A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans.

Reverse cholesterol transport (RCT) is thought to be an atheroprotective function of HDL, and macrophage-specific RCT in mice is inversely associated with atherosclerosis. We developed a novel method using 3H-cholesterol nanoparticles to selectively trace macrophage-specific RCT in vivo in humans. Use of 3H-cholesterol nanoparticles was initially tested in mice to assess the distribution of tracer and response to interventions known to increase RCT. Thirty healthy subjects received 3H-cholesterol nanoparticles intravenously, followed by blood and stool sample collection. Tracer counts were assessed in plasma, nonHDL, HDL, and fecal fractions. Data were analyzed by using multicompartmental modeling. Administration of 3H-cholesterol nanoparticles preferentially labeled macrophages of the reticuloendothelial system in mice, and counts were increased in mice treated with a liver X receptor agonist or reconstituted HDL, as compared with controls. In humans, tracer disappeared from plasma rapidly after injection of nanoparticles, followed by reappearance in HDL and nonHDL fractions. Counts present as free cholesterol increased rapidly and linearly in the first 240 min after nadir; counts in cholesteryl ester increased steadily over time. Estimates of fractional transfer rates of key RCT steps were obtained. These results support the use of 3H-cholesterol nanoparticles as a feasible approach for the measurement of macrophage RCT in vivo in humans.

Protocol for a type 3 hybrid implementation cluster randomized clinical trial to evaluate the effect of patient and clinician nudges to advance the use of genomic medicine across a diverse health system.

BACKGROUND: Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. METHODS: Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. DISCUSSION: This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1.