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Hypoxia is an effective preconditioning stimulus and many cellular responses to hypoxia are mediated through a transcription control complex termed the hypoxia-inducible factor (HIF). The stability and activation of HIF are governed by HIF prolyl-4-hydroxylases 2 (PHD2). Hence, the development of a small molecule inhibitor for prolyl hydroxylase has been suggested as a potentially useful therapeutic strategy for the treatment of oxidative/ischemic stress conditions. Thus, to unveil a novel human PHD2 inhibitor, a custom-based virtual screening was carried out to identify the potential inhibitors against PHD2 based on; (1) the per-residue energy decomposition (PRED)-based pharmacophore model, (2) molecular docking, and (3) MD approaches. The PRED analysis was performed to identify the common interaction pattern of HIF fragment (5L9B) and crystallized ligand (4JZR) to develop a relevant accurate allosteric pharmacophore model. The custom pharmacophore model (AAARR) was developed and further used to screen multiple databases. The docking was performed as a secondary strategy for screening the pharmacophore hits. Furthermore, the docked complexes were screened by molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM-GBSA) based binding free energy calculations to determine the binding energy of the inhibitors and to identify crucial interaction energy fingerprint. One hit has demonstrated good binding free energy and a better binding affinity for PHD2 compared to the other four selected ligands. Thus, the results obtained from pharmacophore, docking, and MD simulations depicted that linker length and metal binding in the scaffold could be effectively used as a potent inhibitor toward human PHD2 in AD therapeutics.

To develop a simplified MRI-based model to predict the risk for positive surgical margins (PSMs) after radical prostatectomy (RP) in patients with prostate cancer (PCa). Consecutive patients who underwent RP for PCa were retrospectively identified from a tertiary referral hospital. Patients who underwent RP between January 2014 and June 2014 were assigned as derivation cohort (n = 330) and those between January 2018 and February 2018 were assigned as validation cohort (n = 100). MRI-based predictors associated with PSM were assessed: tumor size, tumor-capsule contact length, the Prostate Imaging Reporting and Data System (PI-RADS) category, tumor location (tumor contact to the apex or posterolateral side near the neurovascular bundle), apical depth, and prostate volume. A prediction model was developed by using multivariable logistic regression, and then it was transformed into a scoring system. The prediction and calibration performance of this scoring system was evaluated using the C statistics and Hosmer-Lemeshow goodness-of-fit test. A total of 121 (36.7%) and 32 (32.0%) of patients in the derivation and validation cohorts had PSMs after RP. The scoring system consisted of the following variables: tumor-capsule contact length, PI-RADS category, tumor located at the apex and/or posterolateral side. This scoring system provided good prediction performance for PSM in the derivation (C statistics, 0.80 [95% CI: 0.76, 0.85]) and validation (C statistics, 0.77 [95% CI: 0.68, 0.87]) cohorts, and also showed good calibration in both cohorts (p = 0.83 and 0.86, respectively). An MRI-based scoring system can help estimate the risk of PSM after RP. • An MRI-based scoring system served as a tool to estimate the risk of positive surgical margin (C statistics, 0.80 and 0.77 in the derivation and validation cohorts, respectively) after radical prostatectomy. • Tumor with contact to the apex or posterolateral aspect, the tumor contact length to capsule, and higher PI-RADS category were independent predictors for the presence of positive resection margins after radical prostatectomy in men with prostate cancer. • High-risk patients as determined by the scoring system demonstrated adverse post-surgical outcomes compared with low- or intermediate-risk patients, in regard to longer length (mean length, 13.0 mm versus 3.9 mm in low risk or 6.2 mm in intermediate risk; p ≤ 0.001) and higher Gleason grade at the margin (grades 4 and 5 in 69.4% and 20.4% versus 16.7% and 16.7% in low risk or 46.7% and 5.4% in intermediate risk; p < 0.001).

Background: This study compared the treatment outcomes of patients with multidrug-resistant tuberculosis (MDRTB) before and after the implementation of public-private mix (PPM). Factors affecting treatment success were also investigated. Methods: Data from culture-confirmed pulmonary MDR-TB patients who commenced MDR-TB treatment at Pusan National University Hospital between January 2003 and December 2017 were retrospectively reviewed. Patients were divided into two groups in terms of PPM status: pre-PPM period, patients who commenced MDR-TB treatment between 2003 and 2010; and post-PPM period, patients treated between 2011 and 2017. Results: A total of 176 patients were included (64 and 112 in the pre- and post-PPM periods, respectively). 36.9% of the patients were resistant to a fluoroquinolone or a second-line injectable drug, or both. The overall treatment success rate was 72.7%. The success rate of post-PPM patients was higher than that of pre-PPM patients (79.5% vs. 60.9%, p=0.008). Also, loss to follow-up was lower in the post-PPM period (5.4% vs. 15.6%, p=0.023). In multivariate regression analysis, age ≥65 years, body mass index ≤18.5 kg/m2, previous TB treatment, bilateral lung involvement, and extensively drug-resistant (XDR)- or pre-XDR-TB were associated with poorer treatment outcomes. However, the use of bedaquiline or delamanid for ≥1 month increased the treatment success. Conclusion: The treatment success rate in MDR-TB patients was higher in the post-PPM period than in the pre-PPM period, particularly because of the low rate of loss to follow-up. To ensure comprehensive patient-centered PPM in South Korea, investment and other support must be adequate.

Although obesity is associated with numerous diseases, the risks of disease may depend on metabolic health. Associations between the gut microbiota, obesity, and metabolic syndrome have been reported, but differences in microbiomes according to metabolic health in the obese population have not been explored in previous studies. Here, we investigated the composition of gut microbiota according to metabolic health status in obese and overweight subjects. A total of 747 overweight or obese adults were categorized by metabolic health status, and their fecal microbiota were profiled using 16S ribosomal RNA gene sequencing. We classified these adults into a metabolically healthy group (MH, N = 317) without any components of metabolic syndrome or a metabolically unhealthy group (MU, N = 430) defined as having at least one metabolic abnormality. The phylogenetic and non-phylogenetic alpha diversity for gut microbiota were lower in the MU group than the MH group, and there were significant differences in gut microbiota bacterial composition between the two groups. We found that the genus Oscillospira and the family Coriobacteriaceae were associated with good metabolic health in the overweight and obese populations. This is the first report to describe gut microbial diversity and composition in metabolically healthy and unhealthy overweight and obese individuals. Modulation of the gut microbiome may help prevent metabolic abnormalities in the obese population.

Background Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. Method 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. Results Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq. Conclusions [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

Burkholderia cepacia is an opportunistic pathogen that infects patients with debilitating underlying diseases. This study investigated the production of outer membrane vesicles (OMVs) by B. cepacia cultured with sub-minimum inhibitory concentrations (MICs) of antibiotics and examined their pathogenic roles both in vitro and in vivo. B. cepacia ATCC 25416 produced more OMVs under antibiotic stress conditions than controls. OMVs isolated from B. cepacia cultured in Luria-Bertani (LB) broth (OMVs/LB) induced cytotoxicity and the expression of pro-inflammatory cytokine genes in A549 cells in a dose-dependent manner. Host cell cytotoxicity and pro-inflammatory responses were significantly higher in A549 cells treated with B. cepacia OMVs cultured with 1/4 MIC of ceftazidime (OMVs/CAZ) than in the cells treated with OMVs/LB, OMVs cultured with 1/4 MIC of trimethoprim/sulfamethoxazole (OMVs/SXT), or OMVs cultured with 1/4 MIC of meropenem. Intratracheal injection of B. cepacia OMVs also induced histopathology in vivo in mouse lungs. Expressions of IL-1β and TNF-α genes were significantly up-regulatedin the lungs of mice treated with OMVs/CAZ compared to mice administered other OMVs; the expression of the GRO-α gene, however, was significantly up-regulated in OMVs/SXT. In conclusion, OMVs produced by B. cepacia under different antibiotic stress conditions induce different host responses that may contribute to the pathogenesis of B. cepacia.

To investigate whether the detection of clinically significant prostate cancer (csPCa) and the added value of focal saturation biopsy and systematic biopsy (SBx) differ according to index lesion size, and to compare the current guidelines for csPCa detection.This retrospective study included consecutive men who underwent MRI and subsequent SBx and MRI-targeted biopsy (TBx) for a suspicious lesion between April 2019 and February 2020. Lesion visibility on transrectal ultrasound (US) and added value of focal saturation biopsy and SBx were compared according to index lesion size using chi-square and McNemar tests. csPCa detection rates and the proportion of biopsy-indicated men were compared among four biopsy strategies based on current guidelines.Of 313 men evaluated (median age, 65; interquartile range 60‒71), csPCa was detected in 110 (35%). In lesions 10 mm, greater US invisibility (42.7% of lesions 10 mm versus 20.0% of lesions ≥ 10 mm; p 0.001) and higher added value of focal saturation biopsy and SBx (11.1% and 17.1% in lesions 10 mm versus 4.2% and 6.3% in lesions ≥ 10 mm) were observed, compared with lesions ≥ 10 mm. Consideration of prostate-specific antigen (PSA) density 0.15 ng/mL/mL as a cutoff in unsuspicious MRI led to a 14% reduction (44/313) in men who needed biopsy.Determination of the biopsy strategy in terms of the need for focal saturation biopsy or SBx should be made considering lesion size. The use of PSA density in non-suspicious MRI can lead to a reduction in biopsy-indicated men.

Alzheimer’s disease (AD) is the most common dementia in late life memory related issues. It is estimated that worldwide 46.8 million people suffer from dementia. The hypoxia inducible factor (HIF) ...

In recent years, pharmacophore modeling and molecular docking approaches have been extensively used to characterize the structural requirements and explore the conformational space of a ligand in the binding pocket of the selected target protein. Herein, we report a pharmacophore modeling and molecular docking of 45 compounds comprising of the indole scaffold as vitamin D receptor (VDR) inhibitors. Based on the selected best hypothesis (DRRRR.61), an atom-based three-dimensional quantitative structure-activity relationships model was developed to rationalize the structural requirement of biological activity modulating components. The developed model predicted the binding affinity for the training set and test set with R2 (training) = 0.8869 and R2 (test) = 0.8139, respectively. Furthermore, molecular docking and dynamics simulation were performed to understand the underpinning of binding interaction and stability of selected VDR inhibitors in the binding pocket. In conclusion, the results presented here, in the form of functional and structural data, agreed well with the proposed pharmacophores and provide further insights into the development of novel VDR inhibitors with better activity.

Rationale: Unlike traditional biopsy, liquid biopsy, which is a largely non-invasive diagnostic and monitoring tool, can be performed more frequently to better track tumors and mutations over time and to validate the efficiency of a cancer treatment. Circulating tumor cells (CTCs) are considered promising liquid biopsy biomarkers; however, their use in clinical settings is limited by high costs and a low throughput of standard platforms for CTC enumeration and analysis. In this study, we used a label-free, high-throughput method for CTC isolation directly from whole blood of patients using a standalone, clinical setting-friendly platform. Methods: A CTC-based liquid biopsy approach was used to examine the efficacy of therapy and emergent drug resistance via longitudinal monitoring of CTC counts, DNA mutations, and single-cell-level gene expression in a prospective cohort of 40 patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Results: The change ratio of the CTC counts was associated with tumor response, detected by CT scan, while the baseline CTC counts did not show association with progression-free survival or overall survival. We achieved a 100% concordance rate for the detection of EGFR mutation, including emergence of T790M, between tumor tissue and CTCs. More importantly, our data revealed the importance of the analysis of the epithelial/mesenchymal signature of individual pretreatment CTCs to predict drug responsiveness in patients. Conclusion: The fluid-assisted separation technology disc platform enables serial monitoring of CTC counts, DNA mutations, as well as unbiased molecular characterization of individual CTCs associated with tumor progression during targeted therapy.

Background Acinetobacter baumannii is an important opportunistic pathogen responsible for various nosocomial infections. The BfmRS two-component system plays a role in pathogenesis and antimicrobial resistance of A. baumannii via regulation of bacterial envelope structures. This study investigated the role of the sensor kinase, BfmS, in localization of outer membrane protein A (OmpA) in the outer membrane and production of outer membrane vesicles (OMVs) using wild-type A. baumannii ATCC 17978, ΔbfmS mutant, and bfmS-complemented strains. Results The ΔbfmS mutant showed hypermucoid phenotype in the culture plates, growth retardation under static culture conditions, and reduced susceptibility to aztreonam and colistin compared to the wild-type strain. The ΔbfmS mutant produced less OmpA in the outer membrane but released more OmpA via OMVs than the wild-type strain, even though expression of ompA and its protein production were not different between the two strains. The ΔbfmS mutant produced 2.35 times more OMV particles and 4.46 times more OMV proteins than the wild-type stain. The ΔbfmS mutant OMVs were more cytotoxic towards A549 cells than wild-type strain OMVs. Conclusions The present study demonstrates that BfmS controls production of OMVs in A. baumannii. Moreover, BfmS negatively regulates antimicrobial resistance of A. baumannii and OMV-mediated host cell cytotoxicity. Our results indicate that BfmS negatively controls the pathogenic traits of A. baumannii via cell envelope structures and OMV production.

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Objectives Immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor-1 and its ligand have achieved impressive success in treating patients with advanced-stage non-small cell lung cancer (NSCLC) after failed first-line cytotoxic chemotherapy. However, knowledge on clinical biomarkers that could help select patients who will respond well to second-line ICI therapy is limited. Patients and methods Medical records of patients with NSCLC treated with first-line platinum-based chemotherapy and subsequent second-line ICI were collected from 6 medical centers between January 2018 and June 2020. Clinical information, pathologic variables, and radiologic findings of the data collected were reviewed. The patients were followed up until the date of the last visit, the death of any cause, or the end of data recording (December 31, 2020). Results A total of 181 patients with NSCLC were treated with second-line ICI following first-line platinum-based doublet chemotherapy. The median progression-free survival was 2.0 months (interquartile range, 1.0 to 5.5 mo), and the median overall survival was 12.0 months (interquartile range, 6.0 to 20.0 mo). Low body mass index (BMI) was independently associated with progression-free survival (odds ratio [OR], 0.826; 95% confidence interval [CI], 0.723-0.945; P=0.005). Similarly, a low BMI (OR, 0.839; 95% CI, 0.740-0.952; P=0.005) and a high number of metastatic organs (OR, 1.682; 95% CI, 1.156-2.448; P=0.007) were independently associated with the overall survival after second-line ICI therapy. Conclusion BMI and the number of metastatic sites were significantly associated with second-line ICI therapy outcomes in patients with NSCLC receiving first-line platinum-based chemotherapy.

The British Thoracic Society guidelines recommend observation for patients with asymptomatic malignant pleural effusion (MPE). However, asymptomatic MPE can become symptomatic. This study examined the clinical course of asymptomatic MPE in patients with non-small cell lung cancer (NSCLC), including the incidence and timing of symptom development of asymptomatic MPE and the associated factors. Retrospective data of 4822 NSCLC patients between January 2012 and December 2017 were reviewed. Symptom development of asymptomatic MPE was defined as the development of symptoms requiring additional treatment, such as insertion of a chest tube, within 1 year in patients who lacked MPE symptoms at the time of diagnosis. Clinical information, pathological parameters, and radiological characteristics were reviewed. Patient data up to 1 year from the initial diagnosis were reviewed. Of 113 patients with asymptomatic MPE, 46 (41%) became symptomatic within 1 year despite appropriate anticancer treatment. The median time to symptom development was 4 months, and 38 patients (83%) developed symptoms within 6 months. Multivariate logistic regression showed that female sex (odds ratio [OR], 0.256; 95% confidence interval [CI], 0.101–0.649; P = .004) and the depth of pleural effusion on initial computed tomography (CT) (OR, 0.957; 95% CI, 0.932–0.982; P = .001) were independently associated with symptom development of asymptomatic MPE. A fraction of 41% of patients with asymptomatic MPE became symptomatic within 1 year. Female sex and larger MPE on initial CT were independently associated with symptom development of asymptomatic MPE.

Purpose Colistin resistance in gram-negative bacteria from humans and livestock has been increasingly reported worldwide. The aim of this study was to investigate the underlying mechanisms of chromosome-mediated colistin resistance in Escherichia coli isolates from livestock in Korea. Materials and methods Thirty mcr-1-negative isolates were selected from a collection of colistin-resistant E. coli isolates collected from livestock in 2005 and 2015 in Korea. Amino acid alterations in PmrAB, PhoPQ, MgrB, and PmrD were investigated. Colistin-resistant derivatives were produced by serial passage of colistin-susceptible E. coli isolates in colistin-containing media. Results Thirty colistin-resistant mcr-negative E. coli isolates were classified into 26 sequence types. Twenty-two isolates carried diverse amino acid alterations in PmrB, PhoP, PhoQ, MgrB, and/or PmrD, whereas no mutation in any of these genes was found in the remaining eight isolates. Sixteen out of the 22 isolates shared a total of nine polymorphic positions that were found in colistin-susceptible E. coli strains. Colistin-resistant derivatives from two colistin-susceptible isolates showed the same genetic alterations that were observed in colistin-resistant clinical isolates. Conclusion Our results suggest that the mechanism underlying chromosome-mediated colistin resistance remain to be discovered in E. coli. Selective pressure of colistin in vitro induced the same genetic mutations associated with colistin resistance in vivo. Efforts to reduce colistin consumption in livestock should be redoubled, to prevent the occurrence of colistin-resistant E. coli strains.

Background The presence of EGFR mutation in patients with advanced non-small cell lung cancer (NSCLC) plays an important role in determining the appropriate treatment, response, and survival. Therefore, this study attempted to predict the prognosis of NSCLC patients using data from quantitative mutation measurements. Methods The data of patients with advanced NSCLC who underwent EGFR mutation testing using the peptide nucleic acid (PNA) mediated clamping method at the Pusan National University Hospital from October 2015 to December 2017 were retrospectively analyzed. The efficiency of PNA clamping was determined by measuring the threshold cycle (Ct ) value. The ΔCt -1 value (standard Ct value minus sample Ct value) was calculated to quantify EGFR mutation. Results During the study period, 71 patients were treated with EGFR-tyrosine kinase inhibitors. The cutoff point for the ΔCt -1 value derived from the receiver operating characteristic curve was 5.32. A survival benefit was observed in the group with an ΔCt -1 value > 5.32 or with a common EGFR mutation type compared to the group with an ΔCt -1 value Conclusion EGFR mutation testing using PNA clamping may predict patient survival, especially in patients with common EGFR mutations, such as exon 19 deletion or L858R. A higher ΔCt -1 value correlates with better survival.

Previous studies have reported that silicon (Si) has a positive effect on bone health, immune response, and cognitive health. However, basic and important studies on evaluating dietary intake and urinary excretion of Si are limited. The aim of this study was to evaluate dietary Si intake and urinary excretion according to gender and age in healthy and free-living Korean adults and to investigate the relationship between them with gender. In this cross-sectional study, anthropometric measurements, dietary assessment using a food record, and a 24-h urine collection were conducted in 80 healthy Korean adults (40 males and 40 females; groups of 8 subjects representing each decade of life [20s to 60s]) with self-selected diet. The dietary assessment and 24-h urine collection were performed twice at intervals of 3 days. Daily intake of Si was estimated using a Si database of food composition. Urinary excretion of Si was analyzed using ICP-OES. The mean dietary Si intake was 22.8 mg/day for men and 19.3 mg/day for women without significant difference according to their gender and age. Si intake was the highest from vegetables both in men and women, followed by grains, beverages, and fruits in men and by grains, fruits, and milks in women. Urinary Si excretion was significantly higher in men (9.8 mg/day) than women (9.3 mg/day), and significantly increased with age only in women. Regarding the relationship between dietary Si intake and urinary Si excretion, a significantly positive correlation was found in men, but not in women. Longitudinal and balance studies to elucidate gender differences in Si nutrition are needed.

Extracellular vesicles (EVs) that circulate in body fluids possess significant potential for disease diagnosis. Their use in clinical settings, however, has been limited owing to lack of simple and robust isolation methods. To rectify this problem, a centrifugal device for automatic, fast, and efficient isolation of EVs from whole-blood, called Exodisc-B is presented in this paper. Methods: The device comprises a built-in chamber to facilitate plasma separation and two nanoporous filters—one for removing larger particles and the other for enriching EVs. The performance of the device in comparison to ultracentrifugation (UC) was evaluated by analyzing the yield, purity, protein and RNA content of the isolated EVs. Additionally, the EV protein marker expressions were measured by ELISA and statistically analyzed to differentiate prostate cancer patients from healthy donors. Results: Compared with the UC technique, the proposed device is capable of isolating at least an order of magnitude higher number of EVs with about 30-fold higher mRNA count within 40 min. Sandwich ELISA of EV-specific membrane proteins—CD9-CD81—confirmed that Exodisc-B can isolate EVs from a volume of whole blood as low as 30 µL with a capture efficiency exceeding 75%. The device also facilitates temporal monitoring of tumor progression within live mouse xenograft models over a period of 13 weeks while using minimal volumes of weekly collected blood samples. Further, in ELISA analyses of multiple cancer-related proteins, such as prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor 1 (EGFR1), and heat shock protein 90 (HSP90), extracted from EVs isolated from human plasma, 43 patients were differentiated from 30 healthy donors. Conclusion: The results demonstrated the ability of Exodisc-B to provide a rapid, sensitive, and point-of-care-type method for extracting intact EVs from small volumes of clinical blood samples for disease diagnosis and monitoring.

Background and objectives: Cardiac tamponade is potentially fatal medical condition, which rarely occurs as a complication of lung lobectomy. We present the first case of cardiac tamponade to develop in a Post-Anesthesia Care Unit following a lung lobectomy. Case report: A 54-year-old man with pulmonary squamous cell carcinoma underwent an apparently uncomplicated lung lobectomy. His hemodynamics was unremarkable throughout the surgery and initially in the Post-Anesthesia Care Unit. However, after 5 min in the Post-Anesthesia Care Unit, he suddenly became hypotensive and dyspneic. He responded poorly to inotropics and fluid resuscitation. Transesophageal echocardiography conducted by an anesthesiologist who suspected a cardiac etiology revealed a pericardial effusion compressing the heart. After a failed attempt of pericardiocentesis, an emergency pericardial window operation was performed. The patient improved dramatically once the heart was decompressed. Conclusion: Since cardiac tamponade is generally not suspected as a cause of hemodynamic instability after a lung lobectomy, as it was in this case, a misdiagnosis of the patient's condition may have led to improper management resulting in death. As anesthesiologists are often involved in the initial resuscitation of morbid patients in Post-Anesthesia Care Units, their acquaintance with various postoperative complications and competence in echocardiography for assessing cardiac problems may contribute to patient survival. Resumo: Justificativa e objetivos: O tamponamento cardíaco é uma condição médica potencialmente fatal, cuja ocorrência como uma complicação da lobectomia pulmonar é muito rara. Apresentamos o primeiro caso de tamponamento cardíaco desencadeado na sala de recuperação pós-anestésica (SRPA) após uma lobectomia pulmonar. Relato de caso: Paciente do sexo masculino, 54 anos, com carcinoma de células escamosas pulmonares, submetido à lobectomia pulmonar aparentemente sem complicações. Sua hemodinâmica não apresentou alteração durante toda a cirurgia e também inicialmente na sala de resuperação pós-anestésica. Porém, após cinco minutos na SRPA, o paciente apresentou hipotensão e dispneia de forma repentina e respondeu mal ao inotrópico e à reanimação hídrica. Uma ecocardiografia transesofágica feita por um anestesiologista que suspeitou de etiologia cardíaca revelou um derrame pericárdico que comprimia o coração. Após tentativa malsucedida de pericardiocentese, foi feita uma janela pericárdica de emergência. O paciente apresentou melhora dramática com a descompressão do coração. Conclusão: Como o tamponamento cardíaco geralmente não é suspeito como causa de instabilidade hemodinâmica após lobectomia pulmonar, como ocorreu neste caso, um diagnóstico errado da condição do paciente poderia ter levado a um manejo inadequado, que resultaria em morte. Como os anestesiologistas estão frequentemente envolvidos na reanimação inicial de pacientes debilitados em salas de recuperação pós-anestésica, seu conhecimento de várias complicações pós-operatórias e competência na ecocardiografia para avaliar problemas cardíacos podem contribuir para a sobrevivência do paciente. Keywords: Cardiac tamponade, Echocardiography, Transesophageal, Pneumonectomy, Anesthesia recovery period, Palavras-chave: Tamponamento cardíaco, Ecocardiografia, Transesofágica, Pneumonectomia, Recuperação pós-anestésica

In this study, biofilm inactivation potential of micro-plasma discharged water (m-PDW), a commercially available water purifier known as EP purification, was evaluated. Bacterial strains were collected from the various contaminated area of tofu manufacturing industry, overall 15 different types of bacterial strains were isolated and their biofilm formation ability was determined by using crystal violet (CV) staining. Three different strains (20% of the isolated strains), namely, Brevundimonas naejangsanensis, Delfita lacustris and Lactococcus lactis, with biofilm density (OD590) > 0.4, were identified as biofilm-producing strains. These three biofilm-producing strains were used to form biofilm on stainless steel (SS) coupons in a laboratory condition for four days and the biofilm containing coupons were treated with EP purification device. The inactivation obtained after 40 min of treatment was 4.8 and 4.2 log CFU/coupon for Brevundimonas naejangsanensis and Delfita lacustris, respectively, whereas no viable count was detected for Lactococcus lactis after the same treatment time. Biofilm reduction effects of m-PDW treatment differ according to biofilm-producing ability or strain characteristics. SEI (Secondary Electron Images) was obtained by field emission scanning electron microscope (FE-SEM) that showed m-PDW treatment has significant reduction potential on biofilm inactivation for the sample collected from tofu manufacturing industry.

Resumo Justificativa e objetivos O tamponamento cardiaco e uma condicao medica potencialmente fatal, cuja ocorrencia como uma complicacao da lobectomia pulmonar e muito rara. Apresentamos o primeiro caso de tamponamento cardiaco desencadeado na sala de recuperacao pos‐anestesica (SRPA) apos uma lobectomia pulmonar. Relato de caso Paciente do sexo masculino, 54 anos, com carcinoma de celulas escamosas pulmonares, submetido a lobectomia pulmonar aparentemente sem complicacoes. Sua hemodinâmica nao apresentou alteracao durante toda a cirurgia e tambem inicialmente na sala de recuperacao pos‐anestesica. Porem, apos cinco minutos na SRPA, o paciente apresentou hipotensao e dispneia de forma repentina e respondeu mal ao inotropico e a reanimacao hidrica. Uma ecocardiografia transesofagica feita por um anestesiologista que suspeitou de etiologia cardiaca revelou um derrame pericardico que comprimia o coracao. Apos tentativa malsucedida de pericardiocentese, foi feita uma janela pericardica de emergencia. O paciente apresentou melhoria dramatica com a descompressao do coracao. Conclusao Como o tamponamento cardiaco geralmente nao e suspeito como causa de instabilidade hemodinâmica apos lobectomia pulmonar, como ocorreu neste caso, um diagnostico errado da condicao do paciente poderia ter levado a um manejo inadequado, que resultaria em morte. Como os anestesiologistas estao frequentemente envolvidos na reanimacao inicial de pacientes debilitados em salas de recuperacao pos-anestesica, seu conhecimento de varias complicacoes pos‐operatorias e competencia na ecocardiografia para avaliar problemas cardiacos podem contribuir para a sobrevivencia do paciente.

Intestinal commensal bacteria are considered good indicators for monitoring antimicrobial resistance. We investigated the antimicrobial resistance profiles and resistance trends of Enterococcus faecium and Enterococcus faecalis isolated from food animals in Korea between 2010 and 2019. E. faecium and E. faecalis, isolated from chickens and pigs, respectively, presented a relatively high resistance rate to most of the tested antimicrobials. We observed high ciprofloxacin (67.9%), tetracycline (61.7%), erythromycin (59.5%), and tylosin (53.0%) resistance in E. faecium isolated from chickens. Similarly, more than half of the E. faecalis isolates from pigs and chickens were resistant to erythromycin, tetracycline and tylosin. Notably, we observed ampicillin, daptomycin, tigecycline and linezolid resistance in a relatively small proportion of enterococcal isolates. Additionally, the enterococcal strains exhibited an increasing but fluctuating resistance trend (p &lt, 0.05) to some of the tested antimicrobials including daptomycin and/or linezolid. E. faecalis showed higher Multidrug resistance (MDR) rates than E. faecium in cattle (19.7% vs. 8.6%, respectively) and pigs (63.6% vs. 15.6%, respectively), whereas a comparable MDR rate (≈60.0%) was noted in E. faecium and E. faecalis isolated from chickens. Collectively, the presence of antimicrobial-resistant Enterococcus in food animals poses a potential risk to public health.

Background The Prostate Imaging Reporting and Data System (PI-RADS) was introduced in 2012 and updated to version 2.1 (v2.1) in early 2019 to improve diagnostic performance and interreader reliability. Purpose To evaluate the diagnostic performance of PI-RADS v2.1 in comparison with v2. Methods A systematic review and meta-analysis of the literature was performed using MEDLINE, EMBASE, and Cochrane databases to identify studies evaluating the diagnostic performance of PI-RADS v2.1 for diagnosing clinically significant prostate cancer (csPCa). Study type Systematic review and meta-analysis. Subject One thousand two hundred forty-eight patients with 1406 lesions from 10 eligible articles. Field strength/sequence Conventional MR sequences at 1.5 T and 3 T. Assessment Two reviewers independently identified and reviewed the original articles reporting diagnostic performance of PI-RADS v2.1. Statistical tests Meta-analytic summary sensitivity and specificity were calculated using a bivariate random effects model. Meta-analytic sensitivity and specificity between PI-RADS v2 and v2.1 were compared. Results The pooled sensitivity and specificity of PI-RADS v2.1 were 87% (95% confidence intervals, 82-91%) and 74% (63-82%), respectively. In five studies available for a head-to-head comparison between PI-RADS v2.1 and v2, there were no significant differences in either sensitivity (90% [86-94%] vs. 88% [83-93%], respectively) or specificity (76% [59-93%] vs. 61% [39-83%], respectively; P = 0.37). The sensitivity and specificity were 81% (73-87%) and 82% (68-91%), respectively, for a PI-RADS score cutoff of ≥4, and 94% (88-97%) and 56% (35-97%) for ≥3. Regarding the zonal location, the sensitivity and specificity for the transitional zone only were 90% (84-96%) and 76% (62-90%) respectively, whereas for the whole gland they were 85% (79-91%) and 71% (57-85%). Data conclusion PI-RADS v2.1 demonstrated good overall performance for the diagnosis of csPCa. PI-RADS v2.1 tended to show higher specificity than v2, but the difference lacked statistical significance. Level of evidence 3 TECHNICAL EFFICACY STAGE: 3.

BACKGROUND Allergen sensitization and its influence on allergic disease can vary depending on ethnicity and geography. OBJECTIVE To investigate aeroallergen sensitization patterns and their effect on airway hyper-responsiveness (AHR) in Busan, Korea. METHODS We reviewed data for subjects who attended for evaluation of respiratory symptoms between 2011 and 2016. The skin test results of 16 allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, Alternaria, Aspergillus fumigatus, early blossoming tree pollen mix, late blossoming tree pollen mix, alder, birch, oak, grass mix, mugwort, ragweed, and Japanese hop) were analyzed. Age was categorized as group I (15 to < 65 years) or group II (≥ 65 years). RESULTS A total of 2,791 subjects were analyzed (mean age: 50.9 years, female 61.3%). AHR was demonstrated in 15.8%; sputum eosinophilia in 12.1%; and atopy in 31.2%. The most commonly sensitizing allergen was house dust mite (17.4% to D. pteronyssinus and 17.9% to D. farinae), followed by late blossoming tree pollen mix (8.8%) and early blossoming tree pollen mix (8.6%). AHR was associated with sensitization to D. pteronyssinus, D. farina, Alternaria, dog, cat, alder, birch, oak, and mugwort. However, group II did not show any associations between AHR and any of the aeroallergens except D. farina. Multiple logistic regression analyses showed that the independent factors for AHR were ever-smoker status, D. farina, and oak sensitization. CONCLUSIONS Sensitization to house dust mites and tree pollen was found to be common in Busan. These aeroallergens significantly affected AHR, particularly in the younger group.

Background Zinc uptake-regulator (Zur)-regulated lipoprotein A (ZrlA) plays a role in bacterial fitness and overcoming antimicrobial exposure in Acinetobacter baumannii. This study further characterized the zrlA gene and its encoded protein and investigated the roles of the zrlA gene in bacterial morphology, antimicrobial susceptibility, and production of outer membrane vesicles (OMVs) in A. baumannii ATCC 17978. Results In silico and polymerase chain reaction analyses showed that the zrlA gene was conserved among A. baumannii strains with 97–100% sequence homology. Recombinant ZrlA protein exhibited a specific enzymatic activity of D-alanine-D-alanine carboxypeptidase. Wild-type A. baumannii exhibited more morphological heterogeneity than a ΔzrlA mutant strain during stationary phase. The ΔzrlA mutant strain was more susceptible to gentamicin than the wild-type strain. Sizes and protein profiles of OMVs were similar between the wild-type and ΔzrlA mutant strains, but the ΔzrlA mutant strain produced 9.7 times more OMV particles than the wild-type strain. OMVs from the ΔzrlA mutant were more cytotoxic in cultured epithelial cells than OMVs from the wild-type strain. Conclusions The present study demonstrated that A. baumannii ZrlA contributes to bacterial morphogenesis and antimicrobial resistance, but its deletion increases OMV production and OMV-mediated host cell cytotoxicity.

The relatively low specificity and positive predictive value of the Prostate Imaging-Reporting and Data System (PI-RADS) can lead to considerable false-positive results and unnecessary biopsies. The aim of this study was to propose ancillary features (AFs) indicating clinically significant prostate cancer (csPCa) or benign tissues in PI-RADS category ≥3 lesions and determine the usefulness of these AFs in reducing false-positive assessments of suspicious lesions in men at csPCa risk. This was a retrospective study, which included 199 men. A 3T, including turbo spin echo T2 -weighted, echo-planar diffusion-weighted, and spoiled gradient echo dynamic contrast-enhanced (DCE) images, was used. Five AFs (prostate-specific antigen density ≥0.15 ng/mL2 ; size ≥10 mm; heterogeneous T2 signal intensity; circumscribed nodule in the junction of peripheral and transition zone; and DCE time curves) indicating csPCa or non-csPCa were evaluated by three independent readers. The sensitivity and specificity of each AF were calculated. Inter-reader agreement was evaluated using κ statistics. Univariate and multivariate logistic regression analyses were conducted to determine significant AFs. The reduction in positive call rates and csPCa detection rates with combined AF use were calculated and compared with the findings obtained with PI-RADS use alone. The sensitivities and specificities of the AFs indicating csPCa were 72.1%-96.5% and 27.4%-75.2% for reader 1, 66.3%-96.5% and 23.9%-62.0% for reader 2, and 67.4%-96.5% and 34.5%-78.8% for reader 3, with moderate to substantial inter-reader agreement (Fleiss κ, 0.551-0.643). The combined use of two or more AFs for assessing PI-RADS ≥3 lesions resulted in a 19.6%-30.7% reduction in positive calls (p < .05) compared to PI-RADS use alone while preserving the csPCa detection rates (p ≥ .06) for three readers. The use of AFs in combination with PI-RADS can reduce positive calls and false positives without csPCa under-detection.

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. Herein, we studied how to best position the spiro[5.5]undeca ring system in kinase inhibitor space. Notably, late-stage modification of the scaffold 1 into compounds 2a-r enhanced kinase-likeness of the scaffold 1. The improvement could be depicted with (1) selectivity with target shift (from JNK-1 into GSK-3) and (2) potency (> 20-fold). In addition, ATP independent IC50 of compound 2j suggested a unique binding mode of this scaffold between ATP site and substrate site, which was explained by docking based optimal site selection and molecular dynamic simulations of the optimal binding site. Despite the shift of kinase profiling, the anti-inflammatory activity of compounds 2a-r could be retained in hyperactivated microglial cells.

In drug repurposing approaches, the chemically diverse and potentially safe molecules can be explored as therapeutic potential beyond those originally targeted indications. However, accessible information on a limited number of drug pipelines can lead to competitive over-heating issues, and intellectual property rights also restrict the free investigation in chemical space. As a complementary approach to the drawbacks, ring systems of approved drugs (instead of clinical drugs) can be optimized and used for repurposing purposes. In this study, bi-directional target (T) and ring system (R) dual screening (TR screening) was developed for the repurposing of their rarely used ring systems from FDA approved drugs. The TR screening suggested RAR β and cyproheptadine as the best pair of target and ring system to escape a saddle point. The selected ring system was virtually grown and elaborated with the defined criteria: synthesizability, drug-likeness, and docking pose showing the top scores. The achieved compounds were synthesized and biologically tested with an acceptable ADME/T profile.

Altogether, 2547 Staphylococcus aureus isolated from cattle (n = 382), pig (n = 1077), and chicken carcasses (n = 1088) during 2010–2017 were investigated for linezolid resistance and were further characterized using molecular methods. We identified linezolid resistance in only 2.3% of pig carcass isolates. The linezolid-resistant (LR) isolates presented resistance to multiple antimicrobials, including chloramphenicol, clindamycin, and tiamulin. Molecular investigation exhibited no mutations in the 23S ribosomal RNA. Nevertheless, we found mutations in ribosomal proteins rplC (G121A) and rplD (C353T) in one and seven LR strains, respectively. All the LR isolates carried the multi-resistance gene cfr, and six of them co-carried the mecA gene. Additionally, all the LR isolates co-carried the phenicol exporter gene, fexA, and presented a high level of chloramphenicol resistance. LR S. aureus isolates represented 10 genotypes, including major genotypes ST433-t318, ST541-t034, ST5-t002, and ST9-t337. Staphylococcal enterotoxin and leukotoxin-encoding genes, alone or in combination, were detected in 68% of LR isolates. Isolates from different farms presented identical or different pulsed-field gel electrophoresis patterns. Collectively, toxigenic and LR S. aureus strains pose a crisis for public health. This study is the first to describe the mechanism of linezolid resistance in S. aureus isolated from food animal products in Korea.

We studied the presence of the mobile colistin resistance gene mcr-1 in Escherichia coli isolates recovered from fecal and urine samples of companion animals, that were collected from South Korea in 2018 and 2019. The mcr-1 gene was detected in one colistin-resistant E. coli isolated from a diarrheic dog. The isolate exhibited additional resistance to multiple antimicrobials, including fluoroquinolones and third-generation cephalosporins. The mcr-1 carrying isolate belonged to ST160. The pulsed-field gel electrophoresis pattern of our strain differed from those ST160 E. coli strains previously identified from chickens in Korea. The mcr-1 gene was identified in the IncI2 plasmid. It was also transferred to E. coli J53 recipient strain, with a conjugation efficiency of 2.8 × 10−4. Average nucleotide identity analysis demonstrated that the mcr-1-carrying plasmid in this study was closely related to those from patients in Korea. To the best of our knowledge, this is the first report of mcr-1 carrying E. coli from a companion animal in South Korea. Our findings support One Health approach is necessary to prevent the dissemination of this high-risk gene.

We examined the prevalence and molecular characteristics of mcr-3 carrying colistin-resistant Escherichia coli among cattle, pig, and chicken isolates in South Korea. Among a total of 185 colistin-resistant E. coli isolates determined in this study (47 from cattle, 90 from pigs, and 48 from chicken), PCR amplification detected mcr-3 genes in 17 isolates predominantly from diseased pigs. The mcr-3 genes were characterized as mcr-3.1 in 15 isolates and mcr-3.5 in 2 isolates. The mcr-3 gene was transferred to the E. coli J53 recipient strain from more than 50% of the mcr-3-carrying isolates. The mcr-3.1 and mcr-3.5 genes were identified predominantly in IncHI2 and IncP plasmids, respectively. Multi-locus sequence typing analysis revealed eight previously reported sequence types (ST), including ST1, ST10, and ST42. We identified isolates with similar pulsed-field gel electrophoresis patterns from diseased pigs in three farms. Besides, the isolates carried various virulence factors and demonstrated resistance to multiple antimicrobials, including β-lactams and quinolones. Further, the mcr-3.5 encodes three amino acid substitutions compared with mcr-3.1. To the best of our knowledge, this is the first report of pathogenic E. coli carrying mcr-3.5 in South Korea, which implies that mcr-3 variants may have already been widely spread in the pig industry.

Simple Summary Considering the spatiotemporal heterogeneity, more frequent monitoring of the disease progress using less-invasive liquid biopsy technologies is highly desired. Here, we demonstrate that epidermal growth factor receptor (EGFR) mutations could be readily detected from minimally invasive bronchial washing (BW)-derived EVs with good accuracy. The acquisition of T790M resistance mutation was detected earlier in BW-derived EVs than in plasma or tissue samples. The longitudinal analysis of BW-derived EVs showed excellent correlation with the disease progression measured by CT images. We demonstrate the clinical potential of BW-derived EVs as a liquid-biopsy sample for prognosis and precision medicine in patients with lung cancer. Abstract The detection of epidermal growth factor receptor (EGFR) mutation, based on tissue biopsy samples, provides a valuable guideline for the prognosis and precision medicine in patients with lung cancer. In this study, we aimed to examine minimally invasive bronchial washing (BW)-derived extracellular vesicles (EVs) for EGFR mutation analysis in patients with lung cancer. A lab-on-a-disc equipped with a filter with 20-nm pore diameter, Exo-Disc, was used to enrich EVs in BW samples. The overall detection sensitivity of EGFR mutations in 55 BW-derived samples was 89.7% and 31.0% for EV-derived DNA (EV-DNA) and EV-excluded cell free-DNA (EV-X-cfDNA), respectively, with 100% specificity. The detection rate of T790M in 13 matched samples was 61.5%, 10.0%, and 30.8% from BW-derived EV-DNA, plasma-derived cfDNA, and tissue samples, respectively. The acquisition of T790M resistance mutation was detected earlier in BW-derived EVs than plasma or tissue samples. The longitudinal analysis of BW-derived EVs showed excellent correlation with the disease progression measured by CT images. The EGFR mutations can be readily detected in BW-derived EVs, which demonstrates their clinical potential as a liquid-biopsy sample that may aid precise management, including assessment of the treatment response and drug resistance in patients with lung cancer.

In drug discovery, rapid and accurate prediction of protein–ligand binding affinities is a pivotal task for lead optimization with acceptable on-target potency as well as pharmacological efficacy. Furthermore, researchers hope for a high correlation between docking score and pose with key interactive residues, although scoring functions as free energy surrogates of protein–ligand complexes have failed to provide collinearity. Recently, various machine learning or deep learning methods have been proposed to overcome the drawbacks of scoring functions. Despite being highly accurate, their featurization process is complex and the meaning of the embedded features cannot directly be interpreted by human recognition without an additional feature analysis. Here, we propose SMPLIP-Score (Substructural Molecular and Protein–Ligand Interaction Pattern Score), a direct interpretable predictor of absolute binding affinity. Our simple featurization embeds the interaction fingerprint pattern on the ligand-binding site environment and molecular fragments of ligands into an input vectorized matrix for learning layers (random forest or deep neural network). Despite their less complex features than other state-of-the-art models, SMPLIP-Score achieved comparable performance, a Pearson’s correlation coefficient up to 0.80, and a root mean square error up to 1.18 in pK units with several benchmark datasets (PDBbind v.2015, Astex Diverse Set, CSAR NRC HiQ, FEP, PDBbind NMR, and CASF-2016). For this model, generality, predictive power, ranking power, and robustness were examined using direct interpretation of feature matrices for specific targets. Supplementary Information The online version contains supplementary material available at 10.1186/s13321-021-00507-1.

The Prostate Imaging Reporting and Data System (PI-RADS) version 2 (v2) categorizes the likelihood of clinically significant prostate cancer on magnetic resonance imaging and determines the diagnostic pathway. We determined clinically significant prostate cancer and all prostate cancer detection rates in each PI-RADS v2 category.MEDLINE®, EMBASE® and Cochrane databases were searched for prospective studies reporting the detection rates of clinically significant prostate cancer or all prostate cancer. Random effects models were used to determine pooled detection rates of clinically significant prostate cancer and all prostate cancer for each PI-RADS category. The risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2. Meta-regression analysis was performed to identify factors affecting study heterogeneity.Thirteen prospective studies including 4,265 men who underwent magnetic resonance imaging targeted biopsy and/or systematic biopsy for a PI-RADS v2 category 3 or greater, or systematic biopsy for PI-RADS 1-2 were included. The pooled detection rates of clinically significant prostate cancer monotonically increased for each PI-RADS v2 category, ie 4% (95% CI 2-8) for category 1-2, 17% (95% CI 13-21) for category 3, 46% (95% CI 38-55) for category 4 and 75% (95% CI 73-78) for category 5. Substantial study heterogeneity was noted in clinically significant prostate cancer detection rates for categories 1-2 and 4, which were significantly affected by study subject selection (biopsy naïve patients only or not) and studies with a high risk of bias.PI-RADS v2 can be useful for the stratification of the risk of clinically significant prostate cancer in patients at risk for prostate cancer but the limitations in category 4 still remain.

We evaluated interreader agreement with PI-RADS® (Prostate Imaging Reporting and Data System) version 2 for detection of prostate cancer.We searched MEDLINE®, Embase® and the Cochrane Library between 2015 and June 3, 2019 to identify original research reporting interreader agreement in the use of PI-RADS version 2. Quality of the retrieved studies was assessed by 2 independent reviewers using the Guidelines for Reporting Reliability and Agreement Studies. Pooled κ for PI-RADS version 2 was calculated, and a head-to-head comparison with version 1 was performed for the available studies. Subgroup analysis was performed according to zonal anatomy (peripheral or transitional zone), cutoff value (4 or higher, or 3 or higher) and specific imaging sequences (T2-weighted, diffusion-weighted and dynamic contrast enhanced). Meta-regression analysis was performed to assess the cause of study heterogeneity.A total of 30 studies (4,095 patients) were included. Pooled κ of PI-RADS version 2 was 0.61 (95% CI 0.55-0.67). In 4 studies evaluating head-to-head comparisons PI-RADS versions 1 and 2 showed similar pooled κ values (0.61, 95% CI 0.33-0.90 vs 0.68, 95% CI 0.57-0.79; p=0.61). Substantial interreader agreement was noted with a cutoff of 4 or higher (κ=0.61) and moderate agreement was observed with a cutoff of 3 or higher (κ=0.57), peripheral zone (κ=0.64), transitional zone (κ=0.49) and the 3 magnetic resonance imaging sequences (κ 0.42-0.58). Difference in reader experience was the single significant factor affecting study heterogeneity (p=0.01).PI-RADS version 2 provides substantial interreader agreement in overall scoring in patients with suspicious prostate cancer, with a similar level of agreement to version 1.

We identified 199 Staphylococcus aureus isolates from quarter milk samples of 1,289 dairy cattle between 2014 and 2018. About 66% of the isolates were resistant to at least 1 antimicrobial agent; the highest rate of resistance was to penicillin, followed by resistance to ampicillin, erythromycin, and sulfadimethoxine. We obtained 30 methicillin-resistant S. aureus (MRSA) strains from 6 farms in 3 provinces. The MRSA strains exhibited a significantly higher resistance rate to most of the tested antimicrobials than the oxacillin-susceptible strains. The MRSA strains represented 5 genotypes: ST72-t324-SCCmec IV (n = 14), ST30-t1752-SCCmec IV (n = 8), ST188-t189-SCCmec NT (n = 6), ST188-t2284-SCCmec NT (n = 1), and NT-NT-SCCmec IV (n = 1). One of the ST188 MRSA strains represented a novel staphylococcal protein A (spa) type (t2284). In addition, 7 of the 8 ST30 MRSA strains were Panton-Valentine leukocidin (PVL)-positive and carried various staphylococcal enterotoxin encoding genes. This is the first report of PVL-positive ST30 MRSA-t1752-SCCmec IV from bovine mastitis in Korea. All of ST72-t324-SCCmec IV MRSA strains carried staphylococcal enterotoxin and leukotoxin encoding genes. They were also sensitive to most of the tested non-β-lactam antimicrobials. In contrast, ST188-t189 MRSA strains were resistant to multiple antimicrobials and predominantly carried the leukotoxin encoding gene. Taken together, these findings may indicate that dairy cows could be a major source for spreading MRSA strains, and contaminated milk could be a vehicle for transmission. Suitable hygienic measures should be established in dairy farms and processing plants to limit the likelihood of introducing MRSA into the food chain.

3D similarity is useful in predicting the profiles of unprecedented molecular frameworks that are 2D dissimilar to known compounds. When comparing pairs of compounds, 3D similarity of the pairs depends on conformational sampling, the alignment method, the chosen descriptors, and the similarity coefficients. In addition to these four factors, 3D chemocentric target prediction of an unknown compound requires compound&ndash, target associations, which replace compound-to-compound comparisons with compound-to-target comparisons. In this study, quantitative comparison of query compounds to target classes (one-to-group) was achieved via two types of 3D similarity distributions for the respective target class with parameter optimization for the fitting models: (1) maximum likelihood (ML) estimation of queries, and (2) the Gaussian mixture model (GMM) of target classes. While Jaccard&ndash, Tanimoto similarity of query-to-ligand pairs with 3D structures (sampled multi-conformers) can be transformed into query distribution using ML estimation, the ligand pair similarity within each target class can be transformed into a representative distribution of a target class through GMM, which is hyperparameterized via the expectation&ndash, maximization (EM) algorithm. To quantify the discriminativeness of a query ligand against target classes, the Kullback&ndash, Leibler (K&ndash, L) divergence of each query was calculated and compared between targets. 3D similarity-based K&ndash, L divergence together with the probability and the feasibility index, (Fm), showed discriminative power with regard to some query&ndash, class associations. The K&ndash, L divergence of 3D similarity distributions can be an additional method for (1) the rank of the 3D similarity score or (2) the p-value of one 3D similarity distribution to predict the target of unprecedented drug scaffolds.

The gut microbiota has been linked to blood lipids. However, the relationship between the gut microbiome and other lipid markers like apolipoproteins A1 (apoA1) and B (apoB) as well as classical lipid markers in Asians remain unclear. Here, we examined the associations between gut microbial diversity and taxonomic compositions with both apolipoproteins and lipid markers in a large number of Korean patients. The fecal 16S rRNA gene sequencing data from 1141 subjects were analyzed and subjects were categorized into control group (G0) or abnormal group (G1) according to blood lipid measurements. The microbial diversity and several taxa of the gut microbiota were significantly associated with triglyceride, apoA1, and apoB levels, but not with total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. The alpha diversity of the gut microbiota was inversely associated with high triglyceride level. Interestingly, G1 of apoA1 showed increased microbial richness and distinct microbial community compared with G0 of apoA1. A high abundance of Fusobacteria and low abundance of Oscillospira were found in the hypertriglyceridemia group. In this large-scale study, we identified associations of gut microbiota with apolipoproteins and classical lipid markers, indicating that the gut microbiota may be an important target for regulating blood lipids.

Background There are no standardized and well-validated criteria for assessing the risk of extraprostatic extension (EPE) of prostate cancer at preoperative multiparametric MRI. Purpose To compare diagnostic performance, intra- and interreader agreement, and correlations of MRI-based criteria for assessment of EPE after radical prostatectomy, including EPE grade, European Society of Urogenital Radiology (ESUR) score, Likert scale, and capsular contact length (CCL). Materials and Methods This retrospective study included consecutive men who underwent MRI and radical prostatectomy between July 2016 and March 2017. Two genitourinary radiologists independently estimated the probability of EPE by using four MRI-based scoring methods. The diagnostic accuracies and intra- and interobserver agreement were evaluated with area under the receiver operating characteristic curve (AUC) and κ statistics, respectively. Correlations between MRI-based score and histologic extent of EPE were analyzed by using the Spearman correlation coefficient (ρ). Results A total of 301 men (mean age ± standard deviation, 65 years ± 7) were evaluated. A total of 129 (42.9%) men had EPE. The AUC ranges of EPE grade, ESUR score, Likert scale, and CCL for assessment of EPE were 0.77-0.81, 0.79-0.81, 0.78-0.79, and 0.78-0.85, respectively, for the two readers. The Likert scale showed lower sensitivity (68.2% [88 of 129] for reader 1, 72.1% [93 of 129] for reader 2) than did EPE grade (77.5% [100 of 129] for reader 1, 79.8% [103 of 129] for reader 2; P ≤ .04). Intra- and interreader agreement were substantial (κ range, 0.61-0.74) for the four methods, with ESUR score showing the lowest values (κ = 0.61 and κ = 0.63, respectively). EPE grade showed highest correlation with histologic extent of EPE (ρ = 0.53 and ρ = 0.55 for circumferential length; ρ = 0.42 and ρ = 0.55 for radial length for readers 1 and 2, respectively; P < .001). Conclusion Extraprostatic extension (EPE) grade, European Society of Urogenital Radiology score, Likert scale, and capsular contact length showed good overall diagnostic performance; however, the EPE grade resulted in more reliable performance and had the highest correlation with histologic EPE extent. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Padhani and Petralia in this issue.

Malignant melanoma is considered to be a heterogeneous disease that arises from altered genes and transformed melanocytes. In this study, special softjet cold atmospheric plasma was used to treat three different human melanoma cells using air and N2 gases to check the anti-melanoma activity. The physical effects by plasma revealed an increase in the temperature with the gradual reduction in pH at 60 sec, 180 sec and 300 sec air and N2 plasma treatment. Cellular toxicity revealed a decreased in cell survival (~50% cell survival using air gas and 2 gas at 60 sec plasma treatment in G-361 cells). Gene analysis by q-PCR revealed that 3 min and 5 min air and N2 plasma treatment activated apoptotic pathways by triggering apoptotic genes in all three melanoma cell lines. The apoptosis was confirmed by DAPI staining and its related pathways were further explored according to protein-protein docking, and their probable activation mechanism was revealed. The pathways highlighted that activation of apoptosis which leads to cellular cascades and hence stimulation ASK1 (docking method) revealed that softjet plasma can be an effective modality for human melanoma treatment.

Silicon (Si) is important for the growth and development of bone and connective tissues. This study aimed to evaluate the effect of Si supplementation on the balance of calcium (Ca), Si, magnesium (Mg), and bone status in growing female rats fed diets with different Ca levels. Sixty 6-week-old female Wistar rats were divided into 6 groups and fed diets with different levels of Ca (0.1, 0.5, 1.5%) and Si (5, 500 ppm) for 10 weeks. Experimental groups were as follows: Low-Ca group (LCa; 0.1% Ca), Low-Ca with Si supplementation group (LCaSi), adequate-Ca group (ACa; 0.5% Ca), adequate-Ca with Si supplementation group (ACaSi), high-Ca group (HCa; 1.5% Ca), and high-Ca with Si supplementation group (HCaSi). Si retention significantly increased by Si supplementation and significantly decreased by high-Ca diet (1.5%). Mg retention significantly decreased by high-Ca diet. Serum Ca and Si contents were not significantly different among the 6 groups. Low-Ca diet significantly increased serum osteoclain and C-telopeptide cross-link of type 1 collagen (CTx) levels, and Si supplementation significantly decreased CTx levels in the low-Ca diet group. Bone mineral density was significantly increased along with Ca increase in the diet, but was decreased by Si supplementation in the high-Ca diet. Rats in the adequate-Ca diet group had a significant increase in strength of tibia after Si supplementation. These findings indicate that the effect of Si supplementation on bone metabolism may differ according to the Ca-intake level in growing females. Although further research is needed, when supplementing Si to improve bone health in growing females, Ca-intake level should be considered.

Electroporation processes affect the permeability of cell membranes, which can be utilized for the delivery of plasma species in cancer therapy. By means of computational dynamics, many aspects of membrane electroporation have been unveiled at the atomic level for lipid membranes. Herein, a molecular dynamics simulation study was performed on native and oxidized membrane systems with transversal electric fields. The simulation result shows that the applied electric field mainly affects the membrane properties so that electroporation takes place and these pores are lined by hydrophilic headgroups of the lipid components. The calculated hydrophobic thickness, lateral diffusion and pair correlation revealed the role of 5α-CH in creation of water-pore in an oxidized membrane. Additionally, the permeability of reactive oxygen species was examined through these electroporated systems. The permeability study suggested that water pores in the membrane facilitate the penetration of these species across the membrane to the interior of the cell. These findings may have significance in experimental applications in vivo as once the reactive oxygen species reaches the interior of the cell, they may cause oxidative stress and induce apoptosis. Communicated by Ramaswamy H. Sarma

Purpose To evaluate the efficacy of combined vitamin C, hydrocortisone, and thiamine in patients with severe pneumonia. Materials and methods All consecutive patients with severe pneumonia who were treated with the vitamin C protocol (6 g of vitamin C per day) in June 2017-January 2018 (n = 53) were compared to all consecutive patients with severe pneumonia who were treated in June 2016-January 2017 (n = 46). Propensity score analysis was used to adjust for potential baseline differences between the groups. Results In the propensity-matched cohort (n = 36/group), the treated patients had significantly less hospital mortality than the control group (17% vs. 39%; P = 0.04). The vitamin C protocol associated independently with decreased mortality in propensity score-adjusted analysis (adjusted odds ratio = 0.15, 95% confidence interval = 0.04-0.56, P = 0.005). Relative to the control group, the treatment group had a significantly higher median improvement in the radiologic score at day 7 compared with baseline (4 vs. 2; P = 0.045). The vitamin C protocol did not increase the rates of acute kidney injury or superinfection. Conclusions Combined vitamin C, hydrocortisone, and thiamine therapy may benefit patients with severe pneumonia.

The purpose of this study is to characterize and assess the diagnostic utility of sonographic features of minimal-fat angiomyolipoma (AML) and renal cell carcinoma (RCC) with regard to small (4 cm) renal masses with a predominantly low signal intensity (SI) on T2-weighted MR images.Fifty small renal masses with a predominantly low SI on T2-weighted MR images and no macroscopic fat, all of which had US images available, were assessed. MRI variables (T2 ratio, signal intensity index [SII], and tumor-to-spleen ratio on chemical-shift images), CT features (enhancement patterns and attenuations values on unenhanced images and images obtained in the corticomedullary and nephrographic phases), and sonographic features (echogenicity, heterogeneity, and the presence of acoustic shadowing, a hypoechoic rim, or an intratumoral cyst) were recorded in a blinded manner. Echo-genicity was classified as hypo-, iso-, or hyperechoic compared with the renal parenchyma or markedly hyperchoic when equivalent to that of the renal sinus fat.Minimal-fat AML and RCC were confirmed in 22 and 28 patients, respectively. T2 ratios were significantly lower for minimal-fat AML versus RCCs (p = 0.044). Minimal-fat AMLs exhibited echogenicities that were considered hypoechoic (31.8%), isoechoic (4.5%), hyperechoic (18.2%), or markedly hyperechoic (45.5%). No RCC showed marked hyperechogenicity. CT attenuation values were significantly higher for the minimal-fat AMLs seen in all imaging phases. When the combination of the T2 ratio, nephrographic phase attenuation, and echogenicity was assessed, the AUC value was 0.93 (95% CI, 0.81-0.98), which was a significant increase over the AUC value of 0.83 (95% CI, 0.69-0.92) for noted the combination of the T2 ratio and nephrographic phase attenuation.Additional reviews of the echogenicity of small renal masses with low SI on T2-weighted MR images may aid the diagnosis of minimal-fat AML.

Background The diagnostic yields and safety profiles of transbronchial lung biopsy have not been evaluated in inexperienced physicians using the combined modality of radial probe endobronchial ultrasound and a guide sheath (EBUS-GS). This study assessed the utility and safety of EBUS-GS during the learning phase by referring to a database of performed EBUS-GS procedures. Methods From December 2015 to January 2017, all of the consecutive patients who underwent EBUS-GS were registered. During the study period, two physicians with no previous experience performed the procedure. To assess the diagnostic yields, learning curve, and safety profile of EBUS-GS performed by these inexperienced physicians, the first 100 consecutive EBUS-GS procedures were included in the evaluation. Results The overall diagnostic yield of EBUS-GS performed by two physicans in 200 patients with a peripheral lung lesion was 73.0%. Learning curve analyses showed that the diagnostic yields were stable, even when the procedure was performed by beginners. Complications related to EBUS-GS occurred in three patients (1.5%): pneumothorax developed in two patients (1%) and resolved spontaneously without chest tube drainage; another patient (0.5%) developed a pulmonary infection after EBUS-GS. There were no cases of pneumothorax requiring chest tube drainage, severe hemorrhage, respiratory failure, premature termination of the procedure, or procedure-related mortality. Conclusions EBUS-GS is a safe and stable procedure with an acceptable diagnostic yield, even when performed by physicians with no previous experience. Electronic supplementary material The online version of this article (10.1186/s12890-018-0704-7) contains supplementary material, which is available to authorized users.

Background There appears to be less agreement in the identification of cancers in the transition zone (TZ), which is not as reliable as those in peripheral zone when using the Prostate Imaging Reporting and Data System (PI-RADS) version 2 (v2). In response to such shortcomings, the updated version 2.1 was introduced, which incorporated diffusion-weighted imaging (DWI) into category 2 and clarified lexicons. Purpose To compare the diagnostic performance for the detection of clinically significant TZ prostate cancers (csPCa) and interreader agreement between PI-RADS v2.1 and v2. Study type Retrospective study. Population In all, 142 patients, 201 TZ lesions. Field strength/sequence 3.0T; T2 -weighted image and DWI. Assessment Lesions were scored by three independent readers using PI-RADS v2 and v2.1. Statistical tests The sensitivity and specificity at category ≥3 were compared between v2 and v2.1 using the generalized estimating equation model. Detection rates for csPCa of upgraded and downgraded lesions in the use of PI-RADS v2.1 from v2 were assessed. Interreader agreement was assessed using κ statistics. Results PI-RADS v2.1 showed a higher sensitivity and specificity (94.5% and 60.9%) than v2 (91.8% and 56.3%) for category ≥3 lesions in the detection of csPCa, although not significantly. Of eight upgraded lesions from category 2 to 3 (2 + 1) with an incorporated DWI, 50% (4/8) were csPCa. This was significantly higher than category 2 lesions (4.4%; P = 0.003). No csPCa was detected among the 22.8% (46/201) downgraded lesions. There was a moderate interreader agreement for scores ≥3 (κ = 0.565) in v2.1, which was slightly higher than that for v2 (κ = 0.534), although not significantly. Data conclusion PI-RADS v2.1 provides moderate and comparable interreader agreement at category ≥3 than v2 in the TZ lesions. Upgraded lesions from category 2 to 3 demonstrated a higher detection rate of csPCa than category 2 lesions in v2.1. Level of evidence 4 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:577-586.

Gastric-type mucinous adenocarcinoma (GAS) of uterine cervix has been suggested as distinct clinicopathologic behavior. Our study aimed to investigate the distinguishing imaging features and clinical outcomes of GAS.Fifteen cases of GAS and 45 cases of 3:1 age-matched usual-type endocervical carcinoma (UEA) were assessed. Clinical parameters (age, tumor size, clinical stage, and time to recurrence [TTR] or death) and pathologic results confirmed by surgery were recorded. Imaging features (tumor shape, margin, presence of vaginal involvement, or cyst) on magnetic resonance T2-weighed images were evaluated by consensus reading. Parametrial invasion was assessed by 2 independent readers on a 4-point scale system.Gastric-type mucinous adenocarcinomas were associated with a higher stage at presentation and higher rates of deep cervical stromal invasion, parametrial invasion, and lymphovascular invasion. On magnetic resonance images, GASs also demonstrated a more infiltrative shape (93.3% vs 22.2%; P0.001) with/without cysts, ill-defined margin (93.3% vs 31.8%; P0.001), endocervical location (46.7%) or extension to the entire cervix (46.7%), higher rates of vaginal involvement (40.0% vs 4.4%; P = 0.002), and higher grade of parametrial invasion by both readers (66.7% vs 22.2%; P = 0.003) compared with UEAs. Patients with GAS had a significantly shorter TTR compared with UEA cases (P0.001) by log-rank test. A multivariate Cox proportional hazards model revealed that an infiltrative tumor shape (hazard ratio, 5.92; P = 0.004) and stage II or greater (hazard ratio, 4.19; P = 0.011) were prognostic indicators of a shorter TTR.Gastric-type mucinous adenocarcinoma may have characteristic imaging features and poorer outcomes compared with UEA.