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

HP-08-004 Factors involved in sexual function and sexual satisfaction in patients undergoing inflatable penile prosthesis implantation

Objective: Penile prosthesis implantation (PPI) represents the gold standard treatment for erectile dysfunction when conservative approaches (oral PDE-5 inhibitors, transurethral suppositories or prostaglandin injections) fail. Although many studies about PPI have been published so far, data about psychosexual dimensions and attitudes towards sexuality are lacking. The aim of this study was to analyse the factors involved in sexual function and sexual satisfaction in patients undergoing inflatable penile prosthesis implantation. Methods: We revised our institutional database of patients undergoing IPP implantation between January 2010 and June 2015. Exclusion criteria were: simultaneous urinary incontinence, simultaneous surgery for congenital or acquired recurvatum, previous urethral or penile surgery, removal of the prosthesis due to malfunction/infection. All patients were assessed pre- and postoperatively with detailed medical history, physical examination and scoring of sexual outcomes by validated questionnaires including the International Index of Erectile Function (IIEF), ISS (Index of Sexual Satisfaction) and Brief Sexual Attitudes Scale (BSAS) and a questionnaire designed at our referral center for penile surgery to ascertain time to and frequency of PPI use, and postoperative changes in penis size perception. Univariable and multivariable analyses were performed determine predictors of sexual outcomes. Results: Overall, 42 men met study criteria and were included in the analysis. Mean (SD) age was 62.3±7.1 (range 47-77). Among the several findings, the erectile function was the main predictor related to sexual satisfaction ISS total score (F(1,21)¼5.40; p<.05). Moreover, the highest number prosthesis activation, regardless of sexual activity, was positively correlated with a future higher frequency of sexual activity (r¼.69; p<.01). Conclusion: Several factors affect the resumption of sexual activity and the sexual satisfaction of patients after the prosthetic implant. This study revealed some interesting data for the pursuit of the best sexual outcome. Policy of full disclosure: Non

Human bone marrow-derived mesenchymal stromal cells reduce the severity of experimental necrotizing enterocolitis in a concentration-dependent manner

: Necrotizing enterocolitis (NEC) is a devastating gut disease in preterm neonates. In NEC animal models, mesenchymal stromal cells (MSCs) administration has reduced the incidence and severity of NEC. We developed and characterized a novel mouse model of NEC to evaluate the effect of human bone marrow-derived MSCs (hBM-MSCs) in tissue regeneration and epithelial gut repair. NEC was induced in C57BL/6 mouse pups at postnatal days (PND) 3–6 by (A) gavage feeding term infant formula, (B) hypoxia/hypothermia, and (C) lipopolysaccharide. Intraperitoneal injections of PBS or two hBM-MSCs doses (0.5 × 106 or 1 × 106 ) were given on PND2. At PND 6, we harvested intestine samples from all groups. The NEC group showed an incidence of NEC of 50% compared with controls (p < 0.001). Severity of bowel damage was reduced by hBM-MSCs compared to the PBS-treated NEC group in a concentration-dependent manner, with hBM-MSCs (1 × 106 ) inducing a NEC incidence reduction of up to 0% (p < 0.001). We showed that hBM-MSCs enhanced intestinal cell survival, preserving intestinal barrier integrity and decreasing mucosal inflammation and apoptosis. In conclusion, we established a novel NEC animal model and demonstrated that hBM-MSCs administration reduced the NEC incidence and severity in a concentration-dependent manner, enhancing intestinal barrier integrity