KnowTox: pipeline and case study for confident prediction of potential toxic effects of compounds in early phases of development

Risk assessment of newly synthesised chemicals is a prerequisite for regulatory approval. In this context, in silico methods have great potential to reduce time, cost, and ultimately animal testing as they make use of the ever-growing amount of available toxicity data. Here, KnowTox is presented, a novel pipeline that combines three different in silico toxicology approaches to allow for confident prediction of potentially toxic effects of query compounds, i.e. machine learning models for 88 endpoints, alerts for 919 toxic substructures, and computational support for read-across. It is mainly based on the ToxCast dataset, containing after preprocessing a sparse matrix of 7912 compounds tested against 985 endpoints. When applying machine learning models, applicability and reliability of predictions for new chemicals are of utmost importance. Therefore, first, the conformal prediction technique was deployed, comprising an additional calibration step and per definition creating internally valid predictors at a given significance level. Second, to further improve validity and information efficiency, two adaptations are suggested, exemplified at the androgen receptor antagonism endpoint. An absolute increase in validity of 23% on the in-house dataset of 534 compounds could be achieved by introducing KNNRegressor normalisation. This increase in validity comes at the cost of efficiency, which could again be improved by 20% for the initial ToxCast model by balancing the dataset during model training. Finally, the value of the developed pipeline for risk assessment is discussed using two in-house triazole molecules. Compared to a single toxicity prediction method, complementing the outputs of different approaches can have a higher impact on guiding toxicity testing and de-selecting most likely harmful development-candidate compounds early in the development process

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

Die Bestimmung der p-Aminobenzoesäure mit Fluram® im Urin nach Durchführung des Pankreasfunktionstests mit Bentiromid

Peer Reviewe

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

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.Link_to_subscribed_fulltex