Toxicity Testing in the 21st Century: Defining New Risk Assessment Approaches Based on Perturbation of Intracellular Toxicity Pathways

The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) “toxicity pathways” (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Tratamentos superficiais visando à melhoria da aderência entre gesso e taliscas de bambu Surface treatments aimed at improving the adhesion between plaster and bamboo slivers

O gesso é um aglomerante com aplicações sobretudo na fabricação de placas de forro, elementos decorativos e em paredes divisórias. No entanto, utilizando-se de uma baixa relação água/gesso e procedimentos tais como vibração, torna-se possível obter resistências mecânicas compatíveis para outras aplicações na construção civil, como é o caso de elementos estruturais. A investigação reportada no presente trabalho teve como objetivo avaliar, experimentalmente, a possibilidade de se melhorar o compósito estudado. Foram realizados tratamentos para redução da absorção de água pelas taliscas, por meio da utilização de extrato vegetal B Carbon, resina polimérica e piche. Na tentativa de melhorar a aderência na interface gesso/bambu foram utilizados adesivo epóxi, massa plástica e piche, além de confeccionados corpos de prova de gesso reforçados com taliscas de bambu, tratadas com diferentes produtos, cuja eficiência foi avaliada em ensaios mecânicos. Observou-se que, para ocorrer uma boa aderência na interface do compósito, são necessários tratamentos complementares que reduzam os efeitos da instabilidade dimensional.<br>The gypsum is a binder with applications primarily in the manufacture of ceiling tile, decorative elements and partition walls. However, using a low water/plaster ratio and procedures such as vibration, it is possible to obtain mechanical strength compatible to other applications in construction as in the case of structural elements. The research reported in this study aimed to evaluate experimentally the possibility of improving the compound studied. Treatments were carried out to reduce water absorption by slivers through the use of plant extract B Carbon, polymer resin, and tar. In an attempt to improve the adhesion at the interface plaster/epoxy adhesive, bamboo, plastic and tar mass were used. Test specimens were made of plaster reinforced with slivers of bamboo, treated with different products, to assess its efficiency in mechanical tests. It was observed that to obtain a good adhesion at the interface of the composite it is necessary to apply additional treatments that reduce the effects of dimensional instability

A framework to support requirements analysis in engineering design

International audienceComplex system development activities such as requirements analysis to requirements specification, implementation and verification are well defined in the software engineering domain. Interests in using a model driven engineering have increased in this domain. System level requirements analysis and model driven engineering may result in a significant improvement in engineering design. This paper presents a Checklist Oriented Requirement Analysis (CORA) framework to develop and formalize requirements. CORA is an integrated framework that adopts a checklist concept and utilizes logical reasoning operation in conjunction with information management to analyze systematically the initial requirements statement. An underground work machine is used as an application example to illustrate the proposed framework