Demographic Disparities in Proximity to Certified Stroke Care in the United States.

Background and Purpose: Demographic disparities in proximity to stroke care influence time to treatment and clinical outcome but remain understudied at the national level. This study quantifies the relationship between distance to the nearest certified stroke hospital and census-derived demographics. Methods: This cross-sectional study included population data by census tract from the United States Census Bureau's 2014­2018 American Community Survey, stroke hospitals certified by a state or national body and providing intravenous thrombolysis, and geographic data from a public mapping service. Data were retrieved from March to November 2020. Quantile regression analysis was used to compare relationships between road distance to the nearest stroke center for each census tract and tract-level demographics of age, race, ethnicity, medical insurance status, median annual income, and population density. Results: Two thousand three hundred eighty-eight stroke centers and 71 929 census tracts including 316 995 649 individuals were included. Forty-nine thousand nine hundred eighteen (69%) tracts were urban. Demographic disparities in proximity to certified stroke care were greater in nonurban areas than urban areas. Higher representation of individuals with age ≥65 years was associated with increased median distance to a certified stroke center in nonurban areas (0.51 km per 1% increase [99.9% CI, 0.42­0.59]) but not in urban areas (0.00 km [−0.01 to 0.01]). In urban and nonurban tracts, median distance was greater with higher representation of American Indian (urban: 0.10 km per 1% increase [0.06­0.14]; nonurban: 1.06 km [0.98­1.13]) or uninsured populations (0.02 km [0.00­0.03]; 0.27 km [0.15­0.38]). Each $10 000 increase in median income was associated with a decrease in median distance of 5.04 km [4.31­5.78] in nonurban tracts, and an increase of 0.17 km [0.10­0.23] in urban tracts. Conclusions: Disparities were greater in nonurban areas than in urban areas. Nonurban census tracts with greater representation of elderly, American Indian, or uninsured people, or low median income were substantially more distant from certified stroke care.

Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation.

Systemic inflammation occurring around the course of tumor progression and treatment are often correlated with adverse oncological outcomes. As such, it is suspected that neutrophils, the first line of defense against infection, may play important roles in linking inflammation and metastatic seeding. To decipher the dynamic roles of inflamed neutrophils during hematogenous dissemination, we employ a multiplexed microfluidic model of the human microvasculature enabling physiologically relevant transport of circulating cells combined with real-time, high spatial resolution observation of heterotypic cell-cell interactions. LPS-stimulated neutrophils (PMNs) and tumor cells (TCs) form heterotypic aggregates under flow, and arrest due to both mechanical trapping and neutrophil-endothelial adhesions. Surprisingly, PMNs are not static following aggregation, but exhibit a confined migration pattern near TC-PMN clusters. We discover that PMNs are chemotactically confined by self-secreted IL-8 and tumor-derived CXCL-1, which are immobilized by the endothelial glycocalyx. This results in significant neutrophil sequestration with arrested tumor cells, leading to the spatial localization of neutrophil-derived IL-8, which also contributes to increasing the extravasation potential of adjacent tumor cells through modulation of the endothelial barrier. Strikingly similar migration patterns and extravasation behaviors were also observed in an in vivo zebrafish model upon PMN-tumor cell coinjection into the embryo vasculature. These insights into the temporal dynamics of intravascular tumor-PMN interactions elucidate the mechanisms through which inflamed neutrophils can exert proextravasation effects at the distant metastatic site.

The interaction between eukaryotic initiation factor 1A and eIF5 retains eIF1 within scanning preinitiation complexes.

Scanning of the mRNA transcript by the preinitiation complex (PIC) requires a panel of eukaryotic initiation factors, which includes eIF1 and eIF1A, the main transducers of stringent AUG selection. eIF1A plays an important role in start codon recognition; however, its molecular contacts with eIF5 are unknown. Using nuclear magnetic resonance, we unveil eIF1A's binding surface on the carboxyl-terminal domain of eIF5 (eIF5-CTD). We validated this interaction by observing that eIF1A does not bind to an eIF5-CTD mutant, altering the revealed eIF1A interaction site. We also found that the interaction between eIF1A and eIF5-CTD is conserved between humans and yeast. Using glutathione S-transferase pull-down assays of purified proteins, we showed that the N-terminal tail (NTT) of eIF1A mediates the interaction with eIF5-CTD and eIF1. Genetic evidence indicates that overexpressing eIF1 or eIF5 suppresses the slow growth phenotype of eIF1A-NTT mutants. These results suggest that the eIF1A-eIF5-CTD interaction during scanning PICs contributes to the maintenance of eIF1 within the open PIC.

Travel time and distance for bypass and non-bypass routing of stroke patients in the USA.

BACKGROUND: Endovascular thrombectomy is not available at all hospitals that offer intravenous thrombolysis, prompting debate regarding the preferred transport destination for acute ischemic stroke. This study aimed to quantify real-world travel time and distance of bypass and non-bypass transport models for large-vessel occlusion (LVO) and non-LVO stroke. METHODS: This cross-sectional study included population data of census tracts in the contiguous USA from the 2014-2018 United States Census Bureau's American Community Survey, stroke (thrombolysis-capable) and thrombectomy-capable centers certified by a state or national body, and road network data from a mapping service. Census tracts were categorized by urbanization level. Data were retrieved from March to November 2020. Travel times and distances were calculated for each census tract to each of the following: nearest stroke center (nearest), nearest thrombectomy-capable center (bypass), and nearest stroke center then to the nearest thrombectomy-capable center (transfer). Population-weighted median and IQR were calculated nationally and by urbanization. RESULTS: 72 538 census tracts, 2388 stroke hospitals, and 371 thrombectomy-capable centers were included. Nationally, population-weighted median travel time for nearest and bypass routing was 11.7 min (IQR 7.7-19.3) and 26.4 min (14.8-55.1), respectively. For transfer routing, the population-weighted median travel times with 60 min, 90 min, and 120 min door-in-door-out times were 94.1 min (78.5-127.7), 124.1 min (108.5-157.7), and 154.1 min (138.4-187.6), respectively. CONCLUSIONS: Bypass routing offers modest travel time benefits for LVO patients and incurs modest penalties for non-LVO patients. Differences are greatest in rural areas. A majority of Americans live in areas for which current guidelines recommend bypass.

Validation of a Parent Proxy Quality-of-Life Measure for Young Children With Hearing Loss.

OBJECTIVES: No hearing-related quality of life (QL) questionnaire currently exists for children < 7 years. This study aimed to develop and evaluate the construct validity and reliability of a new parent-proxy Preschool Hearing Environments and Reflection on Quality of Life (HEAR-QL) questionnaire. METHODS: Parents of children 2 to 6 years old with any hearing loss (HL) were recruited from multiple sites. To evaluate the new measure's construct validity, participants completed a 70-item preschool HEAR-QL and validated questionnaires measuring hearing and communication functioning (Parents' Evaluation of Aural/Oral Performance of Children), generic pediatric QL (Pediatric Quality of Life Inventory Parent Report, PedsQL), family functioning (PedsQL Family Impact Module), and parent well-being (Patient Reported Outcomes Measurement Information System Adult Global Report). Participants completed the preschool HEAR-QL 2 weeks later to measure test-retest reliability. Exploratory principal components analysis was used to reduce the number of items and determine the underlying HEAR-QL factor structure. Analysis of variance examined HEAR-QL differences by HL. RESULTS: Among 205 parents, 144 had children with bilateral HL, 50 had children with unilateral HL, 10 had children with normal hearing (NH), and one child's hearing status was unspecified. The 70-item questionnaire was reduced to 23 items with five underlying factors: Behavior and Attention, Hearing Environments, New Social Situations, Social Interactions, and Communication. Cronbach's alpha for each factor ranged from 0.80 to 0.91. Test-retest reliability was 0.93. Moderate-to-strong correlations (r > .300) were observed between each Preschool HEAR-QL factor and previously validated measures. Hearing Environments scores differed significantly between children with NH and any HL. CONCLUSION: Preschool HEAR-QL correlations with other measures supported its construct validity. Discriminant validity testing requires a larger sample of children with NH. LEVEL OF EVIDENCE: NA Laryngoscope, 131:663-670, 2021.

On-chip human microvasculature assay for visualization and quantification of tumor cell extravasation dynamics.

Distant metastasis, which results in >90% of cancer-related deaths, is enabled by hematogenous dissemination of tumor cells via the circulation. This requires the completion of a sequence of complex steps including transit, initial arrest, extravasation, survival and proliferation. Increased understanding of the cellular and molecular players enabling each of these steps is key to uncovering new opportunities for therapeutic intervention during early metastatic dissemination. As a protocol extension, this article describes an adaptation to our existing protocol describing a microfluidic platform that offers additional applications. This protocol describes an in vitro model of the human microcirculation with the potential to recapitulate discrete steps of early metastatic seeding, including arrest, transendothelial migration and early micrometastases formation. The microdevice features self-organized human microvascular networks formed over 4-5 d, after which the tumor can be perfused and extravasation events are easily tracked over 72 h via standard confocal microscopy. Contrary to most in vivo and in vitro extravasation assays, robust and rapid scoring of extravascular cells, combined with high-resolution imaging, can be easily achieved because of the confinement of the vascular network to one plane close to the surface of the device. This renders extravascular cells clearly distinct and allows tumor cells of interest to be identified quickly as compared with those in thick tissues. The ability to generate large numbers of devices (∼36) per experiment further allows for highly parametric studies, which are required when testing multiple genetic or pharmacological perturbations. This is coupled with the capability for live tracking of single-cell extravasation events, allowing both tumor and endothelial morphological dynamics to be observed in high detail with a moderate number of data points.