Search

Chronological age has been the standard for quantifying the aging process. While it is simple to quantify it cannot fully discern the biological variability of aging between individuals. The growing body of interest in this variability of human aging has led to the introduction of new biomarkers to operationalize biological age. The inclusion of body composition may provide additional value to biological aging as a prediction and estimation factor of individual health outcomes. Diagnostic images based on radiomic techniques such as Computed Tomography contain an untapped wealth of patient‐specific data that remain inaccessible to healthcare providers. These images are beneficial for collecting information from body composition that adds precision and granularity when compared to traditional measures. This information can subsequently be aggregated to construct models for changes in the human body associated with aging. In addition, aging leads to a natural decline in the best parameter of drug dosing in older adults, glomerular filtration rate. Since the conventional models of kidney function are correlated with age and body composition, the radiomic biomarkers representing age‐related changes in body composition may also serve as potential new imaging biomarkers of kidney function for personalized dosing. Our review introduces potential radiomic biomarkers as measures of body composition change targeting the aging processes. As a functional example, we have hypothesized an age‐related model of radiomics as a covariate of kidney function to improve personalized dosing. Future research focusing on evaluating this hypothesis in human subject studies is acknowledged. [ABSTRACT FROM AUTHOR]

Aims: Dried blood volumetric absorptive microsamples (VAMS) may facilitate home‐based sampling to enhance therapeutic drug monitoring after transplantation. This study aimed to clinically validate a liquid chromatography–tandem mass spectrometry assay using 2 VAMS devices with different sampling locations (Tasso‐M20 for the upper arm and Mitra for the finger). Patient preferences were also evaluated. Methods: Clinical validation was performed for tacrolimus and mycophenolic acid by comparison of paired VAMS and venipuncture samples using Passing–Bablok regression and Bland–Altman analysis. Conversion of mycophenolic acid VAMS to serum concentrations was evaluated using haematocrit‐dependent formulas and fixed correction factors defined a priori. Patients' perspectives, including useability, acceptability and feasibility, were also investigated using established questionnaires. Results: Paired samples (n = 50) were collected from 25 kidney transplant recipients. Differences for tacrolimus whole‐blood concentration were within ±20% for 86 and 88% of samples from the upper arm and fingerstick, respectively. Using correction factors of 1.3 for the upper‐arm and 1.47 for finger‐prick samples, 84 and 76% of the paired samples, respectively, were within ±20% for mycophenolic acid serum concentration. Patient experience surveys demonstrated limited pain and acceptable useability of the upper‐arm device. Conclusions: Tacrolimus and mycophenolic acid can be measured using 2 common VAMS devices with similar analytical performance. Patients are supportive of home‐based monitoring with a preference for the Tasso‐M20 device. [ABSTRACT FROM AUTHOR]

Intranasal insulin is a putative neuroprotective therapy after cardiac arrest, but safety in humans at doses extrapolated from animal models is unknown. This phase I, open‐label adaptive dose‐escalation study explores the maximum tolerated dose of intranasal insulin in healthy human participants. Placebo or insulin at doses from 0 to 1000 units was given to healthy participants intranasally on repeated weekly visits. Serum glucose, insulin, and C‐peptide levels were measured serially at 0, 15, 30, 60, 120, 180, and 240 min after administration. Twenty‐four participants (12 female, median age 53, IQR 35–61) were enrolled. There was minimal change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose‐dependent manner, reaching maximum concentrations at 15 min. C‐peptide decreased over time from administration in all groups. One participant had severe hypoglycemia (24 mg/dL at 45 min) and a different participant had mild hypoglycemia (51 mg/dL at 30 min), both after receiving 600 U intranasal insulin. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. High‐dose intranasal insulin up to 1000 U was generally well tolerated, with minimal measurable systemic absorption and without significant aggregate changes in mean glucose. Idiosyncratic episodic systemic absorption and hypoglycemia require further study and additional caution in potential clinical application. Further study of its target engagement and efficacy as a neuroprotective therapy after cardiac arrest at these doses is warranted. [ABSTRACT FROM AUTHOR]

Introduction High-grade gliomas (HGGs) are common and aggressive pediatric and adult brain tumors. The median overall survival (OS) of adult patients diagnosed with glioblastoma (GBM), grade IV glioma, is 12.6 [...], Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFR[alpha] alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFR[alpha]-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFR[alpha]-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFR[alpha] alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFR[alpha], H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFR[alpha]-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

The goal of this study was to use a model kidney function clearance‐dependent drug (vancomycin) to understand the gain or loss of precision in dosing with use of serum creatinine (Scr), serum cystatin C (Scys) and race and nonrace‐based equations of the estimated glomerular filtration rate (eGFR). In this study of hospitalized patients, we compared Scr, Scys and their combination to estimate kidney function and vancomycin clearance. The nonrace‐based Scys eGFR model outperformed other clearance models and improved the probability of target attainment by 15%. When Scys is not available, we show that the new 2021 CKD‐EPI eGFRcr equation (no race factor) performs as well as the current conventional approach. This improvement in model performance does not negate the need for individualized dosing but exemplifies the need to remove race as a factor of kidney‐function dose adjustment. [ABSTRACT FROM AUTHOR]