Importance

Physicians commonly hospitalize patients presenting to the emergency department (ED) with acute pulmonary embolism (PE), despite eligibility for safe outpatient management. Risk stratification using electronic health record-embedded clinical decision support systems can aid physician site-of-care decision-making and increase safe outpatient management. The long-term sustainability of early improvements after the cessation of trial-based, champion-led promotion is uncertain.

Objective

To evaluate the sustainability of recommended site-of-care decision-making support 4 years after initial physician champion-led interventions to increase outpatient management for patients with acute PE.

Design, setting, and participants

This retrospective cohort study was conducted in 21 US community hospitals in an integrated health system. Participants included adult patients presenting to the ED with acute PE. Study sites had participated in an original decision-support intervention trial 4 years prior to the current study period: 10 sites were intervention sites, 11 sites were controls. In that trial, decision support with champion promotion resulted in significantly higher outpatient management at intervention sites compared with controls. After trial completion, all study sites were given continued access to a modified decision-support tool without further champion-led outreach. Data were analyzed from January 2019 to February 2020.

Exposures

ED treatment with a modified clinical decision support tool.

Main outcomes and measures

The main outcome was frequency of outpatient management, defined as discharge home directly from the ED, stratified by the PE Severity Index. The safety measure of outpatient care was 7-day PE-related hospitalization.

Results

This study included 1039 patients, including 533 (51.3%) women, with a median (IQR) age of 65 (52-74) years. Nearly half (474 patients [45.6%]) were rated lower risk on the PE Severity Index. Overall, 278 patients (26.8%) were treated as outpatients, with only four 7-day PE-related hospitalizations (1.4%; 95% CI, 0.4%-3.6%). The practice gap in outpatient management created by the earlier trial persisted in the outpatient management for patients with lower risk: 109 of 236 patients (46.2%) at former intervention sites vs 81 of 238 patients (34.0%) at former control sites (difference, 12.2; [95% CI, 3.4-20.9] percentage points; P = .007), with wide interfacility variation (range, 7.1%-47.1%).

Conclusions and relevance

In this cohort study, a champion-led, decision-support intervention to increase outpatient management for patients presenting to the ED with acute pulmonary embolism was associated with sustained higher rates of outpatient management 4 years later. The application of our findings to improving sustainability of practice change for other clinical conditions warrants further study.

Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations between primary carcinomas and their matched metastases have the distinct A-to-T signature of the initiating carcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signature associated with oxidative stress. The existence of carcinomas that either did or did not metastasize in the same host animal suggests that there are tumor-intrinsic factors that influence metastatic seeding. We also demonstrate the importance of germline polymorphisms in determining allele-specific mutations, and we identify somatic genetic alterations that are specifically related to initiation of carcinogenesis by Hras or Kras mutations. Mouse tumors that mimic the genetic heterogeneity of human cancers can aid our understanding of the clonal evolution of metastasis and provide a realistic model for the testing of novel therapies.

Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency. However, which tissues depend on exogenous CoQ uptake as well as the mechanism by which CoQ is taken up by cells and the role of this process in BAT function are not well understood. Here, we report that the scavenger receptor CD36 drives the uptake of CoQ by BAT and is required for normal BAT function. BAT from mice lacking CD36 displays CoQ deficiency, impaired CoQ uptake, hypertrophy, altered lipid metabolism, mitochondrial dysfunction, and defective nonshivering thermogenesis. Together, these data reveal an important new role for the systemic transport of CoQ to BAT and its function in thermogenesis.

Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency. However, which tissues depend on exogenous CoQ uptake as well as the mechanism by which CoQ is taken up by cells and the role of this process in BAT function are not well understood. Here, we report that the scavenger receptor CD36 drives the uptake of CoQ by BAT and is required for normal BAT function. BAT from mice lacking CD36 displays CoQ deficiency, impaired CoQ uptake, hypertrophy, altered lipid metabolism, mitochondrial dysfunction, and defective nonshivering thermogenesis. Together, these data reveal an important new role for the systemic transport of CoQ to BAT and its function in thermogenesis.