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A recent genome-wide association study (GWAS) of 59 cerebrospinal fluid (CSF) proteins with a connection to Alzheimer's disease (AD) demonstrated an association between increased levels of chemokine ligand 2 (CCL2) with an atypical chemokine receptor chemokine-binding protein 2 variant V41A (ACKR2-V41A; rs2228467). High levels of CCL2 are associated with increased risk of AD development as well as other inflammatory diseases. In this study we characterized the biological function of the ACKR2-V41A receptor compared to the wild type allele by measuring its ligand binding affinity, CCL2 scavenging efficiency, and cell activation sensitivity. We transfected Chinese hamster ovary cells with plasmids carrying wild type ACKR2 (ACKR2-WT) or the mutant ACKR2-V41A receptor. Binding affinity assays showed that ACKR2-V41A has a lower binding affinity for CCL2 and CCL4 than ACKR2-WT. CCL2 scavenging results aligned with binding affinity assays, with ACKR2-V41A cells scavenging CCL2 with a lower efficiency than ACKR2-WT. Cell activation assays also showed that ACKR2-V41A cells had significantly lower receptor upregulation (β-Arrestin-dependent signaling pathway) upon stimulation compared to ACKR2-WT cells. These findings provide molecular and biological mechanistic insights into the GWAS association of ACKR2-V41A with increased levels of CCL2 in CSF and possibly other chemokine ligands. Increased CCL2 levels are associated with accelerated cognitive decline and increased risk of AD. Understanding how this atypical chemokine receptor allele increases serum markers of inflammation could lead to novel therapeutic solutions for AD. Inflammation is associated with increased risk of developing cancer, autoimmune disorders, and neurodegenerative diseases such as Alzheimer's disease (AD) 1. Acute inflammation plays an essential role in the normal response to tissue injury 2,3. This inflammatory response initiates a cascade of cellular activation signals in innate immune cells (e.g. macrophages, mast cells, and endothelial cells), resulting in increased production of proinflammatory cytokines and chemokines 4-6. These cytokines and chemokines are essential to the recruitment and activation of other cells in the innate and adaptive immune systems. An inappropriate response to inflammation or alterations in the production of these chemokines can result in disease development.

Introduction: Leadership positions occupied by women within academic emergency medicine have remained stagnant despite increasing numbers of women with faculty appointments. We distributed a multi-institutional survey to women faculty and residents to evaluate categorical characteristics contributing to success and differences between the two groups. Methods: An institutional review board-approved electronic survey was distributed to women faculty and residents at eight institutions and were completed anonymously. We created survey questions to assess multiple categories: determination; resiliency; career support and obstacles; career aspiration; and gender discrimination. Most questions used a Likert five-point scale. Responses for each question and category were averaged and deemed significant if the average was greater than or equal to 4 in the affirmative, or less than or equal to 2 in the negative. We calculated proportions for binary questions. Results: The overall response rate was 55.23% (95/172). The faculty response rate was 54.1% (59/109) and residents’ response rate was 57.1% (36/63). Significant levels of resiliency were reported, with a mean score of 4.02. Childbearing and rearing were not significant barriers overall but were more commonly reported as barriers for faculty over residents (P <0.001). Obstacles reported included a lack of confidence during work-related negotiations and insufficient research experience. Notably, 68.4% (65/95) of respondents experienced gender discrimination and 9.5% (9/95) reported at least one encounter of sexual assault by a colleague or supervisor during their career. Conclusion: Targeted interventions to promote female leadership in academic emergency medicine include coaching on negotiation skills, improved resources and mentorship to support research, and enforcement of safe work environments. Female emergency physician resiliency is high and not a barrier to career advancement.

Polygenic scores (or genetic risk scores) quantify the aggregate of small effects from many common genetic loci that have been associated with a trait through genome-wide association. Polygenic scores were first used successfully in schizophrenia and have since been applied to multiple phenotypes including multiple sclerosis, rheumatoid arthritis, and height. Because human height is an easily-measured and complex polygenic trait, polygenic height scores provide exciting insights into the predictability of aggregate common variant effect on the phenotype. Shawn Bradley is an extremely tall former professional basketball player from Brigham Young University and the National Basketball Association (NBA), measuring 2.29 meters (7′6″, 99.99999th percentile for height) tall, with no known medical conditions. Here, we present a case where a rare combination of common SNPs in one individual results in an extremely high polygenic height score that is correlated with an extreme phenotype. While polygenic scores are not clinically significant in the average case, our findings suggest that for extreme phenotypes, polygenic scores may be more successful for the prediction of individuals.