High-Throughput Qualitative and Quantitative Drug Checking by MALDI HRMS.

Illicit drugs are a global health problem, since both their acute and chronic consumption have negative impacts on the drug user's health. Drug checking facilities are receiving growing interest as they allow drug users to chemically analyze their product prior to consumption to assess the presence of adulterants or other non-expected substances. Such harm reduction programs allow the reduction of the risks associated with drug consumption without encouraging it. In particular, the emergence of new psychoactive substances (NPS) emphasizes the risk for the population increasing the diversity and the lability of illicit drugs on the market. Analytical developments are required to catch up with this rapid evolution and reduce the potential harm caused by such consumption. In this study, we developed a matrix-assisted laser desorption/ionization (MALDI) high-resolution mass spectrometry (HRMS) strategy for the high-throughput qualitative and quantitative analysis of drug checking samples. The use of online-based m/z cloud library for untargeted compound search improved the ability to identify unknown compounds. Sixty-seven drug checking samples were analyzed using this analytical strategy, allowing the detection of 10 designer drugs and several classical drugs of abuse (mainly cocaine and MDMA) as well as adulterants and contaminants. The results were then compared with routine analyses of the same samples using conventional approaches showing similar performance while removing the use of chromatographic separation thus resulting in a significant reduction of the time required for sample preparation and analysis. This study enlightens the potential of MALDI-HRMS as a high-throughput approach allowing to speed-up up to six times the identification and quantification of substances enabling to catch the fast changes on the drug of abuse market. This strategy could be an interesting alternative analytical approach, allowing better prevention and harm reduction for drug users

Income Taxes, Sorting, and the Costs of Housing: Evidence from Municipal Boundaries in Switzerland

This paper provides novel evidence on the role of income taxes for residential rents and spatial sorting. Drawing on comprehensive apartment-level data, we identify the effects of tax differentials across municipal boundaries in Switzerland. The boundary discontinuity design (BDD) corrects for unobservable location characteristics such as environmental amenities or the access to public goods and thereby reduces the estimated response of housing prices by one half compared to conventional estimates: we identify an income tax elasticity of rents of about 0.26. We complement this approach with census data on local sociodemographic characteristics and show that about one third of this effect can be traced back to a sorting of high-income households into low-tax municipalities. These findings are robust to a matching approach (MBDD) which compares identical residences on opposite sides of the boundary and a number of further sensitivity checks

Adaptive Patientenunterstützung für Rehabilitationsroboter

Rehabilitation robots support rehabilitation of patients with neurological movement disorders. Newly developed patient-cooperative control approaches aim at enabling the robots to perform more effective trainings, which are tailored to individual patients. This paper presents two approaches to automatically adapt robotic support: The iterative learning feedforward control is able to support movements with defined timing. The iterative learning conservative force field can also support movements with free timing. Both approaches are demonstrated in an example application with the gait rehabilitation robot Lokomat

Plasma ionized magnesium in tubular disorders with and without total hypomagnesemia

Selective electrodes have been designed for determining plasma ionized magnesium. In kidney disease the relationship between ionized and total circulating magnesium is often altered. Hence plasma ionized magnesium (ETH 7025 membrane) was determined in 25 patients with primary renal tubular disorders; 6 patients had total hypomagnesemia. Total plasma magnesium was never reduced in the remaining 19 patients. Plasma ionized magnesium values were low in the 6 patients with total hypomagnesemia. In 18 of the 19 patients without total hypomagnesemia plasma ionized magnesium values were not reduced. Ionized hypomagnesemia was noted in a patient with normal total plasma magnesium in the context of hypercalciuric nephrocalcinosis of unknown origin. The study demonstrates an excellent concordance between plasma total and ionized magnesium in tubular disorders associated with total hypomagnesemia and a good concordance in tubular disorders that are not linked with total hypomagnesemia. The determination of circulating ionized magnesium is of little value in the diagnostic work-up of the vast majority of renal tubular disorders. The determination might perhaps disclose latent hypomagnesemia in nephrocalcinosis of unknown cause

[Oral erythroplakia and erythroleukoplakia: red and red-white dysplastic lesions of the oral mucosa--part 2: cytodiagnosis, pathogenesis, therapy, and prognostic aspects]

The second part of the present review article presents and discusses the current literature regarding cytodiagnostic aspects, pathogenesis, therapy, incidence of recurrence, and malignant transformation rate of oral erythroplakia (OE) and oral erythroleukoplakia (OEL). Oral cytopathology, eventually in combination with DNA cytometry, can add valuable information to conventional histopathology, but is not able yet to replace the aforementioned. Numerous molecular genetic variants have been studied in precancerous lesions to gain knowledge about the prognosis of these lesions. Still, there are no evidence-based parameters available to safely detect precursor lesions that will undergo malignant transformation in the future. Excision of OE and OEL should be performed with a margin of safety using the CO2 laser or a scalpel. Data about incidence of recurrence and malignant tranformation rates of OE are mostly based upon case reports or case series. The OEL has a significantly higher risk of malignant transformation than oral leukoplakias

[Oral erythroplakia and erythroleukoplakia: red and red-white dysplastic lesions of the oral mucosa--part 1: epidemiology, etiology, histopathology and differential diagnosis]

Oral erythroplakia (OE) and oral erythroleukoplakia (OEL; synonym: speckled leukoplakia) are working diagnoses for red and red-white lesions of the oral mucosa after exclusion of all other possible diagnoses for lesions with a similar clinical appearance. A good knowledge of oral medicine and possible differential diagnoses of oral mucosal pathologies is mandatory to correctly detect OE and OEL on this exclusion basis. In the present review article in a series of two, epidemiologic data, etiologic factors, possible differential diagnoses, and the histopathologic characteristics of OE and OEL will be presented and discussed regarding the current literature. A thorough histopathologic examination of these epithelial precursor lesions is mandatory to recognise the presence and the severity of epithelial dysplasia, which is a decisive factor for the subsequent treatment planning

Being over- or underchallenged in class: Effects on students' career aspirations via academic self-concept and boredom

The current study investigated links between students' level of perceived challenge (being over- or underchallenged) and students' career aspirations. We hypothesized indirect effects of over- and underchallenge on career aspirations via academic self-concept and academic trait boredom and tested our hypotheses in a sample of N = 662 Swiss eleventh grade students in the domains of German, French, and mathematics. Our results were consistent across all three domains and showed that being overchallenged had a negative impact on academic self-concept. Lower academic self-concept, in turn, was associated with decreased career aspirations. Being underchallenged enhanced academic self-concept, which was positively related to students' career aspirations. Further, both being over- and underchallenged enhanced students' domain-specific boredom experiences resulting in a decrease in their career aspirations. As such, the effect of being underchallenged was of particular importance as its influence on career aspirations via academic trait boredom was negative, whereas via academic self-concept there was a positive indirect effect

Engineered peptide barcodes for in-depth analyses of binding protein libraries

Binding protein generation typically relies on laborious screening cascades that process candidate molecules individually. We have developed NestLink, a binder selection and identification technology able to biophysically characterize thousands of library members at once without the need to handle individual clones at any stage of the process. NestLink uses genetically encoded barcoding peptides termed flycodes, which were designed for maximal detectability by mass spectrometry and support accurate deep sequencing. We demonstrate NestLink's capacity to overcome the current limitations of binder-generation methods in three applications. First, we show that hundreds of binder candidates can be simultaneously ranked according to kinetic parameters. Next, we demonstrate deep mining of a nanobody immune repertoire for membrane protein binders, carried out entirely in solution without target immobilization. Finally, we identify rare binders against an integral membrane protein directly in the cellular environment of a human pathogen. NestLink opens avenues for the selection of tailored binder characteristics directly in tissues or in living organisms