Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection.

PURPOSE: There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). MATERIALS AND METHODS: Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. RESULTS: Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. CONCLUSION: Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.

Development of a Metabolic Syndrome Classification and Prediction Model for Koreans Using Deep Learning Technology: The Korea National Health and Nutrition Examination Survey (KNHANES) (2013-2018).

The prevalence of metabolic syndrome (MetS) and its cost are increasing due to lifestyle changes and aging. This study aimed to develop a deep neural network model for prediction and classification of MetS according to nutrient intake and other MetS-related factors. This study included 17,848 individuals aged 40-69 years from the Korea National Health and Nutrition Examination Survey (2013-2018). We set MetS (3-5 risk factors present) as the dependent variable and 52 MetS-related factors and nutrient intake variables as independent variables in a regression analysis. The analysis compared and analyzed model accuracy, precision and recall by conventional logistic regression, machine learning-based logistic regression and deep learning. The accuracy of train data was 81.2089, and the accuracy of test data was 81.1485 in a MetS classification and prediction model developed in this study. These accuracies were higher than those obtained by conventional logistic regression or machine learning-based logistic regression. Precision, recall, and F1-score also showed the high accuracy in the deep learning model. Blood alanine aminotransferase (ß = 12.2035) level showed the highest regression coefficient followed by blood aspartate aminotransferase (ß = 11.771) level, waist circumference (ß = 10.8555), body mass index (ß = 10.3842), and blood glycated hemoglobin (ß = 10.1802) level. Fats (cholesterol [ß = -2.0545] and saturated fatty acid [ß = -2.0483]) showed high regression coefficients among nutrient intakes. The deep learning model for classification and prediction on MetS showed a higher accuracy than conventional logistic regression or machine learning-based logistic regression.

Prognostic implication of serum AFP in patients with hepatocellular carcinoma treated with regorafenib.

Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.

Regorafenib is standard second-line therapy for patients with hepatocellular carcinoma (HCC) who show failure to sorafenib treatment, but there is no reliable factor to predict survival. In this multicenter, retrospective study with patients from South Korea and Italy, we have found that both baseline AFP level and on-treatment AFP response have independent predictive value for survival in patients with HCC under regorafenib treatment. We observed similar results when the patients were divided according to their nationality (South Korea vs Italy), despite the fact that the baseline characteristics of the patients from the two cohorts were significantly different.

Classification and Prediction on the Effects of Nutritional Intake on Overweight/Obesity, Dyslipidemia, Hypertension and Type 2 Diabetes Mellitus Using Deep Learning Model: 4-7th Korea National Health and Nutrition Examination Survey.

Few studies have been conducted to classify and predict the influence of nutritional intake on overweight/obesity, dyslipidemia, hypertension and type 2 diabetes mellitus (T2DM) based on deep learning such as deep neural network (DNN). The present study aims to classify and predict associations between nutritional intake and risk of overweight/obesity, dyslipidemia, hypertension and T2DM by developing a DNN model, and to compare a DNN model with the most popular machine learning models such as logistic regression and decision tree. Subjects aged from 40 to 69 years in the 4-7th (from 2007 through 2018) Korea National Health and Nutrition Examination Survey (KNHANES) were included. Diagnostic criteria of dyslipidemia (n = 10,731), hypertension (n = 10,991), T2DM (n = 3889) and overweight/obesity (n = 10,980) were set as dependent variables. Nutritional intakes were set as independent variables. A DNN model comprising one input layer with 7 nodes, three hidden layers with 30 nodes, 12 nodes, 8 nodes in each layer and one output layer with one node were implemented in Python programming language using Keras with tensorflow backend. In DNN, binary cross-entropy loss function for binary classification was used with Adam optimizer. For avoiding overfitting, dropout was applied to each hidden layer. Structural equation modelling (SEM) was also performed to simultaneously estimate multivariate causal association between nutritional intake and overweight/obesity, dyslipidemia, hypertension and T2DM. The DNN model showed the higher prediction accuracy with 0.58654 for dyslipidemia, 0.79958 for hypertension, 0.80896 for T2DM and 0.62496 for overweight/obesity compared with two other machine leaning models with five-folds cross-validation. Prediction accuracy for dyslipidemia, hypertension, T2DM and overweight/obesity were 0.58448, 0.79929, 0.80818 and 0.62486, respectively, when analyzed by a logistic regression, also were 0.52148, 0.66773, 0.71587 and 0.54026, respectively, when analyzed by a decision tree. This study observed a DNN model with three hidden layers with 30 nodes, 12 nodes, 8 nodes in each layer had better prediction accuracy than two conventional machine learning models of a logistic regression and decision tree.

Two Classes of Pigments, Carotenoids and C-Phycocyanin, in Spirulina Powder and Their Antioxidant Activities.

Arthrospira platensis is the widely available source of spirulina that contains distinctive natural pigments, including carotenoids and C-phycocyanin (C-PC). In this study, the major carotenoid and C-PC contents were determined in seven commercially available spirulina powder products and laboratory-prepared A. platensis trichomes (AP-1) by an LC-DAD method and UV-Visible spectrometry, respectively. The correlation of these two pigment content levels with Hunter color coordinates and antioxidant activity was also evaluated. The L* value failed to show a significant correlation with pigment content, but a positive correlation was observed between a* values and the contents of total carotenoid and C-PC. As b* values decreased, the chlorophyll a and C-PC contents increased. AP-1 exhibited the highest content of total carotenoids, chlorophyll a and C-PC, and antioxidant activities among the samples. This observation could be related to degradation of these pigments during the mass production process. The carotenoid profiles suggested that the commercial spirulina powders originated from two different sources, A. platensis and A. maxima. Total carotenoid and C-PC content exhibited positive significant correlations with antioxidant activities measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays. These results provide a strong scientific foundation for the establishment of standards for the commercial distribution of quality spirulina products.

Prevalence of fluoroquinolone-resistant rectal flora in patients undergoing transrectal ultrasound-guided prostate needle biopsy: A prospective multicenter study.

OBJECTIVES: To estimate the prevalence of fluoroquinolone-resistant rectal flora in patients undergoing transrectal ultrasound-guided prostate needle biopsy and to identify the high-risk groups. METHODS: From January 2015 to March 2016, rectal swabs of 557 men who underwent transrectal ultrasound-guided prostate needle biopsy were obtained from five institutions. Clinical variables, including demographics, rectal swab culture results and infectious complications, were evaluated. Univariable and multivariable analyses were used to identify the risk factors for fluoroquinolone resistance of rectal flora and infectious complications. RESULTS: The incidence of fluoroquinolone-resistant and extended-spectrum beta-lactamase production was 48.1 and 11.8%, respectively. The most common fluoroquinolone-resistant bacteria was Escherichia coli (81% of total fluoroquinolone-resistant bacteria, 39% of total rectal flora), and 16 (2.9%) patients had infectious complications. Univariable and multivariable analysis of clinical parameters affecting fluoroquinolone resistance showed no factor associated with fluoroquinolone resistance of rectal flora. The clinical parameter related to infectious complications after prostate biopsy was a history of operation within 6 months (relative risk 6.60; 95% confidence interval 1.99-21.8, P = 0.002). CONCLUSIONS: These findings suggest that a risk-based approach by history taking cannot predict antibiotic resistance of rectal flora, and physicians should consider targeted antibiotic prophylaxis or extended antibiotic prophylaxis for Korean patients undergoing transrectal ultrasound-guided prostate biopsy because of high antibiotic resistance of rectal flora.

Effects of Acidification and Alkalinization on the Lipid Emulsion-Mediated Reversal of Toxic Dose Levobupivacaine-Induced Vasodilation in the Isolated Rat Aorta.

The goal of this in vitro study was to examine the effects of pre-acidification and pre-akalinization on the lipid emulsion-mediated reversal of toxic dose levobupivacaine-induced vasodilation in isolated rat aorta. Isolated aortic rings with and without the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) were exposed to four types of Krebs solution (pH 7.0, 7.2, 7.4, and 7.6), followed by the addition of 60 mM potassium chloride. When the toxic dose of levobupivacaine (3 × 10(-4) M) produced a stable and sustained vasodilation in the isolated aortic rings that were precontracted with 60 mM potassium chloride, increasing lipid emulsion concentrations (SMOFlipid(®): 0.24, 0.48, 0.95 and 1.39%) were added to generate concentration-response curves. The effects of mild pre-acidification alone and mild pre-acidification in combination with a lipid emulsion on endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells were investigated by Western blotting. Mild pre-acidification caused by the pH 7.2 Krebs solution enhanced the lipid emulsion-mediated reversal of levobupivacaine-induced vasodilation in isolated endothelium-intact aortic rings, whereas mild pre-acidification caused by the pH 7.2 Krebs solution did not significantly alter the lipid emulsion-mediated reversal of the levobupivacaine-induced vasodilation in isolated endothelium-denuded aortic rings or endothelium-intact aortic rings with L-NAME. A lipid emulsion attenuated the increased eNOS phosphorylation induced by the pH 7.2 Krebs solution. Taken together, these results suggest that mild pre-acidification enhances the lipid emulsion-mediated reversal of toxic dose levobupivacaine-induced vasodilation in the endothelium-intact aorta via the inhibition of nitric oxide.

Systemic blockage of nitric oxide synthase by L-NAME increases left ventricular systolic pressure, which is not augmented further by Intralipid®.

Intravenous lipid emulsions (LEs) are effective in the treatment of toxicity associated with various drugs such as local anesthetics and other lipid soluble agents. The goals of this study were to examine the effect of LE on left ventricular hemodynamic variables and systemic blood pressure in an in vivo rat model, and to determine the associated cellular mechanism with a particular focus on nitric oxide. Two LEs (Intralipid(®) 20% and Lipofundin(®) MCT/LCT 20%) or normal saline were administered intravenously in an in vivo rat model following induction of anesthesia by intramuscular injection of tiletamine/zolazepam and xylazine. Left ventricular systolic pressure (LVSP), blood pressure, heart rate, maximum rate of intraventricular pressure increase, and maximum rate of intraventricular pressure decrease were measured before and after intravenous administration of various doses of LEs or normal saline to an in vivo rat with or without pretreatment with the non-specific nitric oxide synthase inhibitor N(ω)-nitro-L-arginine-methyl ester (L-NAME). Administration of Intralipid(®) (3 and 10 ml/kg) increased LVSP and decreased heart rate. Pretreatment with L-NAME (10 mg/kg) increased LSVP and decreased heart rate, whereas subsequent treatment with Intralipid(®) did not significantly alter LVSP. Intralipid(®) (10 ml/kg) increased mean blood pressure and decreased heart rate. The increase in LVSP induced by Lipofundin(®) MCT/LCT was greater than that induced by Intralipid(®). Intralipid(®) (1%) did not significantly alter nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-denuded rat aorta. Taken together, systemic blockage of nitric oxide synthase by L-NAME increases LVSP, which is not augmented further by intralipid(®).

The N3 subdomain in a domain of fibronectin-binding protein B isotype I is an independent risk determinant predictive for biofilm formation of Staphylococcus aureus clinical isolates.

Fibronectin-binding proteins (FnBP), FnBPA and FnBPB, are purported to be involved in biofilm formation of Staphylococcus aureus. This study was performed to find which of three consecutive N subdomains of the A domain in the FnBP is the key domain in FnBP. A total of 465 clinical isolates of S. aureus were examined for the biofilm forming capacity and the presence of N subdomains of FnBP. In the biofilm-positive strains, N2 and N3 subdomains of FnBPA, and N1 and N3 subdomains of FnBPB were significantly more prevalent. Multivariate logistic regression analysis of 246 biofilm-positive and 123 biofilm-negative strains identified only the FnBPB-N3 subdomain as an independent risk determinant predictive for biofilm-positive strains of S. aureus (Odds ratio [OR], 13.174; P<0.001). We also attempted to delete each of the fnbA-N2 and -N3 and fnbB-N1 and -N3 from S. aureus strain 8325-4 and examined the biofilm forming capacity in the derivative mutants. In agreement with the results of the multivariate regression analysis, deletion of either the fnbA-N2 or -N3, or fnbB-N1 did not significantly diminish the capacity of strain 8325-4 to develop a biofilm, while deletion of the fnbB-N3 did. Therefore, it is suggested that the FnBPB-N3 subdomain of isotype I may be a key domain in FnBP which is responsible for the causing biofilm formation in S. aureus clinical isolates.

Balloon-occluded percutaneous transhepatic obliteration of isolated vesical varices causing gross hematuria.

Gross hematuria secondary to vesical varices is an unusual presentation. We report such a case recurrent gross hematuria in a male patient who had a history of bladder substitution with ileal segments that had been treated by balloon-occluded percutaneous transhepatic obliteration of vesical varices.

Vasoconstriction potency induced by aminoamide local anesthetics correlates with lipid solubility.

Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED(50)) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED(50)) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED(50) in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r(2) = 0.9563; P < 0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa.

Higher biofilm formation in multidrug-resistant clinical isolates of Staphylococcus aureus.

The biofilm-forming capacity of Staphylococcus aureus contributes to antibiotic resistance, but whether antibiotic-resistant strains have the capacity to form biofilms has not yet been determined. Therefore, we recovered 101 clinical isolates of S. aureus and performed antibiotic susceptibility testing for 30 antibiotics using a VITEK II automatic system. We then carried out a biofilm assay on 96-well polystyrene plates. In addition, the presence of IS256 involved in the variation of biofilm phases of S. aureus was determined by polymerase chain reaction. The prevalence of IS256 was significantly related to multidrug resistance as well as biofilm expression, with biofilm positivity in 27 (39.7%) of the 68 IS256-positive strains and 3 (9.1%) of the 33 IS256-negative strains. In our analysis of the relationship between meticillin resistance and biofilm formation, we found that the rate of biofilm positivity was 37.9% (25/66) for meticillin-resistant strains and 14.3% (5/35) for meticillin-susceptible strains (P<0.05). Staphylococcal cassette chromosome mec (SCCmec) typing found that SCCmec type IV was most prevalent, comprising 14 (56.0%) of the 25 biofilm-positive, meticillin-resistant strains. A statistical analysis testing the relationship between multidrug resistance and biofilm formation revealed a significantly higher rate of biofilm development in strains with greater multiresistance compared with strains with less multiresistance. Our results suggest that the multidrug-resistant clinical isolates of S. aureus have a greater likelihood of developing biofilms on medical devices.

Sparganosis presenting as spermatic cord hydrocele in six-year-old boy.

Sparganosis is a zoonosis that can involve many different areas of the human body. Urogenital sparganosis usually presents as a palpable subcutaneous nodule in the groin, labia, or scrotum. It can also present as a tumor in the epididymis and testis. However, no previous cases have been reported of it presenting as a spermatic cord hydrocele. We present a case of sparganosis with spermatic cord hydrocele in a 6-year-old boy.