Head Impact Exposure in Youth Football: Elementary School Ages 9–12 Years and the Effect of Practice Structure

Head impact exposure in youth football has not been well-documented, despite children under the age of 14 accounting for 70% of all football players in the United States. The objective of this study was to quantify the head impact exposure of youth football players, age 9–12, for all practices and games over the course of single season. A total of 50 players (age = 11.0 ± 1.1 years) on three teams were equipped with helmet mounted accelerometer arrays, which monitored each impact players sustained during practices and games. During the season, 11,978 impacts were recorded for this age group. Players averaged 240 ± 147 impacts for the season with linear and rotational 95th percentile magnitudes of 43 ± 7 g and 2034 ± 361 rad/s(2). Overall, practice and game sessions involved similar impact frequencies and magnitudes. One of the three teams however, had substantially fewer impacts per practice and lower 95th percentile magnitudes in practices due to a concerted effort to limit contact in practices. The same team also participated in fewer practices, further reducing the number of impacts each player experienced in practice. Head impact exposures in games showed no statistical difference. While the acceleration magnitudes among 9–12 year old players tended to be lower than those reported for older players, some recorded high magnitude impacts were similar to those seen at the high school and college level. Head impact exposure in youth football may be appreciably reduced by limiting contact in practices. Further research is required to assess whether such a reduction in head impact exposure will result in a reduction in concussion incidence

Star City, Russia Medical Operations

Since the beginning of the NASA/Mir missions, NASA has had astronauts in training at the Gagarin Cosmonaut Training Center (GCTC), also known as Star City, with crewmembers currently there to train for the International Space Station missions. Agreements have been reached with all International Partners that allow the crewmember's parent agency to provide a flight surgeon to oversee crewmember health and safety during training away from home. NASA Medical Operations through the Bioastronautics Contract employs flight surgeons to provide medical support for U.S. crewmembers and their support staff. This poster presentation reviews the aspects of NASA medical operations at Star City

Evaluating methods for combining rare variant data in pathway-based tests of genetic association

Analyzing sets of genes in genome-wide association studies is a relatively new approach that aims to capitalize on biological knowledge about the interactions of genes in biological pathways. This approach, called pathway analysis or gene set analysis, has not yet been applied to the analysis of rare variants. Applying pathway analysis to rare variants offers two competing approaches. In the first approach rare variant statistics are used to generate p-values for each gene (e.g., combined multivariate collapsing [CMC] or weighted-sum [WS]) and the gene-level p-values are combined using standard pathway analysis methods (e.g., gene set enrichment analysis or Fisher’s combined probability method). In the second approach, rare variant methods (e.g., CMC and WS) are applied directly to sets of single-nucleotide polymorphisms (SNPs) representing all SNPs within genes in a pathway. In this paper we use simulated phenotype and real next-generation sequencing data from Genetic Analysis Workshop 17 to analyze sets of rare variants using these two competing approaches. The initial results suggest substantial differences in the methods, with Fisher’s combined probability method and the direct application of the WS method yielding the best power. Evidence suggests that the WS method works well in most situations, although Fisher’s method was more likely to be optimal when the number of causal SNPs in the set was low but the risk of the causal SNPs was high

Representational oligonucleotide microarray analysis: A high-resolution method to detect genome copy number variation

We have developed a methodology we call ROMA (representational oligonucleotide microarray analysis), for the detection of the genomic aberrations in cancer and normal humans. By arraying oligonucleoticle probes designed from the human genome sequence, and hybridizing with "representations" from cancer and normal cells, we detect regions of the genome with altered "copy number." We achieve an average resolution of 30 kb throughout the genome, and resolutions as high as a probe every 15 kb are practical. We illustrate the characteristics of probes on the array and accuracy of measurements obtained using ROMA. Using this methodology, we identify variation between cancer and normal genomes, as well as between normal human genomes. In cancer genomes, we readily detect amplifications and large and small homozygous and hemizygous deletions. Between normal human genomes, we frequently detect large (100 kb to I Mb) deletions or duplications. Many of these changes encompass known genes. ROMA will assist in the discovery of genes and markers important in cancer, and the discovery of loci that may be important in inherited predispositions to disease

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN