CATMoS: Collaborative Acute Toxicity Modeling Suite.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495

Effect of the gingival display on posed smile with different facial forms: A comparison of dentists and patients concepts

Aim: The aim of this study was to evaluate and compare the importance of amount of gingival display on smile esthetics and facial attractiveness in males and females with different facial forms by orthodontists as well as lay person. Materials and Methods: Frontal photographs of 18 male and female patients (9 male and 9 female) each, at a posed smile, seeking treatment in the Department of Orthodontics and Dentofacial Orthopedics were obtained. The photographs were divided in 3 groups based on their facial forms (Short face, Average face and Long face) and were altered by moving the dentition within the lip frame of the captured photograph to bring about different gingival display at smile. The pictures were divided into six groups with gingival exposures of 0 mm, 1 mm, 2 mm, 3 mm, 4 mm and 5 mm. The pictures were rated for attractiveness by four sets of evaluators - male and female Orthodontists and male and female lay evaluators. The statistical analysis methods used for the study included Mean score calculation, standard deviation and Analysis of variance: [test (Mono- Variance)]. The Student t test (two tailed, independent) has been used to find the significance of rating scores between lay person and orthodontist, and also between males and females evaluators. Results: No significant difference in ratings of gingival display in the 3 groups of photographs was noted by lay person and orthodontists. The results point to the fact that the influence of amount of gingival display on smile esthetics was independent of the facial form. It was also observed that gingival display of 0 mm to 2 mm was acceptable to both the lay person and the orthodontists. Conclusion: As the amount of gingival display increased, the ratings for facial attractiveness by both orthodontists and lay person decreased. Higher scores were given by both orthodontists and lay person for photographs which showed gingival display of 0-2 mm, suggesting this value to be most acceptable

Physiologically-Based Pharmacokinetic Modeling in Lead Optimization I: Evaluation and Adaptation of GastroPlus® to Predict Bioavailability of Medchem Series

When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modify properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models have poor performance and projects have too little data to train local %F QSPR models. Physiologically-based pharmacokinetics (PBPK) models simulate the movement of a drug through an animal. Usually, PBPK simulations are carefully tuned for a few advanced drug candidates, using a combination of in vitro, in vivo and calculated inputs, to estimate human doses for clinical trials, or to prioritize compounds for expensive animal studies. Attempts to build global PBPK models based purely on calculated inputs have not achieved the <2-fold average error needed to guide lead optimization. In this work, local GastroPlus PBPK models are instead customized for individual medchem series. The key innovation was building a local QSPR for a numerically fitted effective intrinsic clearance (CLloc). All inputs are subsequently computed from structure alone, so the models can be applied in advance of synthesis. Training CLloc on the first 15 – 18 rat %F measurements gave adequate predictions, with clear improvements up to about 30 measurements, and incremental improvements beyond that

Accurate Small Deformation Exponential Approximant to Integrate Large Velocity Fields:Application to Image Registration

One of the basic components of diffeomorphic image registration algorithms based on velocity fields is the numerical method used to integrate velocity parameters and obtain spatial transformations as displacement fields. When the input velocity field does not depend on the time parameter, the solution is often referred to as the Lie exponential of the velocity field. In this work, we present an integration method for its numerical computation based both on a generalization of the scaling and squaring algorithm and on a class of numerical integrators aimed to solve systems of ordinary differential equations called exponential integrators. This new method led to the introduction of three numerical integrators, and the subsequent validation are performed on synthetic deformations and real medical images

Parametric non-rigid registration using a stationary velocity field

The Free-Form Deformation (FFD) algorithm is a widely-used approach for non-rigid registration. Modifications have previously been proposed to ensure topology preservation and invertibility within this framework. However, in practice, none of these yield the inverse transformation itself, and one loses the parsimonious B-spline parameterisation. © 2012 IEEE