Implications of Increased Weight Status for the Occurrence of Fall-Induced Intracranial Hemorrhage in Children Aged 4 Years or Younger.

OBJECTIVES: The aim of this study was to investigate the association between increased weight status (IWS), a weight for age/sex at greater than the 95th percentile, and fall-induced intracranial hemorrhage (ICH) in children aged 4 years or younger. METHODS: In 7072 children aged 4 years or younger with head injury who visited a tertiary care hospital emergency department in Korea from 2013 through 2015, the presence of fall-induced ICH was reviewed. The association between IWS and ICH was investigated by multivariable logistic regression. We retrospectively validated the Pediatric Emergency Care Applied Research Network rule alone and in combination with IWS for predicting ICH. RESULTS: Of 7072 children, 547 (7.7%) underwent computed tomography, of whom 451 (6.4%) were enrolled. Of these, 41 (9.1%; estimated event rate, 0.6%) had ICHs, and 26 (5.8%) had IWS. Increased weight status was more common in the children with ICH (P = 0.023). The association between IWS and ICH remained significant after adjustment (odds ratio, 5.24; 95% confidence interval [CI], 1.49-18.46; P = 0.010). The validation of the rule in combination with IWS showed no significant increases in a sensitivity (92.7% [95% CI, 80.1%-98.5%] to 95.7% [95% CI, 83.5%-99.4%]) and negative predictive value (98.2% [95% CI, 94.7%-99.4%] to 98.8% [95% CI, 95.4%-99.8%]). CONCLUSIONS: Increased weight status is associated with fall-induced ICH in children aged 4 years or younger. Information on weight status could be potentially helpful in predicting ICH in young children with fall-induced head injury.

Outcomes and Role of Urgent Endoscopy in High-Risk Patients With Acute Nonvariceal Gastrointestinal Bleeding.

BACKGROUND & AIMS: We investigated clinical outcomes in high-risk patients with acute nonvariceal upper gastrointestinal bleeding (UGIB), and determined if urgent endoscopy is effective. METHODS: Consecutive patients with a Glasgow-Blatchford score greater than 7 who underwent endoscopy for acute nonvariceal UGIB at the emergency department from January 1, 2005, to December 31, 2014, were included. Urgent (<6 h) and elective (6-48 h) endoscopies were defined according to the time to endoscopy after the initial presentation. The primary outcomes were mortality and rebleeding within 28 days of admission. RESULTS: Among 961 patients, 571 patients underwent urgent endoscopy. The 28-day mortality rate was 2.5%, and the rebleeding rate was 10.4%. There were significant differences in mortality rate (1.6% vs 3.8%), the number of transfused packed red blood cells (2.6 ± 2.5 vs 2.3 ± 2.1 packs), need for intervention (69.5% vs 53.5%), and embolization (2.8% vs 0.5%), but no differences in rebleeding, intensive care unit admission, vasopressor use, and length of stay between the urgent and elective endoscopy groups. Mortality was associated with malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.33-9.62), cirrhosis (OR, 4.67; 95% CI, 1.85-11.76), urgent endoscopy (OR, 0.36; 95% CI, 0.14-0.95), failed primary endoscopic treatment (OR, 15.03; 95% CI, 4.63-48.82), and rebleeding (OR, 2.77; 95% CI, 1.03-7.45). Rebleeding was associated with Forrest I ulcers (OR, 7.67; 95% CI, 2.71-21.69), Forrest II ulcers (OR, 2.34; 95% CI, 1.51-3.60), and coagulopathy (OR, 2.34; 95% CI, 1.51-3.60). CONCLUSIONS: Urgent endoscopy was an independent predictor of lower mortality rate but was not associated with rebleeding in high-risk patients with acute nonvariceal UGIB.

Lactate Level Versus Lactate Clearance for Predicting Mortality in Patients With Septic Shock Defined by Sepsis-3.

OBJECTIVES: This study aimed to compare the prognostic value of lactate level and lactate clearance at 6 hours after septic shock recognition. And, we performed it to determine lactate kinetics in the Sepsis-3 defined septic shock. DESIGN: This retrospective study was performed from a prospective septic shock registry. SETTINGS: This study was performed at single urban tertiary center. And, all patients were treated with protocol-driven resuscitation bundle therapy between 2010 and 2016. PATIENTS: We included septic shock patients who met the Sepsis-3 definition, which involves lactate levels greater than or equal to 2 mmol/L and vasopressor use. INTERVENTIONS: Serum lactate levels were measured at initial and 6 hours from septic shock recognition. MEASUREMENTS AND MAIN RESULTS: Lactate clearance was calculated as ([initial lactate - 6-hr lactate]/initial lactate) × 100. The prognostic value of measured lactate levels and lactate clearance for 28-day mortality was analyzed and compared with that of subsequent lactate levels greater than or equal to 2 mmol/L, greater than or equal to 3 mmol/L, and greater than or equal to 4 mmol/L and less than 10%, less than 20%, and less than 30% lactate clearance. A total of 1,060 septic shock patients by Sepsis-3, 265 patients died (28-d mortality: 25%). In survivor, groups had lower median 6-hour lactate level and higher lactate clearance than nonsurvivors (2.5 vs 4.6 mmol/L and 35.4% vs 14.8%; p < 0.01). Both lactate and lactate clearance were associated with mortality after adjusting for confounders (odd ratio, 1.27 [95% CI, 1.21-1.34] and 0.992 [95% CI, 0.989-0.995]), but lactate had a significantly higher prognostic value than lactate clearance (area under the curve, 0.70 vs 0.65; p < 0.01). The prognostic value of subsequent lactate levels (≥ 2, ≥ 3, and ≥ 4 mmol/L) and lactate clearances (< 10%, < 20%, and < 30%) was not significantly differed. However, lactate levels of greater than or equal to 2 mmol/L had the greatest sensitivity (85.3%). CONCLUSIONS: Our findings indicate lactate and lactate clearance are both useful targets in patients with septic shock defined by Sepsis-3. Serum lactate level at 6-hour can be an easier and more effective tool for prognosis of septic shock patients who were treated with protocol-driven resuscitation bundle therapy.

Prognostic value of decision criteria for emergency liver transplantation in patients with wild mushroom induced acute liver injury.

BACKGROUND: The reported mortality rate of mushroom-induced acute liver failure with conventional treatment is 1.4%-16.9%. Emergency liver transplantation may be indicated and can be the only curative treatment option. This study aimed to assess the prognostic value of criteria for emergency liver transplantation in predicting 28-day mortality in patients with mushroom-induced acute liver injury. METHODS: A retrospective cohort study was performed between January 2005 and December 2015. All adult patients aged≥18 years admitted with mushroom intoxication at our emergency department were evaluated. All patients with acute liver injury, defined as elevation of serum liver enzymes (>5 times the upper limit of normal, ULN) or moderate coagulopathy (INR > 2.0) were included. The ability of the King's College, Ganzert's, and Escudié's criteria to predict 28-day mortality was evaluated. RESULTS: Of the 23 patients with acute liver injury following mushroom intoxication, 10 (43.5%) developed acute liver failure and subsequently died. The mean time interval from ingestion to death was 11.3 ±â€¯6.6 days. Eight patients fulfilled Ganzert's criteria, while 10 patients fulfilled the King's College and Escudié's criteria for emergency liver transplantation. King's College and Escudié's criteria had 100% accuracy in predicting 28-day mortality; however, Escudié's criteria were able to identify fatal cases earlier. CONCLUSIONS: Escudié's criteria demonstrated the best performance with 100% accuracy and the ability to promptly identify fatal cases of mushroom-induced acute liver failure.

Risk Factors for Recurrent Intussusception After Fluoroscopy-Guided Air Enema.

OBJECTIVES: The aim of this study was to identify risk factors for recurrent intussusception after a successful reduction by fluoroscopy-guided air enema, the time required for recurrence, and the association between delayed reduction and the recurrence. METHODS: Medical records of 479 consecutive children with intussusception who underwent fluoroscopy-guided air enema between January 2004 and September 2014 were reviewed. Recurrent intussusception was defined as a recurrence within 48 hours of a reduction. Symptom-to-door time was defined as the time from symptom onset to emergency department arrival. Door-to-reduction time was defined as the time from emergency department arrival to reduction. Time-to-recurrence was defined as the time required for recurrence from the first ultrasound diagnosis. RESULTS: Of the 360 eligible children, 32 had recurrent intussusceptions (8.9%). Multivariable logistic regression showed that age 2 years or older is an independent predictor of recurrent intussusception (odds ratio, 2.39; 95% confidence interval, 1.13-5.02; P = 0.02). Median time to recurrence was 25 hours (18.0-36.0 hours). Although symptom-to-door and door-to-reduction times tended to be longer in the recurrence group, these differences were not significant (12.5 vs 7.0 hours, P = 0.18; 154.0 vs 143.0 minutes, P = 0.67, respectively). CONCLUSIONS: Our data suggest that provision for early recurrence and extended observation may be beneficial for children 2 years or older. Delayed reduction was not associated with recurrent intussusception, but further studies with larger sample sizes are needed to explain this issue.

Utility of the simplified Wells and revised Geneva scores to exclude pulmonary embolism in femur fracture patients.

OBJECTIVES: The diagnosis of acute pulmonary embolism (PE) in trauma patients is challenging. This study evaluated the diagnostic value of simplified Wells and simplified revised Geneva scores to predict PE in femur fracture patients in emergency department (ED). METHODS: All consecutive adult patients with femur fractures and elevated D-dimer levels (>0.5µg/mL) who underwent CTPA within 72h of injury from January 2010 to December 2014 were included. The simplified Wells and simplified revised Geneva scores were applied to evaluate the clinical probability of PE. RESULTS: Among 519 femur fracture patients, 446 patients were finally included, and 23 patients (5.2%) were diagnosed with acute PE. The median values of simplified Wells and simplified revised Geneva scores [0 (IQR: 0-1) vs. 0 (IQR: 0-0), P=0.23; 3 (IQR: 2-4) vs. 3 (IQR: 2-3), P=0.48] showed no differences between the PE (n=23) and non-PE (n=423) groups. Using the simplified Wells score, 98% of the patients were categorized into the "PE unlikely" group. The sensitivity, specificity, positive predictive value, and negative predictive value of the simplified revised Geneva score (≥3 points) for the diagnosis of PE were 74%, 35%, 6%, and 96%, respectively. CONCLUSION: In femur fracture patients with elevated D-dimer levels, the simplified Wells and simplified revised Geneva scores have limited predictive value. However, the simplified revised Geneva score of <3 points may be possibly used as a diagnostic tool.

Carbon monoxide poisoning during camping in Korea.

OBJECTIVE: The aim of this study was to evaluate the epidemiology and characteristics of unintentional carbon monoxide (CO) poisoning during camping in Korea. METHODS: We performed a retrospective observational study on patients with unintentional camping-related CO poisoning who were admitted to the emergency department (ED) from 1 January 2010 to 31 December 2014. News reports about incidents of camping-related CO poisoning were collected using news search engines. RESULTS: A total of 72 patients (29 patients involved in 12 incidents, who were admitted to our ED, and 43 victims involved in 17 incidents reported in the media) were identified. Accidental camping-related CO poisoning occurred most frequently in May, late spring in Korea. Gas stove use and the burning of charcoal for tent heating were responsible for camping-related CO exposure. Seventeen victims (39.5%) were found dead when an ambulance arrived at the scene, in the cases reported in the media. In contrast, all the victims at our hospital were alive on hospital discharge. Twelve of the 17 incidents (70.6%) reported in the media were accidental fatalities. The majority of our patients (83.4%) were not aware of the potential danger of charcoal as a source of CO. CONCLUSION: Accidental camping-related CO poisoning occurred because of an ongoing lack of awareness about the potential danger of charcoal grills and stoves, and this caused prehospital mortality. Such accidents could be prevented by increasing the awareness of the potential danger of using charcoal grills and stoves during camping, as well as by establishing appropriate safety regulations.

Nosocomial transmission of severe fever with thrombocytopenia syndrome in Korea.

Of the 27 healthcare workers (HCWs) who had contact with a fatally ill patient with severe thrombocytopenia syndrome in Korea (SFTS), 4 who were involved in cardiopulmonary resuscitation complained of fever and were diagnosed with SFTS via seroconversion. Exposure to respiratory secretions, blood, or gowns soiled by body fluids was significantly associated with infection of HCWs.

Predicting the Occurrence of Hypotension in Stable Patients With Nonvariceal Upper Gastrointestinal Bleeding: Point-of-Care Lactate Testing.

OBJECTIVES: It is difficult to assess risk in normotensive patients with upper gastrointestinal bleeding. The aim of this study was to evaluate whether the initial lactate value can predict the in-hospital occurrence of hypotension in stable patients with acute nonvariceal upper gastrointestinal bleeding. DESIGN: Retrospective, observational, single-center study. SETTING: Emergency department of a tertiary-care, university-affiliated hospital during a 5-year period. PATIENTS: Medical records of 3,489 patients with acute upper gastrointestinal bleeding who were normotensive at presentation to the emergency department. We analyzed the ability of point-of-care testing of lactate at emergency department admission to predict hypotension development (defined as systolic blood pressure <90 mm Hg) within 24 hours after emergency department admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 1,003 patients with acute nonvariceal upper gastrointestinal bleeding, 157 patients experienced hypotension within 24 hours. Lactate was independently associated with hypotension development (odds ratio, 1.6; 95% CI, 1.4-1.7), and the risk of hypotension significantly increased as the lactate increased from 2.5-4.9 mmol/L (odds ratio, 2.2) to 5.0-7.4 mmol/L (odds ratio, 4.0) and to greater than or equal to 7.5 mmol/L (odds ratio, 39.2) (p<0.001). Lactate elevation (≥2.5 mmol/L) was associated with 90% specificity and an 84% negative predictive value for hypotension development. When the lactate levels were greater than 5.0 mmol/L, the specificity and negative predictive value increased to 98% and 87%, respectively. CONCLUSIONS: Point-of-care testing of lactate can predict in-hospital occurrence of hypotension in stable patients with acute nonvariceal upper gastrointestinal bleeding. However, subsequently, prospective validate research will be required to clarify this.

Biphasic reactions in patients with anaphylaxis treated with corticosteroids.

BACKGROUND: Although the incidence of anaphylaxis is rapidly increasing, the clinical characteristics and associated factors of a biphasic reaction are unclear. OBJECTIVE: To determine the incidence and clinical characteristics of biphasic reactions in patients with anaphylaxis treated with corticosteroids. METHODS: A total of 655 patients with anaphylaxis visiting the emergency department of a tertiary teaching hospital from January 2007 through December 2014 were analyzed. Patient characteristics, triggers, symptoms and signs, in-hospital management, and disposition were recorded. A biphasic reaction was defined as the development of anaphylaxis after complete resolution of the initial reaction without further exposure to the offending agent within 7 days. Univariate and multivariate analyses on the predictors of the biphasic reaction were performed. RESULTS: Of the 415 patients with anaphylaxis treated with corticosteroids, 9 patients (2.2%) developed a biphasic reaction. The mean age was 48.4 years, and 221 patients (54.4%) were women. The median time from complete resolution of initial clinical symptoms to occurrence of the biphasic reaction was 15 hours (range 1-45). History of drug anaphylaxis (odds ratio 14.3, 95% confidence interval 2.4-85.8) was a contributing factor to the development of the biphasic reaction. CONCLUSION: The incidence of biphasic reactions was 2.2% in patients treated with corticosteroids and those with a history of drug anaphylaxis were at greater risk.

Model for end-stage liver disease score as a predictor of short-term outcome in patients with drug-induced liver injury.

OBJECTIVES: The purposes of this study were to investigate the clinical presentation, cause and outcome of drug-induced liver injury (DILI) and to evaluate the predictive value of the model for end-stage liver disease (MELD) score in DILI. METHODS: Patients diagnosed with DILI between January 1, 2010 and December 31, 2012 in the Emergency Department at Asan Medical Center in Seoul, Korea were analyzed retrospectively. The primary end point was poor outcome, defined as liver transplantation or death within 30 days of the initial hospital visit. RESULTS: Of 213 patients, 13.1% had a 30-day poor outcome. Folk remedies were the most common cause of DILI in 147 patients (69%). Univariate logistic regression analysis showed that multiple drugs (odds ratio [OR] 2.30, 95% confidence interval [CI]: 1.03-5.15), concurrent alcohol consumption (OR 3.69, 95% CI: 1.03-13.18), white blood cell (WBC) count (OR 1.17, 95% CI: 1.07-1.28), hemoglobin (Hb) (OR 0.60, 95% CI: 0.49-0.74), platelet count (OR 0.993, 95% CI: 0.987-0.998), total bilirubin (OR 1.09, 95% CI: 1.06-1.13) and MELD (OR 1.23, 95% CI: 1.15-1.32) were significantly associated with 30-day poor outcomes. Multivariate analysis showed that the MELD (OR 1.21, 95% CI: 1.12-1.30) and Hb (OR 0.77, 95% CI: 0.61-0.98) were independent predictors of poor outcome. For 30-day mortality, the c-statistics for MELD alone and for combination of MELD and Hb were 0.93 (95% CI: 0.89-0.97) and 0.94 (95% CI: 0.90-0.97), respectively. CONCLUSION: The outcome of patients with DILI was poor. MELD score and Hb were reliable predictors of short-term outcome in patients with DILI.

Prevalence and outcomes of endotracheal intubation-related cardiac arrest in the ED.

BACKGROUND: Emergency endotracheal intubation-related cardiac arrest (CA) is not well documented. This study compares the clinical features and outcomes of intubation-related CA and other causes of inhospital CA. METHODS: All study patients were consecutive adults (≥18 years) who developed CA in the emergency department between January 2007 and December 2011. Emergent endotracheal intubation-related CA was defined as occurring within 20 minutes after successful intubation. Clinical variables were compared between patients with intubation-related CA and intubation-unrelated CA. The primary outcome was a good neurologic outcome defined as a Cerebral Performance Category score of 1 to 2. The secondary outcome was survival to hospital discharge. RESULTS: Of the 251 patients who developed CA, 41 were excluded due to trauma-related CA or "do-not-resuscitate" protocols, thereby leaving 210 patients. The prevalence of intubation-related CA was 23.3%, and the median duration between successful intubation and CA was 5.0 minutes (interquartile range, 2.0-9.5). Pulseless electrical activity was more commonly noted as the first arrest rhythm in the intubation-related CA group (75.5% vs 59.0%; P = .03) compared with patients with other causes of CA. However, the rates of good neurologic outcomes (14.3% vs 21.1%) and survival to discharge (34.7% vs 35.4%) were not significantly higher in intubation-related CA group (both P > .05). CONCLUSION: Endotracheal intubation-related CA occurred higher than commonly recognized, and patient outcomes were not better than other causes of CA. These data highlight the importance of efforts to prevent intubation-related CA. However, further prospective larger study will be required to generalize this result.

Korean, Japanese, and Chinese populations featured similar genes encoding drug-metabolizing enzymes and transporters: a DMET Plus microarray assessment.

BACKGROUND: Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups. METHODS: The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used. RESULTS: On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA. CONCLUSION: Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination.

Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics.

As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.

An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects.

INTRODUCTION: A pegylated recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in reducing the severity and duration of neutropenia. This study was performed to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of GCPGC, a new formulation of pegylated G-CSF, in healthy volunteers and to compare them with those of pegfilgrastim (Neulasta®). METHODS: Twenty-five healthy Korean male volunteers randomly received a single subcutaneous (SC) GCPGC injection at a dose of 30 (n = 10), 100 (n = 10), or 300 (n = 5) µg/kg or placebo in a 4:1 ratio in a double-blind manner. Additionally, 8 subjects received a SC dose of pegfilgrastim at 100 µg/kg. Blood samples were collected up to 14 days after both therapies. The absolute neutrophil count (ANC) and CD34(+) cell counts were the PD markers. RESULTS: After GCPGC administration, 4 different pharmacokinetic phases were identified, indicating target-mediated drug disposition (TMDD) for the elimination of GCPGC, which was slowed down as the dose was increased, resulting in a higher than proportional dose-normalized exposure to GCPGC. Although GCPGC was cleared faster than pegfilgrastim, leading to a 19 % lower systemic exposure to pegylated G-CSF, the increase in ANC and CD34(+) were ~20 % greater by GCPGC at 100 µg/kg than pegfilgrastim. Thrombocytopenia, splenomegaly, and hemoperitoneum occurred in one subject in the 300 µg/kg GCPGC group, which resolved completely with appropriate care. CONCLUSIONS: GCPGC showed a non-linear TMDD. The PK-PD characteristics of GCPGC at 30-100 µg/kg were comparable to those of pegfilgrastim at 100 µg/kg. GCPGC at 30-100 µg/kg was well tolerated in healthy Korean males.

Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.

AIMS: HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. METHODS: Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. RESULTS: Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. CONCLUSIONS: HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.

Trough concentration over 12.1 mg/L is a major risk factor of vancomycin-related nephrotoxicity in patients with therapeutic drug monitoring.

BACKGROUND: High doses of vancomycin increase the risk of nephrotoxicity, but the quantitative relationship between vancomycin exposure and nephrotoxicity is still controversial. This study evaluated the relationship between vancomycin trough concentration and nephrotoxicity, and risk factors for nephrotoxicity in patients undergoing therapeutic drug monitoring. METHODS: A total of 1269 cases from patients who underwent therapeutic drug monitoring were collected from 2006 to 2010. Receiver operating characteristic curve analysis was used to evaluate the relationship between trough concentration and the incidence of nephrotoxicity. Logistic regression using the generalized Least Absolute Shrinkage and Selection Operator (lasso) method was used to evaluate possible risk factors for nephrotoxicity. The data were divided into high/low-concentration groups by the cutoff value obtained from the receiver operating characteristic curve, and additional logistic regression using the generalized lasso method was performed for each group. RESULTS: The cutoff value of the vancomycin trough concentration was 12.1 mg/L. Patients with high concentrations (>12.1 mg/L) were more likely to develop nephrotoxicity (odds ratio = 16.0, 95% confidence interval, 8.2-31.1). The vancomycin trough concentration was the only significant risk factor for nephrotoxicity identified using the generalized lasso (P < 0.001). In contrast, no factor was associated with nephrotoxicity in the low-concentration group. CONCLUSIONS: Vancomycin trough concentrations over 12.1 mg/L were associated with an increased risk of nephrotoxicity. This is lower than the known threshold. Trough vancomycin concentration over the threshold was the only risk factor of nephrotoxicity among demographic factors, dosing regimen, and other clinical conditions in this study. It is suggested that vancomycin trough concentrations greater than 12.1 mg/L require close monitoring for nephrotoxicity.

Cumulative query method for influenza surveillance using search engine data.

BACKGROUND: Internet search queries have become an important data source in syndromic surveillance system. However, there is currently no syndromic surveillance system using Internet search query data in South Korea. OBJECTIVES: The objective of this study was to examine correlations between our cumulative query method and national influenza surveillance data. METHODS: Our study was based on the local search engine, Daum (approximately 25% market share), and influenza-like illness (ILI) data from the Korea Centers for Disease Control and Prevention. A quota sampling survey was conducted with 200 participants to obtain popular queries. We divided the study period into two sets: Set 1 (the 2009/10 epidemiological year for development set 1 and 2010/11 for validation set 1) and Set 2 (2010/11 for development Set 2 and 2011/12 for validation Set 2). Pearson's correlation coefficients were calculated between the Daum data and the ILI data for the development set. We selected the combined queries for which the correlation coefficients were .7 or higher and listed them in descending order. Then, we created a cumulative query method n representing the number of cumulative combined queries in descending order of the correlation coefficient. RESULTS: In validation set 1, 13 cumulative query methods were applied, and 8 had higher correlation coefficients (min=.916, max=.943) than that of the highest single combined query. Further, 11 of 13 cumulative query methods had an r value of ≥.7, but 4 of 13 combined queries had an r value of ≥.7. In validation set 2, 8 of 15 cumulative query methods showed higher correlation coefficients (min=.975, max=.987) than that of the highest single combined query. All 15 cumulative query methods had an r value of ≥.7, but 6 of 15 combined queries had an r value of ≥.7. CONCLUSIONS: Cumulative query method showed relatively higher correlation with national influenza surveillance data than combined queries in the development and validation set.

Kind and estimated stocking amount of antidotes for initial treatment for acute poisoning at emergency medical centers in Korea.

Antidotes for toxicological emergencies can be life-saving. However, there is no nationwide estimation of the antidotes stocking amount in Korea. This study tried to estimate the quantities of stocking antidotes at emergency department (ED). An expert panel of clinical toxicologists made a list of 18 emergency antidotes. The quantity was estimated by comparing the antidote utilization frequency in a multicenter epidemiological study and the nation-wide EDs' data of National Emergency Department Information System (NEDIS). In an epidemiological study of 11 nationwide EDs from January 2009 to December 2010, only 92 (1.9%) patients had been administered emergency antidotes except activated charcoal among 4,870 cases of acute adult poisoning patients. Comparing with NEDIS data, about 1,400,000 patients visited the 124 EDs nationwide due to acute poisoning and about 103,348 adult doses of the 18 emergency antidotes may be required considering poisoning severity score. Of these, 13,224 (1.9%) adult doses of emergency antidotes (575 of atropine, 144 of calcium gluconate or other calcium salts, 2,587 of flumazenil, 3,450 of N-acetylcysteine, 5,893 of pralidoxime, 287 of hydroxocobalamin, 144 of sodium nitrite, and 144 of sodium thiosulfate) would be needed for maintaining the present level of initial treatment with emergency antidotes at EDs in Korea.

Global metabolomics and targeted steroid profiling reveal that rifampin, a strong human PXR activator, alters endogenous urinary steroid markers.

Activation of the pregnane X receptor (PXR) alters the expression of metabolic enzymes and transporters involved in the metabolism of xenobiotics and endobiotics. To identify endogenous biomarkers of PXR activation in humans, rifampin, a strong PXR activator, was administered to 12 healthy male subjects, and their urine was analyzed before and after rifampin administration. Ultraperformance liquid chromatography time-of-flight mass spectrometry (UPLC/QTOF-MS)-based global metabolomics and gas chromatography-mass spectrometry (GC-MS)-based profiling of 75 steroids were used to screen the urine samples. Global metabolomics revealed that hydroxytestosterone sulfate and glycochenodeoxycholate sulfate levels were significantly increased and that androsterone sulfate, dehydroepiandrosterone (DHEA) sulfate, and p-cresol sulfate levels were significantly decreased following rifampin administration compared with controls. Urinary steroid profiling showed that 16α-OH-androstenedione (16α-OH-A-dione), 16α-OH-DHEA, 7α-DHEA, 7ß-DHEA, and 11ß-OH-A-dione levels were increased, whereas DHEA, androsterone, etiocholanolone, estrone, ß-cortolone, and allo-tetrahydrocortisone levels were decreased in the rifampin group. The analysis of the metabolic pathway and the metabolic ratio of steroids enabled the estimation of the induction of CYP1A/3A/7B/11B/2C and the inhibition of CYP17A/19A in response to PXR activation. These human urinary biomarkers may be useful for predicting the extent of PXR activation, monitoring the activity of DMEs, and anticipating drug-drug interactions in patients administered PXR-activating drugs.