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Current treatment approaches for Autism spectrum disorder (ASD) primarily focus on symptom management rather than addressing underlying dysfunctions. The ketogenic diet (KD), a high-fat, low-carbohydrate diet inducing nutritional ketosis, has shown promise in treating epilepsy and may offer therapeutic benefits for ASD by modulating metabolic and neuroprotective pathways. This review examined the potential impact of KD on underlying mechanisms in ASD. While evidence from human studies on underlying mechanisms is limited, animal research has shown a large overlap of mechanisms modulated by KD and dysfunctions in ASD. As such, targeting multiple disrupted pathways at once, KD presents a potential multifaceted treatment approach for ASD. However, more evidence from human studies is needed on the effectiveness of KD in the modulation of underlying dysfunctions in ASD. Additionally, precision medicine approaches could help identify individuals who would benefit most from the intervention, potentially extending its use to other psychiatric conditions with similar metabolic patterns. Consequently, KD interventions might show the potential to induce a drastic paradigm shift in understanding and treating ASD., Competing Interests: Declarations. Ethics: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Speaking up among healthcare professionals plays an essential role in improving patient safety and quality of care, yet it remains complex and multifaceted behaviour. Despite awareness of potential risks and adverse outcomes for patients, professionals often hesitate to voice concerns due to various influencing factors. This complexity has encouraged research into the determinants of speaking-up behaviour in hospital settings. This review synthesises these factors into a multi-layered framework. It aims to provide a more comprehensive perspective on the influencing factors, which provides guidance for interventions aimed at fostering environments contributing to speaking up in hospitals., Methods: A systematic review was conducted in November 2024, searching databases: PubMed, Scopus and Web of Science. Following PRISMA guidelines and the three stages for thematic synthesis, we developed the classification of influencing factors. Out of 1,735 articles identified articles, 413 duplicates were removed, 1,322 titles and abstracts were screened, and 152 full texts (plus six additional articles) were assessed. Ultimately, 45 articles met the inclusion criteria., Results: The review categorised influencing factors into four categories: individual (29 articles, 64%), relational (21 articles, 47%), contextual (19 articles, 42%), and organisational (26 articles, 58%). These categories encompass motivating, hindering and trade-off factors affecting speaking up among healthcare professionals in hospitals., Conclusions: The multi-layered framework highlights the dynamic interplay of factors influencing speaking up among healthcare professionals. A systems approach is essential for identifying barriers and enablers and designing effective speaking up interventions. This framework serves as a foundation for more focused research and practical guidance, enabling healthcare leaders to address barriers across all categories. By fostering environments that support open communication, organisations can enhance patient safety and quality of care., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: The goal of sentinel event (SE) analysis is to prevent recurrence. However, the rate of SEs has remained constant over the past years. Research suggests this is in part due to the quality of recommendations. Currently, standards for the selection of recommendations are lacking. Developing a method to grade recommendations could help in both designing and selecting interventions most likely to improve patient safety. The aim of this study was to (1) develop a user-friendly method to grade recommendations and (2) assess its applicability in a large series of Dutch perioperative SE analysis reports., Methods: Based on two grading methods, we developed the recommendation improvement matrix (RIM). Applicability was assessed by analysing all Dutch perioperative SE reports over a 12-month period. After which interobserver agreement was studied., Results: In the RIM, two elements are crucial: whether the recommendation intervenes before or after an SE and whether it eliminates or controls the hazard. Applicability was evaluated in 115 analysis reports, encompassing 161 recommendations. Recommendation quality varied from the highest, category A, to the lowest, category D, with category A accounting for 44%, category B for 35%, category C for 2% and category D for 19% of recommendations. There was a fair interobserver agreement., Conclusion: The RIM can be used to grade recommendations in SE analysis and could possibly help in both designing and selecting interventions. It is relatively simple, user-friendly and has the potential to improve patient safety. The RIM can help formulate effective and sustainable recommendations, a second key objective of the RIM is to foster and facilitate constructive dialogue among those responsible for patient safety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 ( PKP2 ). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell-derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM.