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In LC full scan based MS screening methods correct mass assignment is essential. Parameters affecting the accuracy of mass assignment, i.e., analyte concentration, complexity of the matrix, and resolving power, were studied using typical examples from the field of residue and contaminant analysis in food and feed. The evaluation was carried out by analyzing samples of honey and animal feed, spiked with 151 pesticides, veterinary drugs, mycotoxins, and plant toxins at levels ranging from 10 to 250 ng/g. Analyses were performed using a single stage Orbitrap with resolving power settings varying from 10,000 to 100,000 (FWHM). For consistent and reliable mass assignment (<2 ppm) of analytes at low levels in complex matrices, a high resolving power (≥50,000) was found to be required. At lower resolving power settings, the error in the assignment of mass increased due to the coelution of analytes with interferences at the same nominal mass. This negatively affected selectivity and quantitative performance due to the inability to use the required narrow mass-extraction windows. In the case of the less complex honey matrix, a resolving power of 25,000 was generally sufficient to obtain a mass assignment error close to the typical instrument mass accuracy (≤2 ppm) down to low concentration levels of 10 ng/g. Mass resolving power and complexity of the sample are major parameters affecting the accuracy of mass assignment in multi-residue screening applications.

Current approaches to discovery-stage drug metabolism studies (pharmacokinetics, microsomal stability, etc.) typically use triple-quadrupole–based approaches for quantitative analysis. This necessitates the optimization of parameters such as Q1 and Q3 m/z values, collision energy, and interface voltages. These studies detect only the specified compound and information about other components, such as metabolites, is lost. The ability to perform full-scan acquisition for quantitative analysis would eliminate the need for compound optimization while enabling the detection of metabolites and other non-drug-related endogenous components. Such an instrument would have to provide sensitivity, selectivity, dynamic range, and scan speed suitable for discovery-stage quantitative studies. In this study, a prototype benchtop Orbitrap-based mass analyzer was used to collect both quantitative and qualitative data from human microsomal incubation samples as well as rat plasma from pharmacokinetic studies. Instrumental parameters such as scan speed, resolution, and mass accuracy are discussed in relation to the requirements for a quantitative–qualitative workflow. The ability to perform highly selective quantitative analysis while simultaneously characterizing metabolites from both in vitro and in vivo studies is discussed. Quantitative and qualitative data acquisition for drug metabolism and pharmacokinetics–related drug discovery assays is achieved using high-resolution mass spectrometry on a benchtop Orbitrap mass spectrometer.

A complete automation package has been developed for data acquisition, processing, interpreting, and e-mailing of high-resolution exact-mass electron impact (EI) and chemical ionization (CI) mass spectrometry data. A commercial high performance magnetic sector mass spectrometer equipped with a commercial programmable robotic direct probe was used. The software package contains a series of modules that automatically performs all the functions necessary for data reduction and reporting. In sequential order, these functions include downloading of sample information from a corporate database, creation of a sample list, acquisition of high-resolution exact-mass data, processing of the data, generation of an exact-mass report, e-mailing of the results to the requesting chemists, and finally shutting down of the instrument. The performance of the system was evaluated with nearly 500 samples. The system was found to be reliable and robust with a small average systematic mass error of −0.47 mmu and a standard deviation of 1.61 mmu.

Results Comparison of mass measurements at medium and high resolution settings clearly indicates the need for high resolution for screening of compounds in complex matrix samples. Since in many cases interferences cannot be resolved from the analytes, medium resolution results in poor mass accuracies (>10 ppm).

The use of antibodies against tumour necrosis factor (TNF) has markedly improved the treatment of Crohn's disease, but only certain patients respond to therapy. Here, Raja Atreya and colleagues have developed an approach using topical fluorescent antibodies to TNF and confocal laser endomicroscopy to evaluate the expression of transmembrane TNF (mTNF) in the intestinal mucosa of patients with active Crohn's disease in order to identify patients likely to respond to subsequent treatment with the anti-TNF therapy, adalimumab. As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF + immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF + cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF + cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.

This paper studies a principal—agent relation in which the principal's private information about the agent's effort choice is more accurate than a noisy public performance measure. For some contingencies the optimal contract has to specify ex post inefficiencies in the form of inefficient termination (firing the agent) or wasteful activities that are formally equivalent to third-party payments (money burning). Under the optimal contract, the use of these instruments depends not only on the precision of public information but also on job characteristics. Money burning is used at most in addition to firing and only if the loss from termination is small. The agent's wage may depend only on the principal's report and not on the public signal. Nonetheless, public information is valuable as it facilitates truthful subjective evaluation by the principal.