elucidate the potential association of MTHFR, TS and TSER polymorphisms with RIF risk in Korean patients.

The aim of this study was to compare the two types of mid-urethral slings for stress urinary incontinence (SUI) with intrinsic sphincter deficiency (ISD).This retrospective study included patients who underwent tension-free vaginal tape (TVT) procedure or transobturator tape (TOT) procedure by a single surgeon for SUI with ISD, defined as Valsalva leak point pressure (VLPP) < 60 cmH2O in a urodynamic study. Cases of neurogenic bladder, previous SUI surgery, and concomitant cystocele repair were excluded. The primary outcome was treatment success at 12 months, defined by self-reported absence of symptoms, no leakage episodes recorded, and no retreatment.Among the 157 women who were included in the final analysis, 105 patients received TVT and 52 patients received TOT. Age, underlying diseases, Stamey grade, cystocele grade, and presence of urge incontinence were not significantly different between the two groups. Urodynamic parameters including maximal urethral closing pressure, detrusor overactivity, VLPP, urethral hypermobility (Q-tip ≥ 30°), were also comparable between the two groups. Success rate was significantly higher in the TVT group than in the TOT group (95.2% vs. 82.7%, p = 0.009). On multivariate analysis, only TOT surgery (OR = 3.922, 95%CI = 1.223-12.582, p = 0.022) was a risk factor for failure following surgical treatment.TVT is more effective than TOT in treatment of female SUI with ISD.

To evaluate the incremental value of a combination of magnetic resonance cholangiopancreatography (MRCP) and ultrasonography (US), compared to US alone, for diagnosing biliary atresia (BA) in neonates and young infants with cholestasis.The institutional review board approved this retrospective study. The US and MRCP studies were both performed on 64 neonates and young infants with BA (n = 41) or without BA (non-BA) (n = 23). Two observers reviewed independently the US alone set and the combined US and MRCP set, and graded them using a five-point scale. Diagnostic performance was compared using pairwise comparison of the receiver operating characteristics (ROC) curve. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value were assessed.The diagnostic performance (the area under the ROC curve [Az]) for diagnosing BA improved significantly after additional review of MRCP images; Az improved from 0.688 to 0.901 (P = .015) for observer 1 and from 0.676 to 0.901 (P = .011) for observer 2. The accuracy of MRCP combined with US (observer 1, 95% [61/64]; observer 2 92% [59/64]) and PPV (observer 1, 95% [40/42]; observer 2 91% [40/44]) were significantly higher than those of US alone for both observers (accuracy: observer 1, 73% [47/64], P = 0.003; observer 2, 72% [46/64], P = 0.004; PPV: observer 1, 76% [35/46], P = 0.016; observer 2, 76% [34/45], P = 0.013). Interobserver agreement of confidence levels was good for US alone (ĸ = 0.658, P < .001) and was excellent for the combined set of US and MRCP (ĸ = 0.929, P < .001).Better diagnostic performance was achieved with the combination of US and MRCP than with US alone for the evaluation of BA in neonates and young infants with cholestasis.

Cisplatin is a first-line chemotherapeutic agent for ovarian cancer that acts by promoting DNA cross links and adduct. However drug resistance and considerable side effects including reproductive toxicity remain a significant challenge. PTEN is well known as a tumor suppressor function which plays a fundamental role in the regulation of the cell cycle, apoptosis and development of cancer. At the same time PTEN has been revealed to be critically important for the maintenance of the primordial follicle pool. In this study, we investigated the role of PTEN/Akt/FOXO3 pathway in cisplatin-induced primordial follicle depletion. Cisplatin induced ovarian failure mouse model was used to evaluate how this pathway involves. In vitro maturation was used for oocyte rescue after cisplatin damage. We found that cisplatin treatment decreased PTEN levels, leading to a subsequent increase in the phosphorylation of key molecules in the pathway. The activation of the PTEN/Akt/FOXO3 pathway cascade increased cytoplasmic translocation of FOXO3a in cisplatin-treated follicles, which in turn increased the pool size of growing follicles, and rapidly depleted the number of dormant follicles. Once activated, the follicles were more prone to apoptosis, and their cumulus cells showed a loss of luteinizing hormone (LH) receptor expression, which leads to failure during final maturation and ovulation. In vitro maturation to rescue oocytes in a cisplatin-treated mouse model resulted in successful maturation and fertilization. This study is the first to show the involvement of the PTEN/Akt/FOXO3 pathway in premature ovarian failure after cisplatin treatment and the possibility of rescue through in vitro maturation.

A better understanding of the kinetics of accumulated immune cells that are involved in pathophysiology during Mycobacterium tuberculosis (Mtb) infection may help to facilitate the development of vaccines and immunological interventions. However, the kinetics of innate and adaptive cells that are associated with pathogenesis during Mtb infection and their relationship to Mtb virulence are not clearly understood. In this study, we used a mouse model to compare the bacterial burden, inflammation and kinetics of immune cells during aerogenic infection in the lung between laboratory-adapted strains (Mtb H37Rv and H37Ra) and Mtb K strain, a hyper-virulent W-Beijing lineage strain. The Mtb K strain multiplied more than 10- and 3.54-fold more rapidly than H37Ra and H37Rv, respectively, during the early stage of infection (at 28 days post-infection) and resulted in exacerbated lung pathology at 56 to 112 days post-infection. Similar numbers of innate immune cells had infiltrated, regardless of the strain, by 14 days post-infection. High, time-dependent frequencies of F4/80-CD11c+CD11b-Siglec-H+PDCA-1+ plasmacytoid DCs and CD11c-CD11b+Gr-1int cells were observed in the lungs of mice that were infected with the Mtb K strain. Regarding adaptive immunity, Th1 and Th17 T cells that express T-bet and RORγt, respectively, significantly increased in the lungs that were infected with the laboratory-adapted strains, and the population of CD4+CD25+Foxp3+ regulatory T cells was remarkably increased at 112 days post-infection in the lungs of mice that were infected with the K strain. Collectively, our findings indicate that the highly virulent Mtb K strain may trigger the accumulation of pDCs and Gr1intCD11b+ cells with the concomitant down-regulation of the Th1 response and the maintenance of an up-regulated Th2 response without inducing a Th17 response during chronic infection. These results will help to determine which immune system components must be considered for the development of tuberculosis (TB) vaccines and immunological interventions.

Mycobacterium bovis bacillus Calmette-Guerin (BCG), the only licensed vaccine, shows limited protection efficacy against pulmonary tuberculosis (TB), particularly hypervirulent Mycobacterium tuberculosis (Mtb) strains, suggesting that a logistical and practical vaccination strategy is urgently required. Boosting the BCG-induced immunity may offer a potentially advantageous strategy for advancing TB vaccine development, instead of replacing BCG completely. Despite the improved protection of the airway immunization by using live BCG, the use of live BCG as an airway boosting agent may evoke safety concerns. Here, we analyzed the protective efficacy of γ-irradiated BCG as a BCG-prime boosting agent for airway immunization against a hypervirulent clinical strain challenge with Mycobacterium tuberculosis HN878 in a mouse TB model. After the aerosol challenge with the HN878 strain, the mice vaccinated with BCG via the parenteral route exhibited only mild and transient protection, whereas BCG vaccination followed by multiple aerosolized boosting with γ-irradiated BCG efficiently maintained long-lasting control of Mtb in terms of bacterial reduction and pathological findings. Further immunological investigation revealed that this approach resulted in a significant increase in the cellular responses in terms of a robust expansion of antigen (PPD and Ag85A)-specific CD4+ T cells concomitantly producing IFN-γ, TNF-α, and IL-2, as well as a high level of IFN-γ-producing recall response via both the local and systemic immune systems upon further boosting. Collectively, aerosolized boosting of γ-irradiated BCG is able to elicit strong Th1-biased immune responses and confer enhanced protection against a hypervirulent Mycobacterium tuberculosis HN878 infection in a boosting number-dependent manner.

The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively). HCC827/GR resistance was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER cells. AUY922 treatment effectively suppressed proliferation and induced cell death in both resistant cell lines. Accordingly, the downregulation of EGFR, MET, and AXL led to decreased Akt activation. The inhibitory effects of AUY922 on each receptor were confirmed in gene-transfected LK2 cells. AUY922 also effectively controlled tumor growth in xenograft mouse models containing HCC827/GR and HCC827/ER cells. In addition, AUY922 reduced invasion and migration by both types of resistant cells. Our study findings thus show that AUY922 is a promising therapeutic option for MET- and AXL-mediated resistance to EGFR-TKI in lung cancer.

Alfalfa (Medicago sativa L.), a perennial forage crop with high nutritional content, is widely distributed in various environments worldwide. We recently demonstrated that the sweetpotato Orange gene (IbOr) is involved in increasing carotenoid accumulation and enhancing resistance to multiple abiotic stresses. In this study, in an effort to improve the nutritional quality and environmental stress tolerance of alfalfa, we transferred the IbOr gene into alfalfa (cv. Xinjiang Daye) under the control of an oxidative stress-inducible peroxidase (SWPA2) promoter through Agrobacterium tumefaciens-mediated transformation. Among the 11 transgenic alfalfa lines (referred to as SOR plants), three lines (SOR2, SOR3, and SOR8) selected based on their IbOr transcript levels were examined for their tolerance to methyl viologen (MV)-induced oxidative stress in a leaf disc assay. The SOR plants exhibited less damage in response to MV-mediated oxidative stress and salt stress than non-transgenic plants. The SOR plants also exhibited enhanced tolerance to drought stress, along with higher total carotenoid levels. The results suggest that SOR alfalfa plants would be useful as forage crops with improved nutritional value and increased tolerance to multiple abiotic stresses, which would enhance the development of sustainable agriculture on marginal lands.

The latency and reactivation of Mycobacterium tuberculosis infection has been well studied. However, there have been few studies of the latency and reactivation of Mycobacterium avium complex (MAC), the most common etiological non-tuberculous Mycobacterium species next to M. tuberculosis in humans worldwide. We hypothesized that latent MAC infections can be reactivated following immunosuppression after combination chemotherapy with clarithromycin and rifampicin under experimental conditions. To this end, we employed a modified Cornell-like murine model of tuberculosis and investigated six strains consisting of two type strains and four clinical isolates of M. avium and M. intracellulare. After aerosol infection of each MAC strain, five to six mice per group were euthanized at 2, 4, 10, 18, 28 and 35 weeks post-infection, and lungs were sampled to analyze bacterial burden and histopathology. One strain of each species maintained a culture-negative state for 10 weeks after completion of 6 weeks of chemotherapy, but was reactivated after 5 weeks of immunosuppression in the lungs with dexamethasone (three out of six mice in M. avium infection) or sulfasalazine (four out of six mice in both M. avium and M. intracellulare infection). The four remaining MAC strains exhibited decreased bacterial loads in response to chemotherapy; however, they remained at detectable levels and underwent regrowth after immunosuppression. In addition, the exacerbated lung pathology demonstrated a correlation with bacterial burden after reactivation. In conclusion, our results suggest the possibility of MAC reactivation in an experimental mouse model, and experimentally demonstrate that a compromised immune status can induce reactivation and/or regrowth of MAC infection.

The influence of body-mass index (BMI) on spinal anesthesia is still controversial, with discrepant results reported in previous studies. To compare spinal anesthesia in obese and non-obese subjects, the anesthesia profiles in patients who underwent spinal anesthesia using intrathecal hyperbaric bupivacaine were compared. A total of 209 patients undergoing elective total knee replacement arthroplasty (TKRA) surgery under spinal anesthesia were divided into an NO (non-obese) group (BMI < 30 kg/m2, n = 141) and an O (obese) group (BMI ≥ 30 kg/m2, n = 68). Anesthesia was deemed successful if a bilateral T12 sensory block occurred within 15 minutes of intrathecal drug administration, and if the level of sensory block was higher than T12 when the surgery ended. Logistic regression analysis with multiple variables known to influence spinal anesthesia was performed to identify which parameters independently determined the spinal anesthesia outcome. Similar doses of bupivacaine were administered to the NO and O groups. The incidence of anesthesia failure was significantly lower in the O group [n = 43 (30.5%) in the NO group vs. n = 10 (18.9%) in the O group, p = 0.014]. The independent predictors for successful anesthesia in all patients were dose of hyperbaric bupivacaine [odds ratio (OR) 2.12, 95% CI: 1.64-2.73] and obese status (BMI ≥ 30 kg/m2, OR 2.86, 95% CI: 1.25-6.52). Time to first report of postoperative pain and time to first self-void were significantly longer in the O group. These results suggest that the duration of block with hyperbaric bupivacaine is prolonged in obese patients and obesity is independently associated with spinal anesthesia outcomes, as is bupivacaine dosage. A further study enrolling patients with morbid obesity and using a fixed bupivacaine dosage is required to confirm the effect of obesity on spinal anesthesia.

Protein kinase CK2 has diverse functions promoting and maintaining cancer phenotypes. We investigated the effect of CK2 inhibition in lung cancer cells with T790M-mediated resistance to the EGFR-TK inhibitor. Resistant sublines of PC-9 to gefitinib (PC-9/GR) and erlotinib (PC-9/ER) were established by previous study, and T790M secondary mutation was found in both resistant sublines. A decrease of EGFR by siRNA treatment effectively controlled the growth of resistant cells, thus suggesting that they still have EGFR-dependency. CX-4945, a potent and selective CK2 inhibitor, induced autophagy in PC-9/GR and PC-9/ER, and which was supported by the induction of autophagic vacuoles and microtubule-associated protein 1 light chain 3 (LC3) expression, and the increase of punctate fluorescent signals in resistant cells pre-transfected with green fluorescent protein (GFP)-tagged LC3. However, the withdrawal of CX-4945 led to the recovery of cancer cells with autophagy. We found that the induction of autophagy by CX-4945 in both resistant cells was CK2 dependent by using small interfering RNA against CK2. The treatment with CX-4945 alone induced a minimal growth inhibition in resistant cells. However, combined treatment of CX-4945 and EGFR-TKI effectively inhibited cancer-cell proliferation and induced apoptosis. CX-4945 increased the translocation of EGFR from the cell surface into the autophagosome, subsequently leading to the decrease of EGFR while inhibition of autophagy by 3MA or Atg7-targeted siRNA pretreatment reduced the decrease of EGFR by CX-4945. Accordingly, apoptosis by a combination of CX-4945 and EGFR-TKI was suppressed by 3MA or Atg7-targeted siRNA pretreatment, thus suggesting that autophagosome-mediated EGFR down-regulation would have an important role regarding apoptotic cell death by EGFR-TKI. Combined treatment of the CK2 inhibitor and EGFR-TKI may be a promising strategy for overcoming T790M-mediated resistance.

The aim of this study was to assess the biological reactions triggered by stem cell transplantation related to phenotypic alteration, host-to-cell response, chromosomal stability, transcriptional alteration, and stem cell-like cell re-expansion. B6CBAF1 mouse embryonic stem cells (ESCs) were injected subcutaneously into homologous or heterologous (B6D2F1) recipients, and heterologous injections were performed with or without co-injection of B6D2F1 fetal fibroblasts. All homologous injections resulted in teratoma formation, whereas a sharp decrease in formation was detected after heterologous injection (100 vs. 14%; p

The purpose of this study was to develop a biobetter version of recombinant human interferon-β 1a (rhIFN-β 1a) to improve its biophysical properties, such as aggregation, production and stability, and pharmacokinetic properties without jeopardizing its activity. To achieve this, we introduced additional glycosylation into rhIFN-β 1a via site-directed mutagenesis. Glycoengineering of rhIFN-β 1a resulted in a new molecular entity, termed R27T, which was defined as a rhIFN-β mutein with two N-glycosylation sites at 80th (original site) and at an additional 25th amino acid due to a mutation of Thr for Arg at position 27th of rhIFN-β 1a. Glycoengineering had no effect on rhIFN-β ligand-receptor binding, as no loss of specific activity was observed. R27T showed improved stability and had a reduced propensity for aggregation and an increased half-life. Therefore, hyperglycosylated rhIFN-β could be a biobetter version of rhIFN-β 1a with a potential for use as a drug against multiple sclerosis.

BACKGROUND: DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls. METHODS: We compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed. RESULTS: In total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2-3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas. CONCLUSIONS: Lower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non-psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation.

OBJECTIVES: Although the incidence of prostate cancer (PCa) is rapidly increasing in Korea, there are few suitable prediction models for disease recurrence after radical prostatectomy (RP). We established pre- and post-operative nomograms estimating biochemical recurrence (BCR)-free probability after RP in Korean men with clinically localized PCa. PATIENTS AND METHODS: Our sampling frame included 3,034 consecutive men with clinically localized PCa who underwent RP at our tertiary centers from June 2004 through July 2011. After inappropriate data exclusion, we evaluated 2,867 patients for the development of nomograms. The Cox proportional hazards regression model was used to develop pre- and post-operative nomograms that predict BCR-free probability. Finally, we resampled from our study cohort 200 times to determine the accuracy of our nomograms on internal validation, which were designated with concordance index (c-index) and further represented by calibration plots. RESULTS: Over a median of 47 months of follow-up, the estimated BCR-free rate was 87.8% (1 year), 83.8% (2 year), and 72.5% (5 year). In the pre-operative model, Prostate-Specific Antigen (PSA), the proportion of positive biopsy cores, clinical T3a and biopsy Gleason score (GS) were independent predictive factors for BCR, while all relevant predictive factors (PSA, extra-prostatic extension, seminal vesicle invasion, lymph node metastasis, surgical margin, and pathologic GS) were associated with BCR in the post-operative model. The c-index representing predictive accuracy was 0.792 (pre-) and 0.821 (post-operative), showing good fit in the calibration plots. CONCLUSIONS: In summary, we developed pre- and post-operative nomograms predicting BCR-free probability after RP in a large Korean cohort with clinically localized PCa. These nomograms will be provided as the mobile application-based SNUH Prostate Cancer Calculator. Our nomograms can determine patients at high risk of disease recurrence after RP who will benefit from adjuvant therapy.

Bcl-w a pro-survival member of the Bcl-2 protein family, is expressed in a variety of cancer types, including gastric and colorectal adenocarcinomas, as well as glioblastoma multiforme (GBM), the most common and lethal brain tumor type. Previously, we demonstrated that Bcl-w is upregulated in gastric cancer cells, particularly those displaying infiltrative morphology. These reports propose that Bcl-w is strongly associated with aggressive characteristic, such as invasive or mesenchymal phenotype of GBM. However, there is no information from studies of the role of Bcl-w in GBM. In the current study, we showed that Bcl-w is upregulated in human glioblastoma multiforme (WHO grade IV) tissues, compared with normal and glioma (WHO grade III) tissues. Bcl-w promotes the mesenchymal traits of glioblastoma cells by inducing vimentin expression via activation of transcription factors, β-catenin, Twist1 and Snail in glioblastoma U251 cells. Moreover, Bcl-w induces invasiveness by promoting MMP-2 and FAK activation via the PI3K-p-Akt-p-GSK3β-β-catenin pathway. We further confirmed that Bcl-w has the capacity to induce invasiveness in several human cancer cell lines. In particular, Bcl-w-stimulated β-catenin is translocated into the nucleus as a transcription factor and promotes the expression of target genes, such as mesenchymal markers or MMPs, thereby increasing mesenchymal traits and invasiveness. Our findings collectively indicate that Bcl-w functions as a positive regulator of invasiveness by inducing mesenchymal changes and that trigger their aggressiveness of glioblastoma cells.

Two closely related bacterial species, Segniliparus rotundus and Segniliparus rugosus, have emerged as important human pathogens, but little is known about the immune responses they elicit or their comparative pathophysiologies. To determine the virulence and immune responses of the two species, we compared their abilities to grow in phagocytic and non-phagocytic cells. Both species maintained non-replicating states within A549 epithelial cells. S. rugosus persisted longer and multiplied more rapidly inside murine bone marrow-derived macrophages (BMDMs), induced more pro-inflammatory cytokines, and induced higher levels of macrophage necrosis. Activation of BMDMs by both species was mediated by toll-like receptor 2 (TLR2), followed by mitogen-activated protein kinases (MAPK) and nuclear factor κB (NF-κB) signaling pathways, indicating a critical role for TLR2 in Segniliparus-induced macrophage activation. S. rugosus triggered faster and stronger activation of MAPK signaling and IκB degradation, indicating that S. rugosus induces more pro-inflammatory cytokines than S. rotundus. Multifocal granulomatous inflammations in the liver and lung were observed in mice infected with S. rugosus, but S. rotundus was rapidly cleared from all organs tested within 15 days post-infection. Furthermore, S. rugosus induced faster infiltration of innate immune cells such as neutrophils and macrophages to the lung than S. rotundus. Our results suggest that S. rugosus is more virulent and induces a stronger immune response than S. rotundus.

Recently, the roles of SIRT1 and deleted in breast cancer 1 (DBC1) in human cancer have been extensively studied and it has been demonstrated that they are involved in many human carcinomas. However, their clinical significance for soft-tissue sarcomas has not been examined. In this study, we evaluated the expression and prognostic significance of the expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 in 104 cases of soft-tissue sarcomas.Immunohistochemical expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were seen in 71%, 74%, 53%, 48%, and 73% of sarcomas, respectively. The expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were significantly correlated with advanced clinicopathological parameters such as higher clinical stage, higher histological grade, increased mitotic counts, and distant metastasis. The expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 were significantly correlated with each other and positive expression of all of these predicted shorter overall survival and event-free survival by univariate analysis. Multivariate analysis revealed the expression of SIRT1 as an independent prognostic indicator for overall survival and event-free survival of sarcoma patients. In conclusion, this study demonstrates that SIRT1- and DBC1-related pathways may be involved in the progression of soft-tissue sarcomas and can be used as clinically significant prognostic indicators for sarcoma patients. Moreover, the SIRT1- and DBC1-related pathways could be new therapeutic targets for the treatment of sarcomas.

Complex regional pain syndrome (CRPS) is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II) and 5 controls (cut-off value: 1.5-fold change and p

[This corrects the article DOI: 10.1371/journal.pone.0068030.].

Although auditory processing has been widely studied with conventional parametric methods, there have been a limited number of independent component analysis (ICA) applications in this area. The purpose of this study was to examine spatiotemporal behavior of brain networks in response to passive auditory stimulation using ICA. Continuous broadband noise was presented binaurally to 19 subjects with normal hearing. ICA was performed to segregate spatial networks, which were subsequently classified according to their temporal relation to the stimulus using power spectrum analysis. Classification of separated networks resulted in 3 stimulus-activated, 9 stimulus-deactivated, 2 stimulus-neutral (stimulus-dependent but not correlated with the stimulation timing), and 2 stimulus-unrelated (fluctuations that did not follow the stimulus cycles) components. As a result of such classification, spatiotemporal subdivisions were observed in a number of cortical structures, namely auditory, cingulate, and sensorimotor cortices, where parts of the same cortical network responded to the stimulus with different temporal patterns. The majority of the classified networks seemed to comprise subparts of the known resting-state networks (RSNs); however, they displayed different temporal behavior in response to the auditory stimulus, indicating stimulus-dependent temporal segregation of RSNs. Only one of nine deactivated networks coincided with the "classic" default-mode network, suggesting the existence of a stimulus-dependent default-mode network, different from that commonly accepted.

Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1(+)/PD-L1(+) pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1-positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy.

The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.

To determine the presence of sexual dimorphic transcription and how in vitro culture environments influence X-linked gene transcription patterns in preimplantation embryos, we analyzed mRNA expression levels in in vivo-derived, in vitro-fertilized (IVF), and cloned porcine blastocysts. Our results clearly show that sex-biased expression occurred between female and male in vivo blastocysts in X-linked genes. The expression levels of XIST, G6PD, HPRT1, PGK1, and BEX1 were significantly higher in female than in male blastocysts, but ZXDA displayed higher levels in male than in female blastocysts. Although we found aberrant expression patterns for several genes in IVF and cloned blastocysts, similar sex-biased expression patterns (on average) were observed between the sexes. The transcript levels of BEX1 and XIST were upregulated and PGK1 was downregulated in both IVF and cloned blastocysts compared with in vivo counterparts. Moreover, a remarkable degree of expression heterogeneity was observed among individual cloned embryos (the level of heterogeneity was similar in both sexes) but only a small proportion of female IVF embryos exhibited variability, indicating that this phenomenon may be primarily caused by faulty reprogramming by the somatic cell nuclear transfer (SCNT) process rather than in vitro conditions. Aberrant expression patterns in cloned embryos of both sexes were not ameliorated by treatment with Scriptaid as a potent HDACi, although the blastocyst rate increased remarkably after this treatment. Taken together, these results indicate that female and male porcine blastocysts produced in vivo and in vitro transcriptional sexual dimorphisms in the selected X-linked genes and compensation of X-linked gene dosage may not occur at the blastocyst stage. Moreover, altered X-linked gene expression frequently occurred in porcine IVF and cloned embryos, indicating that X-linked gene regulation is susceptible to in vitro culture and the SCNT process, which may eventually lead to problems with embryonic or placental defects.