BackgroundDNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures.ResultsAsthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030).ConclusionsShort-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10.Electronic supplementary materialThe online version of this article (10.1186/s13148-017-0433-4) contains supplementary material, which is available to authorized users.

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NASA Ames Research Center, in cooperation with the FAA, has completed research and development of a proof-ofconcept Surface Management System (SMS). This paper reports on two recent SMS field tests as well as final performance and benefits analyses. Field tests and analysis support the conclusion that substantial portions of SMS technology are ready for transfer to the FAA and deployment throughout the National Airspace System (NAS). Other SMS capabilities were accepted in concept but require additional refinement for inclusion in subsequent development spirals. SMS is a decision support tool that helps operational specialists at Air Traffic Control (ATC) and NAS user facilities to collaboratively manage the movements of aircraft on the surface of busy airports, thereby improving capacity, efficiency, and flexibility. SMS provides accurate predictions of the future demand and how that demand will affect airport resources-information that is not currently available. The resulting shared awareness enables the Air Traffic Control Tower (ATCT), Terminal Radar Approach Control (TRACON), Air Route Traffic Control Center (ARTCC), and air carriers to coordinate traffic management decisions. Furthermore, SMS uses its ability to predict how future demand will play out on the surface to evaluate the effect of various traffic management decisions in advance of implementing them, to plan and advise surface operations. The SMS concept, displays, and algorithms were evaluated through a series of field tests at Memphis International Airport (MEM). An operational trial in September, 2003 evaluated SMS traffic management components, such as runway configuration change planning; shadow testing in January, 2004 tested tactical components (e.g., Approval Request (APREQ) coordination, sequencing for departure, and Expected Departure Clearance Time (EDCT) compliance). Participants in these evaluations rated the SMS concept and many of the traffic management displays very positively. Local and Ground controller displays will require integration with other automation systems. Feedback from FAA and NAS user participants support the conclusion that SMS algorithms currently provide information that has acceptable and beneficial accuracy for traffic management applications. Performance analysis results document the current accuracy of SMS algorithms. Benefits/cost analysis of delay cost reduction due to SMS provides the business case for SMS deployment.

Purpose: To compare the degree of corneal light scatter as measured by densitometry in ultrathin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) and Descemet Membrane Endothelial Keratoplasty (DMEK) in the Descemet endothelial thickness comparison trial. Methods: This was a prespecified secondary analysis of the Descemet endothelial thickness comparison trial, which was a prospective, randomized controlled trial. Subjects with isolated endothelial dysfunction were enrolled and were randomized to either UT-DSAEK or DMEK. Corneal opacity was quantitatively measured by Pentacam densitometry (OCULUS) at 3, 6, and 12 months. Results: Fifty eyes of 38 patients were enrolled at the Casey Eye Institute at Oregon Health & Science University and the Byers Eye Institute at Stanford University. Corneal densitometry for the anterior and posterior layers improved in both UT-DSAEK and DMEK after surgery. The decrease was more pronounced in the posterior layer for both groups. However, there was no difference in the degree of corneal light scatter between UT-DSAEK and DMEK at postoperative month 12, and no difference in change in densitometry was observed between the 2 arms from baseline to month 12. Conclusions: Both UT-DSAEK and DMEK experience an improvement in the degree of corneal light scatter after surgery. However, there was no difference in densitometry between the 2 groups at month 12. Therefore, other factors such as higher order aberrations in the posterior cornea rather than stromal–stromal interface haze mediate the superior visual outcomes in DMEK compared with UT-DSAEK.

86As yet undiscovered rare variants are hypothesized to substantially influence an 87 individual's risk for common diseases and traits, but sequencing studies aiming to 88 identify such variants have generally been underpowered. In isolated populations that 89 have expanded rapidly after a population bottleneck, deleterious alleles that passed 90 through the bottleneck may be maintained at much higher frequencies than in other 91 populations. In an exome sequencing study of nearly 20,000 cohort participants from 92 northern and eastern Finnish populations that exemplify this phenomenon, most novel 93 trait-associated deleterious variants are seen only in Finland or display frequencies more 94 than 20 times higher than in other European populations. These enriched alleles underlie 95 34 novel associations with 21 disease-related quantitative traits and demonstrate a 96 geographical clustering equivalent to that of Mendelian disease mutations characteristic 97 of the Finnish population. Sequencing studies in populations without this unique history 98 would require hundreds of thousands to millions of participants for comparable power for 99 these variants. 100 101 (defined here as MAF≤1%) which are not well-tagged by the single-nucleotide 109 polymorphisms (SNPs) on genome-wide genotyping arrays are probably responsible for 110 much of the heritability that remains unexplained 2 . Additionally, because purifying 111 selection acts to remove deleterious alleles from the population, most variants that exert a 112 sizable effect on complex traits, and that likely offer the best prospect for revealing 113 biological mechanisms, should be particularly rare. 114 115 Rare variants are unevenly distributed between populations and difficult to represent 116 effectively on commercial genotyping arrays, as evidenced by relatively sparse 117 association findings even from large array-based studies of coding variants 3-6 . 118Discovering rare variant associations will therefore almost certainly require exome or 119 genome sequencing of very large numbers of individuals. However, the sample size 120 required to reliably identify rare-variant associations remains uncertain; most sequencing 121 studies to date have identified few novel associations, and theoretical analyses confirm 122 that they have been underpowered to do so 7 . These analyses also suggest that power to 123 detect rare variant associations varies enormously between populations that have 124 expanded in isolation from recent bottlenecks compared to those that have not. 125 126In isolated populations that expand rapidly following a bottleneck, alleles that pass 127 through the bottleneck often rise to a much higher frequency than in other populations [8][9][10] . 128If the bottleneck was recent, even deleterious alleles under negative selection may remain 129 relatively frequent in these populations, resulting in increased power to detect association 130 with disease-related traits. The Finnish population exemplifies this type of history. It 131 5 grew from bottle...

Background: Limited information is known about the topographic effect of optic disc drusen (ODD) on peripapillary retinal nerve fibers and microvasculature.Objective: This study aims to understand the structural and functional impact of ODD in different quadrants of the optic disc.Methods: We performed a retrospective case-control study of 22 ODD patients (34 eyes) and 26 controls (33 eyes) to compare optical coherence tomography (OCT) retinal nerve fiber layer (RNFL), OCT angiography (OCTA), and corresponding static perimetry mean deviation (MD) calculated using the modified Garway-Heath map in different quadrants of the optic disc. OCTA was analyzed using custom MATLAB script to measure six parameters in a peripapillary annulus with large vessel removal: vessel area density (VAD), vessel skeleton density (VSD), vessel perimeter index (VPI), vessel complexity index (VCI), flux, and vessel diameter index (VDI).Results: Quadrant analysis revealed that OCTA VAD and VCI were significantly decreased in superior, nasal, and inferior but not temporal quadrant. RNFL, VSD, and VPI were significantly impacted only in the superior and nasal quadrants. Corresponding visual field MDs in all ODD eyes were not different in the four quadrants, although eyes with MD equal or worse than −5 dB (32%) had worst visual field corresponding to the superior quadrant of the optic disc (inferior arcuate visual field). Structure-structure comparison of OCT and OCTA showed high correlation of RNFL with multiple OCTA measurements in the superior, nasal, and inferior quadrants but not temporal quadrant. Structure-function analysis revealed significant correlation of VAD and VCI and visual field MD in every quadrant, but RNFL was only significantly correlated in the superior and inferior quadrants.Conclusions: Peripapillary VAD and VCI are decreased in more quadrants than RNFL, supporting the clinical utility of performing OCTA in addition to OCT. Consistent with the most common locations of ODD, five OCT/OCTA measurements (VAD, VCI, RNFL, VSD, VPI) are decreased in the superior and nasal quadrants. OCT/OCTA measurements were significantly impacted in contrast to the relatively mild effect on corresponding visual field MD, consistent with the idea that a decrease in objective structural and vascular measurements occurs without parallel change in subjective visual function in ODD.

The objective of this study was to describe adults initiating dupilumab for AD, in terms of sociodemographics, comorbidity burden, AD treatment patterns, and persistence on dupilumab. From Truven US MarketScan data, we identified adults with AD with 1 dupilumab dispensation (Rx) between 28 March 2017 (US market launch) and 31 January 2018 with continuous enrolment during the baseline period (12 months prior to index Rx). Patients were followed from first dupilumab Rx until 31 July 2018 or disenrollment. Kaplan-Meier curves were used to estimate persistence at 6 and 12 months, using a 30-day grace period and assuming 14-day injection frequency. 1,637 adults initiated dupilumab (mean[SD] age 42.2[15.8]; 49.9% women, 94.7% commercially insured) and 53.2% had 1 atopic comorbidity (allergic rhinitis [33.7%] and asthma [26.8%] were most prevalent). AD treatments during baseline included: systemic corticosteroids (71.9%), PDE-4 inhibitors (15.8%), phototherapy (10.1%), immunosuppressants (24.7%; 10.8% cyclosporine), topical corticosteroids (81.1%). Over a mean (SD) follow-up of 287.5 (106.2) days, dupilumab persistence (95% CI) at 6 and 12 months was 92.2% (90.9-93.6%) and 78.5% (75.9-81.1%), respectively. Among patients discontinuing dupilumab, 66.9% reinitiated treatment within a mean of 111.5 (65.5) days. Most dupilumab initiators were persistent at 12 months; among those discontinuing, a majority reinitiated treatment. We conclude that 12month persistence on dupilumab in AD is higher than reported persistence for the most commonly used first-line biologic treatment for psoriasis, adalimumab (53.4% 1 ). These findings suggest patient satisfaction with dupilumab effectiveness and tolerability. 1

IMPORTANCE Diversity in the ophthalmology profession is important when providing care for an increasingly diverse patient population. However, implicit bias may inadvertently disadvantage underrepresented applicants during resident recruitment and selection.OBJECTIVE To evaluate the association of the redaction of applicant identifiers with the review scores on ophthalmology residency applications as an intervention to address implicit bias. DESIGN, SETTING, AND PARTICIPANTSIn this quality improvement study, 46 faculty members reviewed randomized sets of 462 redacted and unredacted applications from a single academic institution during the 2019-2020 ophthalmology residency application cycle.INTERVENTIONS Applications electronically redacted for applicant identifiers, including name, sex or gender, race and ethnicity, and related terms. MAIN OUTCOMES AND MEASURESThe main outcome was the distribution of scores on redacted and unredacted applications, stratified by applicant's sex, underrepresentation in medicine (URiM; traditionally comprising American Indian or Alaskan Native, Black, and Hispanic individuals) status, and international medical graduate (IMG) status; the application score β coefficients for redaction and the applicant and reviewer characteristics were calculated. Applications were scored on a scale of 1 to 9, where 1 was the best score and 9 was the worst score. Scores were evaluated for a significant difference based on redaction among female, URiM, and IMG applicants. Linear regression was used to evaluate the adjusted association of redaction, self-reported applicant characteristics, and reviewer characteristics with scores on ophthalmology residency applications. RESULTSIn this study, 277 applicants (60.0%) were male and 71 (15.4%) had URiM status; 32 faculty reviewers (69.6%) were male and 2 (0.4%) had URiM status. The distribution of scores was similar for redacted vs unredacted applications, with no difference based on sex, URiM status, or IMG status. Applicant's sex, URiM status, and IMG status had no association with scores in multivariable analysis (sex, β = -0.08; 95% CI, -0.32 to 0.15; P = .26; URiM status, β = -0.03; (95% CI, -0.36 to 0.30; P = .94; and IMG status, β = 0.39; 95% CI, -0.24 to 1.02; P = .35). In adjusted regression, redaction was not associated with differences in scores (β = −0.06 points on a 1-9 scale; 95% CI, -0.22 to 0.10 points; P = .48). Factors most associated with better scores were attending a top 20 medical school (β = −1.06; 95% CI, -1.37 to -0.76; P < .001), holding an additional advanced degree (β = −0.86; 95% CI, -1.22 to -0.50; P < .001), and having a higher United States Medical Licensing Examination Step 1 score (β = −0.35 per 10-point increase; 95% CI, -0.45 to -0.26; P < .001). CONCLUSIONS AND RELEVANCEThis quality improvement study did not detect an association between the redaction of applicant characteristics on ophthalmology residency applications and the application review scores among underrepresented candidates at this institution. Although the s...