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Object mouthing is associated with several potential deleterious side effects. In the current investigation, we modified the use of noncontingent access to competing items (food) and evaluated the effects of the treatment on object mouthing across three settings. Results demonstrated reductions in mouthing associated with the modified treatment. DESCRIPTORS: automatic reinforcement, object mouthing, noncontingent reinforcement

Stimulus fading was combined with differential reinforcement and extinction to increase intake of a calorie-dense fluid by a 6-year-old child with feeding problems. The fading procedure consisted of adding Carnation Instant Breakfast [TM] and then milk to water (a fluid the child would drink). DESCRIPTORS: fading, food refusal, food selectivity, pervasive developmental disorder

Background: Computed tomography pulmonary angiography (CTPA) detects incidental findings that require follow-up. In just over 50% of cases, those incidental findings are pulmonary nodules. Fleischner guidelines recommend that patients with nodules that have a high risk of malignancy should undergo CT follow-up within 3-12 months., Objective: We examined the proportion of patients with pulmonary nodules requiring follow up who received repeat imaging within six weeks of the time frame recommended by the radiologist., Design: This retrospective cohort study included all patients who underwent CTPA in the emergency department and inpatient settings at three teaching hospitals in Toronto, Canada between September 1, 2014, and August 31, 2015. Natural language processing software was applied to a linked radiology information system to identify all CTPAs that contained pulmonary nodules. Using manual review and prespecified exclusion criteria, we generated a cohort with possible new lung malignancy eligible for follow-up imaging; then we reviewed available health records to determine whether follow-up had occurred., Results: Of the 1,910 CTPAs performed over the study period, 674 (35.3%) contained pulmonary nodules. Of the 259 patients with new nodules eligible for follow-up imaging, 65 received an explicit suggestion for follow-up by radiology (25.1%). Of these 65 patients, 35 (53.8%) did not receive repeat imaging within the recommended time frame. Explicit mention that follow-up was required in the discharge summary (P = .03), attending an outpatient follow-up visit (P < .001), and younger age (P = .03) were associated with receiving timely follow-up imaging., Conclusions: Over 50% of patients with new high-risk pulmonary nodules detected incidentally on CTPA did not receive timely follow-up imaging.

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.

Pharmacological inhibitors of the transforming growth factor β (TGFβ) type I receptor (ALK5) have shown promise in blocking growth of xenotransplanted cancer cell lines but the effect on a multistage cancer model is not known. To test this, we treated mouse skin with SB431542 (SB), a well-characterized ALK5 inhibitor, during a two-stage skin carcinogenesis assay. Topical SB significantly reduced the total number, incidence and size of papillomas compared with 12-O-tetradecanoylphorbol 13-acetate (TPA) promotion alone, and this was linked to increased epidermal apoptosis, decreased proliferation and decreased cutaneous inflammation during promotion. In contrast, the frequency of conversion to squamous cell carcinoma (SCC) was 2-fold higher in papillomas treated with SB. Although there was no difference in tumor cell proliferation in early premalignant lesions, those that formed after SB treatment exhibited reduced squamous differentiation and an altered inflammatory microenvironment similar to SCC. In an inducible epidermal RAS transgenic model, treatment with SB enhanced proliferation and cutaneous inflammation in skin but decreased expression of keratin 1 and increased expression of simple epithelial keratin 18, markers of premalignant progression. In agreement with increased frequency of progression in the multistage model, SB treatment resulted in increased tumor formation with a more malignant phenotype following long-term RAS induction. In contrast to the current paradigm for TGFβ in carcinogenesis, these results demonstrate that cutaneous TGFβ signaling enables promotion of benign tumors but suppresses premalignant progression through context-dependent regulation of epidermal homeostasis and inflammation.