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- Leist, Marcel, et al.
(författare)
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Adverse outcome pathways : opportunities, limitations and open questions
- 2017
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:11, s. 3477-3505
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Tidskriftsartikel (refereegranskat)abstract
- Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event erelationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.
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- Wang, Kate N., et al.
(författare)
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Proton Pump Inhibitors and Infection-Related Hospitalizations Among Residents of Long-Term Care Facilities : A Case-Control Study
- 2019
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Ingår i: Drugs & Aging. - : Springer Science and Business Media LLC. - 1170-229X .- 1179-1969. ; 36:11, s. 1027-1034
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Tidskriftsartikel (refereegranskat)abstract
- Objective Our objective was to investigate associations between proton pump inhibitor (PPIs) use and infection- related hospitalizations among residents of long-term care facilities ( LTCFs).Methods This was a case-control study of residents aged = 65 years admitted to hospital between July 2013 and June 2015. Residents admitted for infections (cases) and falls or fall-related injuries (controls) were matched for age (+/- 2 years), sex, and index date of admission (+/- 6 months). Conditional logistic regression was used to estimate crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between PPI use and infection-related hospitalizations. Analyses were adjusted for age, sex, polypharmacy, diabetes, heart failure, chronic obstructive pulmonary disease, myocardial infarction, cerebrovascular accident, and concomitant use of cancer and immunosuppressant medications. Subgroup analyses were performed for high- and low/moderate-intensity PPIs and for respiratory and non-respiratory infections. Logistic regression was used to compare the odds of infection- related hospitalizations among users of high- and low/moderate-intensity PPIs.Results Overall, 181 cases were matched to 354 controls. Preadmission PPI use was associated with infection-related hospitalizations (aOR 1.66; 95% CI 1.11-2.48). In subgroup analyses, the association was apparent only for respiratory infections (aOR 2.26; 95% CI 1.37-3.73) and high-intensity PPIs (aOR 1.93; 95% CI 1.23-3.04). However, the risk of infection-related hospitalization was not significantly higher among users of high- versus low/moderate-intensity PPIs (aOR 1.25; 95% CI 0.74-2.13).Conclusion Residents who use PPIs may be at increased risk of infection-related hospitalizations, particularly respiratory infections. Study findings provide further support for initiatives to minimize unnecessary PPI use in the LTCF setting.
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- 2017
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Ingår i: Physical Review D. - 2470-0010 .- 2470-0029. ; 96:2
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Tidskriftsartikel (refereegranskat)
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