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This paper puts forth evidence that Adam Smith held liberty as a central principle, but also that he adopted an approach of strategic yielding and caution. Smith associated this accommodating approach with the Athenian official Solon, who put forth laws that attempted to be “the best that the people can bear.” I argue that the view of Smith as Solon, accommodating where necessary, is underrepresented in the modern literature and is in contrast to views suggesting that the liberty principle was not so central to Smith's teachings.

The Alchian Maze uses active learning for teaching important economic concepts like spontaneous order and the power of profit and loss. While the game is an effective teaching tool, it is also chea...

PURPOSE Medical educators have developed no standard way to assess the operative performance of surgical residents. Most residency programs use end-of-rotation (EOR) evaluations for this purpose. Recently, some programs have implemented workplace-based "microassessment" tools that faculty use to immediately rate observed operative performance. The authors sought to determine (1) the degree to which EOR evaluations correspond to workplace-based microassessments and (2) which factors most influence EOR evaluations and directly observed workplace-based performance ratings and how the influence of those factors differs for each assessment method. METHOD In 2017, the authors retrospectively analyzed EOR evaluations and immediate postoperative assessment ratings of surgical trainees from a university-based training program from the 2015-2016 academic year. A Bayesian multivariate mixed model was constructed to predict operative performance ratings for each type of assessment. RESULTS Ratings of operative performance from EOR evaluations vs workplace-based microassessment ratings had a Pearson correlation of 0.55. Postgraduate year (PGY) of training was the most important predictor of operative performance ratings on EOR evaluations: Model estimates ranged from 0.62 to 1.75 and increased with PGY. For workplace-based assessment, operative autonomy rating was the most important predictor of operative performance (coefficient = 0.74). CONCLUSIONS EOR evaluations are perhaps most useful in assessing the ability of a resident to become a surgeon compared with other trainees in the same PGY of training. Workplace-based microassessments may be better for assessing a trainee's ability to perform specific procedures autonomously, thus perhaps providing more insight into a trainee's true readiness for operative independence.

Workplace-based assessment is increasingly prevalent in surgical education, especially for assessing operative skill. With current implementations, not all observed clinical performances are assessed, in part because trainees often have discretion about when they seek assessment. As a result, these samples of observed operative performances may not be representative of the full breadth of experience of surgical trainees. Therefore, analyses of these samples may be biased. We aimed to benchmark patterns of procedures logged in the SIMPL operative performance assessment system against records of trainee experience in Accreditation Council for Graduate Medical Education (ACGME) case logs.We analyzed SIMPL longitudinal intraoperative performance assessments from categorical trainees in US general surgery residency programs. We compared overall patterns of how procedures are logged in SIMPL and in ACGME case logs using a Pearson correlation, and we examined differences in how individual procedures are logged in each system using Fisher's exact test.Total procedure frequency from the SIMPL dataset was strongly correlated with total procedure frequency from ACGME case logs (r = 0.86, 95% CI 0.80-0.90). A subset of these procedures (10 of 116 procedures) was logged more frequently in the SIMPL dataset. These 10 procedures accounted for 56% of SIMPL observations and 30% of ACGME logged cases. Case complexity was comparable for assessments initiated by residents and faculty.Samples of intraoperative performance ratings gathered using the SIMPL application largely resemble ACGME case logs. There is no evidence to indicate that residents preferentially select fewer complex cases for assessment.

Objective To examine the alignment between graduating surgical trainee operative performance and a prior survey of surgical program director expectations. Background Surgical trainee operative training is expected to prepare residents to independently perform clinically important surgical procedures. Methods We conducted a cross-sectional observational study of US general surgery residents' rated operative performance for Core general surgery procedures. Residents' expected performance on those procedures at the time of graduation was compared to the current list of Core general surgery procedures ranked by their importance for clinical practice, as assessed via a previous national survey of general surgery program directors. We also examined the frequency of individual procedures logged by residents over the course of their training. Results Operative performance ratings for 29,885 procedures performed by 1,861 surgical residents in 54 general surgery programs were analyzed. For each Core general surgery procedure, adjusted mean probability of a graduating resident being deemed practice-ready ranged from 0.59 to 0.99 (mean 0.90, standard deviation 0.08). There was weak correlation between the readiness of trainees to independently perform a procedure at the time of graduation and that procedure's historical importance to clinical practice (ρ = 0.22, 95% confidence interval 0.01-0.41, P = 0.06). Residents also continue to have limited opportunities to learn many procedures that are important for clinical practice. Conclusion The operative performance of graduating general surgery residents may not be well aligned with surgical program director expectations.

Objective: Compare Eustachian tube balloon dilation versus continued medical therapy (control) for treating persistent Eustachian tube dysfunction (ETD). Study Design: Prospective, multicenter, randomized controlled trial. Setting: Tertiary care academic center and private practice. Patients: Diagnosed with medically refractory persistent ETD. Interventions: 1:1 Randomization to balloon dilation or control. After 6 weeks, control participants had the option to undergo balloon dilation if symptoms persisted. Main Outcome Measures: Primary efficacy endpoint was the comparison between treatment arms in the mean change from baseline in the 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) score. Primary safety endpoint was complication rate. Results: Sixty participants were randomized (31 balloon dilation, 29 control). Mean (SD) change in overall ETDQ-7 score at 6 weeks was −2.9 (1.4) for balloon dilation compared with −0.6 (1.0) for control: balloon dilation was superior to control (p

Objective Describe the diagnosis and management of spontaneous lateral skull base cerebrospinal fluid (CSF) leaks that originate from the posterior fossa. Study design Retrospective case review. Setting Tertiary university hospital. Patients Adult patients from 2005 to 2015 who underwent surgical repair of a spontaneous lateral skull base CSF leak with intraoperative confirmation of a posterior fossa leak source. Intervention Surgical repair. Main outcome measures CSF leak resolution. Results Five patients had CSF leaks from the posterior fossa. The mean age at presentation was 54 years old (range, 19-79), the mean body mass index (BMI) was 32.6 (standard deviation [SD], 8.4), and the mean follow-up length was 34.6 months (SD, 19.4). Presentations did not differ from CSF leaks through middle fossa defects, including three patients with a history of meningitis and all patients with clear otorrhea following tympanostomy tube placement. All patients had resolution of the leak after surgical repair, but two patients required revision surgery for persistent leaks and one patient had a postoperative infection. Surgical approaches included one middle fossa, two transmastoid, one combined middle fossa/transmastoid, and one transcanal. Radiographic studies suggested a posterior fossa source in all cases but findings were often subtle. Conclusion Posterior fossa CSF leaks represent a rare subset of spontaneous lateral skull base leaks. Diligent radiographic review and intraoperative assessment of the posterior fossa plate are crucial. The size and location of the defect dictates the optimal surgical approach. Surgeons should consider a posterior fossa source in failed repairs or when the initial surgery did not fully evaluate the posterior fossa plate.

Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

Freshwater ecosystems are declining faster than their terrestrial and marine counterparts because of physical pressures on habitats. European legislation requires member states to achieve ecological targets through the effective management of freshwater habitats. Maps of habitats across river networks would help diagnose environmental problems and plan for the delivery of improvement work. Existing habitat mapping methods are generally time consuming, require experts and are expensive to implement. Surveys based on sampling are cheaper but provide patchy representations of habitat distribution. In this study, we present a method for mapping habitat indices across networks using semi-quantitative data and a geostatistical technique called regression kriging. The method consists of the derivation of habitat indices using multivariate statistical techniques that are regressed on map-based covariates such as altitude, slope and geology. Regression kriging combines the Generalised Least Squares (GLS) regression technique with a spatial analysis of model residuals. Predictions from the GLS model are ‘corrected’ using weighted averages of model residuals following an analysis of spatial correlation. The method was applied to channel substrate data from the River Habitat Survey in Great Britain. A Channel Substrate Index (CSI) was derived using Correspondence Analysis and predicted using regression kriging. The model explained 74% of the main sample variability and 64% in a test sample. The model was applied to the English and Welsh river network and a map of CSI was produced. The proposed approach demonstrates how existing national monitoring data and geostatistical techniques can be used to produce continuous maps of habitat indices at the national scale.

There is an increasing need for more advanced, composite biomarkers that can model the complex systems biology driving response and resistance to cancer therapy. However, many cancer diagnostic platforms to date, with their focus on mutational changes in a relatively small panel of genes, provide limited data to support integrative, multidimensional biomarkers that can better predict immunotherapy response. To enable the identification of composite biomarkers that combine tumor- and immune-related information from both DNA and RNA, we have developed ImmunoID NeXT, an enhanced exome/transcriptome-based diagnostic platform that can simultaneously profile the tumor and immune system from a single FFPE sample, across all of the approximately 20,000 genes. By co-optimizing assay and analytics design, we enable sensitive evaluation of clinically-relevant cancer biomarkers from >=25ng of co-extracted DNA/RNA, while also providing a broader evaluation of neoantigens, HLA typing and LOH, antigen processing machinery (APM), TCR/BCR repertoire, immune expression signatures, tumor-infiltrating lymphocytes (TILs), oncoviruses, and germline variants. Leveraging this expansive feature set, we developed methods that combine individual analytes to construct composite biomarker scores that correlate with immunotherapy response. Validation of ImmunoID NeXT demonstrated high sensitivity and specificity to somatic and structural variants across ~20,000 genes at allelic fractions as low as 5%, with clinical diagnostic reporting on actionable mutations (SNVs, indels, CNAs, fusions) in 248 cancer-driver genes that have been boosted further for higher sensitivity, as well as reporting on TMB and MSI status. For neoantigen prediction, immuno-peptidomic data from monoallelic HLA-transfected cell lines were used to train neural networks to predict pMHC binding with higher precision than public tools. For TCRα/β analysis in FFPE tumor samples, strong correlation with targeted TCR kit results was shown (R^2>0.9 and >0.94). For TILs, we developed signatures for eight immune cell types, demonstrating concordance with orthogonal immunofluorescence methods. We achieved genotyping accuracy of 99.1% for HLA Class I, and 95% for HLA Class II, and have developed and verified the performance of a tool for HLA LOH detection. In a cohort of 55 late-stage melanoma patients, the integration of neoantigen burden, HLA LOH, and APM mutational data formed a composite neoantigen score that more accurately predicted response to checkpoint blockade than other markers such as TMB. With ImmunoID NeXT, we have developed a broad diagnostic platform that can be leveraged for the development of advanced composite biomarkers (and novel resistance mechanisms) that combine both tumor and immune features from DNA and RNA; enabling more accurate stratification of patient response to immunotherapy. The platform has been validated and optimized for use with limited FFPE tissue samples, making it ideal for both research and clinical applications. Citation Format: Robert Peter Power, Gabor Bartha, Jason Harris, Sean M. Boyle, Eric Levy, Pamela Milani, Prateek Tandon, Paul McNitt, Mandy Lee, Massimo Morra, Sejal Desai, Sebastian Salvidar, Michael J. Clark, Christian Haudenschild, Sekwon Jang, John West, Richard Chen. A diagnostic platform for precision cancer therapy enabling composite biomarkers by combining tumor and immune features from an enhanced exome and transcriptome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1334.

e15583 Background: While immunotherapy has become a pillar of cancer treatment, diagnostic biomarkers that consistently predict patient response to these therapies have remained elusive. There is an increasing need for the development of integrative, composite biomarkers that can model the complex biology driving response and/or resistance to immunotherapy more effectively than existing single-analyte approaches. However, the majority of current cancer diagnostic panels, with their focus on a small set of genes, provide limited ability to support these emerging advanced biomarkers. Methods: To address these limitations, we developed and validated NeXT Dx, a comprehensive enhanced exome and transcriptome based diagnostic platform designed to simultaneously characterize tumor and immune genomics from a single limited FFPE sample. To achieve higher accuracy and sensitivity for an exome scale diagnostic platform, we developed an augmented exome assay that improves uniformity of coverage across all ~20,000 genes, including boosted coverage of 248 clinically-relevant cancer genes. We validated this assay using genomic DNA and RNA extracted from tumor-derived cell-lines, constructs, clinical FFPE samples, and proficiency testing samples. The assay utilizes > = 25ng of co-extracted DNA and RNA which were sequenced using Illumina NovaSeq instruments at our CAP-accredited, CLIA-certified laboratory. Additional assay enhancements for HLA, immune repertoire, and oncoviruses were designed to further optimize the platform for immunotherapy biomarker discovery applications. Results: Validation of NeXT Dx demonstrated a performance of 99.5% sensitivity and 99.8% positive predictive value (PPV) for SNVs with > = 5% AF; 98.7% sensitivity and 97.4% PPV for indels with > = 10% AF; 97.2% sensitivity and 94.6% PPV for CNAs in samples with > = 30% tumor content; 94.9% sensitivity and 94.9% PPV for fusions; and a 2.1% error rate for MSI classification. TMB was calculated using gold-standard whole exome data from SNVs and indels. Typical median coverage depth was > 1,000X for 248 clinically-relevant genes, ~300X for the remaining (whole exome) footprint. Conclusions: With NeXT Dx, we demonstrate a exome/transcriptome scale diagnostic platform that can detect current clinical biomarkers with high sensitivity as well as support emerging, advanced biomarkers that integrate across both tumor and immune features.

As the first neurological hospital in the world, founded in 1859, the National Hospital, Queen Square, and its affiliated Institute of Neurology remain leading neurological centres providing exceptional clinical services, teaching and research. Illustrated by over 100 historical images and much unpublished archival material, this book provides a comprehensive history of the National Hospital, the Institute, and their staff. It relates the ups and downs of the Hospital and Institute in war and peacetime, their financial struggles, many personality conflicts, efforts to remain independent and to maintain neurological dominance, academic and clinical contributions, issues relating to specialisation and subspecialisation and relations between disciplines, and the changing roles of the Hospital and Institute. The history is told from varying perspectives against the backdrop of the evolution of British clinical neuroscience, the special position of London medicine, and the influence of world wars, and is set in the context of modern British social history.

A theoretical basis for modifying Newtonian dynamics on a galactic scale can be obtained by postulating that cosmic rays interact with graviton exchanges between distant masses. This assumes that these charged particles move under the influence of local electromagnetic fields rather than the weak gravitational fields of distant matter. It leads to an enhancement of graviton exchanges between distant masses via an additional gravitational force term inversely proportional to distance. At planetary and local interstellar distances this predicts an extremely small additional gravitational force, but it can become significant on a galactic scale. The model is used here to predict rotational velocities in a wide range of galaxies including the Milky Way, Andromeda (M31) and some galaxies in the THINGS study. Results are obtained assuming a galactic cosmic ray density consistent with observations in the solar system. This approach is compared with the dark matter hypothesis and with Modified Newtonian Dynamics (MOND), the two primary postulates used to explain the constant rotational velocities observed in most galaxies.

U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30x genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (100 bp), 191,743 small (21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date.

With the advent of next-generation sequencing techniques, tumor mutations that guide therapeutic decisions can be identified on a large scale. The ability to accurately detect these mutations is often impaired by obstacles such as sequencing coverage gaps, small sample amount, low cellularity, and tumor heterogeneity. Two methods commonly used to interrogate the genomic profile of a tumor are: i) cancer gene panels, where a small number of genes (in the range of ~5-500, depending on the specific panel design) is assessed, and ii) cancer exome sequencing, where most human genes are evaluated. Additionally, tumor RNA can be studied to elucidate gene fusions and expression features that may impact treatment. Depending on the goals of the investigator, both methods have certain advantages and disadvantages. Differences between these assays must be clearly understood in order for cancer researchers to make the best decision to achieve their objective. We developed a set of unique sequencing assays to augment and improve detection of major cancer mutations by enhancing coverage over known sequencing gaps and GC-rich regions. We utilize these protocols to create an accuracy and content enhanced whole-exome (ACE Exome) as well as an extended, augmented cancer gene panel (ACE Extended Cancer Panel), targeting over 1,300 cancer genes and 200 miRNA genes at very high depth. We compared these ACE assays to standard exome and gene panels currently available. We then compared the ACE panel to the ACE exome using a set of well-characterized cancer cell lines, cell line mixtures with known genomic perturbations, and primary tumor and matched normal pairs involved in drug resistance. We also performed whole-transcriptome and targeted RNA sequencing as companion assays to the DNA exome and panel, respectively. All data were analyzed using a cancer bioinformatics pipeline optimized for detection of low-representation small variants and indels, as well as somatic copy-number aberrations, gene expression and fusions. The ACE assays were able to detect somatic variants with higher accuracy than standard assays across regions targeted by both. For example, a low-representation BRAF mutation detected by standard exome was confirmed as a false positive using the ACE exome due to 90 times more coverage over that region. Between the ACE assays, we found that 88% of somatic variants identified through ACE exome were also identified with our comprehensive panel within regions targeted by both. Conversely, more than half of the somatic variants discovered in the ACE panel were missed in the ACE exome due to insufficient read depth. For instance, the panel detected two EGFR variants known to be present at 1% that were missed in the ACE exome. About 20 times more somatic variants across some ~18,000 genes were detected in whole-exome that are not targeted on the augmented gene panel. These genes have not yet been associated with cancer in current literature, but may be of potential interest for discovery research. Copy number profiles, although more comprehensive in the exome, were recapitulated using the panel, despite large distances between panel targets. Finally, the integration of RNA analysis to the DNA panel was able to detect expression and fusion patterns. In particular, we detected a DNA mutation associated with resistance in a post-treatment specimen, but accompanying RNA data proved this mutant unexpressed and thereby unlikely to be the driver of resistance. For NGS-based cancer analysis to effectively guide clinical decisions and research, accuracy across all relevant cancer genes is of paramount importance. An enhanced exome may offer a solution for researchers interested in novel cancer associations who desire broad, even coverage. A comprehensive, high-depth panel targeting a large set of genes associated with cancer, accompanied by RNA analysis, may accomplish research goals across a wide range of translational cancer research. Citation Format: Elena Helman, Michael James Clark, Sean Boyle, Richard Chen, Shujun Luo, Christian Haudenschild, Jason Harris, Gabor Bartha, Deanna Church, John West. Augmented targeted NGS in cancer diagnostics: Comparing gene panels and whole exome sequencing for accurate detection of driver mutations. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-39.

This paper looks to Adam Smith’s analysis of an important behavioral quirk to further public choice research. Following Lin Ostrom’s advice to go beyond rationality, the goal is to illuminate how the behavioral quirk impacts political settings and institutional evolution. Under analysis will be Adam Smith’s emphasis upon the peculiar influence that rank plays in society. In political situations Smith sees the concept of rank as being important by helping to establish peace and order, but also as a threat to our ability to self-govern. Our ability to self-govern, our art of association, is entangled with political decisions via connections that are strongly influenced by our perceptions of rank. This paper looks back to Adam Smith to aid in the development of behavioral public choice by seeing his understanding of a certain reverence toward rank and how it impacts the Ostrom’s art of association.

I argue that plausible claims in the logic of partial grounding, when combined with a plausible analysis of that concept, entail the falsity of plausible grounding claims. As our account of the concept of partial grounding and its logic should be consistent with plausible grounding claims, this is problematic. The argument hinges on the idea that some facts about what grounds what are grounded in others, which is an idea the paper aims to motivate.

Immunogenomic profiling of the tumor and the tumor microenvironment (TME) is critical for identifying new biomarkers of immunotherapy response, understanding resistance, and enabling the development of personalized immunotherapies. However, running a comprehensive array of biomarker assays for each patient sample is often impractical given limited sample quantity, processing complexity, and prohibitive cost. To address these challenges, we developed a novel, augmented exome and transcriptome-based platform that simultaneously characterizes the tumor and TME from a single FFPE sample. We co-optimized the design of our sequencing assays and analytics to increase performance for the detection of somatic SNVs, indels, CNAs, and fusions across ~20,000 genes, as well as the evaluation of neoantigens, expression signatures, HLA typing and LOH, TCR/BCR repertoires, oncoviruses, tumor-infiltrating lymphocytes (TILs), clinically-actionable mutations, tumor mutational burden (TMB), and MSI status. We developed novel methods to sequence difficult regions of the exome and to extend coverage to key immunogenomic biomarkers. Analytic pipelines were designed to utilize assay optimizations to achieve higher accuracy than with other platforms. We then validated the platform for diagnostic and therapeutic use. With as little as 50ng of DNA per FFPE sample and co-extracted RNA, this platform completely covers between 17% to 40% more genes compared to a non-augmented exome, thus increasing sensitivity to somatic mutations and putative neoantigens. For neoantigen performance, we generated immune-peptidomic data from mono-allelic HLA transfected cell-lines and trained neural networks to predict neoepitope binding to MHC, demonstrating a higher precision (0.88) across alleles than publicly available tools (0.9 and >0.94, respectively). For TILs, we developed signatures for CD4, CD8 T-cells, and other immune cells, demonstrating concordance with synthetic and CyTOF-derived validation sets. For HLA typing, we achieve an accuracy of 99.1% for HLA Class I, and 95% for HLA Class II typing calls, and have developed a novel tool for HLA LOH detection. We demonstrate sensitive detection of HPV, EBV, HCV, HTLV, and KSHV in known samples, and accurate MSI and TMB assessment. Finally, for diagnostic reporting, we achieve high sensitivity and specificity for clinically-reportable mutations comparable with diagnostic cancer panels. With this platform, we have developed a novel immunogenomics platform that can characterize both the tumor and TME from a single sample. By co-optimizing our assay and analytics for immuno-oncology, we enhance biomarker sensitivity compared to non-optimized genomics assays. Validation of the platform extends its use to diagnostics and personalized immunotherapy development. Citation Format: Robert Power, Gabor Bartha, Jason Harris, Sean Michael Boyle, Eric Levy, Pamela Milani, Prateek Tandon, Robin Li, Manjula Chinnappa, Paul McNitt, Rena McClory, Massimo Morra, Sebastian Saldivar, Michael Clark, Christian Haudenschild, Erin Newburn, Christelle Johnson, John West. A comprehensive, highly accurate genomics platform for precision immunotherapy: Simultaneously characterize tumors and the TME from a single FFPE sample [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A051. doi:10.1158/1535-7163.TARG-19-A051

'In virtue of' is a mainstay of philosophical discourse. So are similar expressions, such as 'depends on', 'is prior to', and 'is determined by'. It is reasonable to suppose that these expressions are all used to express claims of non-causal dependence, or ? as is becoming the standard term ? 'grounding'. Whilst causation has been studied extensively, it is only in recent years that grounding has become established as a major concern of metaphysics. In this paper we will take stock by bringing together some of the main themes to have emerged in the recent debate. We begin by introducing the notion of grounding. Then we discuss scepticism about grounding before setting out some of the main questions about grounding under current investigation. The final section introduces further avenues for future research.

SummaryPersonalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

A good deal of experimental work has assessed the intelligibility of sinewave speech (SWS), synthesized by mixing sinusoids that follow the formants of natural utterances. While SWS is clearly intelligible at some level, most SWS work has been conducted using sentences, whose intelligibility is affected by many factors in addition to those related to recognition at the phonetic level. Earlier work [Hillenbrand et al., J. Acoust. Soc. Am, 129, 3991–4000] measuring the intelligibility of SWS vowels in isolated syllables reported an identification rate of 55%, far above chance but ~40 percentage points lower that of the original signals. The present work tested the intelligibility of SWS versions of 23 consonant types in CV and VCV syllables with three vowel types ([ɑ i u]) spoken by one man and one woman. SW signals were generated from unedited envelope peaks rather than formants. Intelligibility averaged across 59 listeners was 59%, with large variability across both listeners (sd = 9.9) and, especially, c...

Whole-genome sequencing is becoming commonplace, but the accuracy and completeness of variant calling by the most widely used platforms from Illumina and Complete Genomics have not been reported. Here we sequenced the genome of an individual with both technologies to a high average coverage of ~76×, and compared their performance with respect to sequence coverage and calling of single-nucleotide variants (SNVs), insertions and deletions (indels). Although 88.1% of the ~3.7 million unique SNVs were concordant between platforms, there were tens of thousands of platform-specific calls located in genes and other genomic regions. In contrast, 26.5% of indels were concordant between platforms. Target enrichment validated 92.7% of the concordant SNVs, whereas validation by genotyping array revealed a sensitivity of 99.3%. The validation experiments also suggested that >60% of the platform-specific variants were indeed present in the genome. Our results have important implications for understanding the accuracy and completeness of the genome sequencing platforms.

Whole exome sequencing by high-throughput sequencing of target-enriched genomic DNA (exome-seq) has become common in basic and translational research as a means of interrogating the interpretable part of the human genome at relatively low cost. Presented here is a comparison of three major commercial exome sequencing platforms from Agilent, Illumina and Nimblegen applied to the same human blood sample. The Nimblegen platform, which is the only one to use high-density overlapping baits, provides increased efficiency of enrichment and sensitivity for detecting variants but covers fewer genomic regions than the other platforms. As a result, Nimblegen requires the least amount of sequencing to sensitively detect small variants, but Agilent and Illumina are able to detect a greater total number of variants with additional sequencing. Illumina in particular captures the untranslated regions, which are missing from the Nimblegen and Agilent platforms. Exome sequencing and whole genome sequencing (WGS) of the same sample were also compared, demonstrating that exome-seq allows for the detection of additional small variants missed by WGS. These data suggest that WGS experiments benefit from being supplemented with targeted exome-seq data. This study serves to assist the community in selecting the optimal exome-seq platform for their experiments, as well as proving that exome-seq is capable of identifying important coding variations that are missed by a typical WGS experiment.

There is a significant body of research examining the intelligibility of sinusoidal replicas of natural speech. Discussion has followed about what the sinewave speech phenomenon might imply about the mechanisms underlying phonetic recognition. However, most of this work has been conducted using sentence material, making it unclear what the contributions are of listeners’ use of linguistic constraints versus lower level phonetic mechanisms. This study was designed to measure vowel intelligibility using sinusoidal replicas of naturally spoken vowels. The sinusoidal signals were modeled after 300 ∕hVd∕ syllables spoken by men, women, and children. Students enrolled in an introductory phonetics course served as listeners. Recognition rates for the sinusoidal vowels averaged 55%, which is much lower than the ∼95% intelligibility of the original signals. Attempts to improve performance using three different training methods met with modest success, with post-training recognition rates rising by ∼5–11 percentage points. Follow-up work showed that more extensive training produced further improvements, with performance leveling off at ∼73%–74%. Finally, modeling work showed that a fairly simple pattern-matching algorithm trained on naturally spoken vowels classified sinewave vowels with 78.3% accuracy, showing that the sinewave speech phenomenon does not necessarily rule out template matching as a mechanism underlying phonetic recognition.

The hybrid orchid Dactylorhiza praetermissa (Druce) Soo (Southern Marsh-orchid)×Gymnadenia densiflora (Wahlenb.) A. Dietr. (Marsh Fragrant-orchid) is reported from Kenfig National Nature Reserve, Glamorgan, v.c. 41, a first record for Wales. It is described under the new binomial×Dactylodenia ettlingeriana M J Clark & L Lewis. References are made to a previous record of this hybrid from the fen at Greywell Pumping Station, N. Hants., v.c. 12, in 1981/2, and to another probable record from Southwick, S. Hants., v.c. 11, in 1931.

I discuss a modification of Lewisian modal realism called ‘inclusionism’. Inclusionism is the thesis that some worlds contain other worlds as proper parts. Inclusionism has some attractive consequences for theories of modality. Josh Parsons, however, has raised a problem for inclusionism: the problem of unmarried husbands. In this paper I reply to this problem. My strategy is twofold: first I claim, pace Parsons, that it is not clear why the inclusionist cannot avail herself of an obvious solution to the problem; and second, I argue that even if there is no available solution, the same problem also afflicts Lewis’ original theory. Therefore, even if the problem remains unsolved, we have not been given any reason to think that an inclusionist version of Lewisian realism is worse than the original.

Three American English diphthongs involving onsets in the back of the vowel space were investigated by means of acoustic measurements, discriminant analysis, and perceptual experiments. These diphthongs, termed DOOR/WAR, TOY, and STAR, were observed in the speech of ten young women residing in southern Michigan. The diphthongs were elicited in a variety of /b/-, /ɡ/-, and /h/-initial words (e.g. board, Boyd, and barred). Words with similar consonantal margins but different nuclei (e.g. bode, baud, and bod) were elicited, as well. The DOOR/WAR and TOY words were compared with bode and baud (and similar words with initial /ɡ/ and /h/), while the STAR words were compared with baud and bod (and similar words with initial /ɡ/ and /h/). All three methods of investigation showed that the initial part of the DOOR/WAR and TOY diphthongs more closely resembles that of bode than baud. On the other hand, the initial part of the STAR diphthong was shown to be intermediate between that of baud and that of bod.

Objective— Oxidized 1-palmitoyl-2-arachidonyl- sn -3-glycero-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-(5,6 epoxyisoprostanoyl)- sn -glycero-3-phosphocholine (PEIPC), which are present in atherosclerotic lesions, activate endothelial cells to induce a complex inflammatory and pro-oxidant response. Previously, we demonstrated induction of genes regulating chemotaxis, sterol biosynthesis, the unfolded protein response, and redox homeostasis by Ox-PAPC in human aortic endothelial cells (HAECs). Activation of the c-Src kinase/signal transducer and activator of transcription 3 and the endothelial nitric oxide synthase/sterol regulatory element binding protein (SREBP) pathways were shown to regulate several of these inflammatory effects of Ox-PAPC in HAECs. The goal of the current studies was to determine the role of high-density lipoprotein (HDL) in regulating Ox-PAPC signaling in HAECs. Methods and Results— Using quantitative real-time polymerase chain reaction, Western analysis, and functional studies, we demonstrated that pretreatment of HAECs with HDL reduced the induction of inflammatory, sterol biosynthetic, and unfolded protein response genes by Ox-PAPC and PEIPC; Ox-PAPC-induced chemotactic activity and monocyte binding were also decreased. These effects were associated with HDL inhibition of Ox-PAPC-induced c-Src , signal transducer and activator of transcription 3, and SREBP activation, alterations in endothelial nitric oxide synthase phosphorylation (previously associated with the inflammatory action of Ox-PAPC), and a decrease in superoxide formation. Finally, we demonstrated that treatment with HDL did not inhibit Ox-PAPC and PEIPC-induced activation of redox pathways, which protect the cell from the effects of oxidative stress. Conclusions— Taken together, these studies demonstrated that HDL inhibits the pro-inflammatory effects of Ox-PAPC and PEIPC, while maintaining the antioxidant activities of these lipids.

Author(s): Strom, Samuel P; Clark, Michael J; Martinez, Ariadna; Garcia, Sarah; Abelazeem, Amira A; Matynia, Anna; Parikh, Sachin; Sullivan, Lori S; Bowne, Sara J; Daiger, Stephen P; Gorin, Michael B | Abstract: BackgroundRetinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa.MethodsVariant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing.Results and conclusionsA total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269AgG (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon.

The UK floods in late 2000 reinforced an emerging awareness which questioned the long-term sustainability of an exclusive reliance on hard-engineered flood defences to protect the UK population against increased flood risk. The debate has subsequently focused on a broader interpretation of the risks associated with flooding. This paper explores the notion that, although social and technical issues are already being integrated to understand and manage flood, practitioners are now realising the importance of accommodating public hazard understanding and perception of risk into their management models, and there remains a need to fit such ideas to the insurance-based system of flood management in the UK.

The classical liberal character of economics emerged in the eighteenth century, notably with Adam Smith’s view that politics is prone to an under-appreciation the relative virtues of natural liberty. Smith centered political economy on the presumption of liberty. The Journal of Economic Literature published a review of The Economic Report of the President. Five authors writing separately raised numerous omissions in The Economic Report of the President. The authors do not suggest as worthy reform a single ERP-omitted potential liberalization. The review shows little trace of the Smithian character.

Increasing concern about flooding and its potentially socially-devastating effects has reinforced the need for an effective mechanism to deal with the recovery of losses from these events. This paper highlights the problem of uninsurance in the UK and the potentially growing number of people who do not have flood insurance. A dual challenge of uninsurance is emerging: those who have been traditionally excluded from insurance cover due to price and a new phenomenon, those who live in high-risk areas who may become cost-prohibited through the introduction of risk-related premiums.

Participation in the coastal zone management decision-making system by expert and nonexpert stakeholders has a broadly acknowledged potential, but in practice the implementation of participatory roles varies greatly from country to country. The traditional "linear" model by which expert information is deemed to lead directly to enhanced awareness and convergent decisions/actions is largely discredited. An alternative and more flexible system, based on a series of equal-status roles that are adopted by stakeholders in relation to their needs at a specific time, is proposed. It is suggested that coastal management practice in the United Kingdom currently tends towards the conventional and conservative interpretation of participation and thus fails to exploit the full potential of a broader arrangement. The importance of a practical model through which to engage stakeholders in what has until recently been an expert-led process remains a worthwhile but challenging target.

A shortcoming of Internet-based retailing efforts is consumers' inability to touch products during their purchase decision-making processes. This research is a preliminary effort to examine the construct of need for tactile input by consumers and its impact on the likelihood to purchase products over the Internet. Initial measurement of the construct is developed through a survey of 272 respondents. This consumer characteristic is then shown to impact negatively the purchase of products on the Internet, particularly those requiring more tactile cues for their evaluation. Further, women showed a higher need for tactile input compared to men in making product evaluations. Strategic implications of the importance of considering consumers' need for tactile input for Internet retailers are provided.

The vowels /i/ and /I/ are not contrastive before /r/ in American English, and the phonetics literature is equivocal about which symbol to use for the nucleus in words such as beer. Similarly /e/ and /ε/ are not contrastive before /r/, and the literature contains varied references to one or the other in words such as bear. The purpose of this study was to investigate these vowels by acoustic measurements, discriminant analyses, and listening tests. Eleven men and ten women residing in southern Michigan recorded /r/-final monosyllables (beer, bear, hear, hair), as well as words containing /i, I e, ε with other finals, such as beet, bit, bait, bet. Acoustic measurements included the first three formants at steady state. The high front vowel in /r/-final syllables (beer, hear) showed formant values intermediate between /i/ and /I/, but closer to /i/, and the mid front vowel (in bear and hair) was intermediate between /e/ and /ε/, but closer to /e/. Discriminant analysis using the first three formants and listening tests using 60 ms vowel excerpts yielded results consistent with the idea that the pre-/r/ vowels are acoustically intermediate between their tense and lax neighbors but resemble /i/ and /e/ more closely than /I/ and /ε/.

Background Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet the variation of coverage and sensitivity over medically relevant parts of the genome remains poorly understood. Several sequencing-based assays continue to provide coverage that is inadequate for clinical assessment. Methods Using sequence data obtained from the NA12878 reference sample and pre-defined lists of medically-relevant protein-coding and noncoding sequences, we compared the breadth and depth of coverage obtained among four commercial exome capture platforms and whole genome sequencing. In addition, we evaluated the performance of an augmented exome strategy, ACE, that extends coverage in medically relevant regions and enhances coverage in areas that are challenging to sequence. Leveraging reference call-sets, we also examined the effects of improved coverage on variant detection sensitivity. Results We observed coverage shortfalls with each of the conventional exome-capture and whole-genome platforms across several medically interpretable genes. These gaps included areas of the genome required for reporting recently established secondary findings (ACMG) and known disease-associated loci. The augmented exome strategy recovered many of these gaps, resulting in improved coverage in these areas. At clinically-relevant coverage levels (100 % bases covered at ≥20×), ACE improved coverage among genes in the medically interpretable genome (>90 % covered relative to 10-78 % with other platforms), the set of ACMG secondary finding genes (91 % covered relative to 4-75 % with other platforms) and a subset of variants known to be associated with human disease (99 % covered relative to 52-95 % with other platforms). Improved coverage translated into improvements in sensitivity, with ACE variant detection sensitivities (>97.5 % SNVs, >92.5 % InDels) exceeding that observed with conventional whole-exome and whole-genome platforms. Conclusions Clinicians should consider analytical performance when making clinical assessments, given that even a few missed variants can lead to reporting false negative results. An augmented exome strategy provides a level of coverage not achievable with other platforms, thus addressing concerns regarding the lack of sensitivity in clinically important regions. In clinical applications where comprehensive coverage of medically interpretable areas of the genome requires higher localized sequencing depth, an augmented exome approach offers both cost and performance advantages over other sequencing-based tests. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0197-4) contains supplementary material, which is available to authorized users.

A model of habitat suitability linked to a Geographic Information System was developed for the red squirrel (Sciurus vulgaris) in 2800 ha of Thetford Forest, East England, to assess red squirrel population numbers in relation to forest management. We defined each forest sub-compartment or parcel of land in terms of its tree species and age between 1995 and 2015, and categorised each parcel of land as low, moderate or high red squirrel suitability. Resident squirrels may live in more than one habitat patch providing the distance between patches is within the foraging range of the animals and the land between the patches does not act as a barrier to foraging movements. Moreover, squirrels require a minimum area (home range area) of suitable habitat that will provide them with sufficient food resources. To examine these two factors, we explored 120 different model scenarios using three different distances to link patches together and four different sized minimum areas, termed minimum linked areas (MLA), that would hold resident red squirrels, at five year intervals between 1995 and 2015. As an overall measure of suitability, we summed all the MLAs in the reserve for high plus moderate suitability, which we have called the total linked area (TLA), and forecast how this may change in the future. We show that TLA will increase from 39% in 1995 to 67% of the study area by 2015, demonstrating that the reserve will get better for red squirrels over this time. We also demonstrate how changes in forest management would further increase TLA to 82% by 2015. Our results demonstrate how a habitat suitability model operating at the scale of an individual forest, coupled with a GIS and based on an understanding of the species' ecology, provides an objective way of assessing the impact of forest management prescriptions on red squirrel populations.

Major ion, silica and pH data from a high Arctic proglacial stream network are examined. Factor analysis shows that the major controls upon hydrochemistry in the basin include snowpack solute elution, rapid alteration of minerals via surface reactions and slow, incongruent silicate dissolution. The importance of chemical weathering is found to increase downstream at the expense of solute acquisition from the transient snowpack. Data from a series of snow pits show that snowpack solute elution is characterised by the preferential elution of SO42−. Evidence for the preferential elution of NO3− is equivocal. However, NO3− levels in proglacial runoff may be enhanced by the leaching of cryotic soils later in the ablation season. Chemical weathering is dominated by calcite dissolution at high elevations and a combination of calcite and dolomite dissolution in the downstream proglacial environment. Silicate weathering at high elevations is characterised by the enrichment of K+ relative to Si. Concentrated active layer soil waters show less enrichment of K+ and constitute a potentially important source of dissolved silica to the river system. Na+ is also produced by silicate weathering, but its mobility is believed to be largely governed by ion exchange with Ca2+ early in the ablation season. All chemical weathering environments are characterised by high p(CO2) due to either respiration within the soil or, at higher elevations within the catchment, H+ provision from acid aerosol and sulphide oxidation. However, rates of sulphide oxidation are limited because the cold-based thermal regime of the glaciers effectively prevents access of meltwaters to freshly comminuted sub-glacial sulphide minerals. The restricted sub-glacial weathering therefore means that ice marginal and proglacial environments are the most important zones of solute acquisition by meltwaters, causing significant enrichment of major ions, silica and dissolved CO2 within only a short distance of the contemporary ice margin.

1. Sustainable river management is the proclaimed aim of many agencies and institutions, but it remains challenging to bring this worthy ideal from the level of political rhetoric to that of practical river management. 2. Amongst the many drivers that already pressure the river manager, from internal institutional goals, through political aspirations to systemic change within the biophysical process system, one common element emerges, that of prevailing uncertainty. 3. Once it has been accepted that conventional science and engineering approaches to uncertainty (risk) minimization may be sub-optimal in a truly holistic (biophysical, socio-economic, political) system, the challenge emerges of developing a more appropriate framework without destroying over-burdened managers and management systems in the process. 4. It is argued that the necessary components are often already in place or under consideration. A linked model is proposed comprising practical measures of sustainability, robust approaches to uncertainty (if necessary, involving attitude change), responsive (adaptive) management frameworks, and an important underpinning of fuzzy decision support.