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Rodent cancer bioassays have been long-required studies for regulatory assessment of human cancer hazard and risk. These studies use hundreds of animals, are resource intensive, and certain aspects of these studies have limited human relevance. The past 10 years have seen an exponential growth of new technologies with the potential to effectively evaluate human cancer hazard and risk while reducing, refining, or replacing animal use. To streamline and facilitate uptake of new technologies, a workgroup comprised of scientists from government, academia, non-governmental organizations, and industry stakeholders developed a framework for waiver rationales of rodent cancer bioassays for consideration in agrochemical safety assessment. The workgroup used an iterative approach, incorporating regulatory agency feedback, and identifying critical information to be considered in a risk assessment-based weight of evidence determination of the need for rodent cancer bioassays. The reporting framework described herein was developed to support a chronic toxicity and carcinogenicity study waiver rationale, which includes information on use pattern(s), exposure scenario(s), pesticidal mode-of-action, physicochemical properties, metabolism, toxicokinetics, toxicological data including mechanistic data, and chemical read-across from similar registered pesticides. The framework could also be applied to endpoints other than chronic toxicity and carcinogenicity, and for chemicals other than agrochemicals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study sought to determine pharmacy students' self-assessment of their level of competency in specified global health statements across various schools. It also evaluated attributes associated with competency and perception of importance, as well as explored students' perspectives on how best to incorporate global health content into pharmacy education., Methods: Cross-sectional survey administered online to pharmacy students from three pharmacy schools in the United States., Results: The self-assessed competency of pharmacy students in global health topic areas was low. Current or prior exposures outside of the PharmD curriculum to the global health content presented in the survey were significant indicators of self-assessed competency scores. Within individual participating schools, demographic characteristics such as gender, age category, speaking a non-English language, and progression through the PharmD curriculum were also significantly associated with competency scores reported. Most respondents (96%) agreed that relevant global health education should be incorporated into the pharmacy curriculum., Conclusions: Pharmacy students generally perceive global health competencies to be of great importance in practice, but acknowledge their deficiencies in this area. The current burden of global health education at the schools surveyed relies on individual student experience rather than curricular support. Ensuring that future pharmacists understand their role in global health teams and are able to achieve the necessary level of competency to function in interdisciplinary initiatives will require more strategic incorporation of relevant content into the curriculum., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This article describes a qualitative research study using a semi-structured interview process to describe barriers surrounding medication access, use, and adherence for recently discharged patients of a federally qualified health center. Common themes which emerged were: 1) Team assumptions regarding patient plans to access or appropriately use discharge medications negatively impact adherence; 2) Unmet expectation for care coordination between primary care physician (PCP) and hospital; 3) Disconnect between patients and health care workers leads to disengagement; and 4) Lack of personal contact hinders access to services., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The liver is known to be structurally abnormal in long-standing Fontan circulation. The degree of liver dysfunction associated with such abnormalities is however largely unknown. We assessed structural changes (serum fibrosis markers) and function (indocyanine green clearance (ICG)) in Fontan patients., Methods: 21 stable Fontan patients were prospectively assessed and compared with 8 histologically proven compensated viral cirrhotic patients. All subjects had standard liver profile, "Enhanced Liver Fibrosis" (ELF) score (including hyaluronic acid, aminoterminal type III procollagen peptide P3NP and tissue inhibitor of metalloproteinase TIMP-1 levels), and ICG using the LiMON Device. Plasma disappearance rate (PDR) and 15-minute retention (R15) were recorded after ICG infusion., Results: Indocyanine clearance and retention (PDR and R15) were similar between Fontan and compensated cirrhotic patients (17 ± 5 vs 18 ± 6 (p=0.75) and 11 ± 10 vs 10 ± 10 (p=0.75)), as was degree of fibrosis (7.97 ± 1.16 vs 9.0 ± 1.43, p=NS). There was a positive correlation between PDR and ELF (R=0.77, p=0.028) as well as R15 and ELF (R=0.905, p=0.002) in the viral cirrhotics but not in the Fontan group. (R=-0.243, p=0.302; and R=0.226, p=0.338). PDR (17 ± 5) and R15 (11 ± 10) were not significantly different in Fontan as compared with the established cirrhotics., Conclusions: Fontan patients have similar global hepatic function and fibrosis as compared with viral cirrhotic patients. However in Fontan patients, fibrosis was not closely correlated with global liver function, whereas viral cirrhotic patients exhibited a close correlation between function and fibrosis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Hypervascular nodules occur commonly when there is hepatic venous outlet obstruction. Their nature and determinants in the Fontan circulation is poorly understood. We reviewed the records of 27 consecutive Fontan patients who had computerized tomography scan (CT) over a 4 year period for arterialised nodules and alterations in hepatic flow patterns during contrast enhanced CT scans and related these findings to cardiac characteristics. Mean patient age was 24 ± 5.8 years, (range 16.7-39.8) and mean Fontan duration was 16.8 ± 4.8 years (range 7.3-28.7). Twenty-two patients demonstrated a reticular pattern of enhancement, 4 a zonal pattern and only 1 demonstrated normal enhancement pattern. Seven (26%) patients had a median of 4 (range 1-22) arterialised nodules, mean size 1.8 cm (range 0.5 to 3.2 cm). All nodules were located in the liver periphery, their outer aspect lying within 2 cm of the liver margin. Patients with nodules had higher mean RA pressures (18 mmHg ± 5.6 vs. 13 mmHg ± 4, p=0.025), whereas their mixed venous saturation and aortic saturation was not significantly different (70% ± 11 vs. 67% ± 9 and 92% ± 10 vs. 94% ± 4, p>0.05). Post-mortem histology suggests focal nodular hyperplasia is the underlying pathology. ConclusionsAbnormalities of hepatic blood flow and the presence of arterialised nodules are common in the failing Fontan circulation. They occur especially when central venous pressures are high, and very likely indicate arterialisation of hepatic blood flow and reciprocal portal venous deprivation. The underlying pathology is most likely focal nodular hyperplasia., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Dietary fats modulate a wide variety of T cell functions in mice and humans. This study examined the effects of four different dietary fats, predominantly polyunsaturated sunflower oil, margarine, and predominantly saturated butter, clarified butter, on the T cell-mediated, systemic suppression of contact hypersensitivity by ultraviolet radiation in the Skh:HR-1 hairless mouse. Diets containing either 200 g/kg or 50 g/kg butter or clarified butter as the sole fat source protected against systemic photoimmunosuppression, whether the radiation source was unfiltered ultraviolet B (280-320 nm) or filtered solar simulated ultraviolet radiation (290-400 nm), in comparison with diets containing either 200 or 50 g/kg margarine or sunflower oil. There was a linear relationship (r > 0.9) between protection against photoimmunosuppression and the proportion of clarified butter in mice fed a series of 200 g/kg mixed fat diets that provided varying proportions of clarified butter and sunflower oil. The dietary fats did not modulate the contact hypersensitivity reaction in unirradiated animals. The observed phenomena were not primary due to the carotene, tocopherol, cholecalciferol, retinol, lipid hydroperoxide or the nonfat solid content of the dietary fats used and appeared to be a result of the different fatty acid composition of the fats.

Evidence exists implicating the epidermal ultraviolet B (UVB) photoproduct cis-urocanic acid as an immunogenic mediator of the systemic suppression of T cell-mediated immunity by UVB exposure. Cis-urocanic acid appears to act via histamine receptor pathways, and histamine receptor antagonists and other imidazole ring compounds may modify its immune suppressing action. A component of the food coloring substance ammonia caramel, 2-acetyl-4-tetrahydroxybutylimidazole (THI), which is known to cause lymphopenia in rats, appears to suppress immunity by a similar pathway when the contact hypersensitivity reaction has been the immune function assay in mice. The induction of lymphopenia in rats by THI is inhibited by the vitamin pyridoxine. This study demonstrates that the suppression of contact hypersensitivity in mice by UVB radiation, cis-urocanic acid, or THI is strongly inhibited by supplemental pyridoxine, fed at 30 mg/kg diet, in comparison with the normal diet, which supplies 7 mg pyridoxine/kg diet. These results suggest that pyridoxine competes with cis-urocanic acid and THI for the same binding site or receptor, which we postulate to be a histamine-like T lymphocyte receptor, and that a role may exist for the control of photoimmunosuppression by this vitamin.