The Landscape of Resource Utilization After Resuscitation of 22-, 23-, and 24-Weeks' Gestation Infants.

OBJECTIVE: To compare estimated healthcare resources needed to care for 22 through 24 weeks' gestation infants. STUDY DESIGN: This multicenter, retrospective cohort study included 1505 live in-born and out-born infants 22 through 24 weeks' gestational age at delivery from 6 pediatric tertiary care hospitals from 2011 through 2020. Median neonatal intensive care unit (NICU) length of stay (LOS) for each gestational age was used as a proxy for hospital resource utilization, and the number of comorbidities and medical technology use for each infant were used as estimates of future medical care needs. Data were analyzed using Kruskal-Wallis with Nemenyi's posthoc test and Fisher's exact test. RESULTS: Of the identified newborns, 22-week infants had shorter median LOS than their 23- and 24-week counterparts due to low survival rates. There was no significant difference in LOS for surviving 22-week infants compared with surviving 23-week infants. Surviving 22-week infants had similar proportions of comorbidities and medical technology use as 23-week infants. CONCLUSIONS: Compared with 23- and 24-week infants, 22-week infants did not use a disproportionate amount of hospital resources. Twenty-two-week infants should not be excluded from resuscitation based on concern for increased hospital care and medical technology requirements. As overall resuscitation efforts and survival rates increase for 22-week infants, future research will be needed to assess the evolution of these results.

Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood-Brain Barrier.

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood-brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.

Proteomic Discovery of Noninvasive Biomarkers Associated With Sport-Related Concussions.

BACKGROUND AND OBJECTIVES: Sport-related concussions affect millions of individuals across the United States each year, and current techniques to diagnose and monitor them rely largely on subjective measures. Our goal was to discover and validate objective, quantifiable noninvasive biomarkers with the potential to be used in sport-related concussion diagnosis. METHODS: Urine samples from a convenience series of healthy control collegiate athletes who had not sustained a concussion and athletes who sustained a concussion as diagnosed by a sports medicine physician within 7 days were collected prospectively and studied. Participants also completed an instrumented single-task gait analysis as a functional measure. Participants were recruited from a single collegiate athletic program and were ≥18 years of age and were excluded if they had a concomitant injury, active psychiatric conditions, or preexisting neurologic disorders. Using Tandem Mass Tags (TMT) mass spectroscopy and ELISA, we identified and validated urinary biomarkers of concussion. RESULTS: Forty-eight control and 47 age- and sex-matched athletes with concussion were included in the study (51.6% female, 48.4% male, average age 19.6 years). Participants represented both contact and noncontact sports. All but 1 of the postconcussion participants reported experiencing symptoms at the time of data collection. Insulin-like growth factor 1 (IGF-1) and IGF binding protein 5 (IGFBP5) were downregulated in the urine of athletes with concussions compared to healthy controls. Multivariable risk algorithms developed to predict the probability of sport-related concussion showed that IGF-1 multiplexed with single-task gait velocity predicts concussion risk across a range of postinjury time points (area under the curve [AUC] 0.786, 95% confidence interval [CI] 0.690-0.884). When IGF-1 and IGFBP5 are multiplexed with single-task gait velocity, they accurately distinguish between healthy controls and individuals with concussion at acute time points (AUC 0.835, 95% CI 0.701-0.968, p < 0.001). DISCUSSION: These noninvasive biomarkers, discovered in an objective and validated manner, may be useful in diagnosing and monitoring sport-related concussions in both acute phases of injury and several days after injury. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02354469 (submitted February 2015, first patient enrolled August 2015). CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that urinary IGF-1 and IGFBP5 multiplexed with single-task gait velocity may be useful in diagnosing sport-related concussion.

Tumor-Derived Extracellular Vesicles Breach the Intact Blood-Brain Barrier via Transcytosis.

The restrictive nature of the blood-brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking the ability to cross the BBB. Extracellular vesicles (EVs) have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer and have been suggested as promising therapeutics and drug delivery vehicles. However, the ability of native tumor-derived EVs to breach the BBB and the mechanism(s) involved in this process remain unknown. Here, we demonstrate that tumor-derived EVs can breach the intact BBB in vivo, and by using state-of-the-art in vitro and in vivo models of the BBB, we have identified transcytosis as the mechanism underlying this process. Moreover, high spatiotemporal resolution microscopy demonstrated that the endothelial recycling endocytic pathway is involved in this transcellular transport. We further identify and characterize the mechanism by which tumor-derived EVs circumvent the low physiologic rate of transcytosis in the BBB by decreasing the brain endothelial expression of rab7 and increasing the efficiency of their transport. These findings identify previously unknown mechanisms by which tumor-derived EVs breach an intact BBB during the course of brain metastasis and can be leveraged to guide and inform the development of drug delivery approaches to deliver therapeutic cargoes across the BBB for treatment of a variety of brain diseases including, but not limited to, brain malignancies.