An MEKC assay for the therapeutic drug monitoring of cefepime

The development of a robust assay based on MEKC for cefepime in human serum and plasma with internal quality assurance is reported. Sample preparation comprises protein precipitation in the presence of SDS at pH 4.5. This is a gentle approach for which decomposition of cefepime during sample handling is negligible. After hydrodynamic sample injection of the supernatant, analysis occurs in a phosphate/borate buffer at pH 9.1 with 75 mM SDS using normal polarity and analyte detection at 257 nm. The MEKC run time interval and throughput are about 5 min and seven samples per hour, respectively. The calibration range for cefepime is 1-60 μg/mL, with 1 μg/mL being the LOQ. The performance of the assay with multilevel internal calibration was assessed with calibration and control samples. The assay is shown to be simple, inexpensive, reproducible, and robust. It was applied to determine cefepime levels in the sera of critically ill patients and to assess the instability of cefepime in patient and control samples. Our data revealed that serum containing cefepime can be stored at -20°C for a short time, whereas for long-term storage, samples have to be kept at -70°C.

Multiplex Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir, and Telaprevir

New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy.

Electrocardiographic ST-segment monitoring during controlled occlusion of coronary arteries

Background: Ischemia monitoring cannot always be performed by 12-lead ECG. Hence, the individual performance of the ECG leads is crucial. No experimental data on the ECG's specificity for transient ischemia exist. Methods: In 45 patients a 19-lead ECG was registered during a 1-minute balloon occlusion of a coronary artery (left anterior descending artery [LAD], right coronary artery [RCA] or left circumflex artery [LCX]). ST-segment shifts and sensitivity/specificity of the leads were measured. Results: During LAD occlusion, V3 showed maximal ST-segment elevation (0.26 mV [IQR 0.16–0.33 mV], p = 0.001) and sensitivity/specificity (88% and 80%). During RCA occlusion, III showed maximal ST-elevation (0.2 mV [IQR 0.09–0.26 mV], p = 0.004), aVF had the best sensitivity/specificity (85% and 68%). During LCX occlusion, V6 showed maximal ST-segment elevation (0.04 mV [IQR 0.02–0.14 mV], p = 0.005), and sensitivity/specificity was (31%/92%) but could be improved (63%/72%) using an optimized cut-off for ischemia. Conclusion: V3, aVF and V6 show the best performance to detect transient ischemia.

Beyond monitoring: After-effects of responding to prospective memory targets

Responding to bivalent stimuli (i.e., stimuli with features relevant for different tasks) slows subsequent performance. In prospective memory research, prospective memory targets can be considered as bivalent stimuli because they typically involve features relevant for both the prospective memory task and the ongoing task. The purpose of this study was to investigate how responding to a prospective memory target slows subsequent performance. In two experiments, we embedded the prospective memory task in a task-switching paradigm and we manipulated the degree of task-set overlap between the prospective memory task and the ongoing task. The results showed consistent after-effects of responding to prospective memory targets. The specific trajectory of the slowing depended on the amount of task-set overlap. These results demonstrate that responding to prospective memory targets results in after-effects, a so far neglected cost on ongoing task performance.

Comparative evaluation of the My5-FU™ immunoassay and LC-MS/MS in monitoring the 5-fluorouracil plasma levels in cancer patients

BACKGROUND: Chemotherapies of solid tumors commonly include 5-fluorouracil (5-FU). With standard doses of 5-FU, substantial inter-patient variability has been observed in exposure levels and treatment response. Recently, improved outcomes in colorectal cancer patients due to pharmacokinetically guided 5-FU dosing were reported. We aimed at establishing a rapid and sensitive method for monitoring 5-FU plasma levels in cancer patients in our routine clinical practice. METHODS: Performance of the Saladax My5-FU™ immunoassay was evaluated on the Roche Cobas® Integra 800 analyzer. Subsequently, 5-FU concentrations of 247 clinical plasma samples obtained with this assay were compared to the results obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and other commonly used clinical analyzers (Olympus AU400, Roche Cobas c6000, and Thermo Fisher CDx90). RESULTS: The My-FU assay was successfully validated on the Cobas Integra 800 analyzer in terms of linearity, precision, accuracy, recovery, interference, sample carryover, and dilution integrity. Method comparison between the Cobas Integra 800 and LC-MS/MS revealed a proportional bias of 7% towards higher values measured with the My5-FU assay. However, when the Cobas Integra 800 was compared to three other clinical analyzers in addition to LC-MS/MS including 50 samples representing the typical clinical range of 5-FU plasma concentrations, only a small proportional bias (≤1.6%) and a constant bias below the limit of detection was observed. CONCLUSIONS: The My5-FU assay demonstrated robust and highly comparable performance on different analyzers. Therefore, the assay is suitable for monitoring 5-FU plasma levels in routine clinical practice and may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies.

The Swiss Neonatal Quality Cycle, a monitor for clinical performance and tool for quality improvement

BACKGROUND We describe the setup of a neonatal quality improvement tool and list which peer-reviewed requirements it fulfils and which it does not. We report on the so-far observed effects, how the units can identify quality improvement potential, and how they can measure the effect of changes made to improve quality. METHODS Application of a prospective longitudinal national cohort data collection that uses algorithms to ensure high data quality (i.e. checks for completeness, plausibility and reliability), and to perform data imaging (Plsek's p-charts and standardized mortality or morbidity ratio SMR charts). The collected data allows monitoring a study collective of very low birth-weight infants born from 2009 to 2011 by applying a quality cycle following the steps 'guideline - perform - falsify - reform'. RESULTS 2025 VLBW live-births from 2009 to 2011 representing 96.1% of all VLBW live-births in Switzerland display a similar mortality rate but better morbidity rates when compared to other networks. Data quality in general is high but subject to improvement in some units. Seven measurements display quality improvement potential in individual units. The methods used fulfil several international recommendations. CONCLUSIONS The Quality Cycle of the Swiss Neonatal Network is a helpful instrument to monitor and gradually help improve the quality of care in a region with high quality standards and low statistical discrimination capacity.

Growth Codes: Intermediate Performance Analysis and Application to Video

Growth codes are a subclass of Rateless codes that have found interesting applications in data dissemination problems. Compared to other Rateless and conventional channel codes, Growth codes show improved intermediate performance which is particularly useful in applications where partial data presents some utility. In this paper, we investigate the asymptotic performance of Growth codes using the Wormald method, which was proposed for studying the Peeling Decoder of LDPC and LDGM codes. Compared to previous works, the Wormald differential equations are set on nodes' perspective which enables a numerical solution to the computation of the expected asymptotic decoding performance of Growth codes. Our framework is appropriate for any class of Rateless codes that does not include a precoding step. We further study the performance of Growth codes with moderate and large size codeblocks through simulations and we use the generalized logistic function to model the decoding probability. We then exploit the decoding probability model in an illustrative application of Growth codes to error resilient video transmission. The video transmission problem is cast as a joint source and channel rate allocation problem that is shown to be convex with respect to the channel rate. This illustrative application permits to highlight the main advantage of Growth codes, namely improved performance in the intermediate loss region.

Therapeutic drug monitoring of once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling strategy.

PURPOSE Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC0-24 and peak concentrations (C max). METHODS We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method). RESULTS For tobramycin and gentamicin, AUC0-24 and C max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC0-24 could reliably be estimated by both methods. C max was underestimated by 10-20% by the two-point method and by up to 30% with a large variation by the Bayesian method. CONCLUSIONS The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8-10 h after start of the infusion for the second time-point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions.

Monitoring and data quality assessment of the ATLAS liquid argon calorimeter

The liquid argon calorimeter is a key component of the ATLAS detector installed at the CERN Large Hadron Collider. The primary purpose of this calorimeter is the measurement of electron and photon kinematic properties. It also provides a crucial input for measuring jets and missing transverse momentum. An advanced data monitoring procedure was designed to quickly identify issues that would affect detector performance and ensure that only the best quality data are used for physics analysis. This article presents the validation procedure developed during the 2011 and 2012 LHC data-taking periods, in which more than 98% of the proton-proton luminosity recorded by ATLAS at a centre-of-mass energy of 7–8 TeV had calorimeter data quality suitable for physics analysis.

Oxygen-transfer performance of a newly designed, very low-volume membrane oxygenator.

OBJECTIVES Oxygenation of blood and other physiological solutions are routinely required in fundamental research for both in vitro and in vivo experimentation. However, very few oxygenators with suitable priming volumes (<2-3 ml) are available for surgery in small animals. We have designed a new, miniaturized membrane oxygenator and investigated the oxygen-transfer performance using both buffer and blood perfusates. METHODS The mini-oxygenator was designed with a central perforated core-tube surrounded by parallel-oriented microporous polypropylene hollow fibres, placed inside a hollow shell with a lateral-luer outlet, and sealed at both extremities. With this design, perfusate is delivered via the core-tube to the centre of the mini-oxygenator, and exits via the luer port. A series of mini-oxygenators were constructed and tested in an in vitro perfusion circuit by monitoring oxygen transfer using modified Krebs-Henseleit buffer or whole porcine blood. Effects of perfusion pressure and temperature over flows of 5-60 ml × min(-1) were assessed. RESULTS Twelve mini-oxygenators with a mean priming volume of 1.5 ± 0.3 ml were evaluated. With buffer, oxygen transfer reached a maximum of 14.8 ± 1.0 ml O2 × l(-1) (pO2: 450 ± 32 mmHg) at perfusate flow rates of 5 ml × min(-1) and decreased with an increase in perfusate flow to 7.8 ± 0.7 ml ml O2 × l(-1) (pO2: 219 ± 24 mmHg) at 60 ml × min(-1). Similarly, with blood perfusate, oxygen transfer also decreased as perfusate flow increased, ranging from 33 ± 5 ml O2 × l(-1) at 5 ml × min(-1) to 11 ± 2 ml O2 × l(-1) at 60 ml × min(-1). Furthermore, oxygen transfer capacity remained stable with blood perfusion over a period of at least 2 h. CONCLUSIONS We have developed a new miniaturized membrane oxygenator with an ultra-low priming volume (<2 ml) and adequate oxygenation performance. This oxygenator may be of use in overcoming current limitations in equipment size for effective oxygenation in low-volume perfusion circuits, such as small animal extracorporeal circulation and ex vivo organ perfusion.

A simulation study on the statistical monitoring of condemnation rates from slaughterhouses for syndromic surveillance: an evaluation based on Swiss data

Syndromic surveillance (SyS) systems currently exploit various sources of health-related data, most of which are collected for purposes other than surveillance (e.g. economic). Several European SyS systems use data collected during meat inspection for syndromic surveillance of animal health, as some diseases may be more easily detected post-mortem than at their point of origin or during the ante-mortem inspection upon arrival at the slaughterhouse. In this paper we use simulation to evaluate the performance of a quasi-Poisson regression (also known as an improved Farrington) algorithm for the detection of disease outbreaks during post-mortem inspection of slaughtered animals. When parameterizing the algorithm based on the retrospective analyses of 6 years of historic data, the probability of detection was satisfactory for large (range 83-445 cases) outbreaks but poor for small (range 20-177 cases) outbreaks. Varying the amount of historical data used to fit the algorithm can help increasing the probability of detection for small outbreaks. However, while the use of a 0·975 quantile generated a low false-positive rate, in most cases, more than 50% of outbreak cases had already occurred at the time of detection. High variance observed in the whole carcass condemnations time-series, and lack of flexibility in terms of the temporal distribution of simulated outbreaks resulting from low reporting frequency (monthly), constitute major challenges for early detection of outbreaks in the livestock population based on meat inspection data. Reporting frequency should be increased in the future to improve timeliness of the SyS system while increased sensitivity may be achieved by integrating meat inspection data into a multivariate system simultaneously evaluating multiple sources of data on livestock health.