Detection of DHCMT long-term metabolite glucuronides with LC-MSMS as an alternative approach to conventional GC-MSMS analysis

Dehydrochloromethyltestosterone (DHCMT) is one of the most detected illicit used anabolic–androgenic steroids in professional sports. Therefore, a fast and accurate analysis of this substance is of great importance for a constructive fight against doping abuse. The conventional method for the analysis of this drug, GC-MSMS, is very sensitive and selective but also very time- and resource-consuming. With the presented work, a new approach for simple detection with LC-HRMSMS without any sample preparation is introduced. The method is based on the direct analysis of two newly described phase-II metabolites of the DHCMT long-term metabolite 4-chloro-18-nor-17β-hydroxymethyl-17α-methyl-5β-androst-13-en-3α-ol (M3). LC-HRMSMS, GC-MSMS, fractionation and derivatization experiments are combined to identify and characterize for the first time two different glucuronide-acid conjugates of this metabolite in positive human urine samples. In addition, a third glucuronide metabolite was identified, however without isomeric structure determination. The detection of these metabolites is particularly interesting for confirmation analyses, as the method is rapid and requires little sample material

Detection of DHCMT long-term metabolite glucuronides with LC-MSMS as an alternative approach to conventional GC-MSMS analysis

Dehydrochloromethyltestosterone (DHCMT) is one of the most detected illicit used anabolic–androgenic steroids in professional sports. Therefore, a fast and accurate analysis of this substance is of great importance for a constructive fight against doping abuse. The conventional method for the analysis of this drug, GC-MSMS, is very sensitive and selective but also very time- and resource-consuming. With the presented work, a new approach for simple detection with LC-HRMSMS without any sample preparation is introduced. The method is based on the direct analysis of two newly described phase-II metabolites of the DHCMT long-term metabolite 4-chloro-18-nor-17β-hydroxymethyl-17α-methyl-5β-androst-13-en-3α-ol (M3). LC-HRMSMS, GC-MSMS, fractionation and derivatization experiments are combined to identify and characterize for the first time two different glucuronide-acid conjugates of this metabolite in positive human urine samples. In addition, a third glucuronide metabolite was identified, however without isomeric structure determination. The detection of these metabolites is particularly interesting for confirmation analyses, as the method is rapid and requires little sample material

Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study

Purpose: To determine the incidence of and risk factors for adverse cardiac events during catecholamine vasopressor therapy in surgical intensive care unit patients with cardiovascular failure. Methods: The occurrence of any of seven predefined adverse cardiac events (prolonged elevated heart rate, tachyarrhythmia, myocardial cell damage, acute cardiac arrest or death, pulmonary hypertension-induced right heart dysfunction, reduction of systemic blood flow) was prospectively recorded during catecholamine vasopressor therapy lasting at least 12h. Results: Fifty-four of 112 study patients developed a total of 114 adverse cardiac events, an incidence of 48.2% (95% CI, 38.8-57.6%). New-onset tachyarrhythmia (49.1%), prolonged elevated heart rate (23.7%), and myocardial cell damage (17.5%) occurred most frequently. Aside from chronic liver diseases, factors independently associated with the occurrence of adverse cardiac events included need for renal replacement therapy, disease severity (assessed by the Simplified Acute Physiology Score II), number of catecholamine vasopressors (OR, 1.73; 95% CI, 1.08-2.77; p=0.02) and duration of catecholamine vasopressor therapy (OR, 1.01; 95% CI, 1-1.01; p=0.002). Patients developing adverse cardiac events were on catecholamine vasopressors (p<0.001) and mechanical ventilation (p<0.001) for longer and had longer intensive care unit stays (p<0.001) and greater mortality (25.9 vs. 1.7%; p<0.001) than patients who did not. Conclusions: Adverse cardiac events occurred in 48.2% of surgical intensive care unit patients with cardiovascular failure and were related to morbidity and mortality. The extent and duration of catecholamine vasopressor therapy were independently associated with and may contribute to the pathogenesis of adverse cardiac event

Multivariate statistical assessment of a polluted river under nitrification inhibition in the tropics.

A large complex water quality data set of a polluted river, the Tay Ninh River, was evaluated to identify its water quality problems, to assess spatial variation, to determine the main pollution sources, and to detect relationships between parameters. This river is highly polluted with organic substances, nutrients, and total iron. An important problem of the river is the inhibition of the nitrification. For the evaluation, different statistical techniques including cluster analysis (CA), discriminant analysis (DA), and principal component analysis (PCA) were applied. CA clustered 10 water quality stations into three groups corresponding to extreme, high, and moderate pollution. DA used only seven parameters to differentiate the defined clusters. The PCA resulted in four principal components. The first PC is related to conductivity, NH4-N, PO4-P, and TP and determines nutrient pollution. The second PC represents the organic pollution. The iron pollution is illustrated in the third PC having strong positive loadings for TSS and total Fe. The fourth PC explains the dependence of DO on the nitrate production. The nitrification inhibition was further investigated by PCA. The results showed a clear negative correlation between DO and NH4-N and a positive correlation between DO and NO3-N. The influence of pH on the NH4-N oxidation could not be detected by PCA because of the very low nitrification rate due to the constantly low pH of the river and because of the effect of wastewater discharge with very high NH4-N concentrations. The results are deepening the understanding of the governing water quality processes and hence to manage the river basins sustainably

Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial

Purpose: To compare the effects of two arginine vasopressin (AVP) dose regimens on the hemodynamic response, catecholamine requirements, AVP plasma concentrations, organ function and adverse events in advanced vasodilatory shock. Methods: In this prospective, controlled, open-label trial, patients with vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery requiring norepinephrine >0.6μg/kg/min were randomized to receive a supplementary AVP infusion either at 0.033IU/min (n=25) or 0.067IU/min (n=25). The hemodynamic response, catecholamine doses, laboratory and organ function variables as well as adverse events (decrease in cardiac index or platelet count, increase in liver enzymes or bilirubin) were recorded before, 1, 12, 24 and 48h after randomization. A linear mixed effects model was used for statistical analysis in order to account for drop-outs during the observation period. Results: Heart rate and norepinephrine requirements decreased while MAP increased in both groups. Patients receiving AVP at 0.067IU/min required less norepinephrine (P=0.006) than those infused with AVP at 0.033IU/min. Arterial lactate and base deficit decreased while arterial pH increased in both groups. During the observation period, AVP plasma levels increased in both groups (both P<0.001), but were higher in the 0.067IU/min group (P<0.001) and in patients on concomitant hydrocortisone. The rate of adverse events and intensive care unit mortality was comparable between groups (0.033IU/min, 52%; 0.067IU/min, 52%; P=1). Conclusions: A supplementary AVP infusion of 0.067IU/min restores cardiovascular function in patients with advanced vasodilatory shock more effectively than AVP at 0.033IU/mi

Discovering Water Quality Changes and Patterns of the Endangered Thi Vai Estuary in Southern Vietnam through Trend and Multivariate Analysis

Temporal and spatial water quality data are essential to evaluate human health risks. Understanding the interlinking variations between water quality and socio-economic development is the key for integrated pollution management. In this study, we applied several multivariate approaches, including trend analysis, cluster analysis, and principal component analysis, to a 15-year dataset of water quality monitoring (1999 to 2013) in the Thi Vai estuary, Southern Vietnam. We discovered a rapid improvement for most of the considered water quality parameters (e.g., DO, NH4, and BOD) by step trend analysis, after the pollution abatement in 2008. Nevertheless, the nitrate concentration increased significantly at the upper and middle parts and decreased at the lower part of the estuary. Principal component (PC) analysis indicates that nowadays the water quality of the Thi Vai is influenced by point and diffuse pollution. The first PC represents soil erosion and stormwater loads in the catchment (TSS, PO4, and Fetotal); the second PC (DO, NO2, and NO3) determines the influence of DO on nitrification and denitrification; and the third PC (pH and NH4) determines point source pollution and dilution by seawater. Therefore, this study demonstrated the need for stricter pollution abatement strategies to restore and to manage the water quality of the Thi Vai Estuary

Antifactor Xa activity in critically ill patients receiving antithrombotic prophylaxis with standard dosages of certoparin: a prospective, clinical study

INTRODUCTION: Deep venous thrombosis with subsequent pulmonary embolism or post-thrombotic syndrome is a feared complication in the intensive care unit. Therefore, routine prophylactic anticoagulation is widely recommended. Aside from unfractionated heparin, low molecular weight heparins, such as certoparin, have become increasingly used for prophylactic anticoagulation in critically ill patients. In this prospective study, we evaluated the potency of 3,000 IU certoparin administered once daily to reach antithrombotic antifactor Xa (aFXa) levels of 0.1 to 0.3 IU/ml in 62 critically ill patients. METHODS: AFXa levels were determined 4, 12 and 24 h after injection of certoparin. Prothrombin time, activated partial thromboplastin time, antithrombin, fibrinogen, hemoglobin, platelet count, serum urea and creatinine concentrations were documented before and 12 and 24 h after injection of certoparin. RESULTS: Four hours after certoparin injection (n = 32), 28% of patients were within the antithrombotic aFXa range. After 12 and 24 h, 6% achieved antithrombotic aFXa levels. Because of a severe pulmonary embolism in one study patient, an interim analysis was performed, and the dosage of certoparin was increased to 3,000 IU twice daily. This regime attained recommended antithrombotic aFXa levels in 47%, 27%, 40% and 30% of patients at 4, 12, 16 and 24 h, respectively, after twice daily certoparin injection (n = 30). Antithrombin and fibrinogen concentrations slightly increased during the observation period. Low antithrombin concentrations before certoparin were independently correlated with underdosing of certoparin. Patients with aFXa levels <0.1 IU/ml 4 h after certoparin injection required vasopressors more often and had lower serum concentrations of creatinine and urea than patients with antithrombotic aFXa levels. CONCLUSION: Standard dosages of certoparin of 3,000 IU given once or twice daily are ineffective for attaining the recommended aFXa levels of 0.1 to 0.3 IU/ml in critically ill patients. Low antithrombin levels before certoparin administration were independently associated with low aFXa levels. Renal function and vasopressor therapy may further influence the effectiveness of certoparin in ensuring adequate antithrombotic prophylaxis

MHD simulations of formation, sustainment and loss of Quiescent H-mode in the all-tungsten ASDEX Upgrade

Periodic edge localized modes (ELMs) are the non-linear consequences of pressure-gradient-driven ballooning modes and current-driven peeling modes becoming unstable in the pedestal region of high confinement fusion plasmas. In future tokamaks like ITER, large ELMs are foreseen to severely affect the lifetime of wall components as they transiently deposit large amounts of heat onto a narrow region at the divertor targets. Several strategies exist for avoidance, suppression, or mitigation of these instabilities, such as the naturally ELM-free quiescent H-mode (QH-mode). In the present article, an ASDEX Upgrade equilibrium that features a QH-mode is investigated through non-linear extended MHD simulations covering the dynamics over tens of milliseconds. The equilibrium is close to the ideal peeling limit and non-linearly develops saturated modes at the edge of the plasma. A dominant toroidal mode number of $n=1$ is found, for which the characteristic features of the edge harmonic oscillation are recovered. The saturated modes contribute to heat and particle transport preventing pedestal build-up to the ELM triggering threshold. The non-linear dynamics of the mode, in particular its interaction with the evolution of the edge safety factor is studied, which suggest a possible new saturation mechanism for the QH-mode. The simulations show good qualitative and quantitative agreement to experiments in AUG. In particular, the processes leading to the termination of QH-mode above a density threshold is studied, which results in the transition into an ELM regime. In the vicinity of this threshold, limit cycle oscillations are observed.Comment: Revised version with modifications from review process include

Few smooth d-polytopes with n lattice points

We prove that, for fixed n there exist only finitely many embeddings of Q-factorial toric varieties X into P^n that are induced by a complete linear system. The proof is based on a combinatorial result that for fixed nonnegative integers d and n, there are only finitely many smooth d-polytopes with n lattice points. We also enumerate all smooth 3-polytopes with at most 12 lattice points. In fact, it is sufficient to bound the singularities and the number of lattice points on edges to prove finiteness.Comment: 20+2 pages; major revision: new author, new structure, new result