Mental Health on U.S. College Campuses

This brief addresses the failing state of college counseling centers in the United States. Across the country, college counseling centers are receiving a surge in demand for mental health services, but they are unable to provide an adequate amount of resources to see to the needs of every student. This brief outlines in detail the shortcomings of existing policies while providing the framework for future reform, which will increase accessibility, equity, and efficiency, and speak true to the mission of both the department and the nation

Automatically Deriving Spreadsheet Cell Values Using Natural Language

This disclosure describes techniques to populate spreadsheet cells that depend on, but aren’t numerically calculable from, other cells. Based on a natural language query, the empty cells of a partially populated sheet that are contextually dependent on the thus-far-filled cells are automatically filled. The techniques provide greater speed, accuracy, and scalability for datasets small and large, enabling users to efficiently explore data. The techniques obviate the need to manually populate each cell in the sheet, a time-consuming and error prone procedure that does not scale well. Automatically filling in values in a spreadsheet, as described herein, opens up possibilities for the user that don’t currently exist, e.g., answering hundreds or thousands of questions based on the context in a sheet using simple, templated, natural-language queries

Effect of weekend admission on in-hospital mortality and functional outcomes for patients with acute subarachnoid haemorrhage (SAH)

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is an acute cerebrovascular event with high socioeconomic impact as it tends to affect younger patients. The recent NCEPOD study looking into management of aSAH has recommended that neurovascular units in the United Kingdom should aim to secure cerebral aneurysms within 48 h and that delays because of weekend admissions can increase the mortality and morbidity attributed to aSAH. METHOD: We used data from a prospective audit of aSAH patients admitted between January 2009 and December 2011. The baseline demographic and clinical features of the weekend and weekday groups were compared using the chi-squared test and T-test. Cox proportional hazards models (Proc Phreg in SAS) were used to calculate the adjusted overall hazard of in-hospital death associated with admission on weekend, adjusting for age, sex, baseline WFNS grade, type of treatment received and time from scan to treatment. Sliding dichotomy analysis was used to estimate the difference in outcomes after SAH at 3 months in weekend and weekday admissions. RESULTS: Those admitted on weekends had a significantly higher scan to treatment time (83.05 ± 83.4 h vs 40.4 ± 53.4 h, P < 0.0001) and admission to treatment (71.59 ± 79.8 h vs 27.5 ± 44.3 h, P < 0.0001) time. After adjustments for adjusted for relevant covariates weekend admission was statistically significantly associated with excess in-hospital mortality (HR = 2.1, CL [1.13–4.0], P = 0.01). After adjustments for all the baseline covariates, the sliding dichotomy analysis did not show effects of weekend admission on long-term outcomes on the good, intermediate and worst prognostic bands. CONCLUSIONS: This study provides important data showing excess in-hospital mortality of patients with SAH on weekend admissions served by the United Kingdom’s National Health Service.; However, there were no effects of weekend admission on long-term outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00701-016-2746-z) contains supplementary material, which is available to authorized users

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Development of Patient-specific AAV Vectors After Neutralizing Antibody Selection for Enhanced Muscle Gene Transfer

A major hindrance in gene therapy trials with adeno-associated virus (AAV) vectors is the presence of neutralizing antibodies (NAbs) that inhibit AAV transduction. In this study, we used directed evolution techniques in vitro and in mouse muscle to select novel NAb escape AAV chimeric capsid mutants in the presence of individual patient serum. AAV mutants isolated in vitro escaped broad patient-specific NAb activity but had poor transduction ability in vivo. AAV mutants isolated in vivo had enhanced NAb evasion from cognate serum and had high muscle transduction ability. More importantly, structural modeling identified a 100 amino acid motif from AAV6 in variable region (VR) III that confers this enhanced muscle tropism. In addition, a predominantly AAV8 capsid beta barrel template with a specific preference for AAV1/AAV9 in VR VII located at threefold symmetry axis facilitates NAb escape. Our data strongly support that chimeric AAV capsids composed of modular and nonoverlapping domains from various serotypes are capable of evading patient-specific NAbs and have enhanced muscle transduction

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2–2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/0.1038/ncomms1097

A late-surviving apatemyid (Mammalia: Apatotheria) from the latest Oligocene of Florida, USA

A new species of Apatemyidae, Sinclairella simplicidens, is based on four isolated teeth that were screenwashed from fissure fillings at the late Oligocene Buda locality, Alachua County, Florida. Compared to its only congener Sinclairella dakotensis, the new species is characterized by upper molars with more simplified crowns, with the near absence of labial shelves and stylar cusps except for a strong parastyle on M1, loss of paracrista and paraconule on M2 (paraconule retained but weak on M1), lack of anterior cingulum on M1–M3, straighter centrocristae, smaller hypocone on M1 and M2, larger hypocone on M3, distal edge of M2 continuous from hypocone to postmetacrista supporting a large posterior basin, and with different tooth proportions in which M2 is the smallest rather than the largest molar in the toothrow. The relatively rare and poorly-known family Apatemyidae has a long temporal range in North America from the late Paleocene (early Tiffanian) to early Oligocene (early Arikareean). The new species from Florida significantly extends this temporal range by roughly 5 Ma to the end of the Paleogene near the Oligocene-Miocene boundary (from early Arikareean, Ar1, to late Arikareean, Ar3), and greatly extends the geographic range of the family into eastern North America some 10° of latitude farther south and 20° of longitude farther east (about 2,200 km farther southeast) than previously known. This late occurrence probably represents a retreat of this subtropically adapted family into the Gulf Coastal Plain subtropical province at the end of the Paleogene and perhaps the end of the apatemyid lineage in North America.Ye

Wild flies hedge their thermal preference bets in response to seasonal fluctuations

Fluctuating environmental pressures can challenge organisms by repeatedly shifting the optimum phenotype. Two contrasting evolutionary strategies to cope with these fluctuations are 1) evolution of the mean phenotype to follow the optimum (adaptive tracking) or 2) diversifying phenotypes so that at least some individuals have high fitness in the current fluctuation (bet-hedging). Bet-hedging could underlie stable differences in the behavior of individuals that are present even when genotype and environment are held constant. Instead of being simply ‘noise,’ behavioral variation across individuals may reflect an evolutionary strategy of phenotype diversification. Using geographically diverse wild-derived fly strains and high-throughput assays of individual preference, we tested whether thermal preference variation in Drosophila melanogaster could reflect a bet-hedging strategy. We also looked for evidence that populations from different regions differentially adopt bet-hedging or adaptive-tracking strategies. Computational modeling predicted regional differences in the relative advantage of bet-hedging, and we found patterns consistent with that in regional variation in thermal preference heritability. In addition, we found that temporal patterns in mean preference support bet-hedging predictions and that there is a genetic basis for thermal preference variability. Our empirical results point to bet-hedging in thermal preference as a potentially important evolutionary strategy in wild populations

Wild flies hedge their thermal preference bets in response to seasonal fluctuations

Fluctuating environmental pressures can challenge organisms by repeatedly shifting the optimum phenotype. Two contrasting evolutionary strategies to cope with these fluctuations are 1) evolution of the mean phenotype to follow the optimum (adaptive tracking) or 2) diversifying phenotypes so that at least some individuals have high fitness in the current fluctuation (bet-hedging). Bet-hedging could underlie stable differences in the behavior of individuals that are present even when genotype and environment are held constant. Instead of being simply ‘noise,’ behavioral variation across individuals may reflect an evolutionary strategy of phenotype diversification. Using geographically diverse wild-derived fly strains and high-throughput assays of individual preference, we tested whether thermal preference variation in Drosophila melanogaster could reflect a bet-hedging strategy. We also looked for evidence that populations from different regions differentially adopt bet-hedging or adaptive-tracking strategies. Computational modeling predicted regional differences in the relative advantage of bet-hedging, and we found patterns consistent with that in regional variation in thermal preference heritability. In addition, we found that temporal patterns in mean preference support bet-hedging predictions and that there is a genetic basis for thermal preference variability. Our empirical results point to bet-hedging in thermal preference as a potentially important evolutionary strategy in wild populations

Analysis of High-Risk Pedigrees Identifies 12 Candidate Variants for Alzheimer\u27s Disease

INTRODUCTION: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants. METHODS: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer\u27s disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members. RESULTS: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91). DISCUSSION: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants