Adverse outcome pathways (AOPs) were introduced in modern toxicology to provide evidence-based representations of the events and processes involved in the progression of toxicological effects across varying levels of the biological organisation to better facilitate the safety assessment of chemicals. AOPs offer an opportunity to address knowledge gaps and help to identify novel therapeutic targets. They also aid in the selection and development of existing and new in vitro and in silico test methods for hazard identification and risk assessment of chemical compounds. However, many toxicological processes are too intricate to be captured in a single, linear AOP. As a result, AOP networks have been developed to aid in the comprehension and placement of associated events underlying the emergence of related forms of toxicity—where complex exposure scenarios and interactions may influence the ultimate adverse outcome. This study utilised established criteria to develop an AOP network that connects thirteen individual AOPs associated with nephrotoxicity (as sourced from the AOP-Wiki) to identify several key events (KEs) linked to various adverse outcomes, including kidney failure and chronic kidney disease. Analysis of the modelled AOP network and its topological features determined mitochondrial dysfunction, oxidative stress, and tubular necrosis to be the most connected and central KEs. These KEs can provide a logical foundation for guiding the selection and creation of in vitro assays and in silico tools to substitute for animal-based in vivo experiments in the prediction and assessment of chemical-induced nephrotoxicity in human health.

Atrial fibrillation (AF) is a frequent complication of acute coronary syndromes (ACS) and is associated with an increased risk of in-hospital and long-term mortality. Our objective was to determine whether patients with previous AF and those who presented with or developed AF during their ACS hospitalization (new onset) have an associated increased risk of short- and mid-term cardiovascular events, death, or a composite. We included 7,228 patients from the Global Registry of Acute Coronary Events electrocardiogram core laboratory substudy, who presented with an ACS. Associated multivariable-adjusted risk of death and major adverse cardiovascular events (MACE) of death, re-infarction, or stroke in-hospital and at 6 months were estimated. New-onset AF and previous AF patients had higher rates of in-hospital mortality (14.9% and 10.9%, respectively) compared with patients without AF (3.8%; both p < 0.001). New-onset AF and previous AF patients had higher rates of 6-month mortality (22.3% and 21.3%, respectively) compared with patients without AF (7.0%; both p <0.001). After adjustment for clinical prognosticators, including those in the Global Registry of Acute Coronary Events risk model, new-onset AF was associated with higher mortality in-hospital (ORadj 1.87, 95% CI 1.30 to 2.70) and at 6 months (ORadj 1.75, 95% CI 1.29 to 2.39) as well as MACE at 6 months (ORadj 1.43, 95% CI 1.12 to 1.81) compared with patients without AF, but were at similar risk compared to those with previous AF (all p > 0.40). In conclusion, the risk of death and MACE after ACS in patients with new-onset and previous AF appears similar and significantly increased compared with patients without AF.