On-Field Deployment and Validation for Wearable Devices

Wearable sensors are an important tool in the study of head acceleration events and head impact injuries in sporting and military activities. Recent advances in sensor technology have improved our understanding of head kinematics during on-field activities; however, proper utilization and interpretation of data from wearable devices requires careful implementation of best practices. The objective of this paper is to summarize minimum requirements and best practices for on-field deployment of wearable devices for the measurement of head acceleration events in vivo to ensure data evaluated are representative of real events and limitations are accurately defined. Best practices covered in this document include the definition of a verified head acceleration event, data windowing, video verification, advanced post-processing techniques, and on-field logistics, as determined through review of the literature and expert opinion. Careful use of best practices, with accurate acknowledgement of limitations, will allow research teams to ensure data evaluated is representative of real events, will improve the robustness of head acceleration event exposure studies, and generally improve the quality and validity of research into head impact injuries

On-field deployment and validation for wearable devices

Wearable sensors are an important tool in the study of head acceleration events and head impact injuries in sporting and military activities. Recent advances in sensor technology have improved our understanding of head kinematics during on-field activities; however, proper utilization and interpretation of data from wearable devices requires careful implementation of best practices. The objective of this paper is to summarize minimum requirements and best practices for on-field deployment of wearable devices for the measurement of head acceleration events in vivo to ensure data evaluated are representative of real events and limitations are accurately defined. Best practices covered in this document include the definition of a verified head acceleration event, data windowing, video verification, advanced post-processing techniques, and on-field logistics, as determined through review of the literature and expert opinion. Careful use of best practices, with accurate acknowledgement of limitations, will allow research teams to ensure data evaluated is representative of real events, will improve the robustness of head acceleration event exposure studies, and generally improve the quality and validity of research into head impact injuries

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

Head Impact Exposure in Youth and Collegiate American Football

The relationship between head impact and subsequent brain injury for American football players is not well defined, especially for youth. The objective of this study is to quantify and assess Head Impact Exposure (HIE) metrics among youth and collegiate football players. This multiseason study enrolled 639 unique athletes (354 collegiate; 285 youth, ages 9–14), recording 476,209 head impacts (367,337 collegiate; 108,872 youth) over 971 sessions (480 collegiate; 491 youth). Youth players experienced 43 and 65% fewer impacts per competition and practice, respectively, and lower impact magnitudes compared to collegiate players (95th percentile peak linear acceleration (PLA, g) competition: 45.6 vs 61.9; 95th percentile PLA practice: 42.6 vs 58.8; 95th percentile peak rotational acceleration (PRA, rad∙s–2) competition: 2262 vs 4422; 95th percentile PRA practice: 2081 vs 4052; 95th percentile HITsp competition: 25.4 vs 32.8; 95th percentile HITsp practice: 23.9 vs 30.2). Impacts during competition were more frequent and of greater magnitude than during practice at both levels. Quantified comparisons of head impact frequency and magnitude between youth and collegiate athletes reveal HIE differences as a function of age, and expanded insight better informs the development of age-appropriate guidelines for helmet design, prevention measures, standardized testing, brain injury diagnosis, and recovery management

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Replication of direction selectivity in retinal ganglion cells via simulated artificial neural networks

A primary task of the retina is to frequency encode light absorption into action potentials. Using simulated artificial neural networks (SANN), the direction selective component of these electrical signals was replicated. The SANN was constructed to mimic the retinal architecture and was trained using published extracellular recordings from ganglion cells. Analysis of the trained model supported the hypothesis that Direction Selectivity arises from asymmetric connections among retinal cells. This project contributes to development of a biology-inspired artificial vision solution