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Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids. [ABSTRACT FROM AUTHOR]

Highlights • Vancomycin AUC thresholds were assessed using two-point pharmacokinetic monitoring. • AUC thresholds for success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L. • Rates of clinical failure (18.2%) and nephrotoxicity (13.0%) were low. • These data support evidence to target a vancomycin AUC range of 400–600 mg·h/L. • Adoption of AUC-based vancomycin monitoring may improve safety and efficacy. ABSTRACT Limited evidence exists evaluating pharmacokinetic thresholds for vancomycin efficacy and nephrotoxicity using non-Bayesian methods. The objective of this study was to evaluate the 24-h steady-state vancomycin area under the concentration–time curve (AUC 24) thresholds for efficacy and nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSA-B) after implementing two-point pharmacokinetic therapeutic drug monitoring. A single-centre, retrospective cohort study was performed including adult patients admitted between 1 June 2016 and 1 January 2018 with MRSA-B treated with vancomycin for ≥72 h. The AUC 24 was calculated using peak and trough vancomycin serum concentrations. Clinical success was defined as defervescence and blood culture sterilisation by Day 7. Nephrotoxicity was defined as an increase in serum creatinine of >0.5 mg/dL (or ≥50%) from baseline. Classification and regression tree (CART) analyses were performed to identify AUC 24 thresholds for efficacy and nephrotoxicity. Forty-six patients were included in the study. Clinical success and nephrotoxicity were observed in 81.8% and 13.0%, respectively. The CART-derived vancomycin AUC 24 thresholds for clinical success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L, respectively. Patients with an AUC 24 ≥297 mg·h/L had a >2.7-fold increase in clinical success compared with those who did not (89.5% vs. 33.3%, respectively; P = 0.01), and patients with an AUC 24 ≥710 mg·h/L had a >7-fold increase in nephrotoxicity compared with those with an AUC 24 <710 mg·h/L (66.7% vs. 9.3%, respectively; P = 0.04). This study supports current recommendations to target vancomycin AUC 24 values of 400–600 mg·h/L when calculated using two-point pharmacokinetics, although a wider range may exist. [ABSTRACT FROM AUTHOR]