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The increasing threat of antimicrobial resistance (AMR) to human health has prompted many countries to adopt national action plans to reduce antimicrobial use (AMU) in farm animals. To achieve this goal, it is necessary to gain a deeper understanding of the factors driving AMU in farm animals. While previous research has focused on gaining a better understanding of AMU from the perspective of farmers and veterinarians, less emphasis has been placed on examining the systemic and contextual factors that influence AMU from multiple viewpoints within the food supply chain. To this end, this paper describes a participatory approach involving multiple stakeholders from two distinct livestock sectors to identify the underlying drivers of AMU and explore their case-specificity. For each sector, we identified causes of AMU during four online focus groups, by co-creating a "problem tree", which resulted in the identification of over 50 technical, economic, regulatory, and sociocultural causes per sector and exploration of causal links. Following this, we analysed the focus group discussion through a content analysis and clustered causes of AMU that were related into 17 categories (i.e. main drivers of AMU), that we then classified as drivers of AMU at sector level or drivers of AMU at farm level. Finally, we compared the two sectors by assessing whether the generated categories (i.e. main drivers for AMU) had been discussed for both sectors and, if so, whether they involved the same causes and had the same implications. Through our analysis, we gained a better understanding of several main drivers of AMU at sector level, that result from systemic and/or contextual causes. As these cannot always be addressed by farmers and/or their veterinarian, we suggest that interventions should also target other actors related to these causes or consider them to help implement certain strategies. Furthermore, based on the results of our comparative analysis, we suggest that systemic structural differences, such as size and level of supply chain integration/fragmentation, may lead to differences in how animal health management is approached. This in turn may influence AMU's decision-making and the effectiveness of interventions, if they are generic and not tailored to the specificities of the sector., Competing Interests: Declaration of Competing Interest The authors declare that they have no known conflict of interest that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Plasma membrane calcium ATPase 1 (PMCA1, Atp2b1) is emerging as a key contributor to cardiac physiology, involved in calcium handling and myocardial signalling. In addition, genome wide association studies have associated PMCA1 in several areas of cardiovascular disease including hypertension and myocardial infarction. Here, we investigated the role of PMCA1 in basal cardiac function and heart rhythm stability. Cardiac structure, heart rhythm and arrhythmia susceptibility were assessed in a cardiomyocyte-specific PMCA1 deletion (PMCA1 CKO ) mouse model. PMCA1 CKO mice developed abnormal heart rhythms related to ventricular repolarisation dysfunction and displayed an increased susceptibility to ventricular arrhythmias. We further assessed the levels of cardiac ion channels using qPCR and found a downregulation of the voltage-dependent potassium channels, K v 4.2, with a corresponding reduction in the transient outward potassium current which underlies ventricular repolarisation in the murine heart. The changes in heart rhythm were found to occur in the absence of any structural cardiomyopathy. To further assess the molecular changes occurring in PMCA1 CKO hearts, we performed proteomic analysis. Functional characterisation of differentially expressed proteins suggested changes in pathways related to metabolism, protein-binding, and pathways associated cardiac function including β-adrenergic signalling. Together, these data suggest an important role for PMCA1 in basal cardiac function in relation to heart rhythm control, with reduced cardiac PMCA1 expression resulting in an increased risk of arrhythmia development., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development. We aimed to investigate if mitochondrial structure-function remodelling occurs in the early stages of diabetes by employing a mouse model (GENA348) of Maturity Onset Diabetes in the Young, exhibiting hyperglycemia, but not hyperinsulinemia, with mild left ventricular dysfunction. Employing 3-D electron microscopy (SBF-SEM) we determined that compared to wild-type, WT, the GENA348 subsarcolemma mitochondria (SSM) are ~ 2-fold larger, consistent with up-regulation of fusion proteins Mfn1, Mfn2 and Opa1. Further, in comparison, GENA348 mitochondria are more irregular in shape, have more tubular projections with SSM projections being longer and wider. Mitochondrial density is also increased in the GENA348 myocardium consistent with up-regulation of PGC1-α and stalled mitophagy (down-regulation of PINK1, Parkin and Miro1). GENA348 mitochondria have more irregular cristae arrangements but cristae dimensions and density are similar to WT. GENA348 Complex activity (I, II, IV, V) activity is decreased but the OCR is increased, potentially linked to a shift towards fatty acid oxidation due to impaired glycolysis. These novel data reveal that dysregulated mitochondrial morphology, dynamics and function develop in the early stages of diabetes., (© 2022. The Author(s).)