Musculoskeletal infections (MSKIs) remain a major health burden in orthopaedics. Bacterial toxins are foundational to pathogenesis in MSKI, but poorly understood by the community of providers that care for patients with MSKI, inducing an international group of microbiologists, infectious diseases specialists, orthopaedic surgeons and biofilm scientists to review the literature in this field to identify key topics and compile the current knowledge on the role of toxins in MSKI, with the goal of illuminating potential impact on biofilm formation and dispersal as well as therapeutic strategies. The group concluded that further research is needed to maximize our understanding of the effect of toxins on MSKIs, including (i) further research to identify the roles of bacterial toxins in MSKIs, (ii) establish the understanding of the importance of environmental and host factors and in vivo expression of toxins throughout the course of an infection, (iii) establish the principles of drug-ability of antitoxins as antimicrobial agents in MSKIs, (iv) have well-defined metrics of success for antitoxins as antiinfective drugs, (v) design a cocktail of antitoxins against specific pathogens to (a) inhibit biofilm formation and (b) inhibit toxin release. The applicability of antitoxins as potential antimicrobials in the era of rising antibiotic resistance could meet the needs of day-to-day clinicians. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.The protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such study have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg 2+ leading to the discovery of metal ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective and drug-like 14-3-3 PPI stabilizers. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.BACKGROUND AND PURPOSE The process of myelination starts in utero around 20 weeks of gestation and continues through adulthood. We first set out to characterize the maturation of the tract-specific myelin content in healthy subjects from childhood (7-12 years) into adulthood (18-32 years). Second, we apply the resulting development graph to children with childhood absence epilepsy (CAE), a pediatric epilepsy that was previously characterized by changes in myelin content. METHODS In a prospective cross-sectional study, 15 healthy children (7-12 years), 14 healthy adult participants (18-32 years) and 17 children with a clinical diagnosis of CAE (6-12 years) were included. For each participant, diffusion weighted images were acquired to reconstruct bundles of white matter tracts and multi-echo multi-slice GRASE images were acquired for myelin-water estimation. Subsequently, a tract-specific myelin development graph was constructed using the percentual difference in myelin-water content from childhood (12 year) to adulthood (25 year). RESULTS The graph revealed myelination patterns, where tracts in the central regions myelinate prior to peripheral tracts and intra-hemispheric tracts as well as tracts in the left hemisphere myelinate prior to inter-hemispheric tracts and tracts in the right hemisphere, respectively. No significant differences were found in myelin-water content between children with CAE and healthy children for neither the early developing tracts, nor the tracts that develop in a later stage. However, the difference between the myelin-water of late and early developing tracts is significantly smaller in the children with CAE. CONCLUSION These results indicate that CAE is associated with widespread neurodevelopmental myelin differences. © 2020 Maastricht University. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.BACKGROUND Long-term use of doxorubicin (DOX) is limited by cumulative dose-dependent cardiotoxicity. OBJECTIVES Identify plasma extracellular vesicle (EV)-associated microRNAs (miRNAs) as a biomarker for cardiotoxicity in dogs by correlating changes with cardiac troponin I (cTnI) concentrations and, echocardiographic and histologic findings. ANIMALS Prospective study of 9 client-owned dogs diagnosed with sarcoma and receiving DOX single-agent chemotherapy (total of 5 DOX treatments). Dogs with clinically relevant metastatic disease, preexisting heart disease, or breeds predisposed to cardiomyopathy were excluded. METHODS Serum concentration of cTnI was monitored before each treatment and 1 month after the treatment completion. Echocardiography was performed before treatments 1, 3, 5, and 1 month after completion. The EV-miRNA was isolated and sequenced before treatments 1 and 3, and 1 month after completion. RESULTS Linear mixed model analysis for repeated measurements was used to evaluate the effect of DOX. The miR-107 (P = .03) and miR-146a (P = .02) were significantly downregulated whereas miR-502 (P = .02) was upregulated. Changes in miR-502 were significant before administration of the third chemotherapeutic dose. When stratifying miRNA expression for change in left ventricular ejection fraction, upregulation of miR-181d was noted (P = .01). Serum concentration of cTnI changed significantly but only 1 month after treatment completion, and concentrations correlated with left ventricular ejection fraction and left ventricular internal dimension in diastole. Inhibitor Library CONCLUSION AND CLINICAL SIGNIFICANCE Downregulation of miR-502 was detected before significant changes in cTnI concentrations or echocardiographic parameters. Further validation using a larger sample size will be required. © 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.