Rapid assessment of T-cell receptor specificity of the immune repertoire

Accurate assessment of T-cell-receptor (TCR)–antigen specificity across the whole immune repertoire lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR–peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR–peptide systems. Here, we introduce RACER, a pairwise energy model capable of rapid assessment of TCR–peptide affinity for entire immune repertoires. RACER applies supervised machine learning to efficiently and accurately resolve strong TCR–peptide binding pairs from weak ones. The trained parameters further enable a physical interpretation of interacting patterns encoded in each TCR–peptide system. When applied to simulate thymic selection of a major-histocompatibility-complex (MHC)-restricted T-cell repertoire, RACER accurately estimates recognition rates for tumor-associated neoantigens and foreign peptides, thus demonstrating its utility in helping address the computational challenge of reliably identifying properties of tumor antigen-specific T-cells at the level of an individual patient’s immune repertoire

Baseline Social Characteristics and Barriers to Care from a Special Projects of National Significance Women of Color with HIV Study: A Comparison of Urban and Rural Women and Barriers to HIV Care

We describe the baseline sociodemographic characteristics of the Health Resources and Services Administration's Special Programs of National Significance Women of Color (WOC) Initiative. Between November 2010 and July 2013, 921 WOC were prospectively enrolled in HIV medical care at nine sites, six urban (N=641) and three rural sites (N=280) across the US. We describe the study sample, drawing comparisons between urban and rural sites on sociodemographics, barriers to HIV care, HIV care status at study entry, substance use and sexual risk factors, and the relationship among these variables. Urban sites' participants differed from rural sites on all sociodemographic variables except age (median=42.3). Women at urban sites were more likely to be Hispanic, less educated, single, living alone, unstably housed, unemployed, and to have reported lower income. More urban women were transferring care to HIV care or had been lost to care. Urban women reported more barriers to care, many relating to stigma or fatalism about HIV care. Urban women reported more substance use and sexual risk behaviors. A better understanding of how HIV care is embedded in communities or fragmented across many sites in urban areas may help understand barriers to long-term engagement in HIV care encountered by WOC

A multicenter assessment of interreader reliability of LI-RADS version 2018 for MRI and CT

Background: Various limitations have impacted research evaluating reader agreement for Liver Imaging-Reporting and Data System (LI-RADS). Purpose: To assess reader agreement of LI-RADS in an international multi-center, multireader setting using scrollable images. Materials and Methods: This retrospective study used de-identified clinical multiphase CT and MRI examinations and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 – August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS v2018 category was computed as a re-scored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1/2, LR-3, LR-4, LR-5/M/tumor in vein) was computed using intra-class correlation coefficients (ICC). Agreement was also computed for dichotomized malignancy (LR-4/LR5/LR-M/LR-tumor in vein), LR-5, and LR-M. Agreement was compared between researchversus-research reads and research-versus-clinical reads. Results: 484 patients (mean age, 62 years ±10 [SD]; 156 women; 93 CT, 391 MRI) were included. ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.62, 0.74), 0.63 (95% CI: 0.56, 0.71), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs. 0.62, P = .03) and for dichotomized malignancy (ICC, 0.63 vs. 0.53, P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion: There was moderate agreement for Liver Imaging-Reporting and Data System v2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes

The Musicality of Non-Musicians: An Index for Assessing Musical Sophistication in the General Population

Musical skills and expertise vary greatly in Western societies. Individuals can differ in their repertoire of musical behaviours as well as in the level of skill they display for any single musical behaviour. The types of musical behaviours we refer to here are broad, ranging from performance on an instrument and listening expertise, to the ability to employ music in functional settings or to communicate about music. In this paper, we first describe the concept of ‘musical sophistication’ which can be used to describe the multi-faceted nature of musical expertise. Next, we develop a novel measurement instrument, the Goldsmiths Musical Sophistication Index (Gold-MSI) to assess self-reported musical skills and behaviours on multiple dimensions in the general population using a large Internet sample (n = 147,636). Thirdly, we report results from several lab studies, demonstrating that the Gold-MSI possesses good psychometric properties, and that self-reported musical sophistication is associated with performance on two listening tasks. Finally, we identify occupation, occupational status, age, gender, and wealth as the main socio-demographic factors associated with musical sophistication. Results are discussed in terms of theoretical accounts of implicit and statistical music learning and with regard to social conditions of sophisticated musical engagement

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.Peer reviewe

Getting Stoned From Being Too High: Accidental Discovery That Optic Disc Drusen May Arise From High Intracranial Pressure of Pseudotumor Cerebri / Idiopathic Intracranial Hypertension (.pdf)

To evaluate the prevalence of optic disc drusen (ODD) in the setting of papilledema from pseudotumor cerebri/idiopathic intracranial hypertension (IIH), and to assess if the coexistence of both conditions may worsen the visual outcomes as compared with either condition alone

Baseline Social Characteristics and Barriers to Care from a Special Projects of National Significance Women of Color with HIV Study: A Comparison of Urban and Rural Women and Barriers to HIV Care

We describe the baseline sociodemographic characteristics of the Health Resources and Services Administration's Special Programs of National Significance Women of Color (WOC) Initiative. Between November 2010 and July 2013, 921 WOC were prospectively enrolled in HIV medical care at nine sites, six urban (N=641) and three rural sites (N=280) across the US. We describe the study sample, drawing comparisons between urban and rural sites on sociodemographics, barriers to HIV care, HIV care status at study entry, substance use and sexual risk factors, and the relationship among these variables. Urban sites' participants differed from rural sites on all sociodemographic variables except age (median=42.3). Women at urban sites were more likely to be Hispanic, less educated, single, living alone, unstably housed, unemployed, and to have reported lower income. More urban women were transferring care to HIV care or had been lost to care. Urban women reported more barriers to care, many relating to stigma or fatalism about HIV care. Urban women reported more substance use and sexual risk behaviors. A better understanding of how HIV care is embedded in communities or fragmented across many sites in urban areas may help understand barriers to long-term engagement in HIV care encountered by WOC