Extracting regulatory modules from gene expression data by sequential pattern mining

Abstract Background Identifying a regulatory module (RM), a bi-set of co-regulated genes and co-regulating conditions (or samples), has been an important challenge in functional genomics and bioinformatics. Given a microarray gene-expression matrix, biclustering has been the most common method for extracting RMs. Among biclustering methods, order-preserving biclustering by a sequential pattern mining technique has native advantage over the conventional biclustering approaches since it preserves the order of genes (or conditions) according to the magnitude of the expression value. However, previous sequential pattern mining-based biclustering has several weak points in that they can easily be computationally intractable in the real-size of microarray data and sensitive to inherent noise in the expression value. Results In this paper, we propose a novel sequential pattern mining algorithm that is scalable in the size of microarray data and robust with respect to noise. When applied to the microarray data of yeast, the proposed algorithm successfully found long order-preserving patterns, which are biologically significant but cannot be found in randomly shuffled data. The resulting patterns are well enriched to known annotations and are consistent with known biological knowledge. Furthermore, RMs as well as inter-module relations were inferred from the biologically significant patterns. Conclusions Our approach for identifying RMs could be valuable for systematically revealing the mechanism of gene regulation at a genome-wide level.</p

Effect of typhoons on the Korean national emergency medical service system

Objective While the effect of typhoons on emergency medicine has been evaluated, data are scarce on their effects on the emergency medical service (EMS). This study evaluated the effect of typhoons on EMS patients and performance. Methods The study period was January 2010 to December 2012. Meteorological data regarding typhoons were provided by the Korean Meteorological Administration. EMS data were retrieved from the EMS database of the national emergency management agency. The database includes ambulance run sheets, which contain clinical and operational data. In this case-crossover study, the cases and controls were EMS calls on the day of typhoon warnings and calls one week prior to the typhoon warnings, respectively. Results During the study period, 11 typhoons affected Korea. A total of 14,521 cases were selected for analysis. Overall, there were no obvious differences between the case and control groups. However, there were statistically significant differences in age, place, and time requests. There were fewer patients between 0 and 15 years of age (P=0.01) and more unconscious patients (P=0.01) in the case group. The EMS operational performance, as measured by the times elapsed between call to start, call to field, and call to hospital did not differ significantly. There was also no significant difference in the time from hospital arrival between the cases (28.67, standard deviation 16.37) and controls (28.97, standard deviation 28.91) (P=0.39). Conclusion Typhoons did not significantly affect the EMS system in this study. Further study is necessary to understand the reasons for this finding

Ketamine use for endotracheal intubation in severe sepsis and septic shock

Objective. We conducted this study to evaluate the clinical outcomes of patients with severe sepsis and septic shock who were treated with ketamine for endotracheal intubation. Methods. A single-center, retrospective study was carried out to compare the outcomes of patients with severe sepsis and septic shock who received a ketamine or non-ketamine agent for rapid sequence intubation (RSI). We analyzed the sepsis registry for adult patients who presented to the emergency department (ED), met the criteria for severe sepsis or septic shock, and underwent endotracheal intubation between August 2008 and March 2014. Te primary outcome was 28-day mortality. We performed a multivariable logistic regression analysis to assess the association between ketamine use for intubation and 28-day mortality. Results. In all, 170 patients were intubated during the study period. Of the eligible patients, 95 received ketamine and 75 received a non-ketamine agent. Te 28-day mortality of the ketamine group was not signifcantly diferent from that of the nonketamine group (38% vs. 40%, respectively,P=0.78). Te unadjusted odds ratio (OR) of ketamine use for 28-day mortality was 0.92 (95% CI: 0.49–1.70, P=0.78). Te association remained insignifcant afer adjusting for age, gender, malignancy, initial lactate level on ED admission, time to frst antibiotic administration, Acute Physiology and Chronic Health Evaluation II score on admission day, and propensity score regarding ketamine use (adjusted OR: 1.09; 95% confdence interval [CI]: 0.49–2.40;P=0.84). Initial serum lactate on ED admission was the only signifcant predictive factor of 28-day mortality (adjusted OR: 1.23; 95% CI: 1.10–1.38; P<0.01). Conclusions. For patients with severe sepsis and septic shock who were intubated using RSI, we found no signifcant diference in 28-day mortality between those who received ketamine as a sedative agent and those who received alternative sedatives

Effects of exercise on myokine gene expression in horse skeletal muscles

Objective To examine the regulatory effects of exercise on myokine expression in horse skeletal muscle cells, we compared the expression of several myokine genes (interleukin 6 [IL-6], IL-8, chemokine [C-X-C motif] ligand 2 [CXCL2], and chemokine [C-C motif] ligand 4 [CCL4]) after a single bout of exercise in horses. Furthermore, to establish in vitro systems for the validation of exercise effects, we cultured horse skeletal muscle cells and confirmed the expression of these genes after treatment with hydrogen peroxide. Methods The mRNA expression of IL-6, IL-8, CXCL2, and CCL4 after exercise in skeletal muscle tissue was confirmed using quantitative-reverse transcriptase polymerase chain reactions (qRT-PCR). We then extracted horse muscle cells from the skeletal muscle tissue of a neonatal Thoroughbred. Myokine expression after hydrogen peroxide treatments was confirmed using qRT-PCR in horse skeletal muscle cells. Results IL-6, IL-8, CXCL2, and CCL4 expression in Thoroughbred and Jeju horse skeletal muscles significantly increased after exercise. We stably maintained horse skeletal muscle cells in culture and confirmed the expression of the myogenic marker, myoblast determination protein (MyoD). Moreover, myokine expression was validated using hydrogen peroxide (H2O2)-treated horse skeletal muscle cells. The patterns of myokine expression in muscle cells were found to be similar to those observed in skeletal muscle tissue. Conclusion We confirmed that several myokines involved in inflammation were induced by exercise in horse skeletal muscle tissue. In addition, we successfully cultured horse skeletal muscle cells and established an in vitro system to validate associated gene expression and function. This study will provide a valuable system for studying the function of exercise-related genes in the future

SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19

Epidemiologic trends of patients who visited nationwide emergency departments: a report from the National Emergency Department Information System (NEDIS) of Korea, 2018–2022

Objective This study analyzed trends in emergency department (ED) visits in Korea using the National Emergency Department Information System (NEDIS) data from 2018 to 2022. Methods This was a retrospective observational study using data from the NEDIS database from 2018 to 2022. Age- and sex-standardized ED visits per 100,000 population, as well as age- and sex-standardized rates for mortality, admission, and transfer, were calculated. Results The standardized ED visits per 100,000 population was approximately 20,000 from 2018 to 2019 and decreased to about 18,000 in 2022. The standardized mortality rate ranged from 1.4% to 1.7%. The admission rate (18.4%–19.4%) and the transfer rates (1.6%–1.8%) were similar during the study period. Approximately 5.5% of patients were triaged as Korean Triage and Acuity Scale score 1 or 2. About 91% of patients visited the ED directly and 21.7% of patients visited the ED with an ambulance. The ED length of stay was less than 6 hours in 90.3% of patients and the ED mortality rate was 0.6%. Acute gastroenteritis was the most common diagnosis. Respiratory virus symptoms, such as fever and sore throat, were also common chief complaints. Conclusion ED visits decreased during the 5-year period, while admission, transfer, and death rates remained relatively stable

Heart Transplantation in Pediatric Patients: Twelve-Year Experience of the Asan Medical Center

Heart transplantation is a standard treatment for end-stage heart disease. Pediatric heart transplantation, however, is not frequently performed due to the shortage of pediatric heart donors. This is the first report of pediatric heart transplantation in Korea. Our retrospective study included 37 patients younger than 18 yr of age who underwent heart transplantation at Asan Medical Center between August 1997 and April 2009. Preoperative diagnosis was either cardiomyopathy (n = 29, 78.3%) or congenital heart disease (n = 8, 22.7%). Mean follow up period was 56.9 ± 44.6 months. There were no early death, but 7 late deaths (7/37, 18.9%) due to rejection after 11, 15, 41 months (n = 3), infection after 5, 8, 10 months (n = 3), suspicious ventricular arrhythmia after 50 months (n = 1). There was no significant risk factor for survival. There were 25 rejections (25/37, 67.6%); less than grade II occurred in 17 patients (17/25, 68%) and more than grade II occurred in 8 patients (8/25, 32%). Actuarial 1, 5, and 10 yr survival was 88.6%, 76.8%, and 76.8%. Our midterm survival of pediatric heart transplantation showed excellent results. We hope this result could be an encouraging message to do more pediatric heart transplantation in Korean society

Modified cardiovascular SOFA score in sepsis: development and internal and external validation

Background : The Sepsis-3 criteria introduced the system that uses the Sequential Organ-Failure Assessment (SOFA) score to define sepsis. The cardiovascular SOFA (CV SOFA) scoring system needs modification due to the change in guideline-recommended vasopressors. In this study, we aimed to develop and to validate the modified CV SOFA score. Methods : We developed, internally validated, and externally validated the modified CV SOFA score using the suspected infection cohort, sepsis cohort, and septic shock cohort. The primary outcome was 28-day mortality. The modified CV SOFA score system was constructed with consideration of the recently recommended use of the vasopressor norepinephrine with or without lactate level. The predictive validity of the modified SOFA score was evaluated by the discrimination for the primary outcome. Discrimination was assessed using the area under the receiver operating characteristics curve (AUC). Calibration was assessed using the calibration curve. We compared the prognostic performance of the original CV/total SOFA score and the modified CV/total SOFA score to detect mortality in patients with suspected infection, sepsis, or septic shock. Results : We identified 7,393 patients in the suspected cohort, 4038 patients in the sepsis cohort, and 3,107 patients in the septic shock cohort in seven Korean emergency departments (EDs). The 28-day mortality rates were 7.9%, 21.4%, and 20.5%, respectively, in the suspected infection, sepsis, and septic shock cohorts. The model performance is higher when vasopressor and lactate were used in combination than the vasopressor only used model. The modified CV/total SOFA score was well-developed and internally and externally validated in terms of discrimination and calibration. Predictive validity of the modified CV SOFA was significantly higher than that of the original CV SOFA in the development set (0.682 vs 0.624, p < 0.001), test set (0.716 vs 0.638), and all other cohorts (0.648 vs 0.557, 0.674 vs 0.589). Calibration was modest. In the suspected infection cohort, the modified model classified more patients to sepsis (66.0 vs 62.5%) and identified more patients at risk of septic mortality than the SOFA score (92.6 vs 89.5%). Conclusions : Among ED patients with suspected infection, sepsis, and septic shock, the newly-developed modified CV/total SOFA score had higher predictive validity and identified more patients at risk of septic mortality.National Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF2020R1A2C3004508) to Kyuseok Kim. National Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF2020R1F1A1052908) to Tae Gun Shin