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Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10−41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

Purpose: Macular edema resulting from retinal vascular leakage is the leading cause of vision loss in diabetic retinopathy (DR) . The nuclear factor of activated T-cells (NFAT) family of transcription factors is known to upregulate inflammatory cytokines in response to high glucose. This study explored the effect of NFAT inhibition on retinal vascular leakage and inflammation in DR in vivo and in vitro. Methods: The streptozocin-induced (STZ) model was used as the mouse model of diabetic retinopathy. Hyperglycemia was induced at 4 weeks in C57BL/6J mice and confirmed when fasting plasma glucose became persistently elevated (>300 mg/dL) . Experiments were performed at weeks of hyperglycemia. STZ mice were injected intravitreally with the NFAT signaling inhibitor INCA-6 (25 uM) or vehicle (0.1% DMSO in PBS) . Uninjected eyes of both STZ and control mice served as additional controls. Evans blue dye (EBD) was used to measure retinal vascular leakage. Primary mouse retinal microvascular endothelial cells (MRMECs) were used for in vitro experiments. MRMEC monolayers were treated with INCA-6 (2.5 uM) or with vehicle and cell permeability was induced with mouse VEGF165. The transendothelial electrical resistance (TEER) was measured with the electrical cell-substrate impedance sensing method. MRMEC IL-6 production was investigated by ELISA. Results: In the STZ model of diabetic retinopathy, EBD vascular leakage was significantly reduced in INCA-6-treated eyes (INCA-6: 0.85 ± 0.57, n=5; vehicle: 1.78 ± 0.38, n= 7; P=0.007) , and in INCA-6 treated eyes compared to untreated eyes (untreated: 2.83 ± 1.63, n=4, P=0.04) . In the VEGF-induced MRMEC monolayer permeability model, INCA-6 significantly preserved TEER compared to vehicle (n=12, P Conclusions: NFAT inhibition has therapeutic potential to prevent and treat retinal vascular leakage and inflammation in DR. Disclosure I.De la huerta: None. J.L.Nunez: None. J.M.Poloway: None. V.Reddy: None. J.Penn: None. Funding National Institutes of Health (EY032620) International Retinal Research Foundation Grant Knights Templar Foundation Career Starter Grant

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community., Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Future radar transmitters will need to be able to quickly reconfigure their radio-frequency circuitry to change operating frequency and spectral output while maintaining high power-added efficiency (PAE). In this paper, fast tuning of a tunable-varactor matching network is demonstrated to optimize the PAE while meeting requirements on the adjacent-channel power ratio. The tunable varactor network, a first-level prototype of a tunable radar amplifier matching network, incurs nonlinear performance, providing possible challenges to measurement accuracy. To address the issue of nonlinearities while maintaining ability to quickly reconfigure, the tunable-varactor network is characterized at different input power levels to allow useful performance in its nonlinear regime. The power-dependent characterization is used in an algorithm for optimization of an amplifier's PAE, by looking up the matching network characterization performed at the power estimated to be output by the amplifier. Measurement results show that this characterization enhances the consistency of the optimized PAE. Using the tunable varactor network reduces the optimization time to one-fourth of the time required when using the algorithm with a traditional mechanical load-pull tuner.

Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in-line with expectations given the underlying population and ascertainment approach. For example, we identified ∼66,000 close (first- and second-degree) relationships within DiscovEHR involving 55.6% of study participants. Our simulation results project that >70% of the cohort will be involved in these close relationships as DiscovEHR scales to 250,000 recruited individuals. We reconstructed 12,574 pedigrees using these relationships (including 2,192 nuclear families) and leveraged them for multiple applications. The pedigrees substantially improved the phasing accuracy of 20,947 rare, deleterious compound heterozygous mutations. Reconstructed nuclear families were critical for identifying 3,415 de novo mutations in ∼1,783 genes. Finally, we demonstrate the segregation of known and suspected disease-causing mutations through reconstructed pedigrees, including a tandem duplication in LDLR causing familial hypercholesterolemia. In summary, this work highlights the prevalence of cryptic relatedness expected among large healthcare population genomic studies and demonstrates several analyses that are uniquely enabled by large amounts of cryptic relatedness.

BackgroundLoss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. MethodsWe sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. ResultsIn th...

SUMMARYThe UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the first tranche of large-scale exome sequence data for 49,960 study participants, revealing approximately 4 million coding variants (of which ~98.4% have frequency < 1%). The data includes 231,631 predicted loss of function variants, a >10-fold increase compared to imputed sequence for the same participants. Nearly all genes (>97%) had ≥1 predicted loss of function carrier, and most genes (>69%) had ≥10 loss of function carriers. We illustrate the power of characterizing loss of function variation in this large population through association analyses across 1,741 phenotypes. In addition to replicating a range of established associations, we discover novel loss of function variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical significance in this population, finding that 2% of the population has a medically actionable variant. Additionally, we leverage the phenotypic data to characterize the relationship between rare BRCA1 and BRCA2 pathogenic variants and cancer risk. Exomes from the first 49,960 participants are now made accessible to the scientific community and highlight the promise offered by genomic sequencing in large-scale population-based studies.

This paper presents a microwave implementation of the novel sequentially-switched delay line (SSDL) for simultaneous transmit and receive (STAR) applications. The circuit is nonreciprocal and non-magnetic and is implemented in a high frequency GaN MMIC process. It isolates the transmit and receive paths. Measurements confirm the non-reciprocal nature of the circuit. The insertion loss is 5 – 8 dB with 20 – 35 dB isolation over DC-2 GHz.

BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS: A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was found to be associated with reduced levels of ALT (P=4.20×10(−12)) and AST (P=6.2×10(−10)). Among DiscovEHR study participants, this variant was found to be associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS: A loss-of-function variant in HSD17B13 is associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.)

A fast interval-halving search is demonstrated that can be used to optimize power-amplifier load impedance in real-time with a high-power evanescent-mode cavity tuner, consisting of two evanescent-mode resonant cavities. The power-added efficiency is optimized by tuning the resonator position numbers, which map to resonant frequencies, without need for a load-pull characterization. Because no characterization is required, significant time savings in computation is expected, and tuning is expected to be more robust to drift and hysteresis of the tuner characteristics.

MotivationDetection of abnormal karyotypes from whole-exome sequencing has significant clinical potential, enabling a primary screen for chromosomal anomalies among samples undergoing short-read sequencing for nucleotide resolution genomic characterization.ResultsWe present KaryoScan, a high-throughput method for detecting chromosomal anomalies within large cohort exome sequencing studies. We detect and validate autosomal and sex chromosomal aneuploidies in a large exome sequencing cohort, and demonstrate detection of smaller and complex events (partial chromosome, mosaic, copy neutral, and complex rearrangements), representing the range of anomalies that can be uncovered from the exome.Availabilityhttps://github.com/rgcgithub/karyoscan

The rapid progress towards 5G wireless systems is accelerating the development of mm-wave semiconductor processes, broadband circuits, and system technologies. Similarly, next-generation radar is being expanded and redefined. Legacy radar systems are nearing the end of their life cycle and systems developers are aiming to upgrade their capability while reducing cost, size, and weight. Radar systems have requirements that result in technical circuit design challenges including high power, broadband, and low distortion. This paper focuses on MMIC design challenges specific to the design of next-generation radars that will operate in a crowded wireless environment, allow spectrum sharing, and dynamic frequency selection. Simulated and measured data are presented.

Background Sarilumab is a human mAb that blocks IL-6 from binding to both membrane-bound and soluble IL-6Rα (sIL-6R). A missense variant in the IL6R gene, Asp358Ala (rs2228145), falls within a proteolytic cleavage site and individuals with an alanine at this position have increased sIL-6R in circulation. 1 In addition, this variant has been associated with several diseases including RA. 2 Objectives To determine the impact of the Asp358Ala variant on sIL-6R concentrations and response of RA patients to sarilumab. Methods DNA was collected from patients enrolled in the MOBILITY study (NCT01061736) that evaluated the efficacy and safety of sarilumab + methotrexate (MTX) in RA patients with inadequate response to MTX. The pharmacogenetic analysis was conducted on 599 Caucasian patients (396 sarilumab 150 or 200 mg q2w + MTX, 203 placebo + MTX). Results Concentrations of sIL-6R were strongly associated with the Asp358Ala genotypes at baseline ( p =4.2 × 10 -11 ). The difference in sIL-6R concentrations between genotype groups continued to increase in sarilumab-treated patients through the end of treatment, particularly for the CC genotype (Figure; p =7.8 × 10 -12 ). There was a modest association for change in sIL-6R in placebo + MTX–treated patients ( p =0.0052). Variation in Asp358Ala was not associated with sarilumab efficacy, including mTSS at week 52 and ACR scores (Table). Conclusions The Asp358Ala variant in the IL6R gene is significantly associated with differences in sIL-6R levels at baseline and after sarilumab treatment. The differences across genotypes may be due to increases in sIL-6R production. Importantly, this variant was not associated with differences in sarilumab treatment response. These data suggest that the sarilumab doses used for this clinical study saturate both the membrane and soluble forms of IL-6R and effectively block IL-6 signaling. Sarilumab provides therapeutic benefit for RA patients irrespective of their Asp358Ala genotype status. References Garbers et al. Biochim Biophys Acta. 2014;1842:1485–1494. Okada et al. Nature. 2014;506:376–381. Acknowledgements This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Editorial support was provided by MedThink SciCom and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Disclosure of Interest A. Damask Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Hamilton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, S. Hamon Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paccard Shareholder of: Sanofi R&D, Employee of: Sanofi R&D, J. Parrino Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, N. Graham Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Penn Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Lopez Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Reid Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Overton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Baras Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Shuldiner Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paulding Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc

Background Sarilumab is a human mAb that blocks IL-6 from binding to both membrane-bound and soluble IL-6Rα. Variants in the UGT1A1 gene have been shown to be strongly associated with increased unconjugated bilirubin levels in patients treated with tocilizumab, another IL-6Rα inhibitor.1,2UGT1A1 encodes the enzyme responsible for the glucuronidation of bilirubin and variation in this gene is also responsible for Gilbert9s syndrome, a mild benign condition characterized by elevations in unconjugated bilirubin and jaundice. The underlying main genetic variation responsible for Gilbert9s syndrome has been identified as a TA repeat located in the promoter of UGT1A1 (UGT1A1*28 allele), which is in linkage disequilibrium with a single nucleotide polymorphism, rs6742078, previously associated with higher bilirubin levels after tocilizumab treatment.1 Objectives To test for an association between rs6742078 and bilirubin levels in RA patients treated with sarilumab. Methods DNA was collected from patients enrolled in MOBILITY (NCT01061736), which evaluated the efficacy and safety of sarilumab + methotrexate (MTX) in RA patients with inadequate response to MTX. The pharmacogenetic analysis was conducted in 599 Caucasian patients treated with MTX + sarilumab (150 or 200 mg q2w) or placebo. Log-transformed unconjugated and total bilirubin levels were analyzed at baseline and over the treatment period (using maximum bilirubin). Results There was a strong association between the rs6742078 TT genotype and higher unconjugated bilirubin levels. The least squares mean (SE) for patients at baseline with the TT genotype was 0.48 (0.02) mg/dL vs 0.25 (0.009) and 0.21 (0.009) mg/dL for those with GT and GG genotypes, respectively (p=1.02×10-21). After sarilumab treatment, the difference between genotype groups increased over the course of the study (p=4.3×10-10; Figure). In the binary analysis of maximum total bilirubin in sarilumab-treated patients, the TT genotype was significantly associated with mild bilirubin elevations (OR =34.7; p=1.2×10-8; Table). Conclusions The association observed between the rs6742078 TT genotype in UGT1A1 and unconjugated bilirubin elevations in sarilumab-treated patients is consistent with previous observations in tocilizumab-treated patients. These findings suggest that sarilumab-related increases in bilirubin levels are likely benign and caused by common genetic variation in UGT1A1 and are not due to underlying liver injury. References Mori et al. Mod Rheumatol. 2012;22:515–523. Lee et al. Pharmacogenet Genomics. 2011;21:365–374. Acknowledgements This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Editorial support was provided by MedThink SciCom and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Disclosure of Interest A. Damask Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Hamilton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, S. Hamon Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paccard Shareholder of: Sanofi R&D, Employee of: Sanofi R&D, J. Parrino Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, N. Graham Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Penn Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Lopez Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Reid Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Overton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Baras Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Shuldiner Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paulding Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc

For future adaptive radio and radar transmission in a dynamic spectrum access environment, the radio-frequency circuitry will be need to be reconfigurable to allow adjustment of the operating frequency and the transmission spectrum in a congested environment. A prototype tunable amplifier matching network was implemented using varactors as the tunable elements. A method in which the control bias voltages of the varactors are directly tuned is compared with a previously demonstrated algorithm that tunes based on the reflection coefficient through a nonlinear characterization of the varactor matching network. The algorithms are both designed to optimize the power-added efficiency of the amplifier while keeping the adjacent-channel power ratio below a pre-specified constraint value. Lower average time per measurement is achieved for the voltage-based search, but the total search time is lower for the reflection-coefficient based search. This comparison of algorithms is useful in developing a reconfigurable transmitter amplifier that can adapt on the fly to meet changing spectral requirements.

Chemistry courses remain a challenge for many undergraduate students. In particular, first-semester organic chemistry has been labeled as a gatekeeper with high attrition rates, especially among students of color. Our study examines a key factor related to conceptual understanding in science and predictive of course outcomes—knowledge structures. Previous research on knowledge structures has focused on differences between experts and novices. Given the increasing ethnic diversity of college classrooms and research indicating unique differences in certain higher order cognitive processes associated cultural practices and ethnicity, it is important to investigate whether similar patterns exist with respect to knowledge structures. Our study utilized concept maps to measure knowledge structures. Two separate analyses where performed to determine whether or not ethnically diverse students' organize their knowledge of organic chemistry content in structurally different ways. The first analysis utilized concept map proposition scoring to examine the influence of prior science achievement and ethnicity on knowledge structures. The second analysis examined holistic map structures to determine whether or not ethnically diverse students show qualitatively distinct structures overall. Results show significant mean differences on concept map proposition scores related to both prior science achievement and ethnic group membership. However, examination of holistic structures revealed that students' qualitative holistic structures did not vary by ethnic group membership. Taken together, our findings suggest that variation in students' knowledge structures are related to prior science achievement across ethnic groups, not qualitative differences in the ways ethnically diverse students' structure knowledge. Implications for teaching and learning in organic chemistry are discussed. © 2014 Wiley Periodicals, Inc. J Res Sci Teach 51: 741–758, 2014

Fast load impedance tuning of a varactor diode matching network to maximize amplifier gain in real-time reconfigurable circuitry is demonstrated. A published tunable varactor-diode matching topology is designed for operation at 1.3 GHz to provide significant Smith Chart coverage. A steepest-ascent algorithm is applied for fast optimization, and measurement results indicate excellent convergence from multiple starting points within the Smith Chart. Algorithm data compares well with traditional loadpull results measured with both a commercially available tuner and the tunable-varactor network, and searching with the varactor tuner search is much faster than a traditional mechanical tuner.

Unleashing the power of precision medicine Precision medicine promises the ability to identify risks and treat patients on the basis of pathogenic genetic variation. Two studies combined exome sequencing results for over 50,000 people with their electronic health records. Dewey et al. found that ∼3.5% of individuals in their cohort had clinically actionable genetic variants. Many of these variants affected blood lipid levels that could influence cardiovascular health. Abul-Husn et al. extended these findings to investigate the genetics and treatment of familial hypercholesterolemia, a risk factor for cardiovascular disease, within their patient pool. Genetic screening helped identify at-risk patients who could benefit from increased treatment. Science , this issue p. 10.1126/science.aaf6814 , p. 10.1126/science.aaf7000

PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.

The Trick Simulation Toolkit is a simulation development environment used to create high fidelity training and engineering simulations at the NASA Johnson Space Center and many other NASA facilities. Its purpose is to generate a simulation executable from a collection of user-supplied models and a simulation definition file. For each Trick-based simulation, Trick automatically provides job scheduling, numerical integration, the ability to write and restore human readable checkpoints, data recording, interactive variable manipulation, a run-time interpreter, and many other commonly needed capabilities. This allows simulation developers to concentrate on their domain expertise and the algorithms and equations of their models. Also included in Trick are tools for plotting recorded data and various other supporting utilities and libraries. Trick is written in C/C++ and Java and supports both Linux and MacOSX computer operating systems. This paper describes Trick's design and use at NASA Johnson Space Center.

Electronic health records (EHR) provide a comprehensive resource for discovery, allowing unprecedented exploration of the impact of genetic architecture on health and disease. The data of EHRs also allow for exploration of the complex interactions between health measures across health and disease. The discoveries arising from EHR based research provide important information for the identification of genetic variation for clinical decision-making. Due to the breadth of information collected within the EHR, a challenge for discovery using EHR based data is the development of high-throughput tools that expose important areas of further research, from genetic variants to phenotypes. Phenome-Wide Association studies (PheWAS) provide a way to explore the association between genetic variants and comprehensive phenotypic measurements, generating new hypotheses and also exposing the complex relationships between genetic architecture and outcomes, including pleiotropy. EHR based PheWAS have mainly evaluated associations with case/control status from International Classification of Disease, Ninth Edition (ICD-9) codes. While these studies have highlighted discovery through PheWAS, the rich resource of clinical lab measures collected within the EHR can be better utilized for high-throughput PheWAS analyses and discovery. To better use these resources and enrich PheWAS association results we have developed a sound methodology for extracting a wide range of clinical lab measures from EHR data. We have extracted a first set of 21 clinical lab measures from the de-identified EHR of participants of the Geisinger MyCodeTM biorepository, and calculated the median of these lab measures for 12,039 subjects. Next we evaluated the association between these 21 clinical lab median values and 635,525 genetic variants, performing a genome-wide association study (GWAS) for each of 21 clinical lab measures. We then calculated the association between SNPs from these GWAS passing our Bonferroni defined p-value cutoff and 165 ICD-9 codes. Through the GWAS we found a series of results replicating known associations, and also some potentially novel associations with less studied clinical lab measures. We found the majority of the PheWAS ICD-9 diagnoses highly related to the clinical lab measures associated with same SNPs. Moving forward, we will be evaluating further phenotypes and expanding the methodology for successful extraction of clinical lab measurements for research and PheWAS use. These developments are important for expanding the PheWAS approach for improved EHR based discovery.

Objective Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare myocardial disorder. Genetic etiology is ascribed to variants in 8 genes ( PKP2 , DSP , DSC2 , DSG2 , JUP , TMEM43 , TGFβ2 , RYR2 ). We aimed to establish the prevalence and clinical phenotype of individuals with pathogenic variants (PV) in these genes from an unselected cohort. Methods Whole-exome sequences for 31,036 patients in the MyCode™ Biorepository were evaluated for pathogenic or likely pathogenic (P/LP) ARVC variants reported in ClinVar or the ARVC database. Composite ICD-9 data from the electronic health records of PV individuals vs a non-PV control group were analyzed. Results 57 P/LP variants were identified in 240 individuals (0.77%), aged 61 ± 19 years. Characteristics of this PV group versus a non-PV control group are summarized in the table. Zero patients in the PV group had a documented diagnosis of ARVC. Use of implantable cardioverter defibrillators—the primary treatment for ARVC—was rare. Of individuals ≥55 years, 24% with PV had no history of cardiac disease (vs. 22% for non-PV). However, there was a modest increase in the prevalence of cardiac electrical abnormalities (e.g., tachycardia, fibrillation) in PV vs. non-PV. There was also a trend towards increased diagnoses of 'other primary cardiomyopathy'. Conclusions The prevalence of reported pathogenic ARVC variants (0.77%) greatly exceeds the disease prevalence (0.02 - 0.10%). In this cohort of 240 genotype-positive subjects, there was little evidence of overt ARVC disease, suggesting that the positive-predictive value for classic ARVC in individuals with an incidental positive genetic finding is low. The increased risk of certain clinical findings, not specific to ARVC, supports the notion that the spectrum of phenotypes associated with pathogenic variants in these genes is broader than classically described. Targeted “deep phenotyping” is needed to assess subclinical phenotypes in genomically screened populations.

Purpose To test whether Müller glia of the mammalian retina have circadian rhythms. Methods We used Müller glia cultures isolated from mouse lines or from humans and bioluminescent reporters of circadian clock genes to monitor molecular circadian rhythms. The clock gene dependence of the Müller cell rhythms was tested using clock gene knockout mouse lines or with siRNA for specific clock genes. Results We demonstrated that retinal Müller glia express canonical circadian clock genes, are capable of sustained circadian oscillations in isolation from other cell types, and exhibit unique features of their molecular circadian clock compared to the retina as a whole. Mouse and human Müller cells demonstrated circadian clock function; however, they exhibited species-specific differences in the gene dependence of their clocks. Conclusions Müller cells are the first mammalian retinal cell type in which sustained circadian rhythms have been demonstrated in isolation from other retinal cells.

This paper describes the adoption of a Test Driven Development approach and a Continuous Integration System in the development of the Trick Simulation Toolkit, a generic simulation development environment for creating high fidelity training and engineering simulations at the NASA Johnson Space Center and many other NASA facilities. It describes the approach, and the significant benefits seen, such as fast, thorough and clear test feedback every time code is checked into the code repository. It also describes an approach that encourages development of code that is testable and adaptable.

Background The small GTP ase Rad is a negative regulator of voltage‐dependent L‐type calcium channel current ( I C aL ); however, the effects of Rad ablation on cardiomyocyte function are unknown. The objective of this study is to test the hypothesis that Rad‐depletion causes positive inotropic effects without inducing cardiac hypertrophy. Methods and Results Ventricular myocytes from adult Rad −/− mice were isolated and evaluated by patch‐clamp recordings for I Ca,L and action potentials, Ca 2+ transients, and sarcomere shortening. Maximum I CaL is elevated in Rad −/− (maximal conductance 0.35±0.04 picoSiemens/picoFarad ( pS / pF ) wild‐type; 0.61±0.14 pS / pF Rad −/− ), decay kinetics are faster, and I Ca,L activates at lower voltages (activation midpoint −7.2±0.6 wild‐type; −11.7±0.9 Rad −/− ) mimicking effects of β‐adrenergic receptor stimulation. Diastolic and twitch calcium are elevated in Rad −/− ( F 340/380 : 1.03 diastolic and 0.35 twitch for wild‐type; 1.47 diastolic and 0.736 twitch for Rad −/− ) and sarcomere shortening is enhanced (4.31% wild‐type; 14.13% Rad −/− ) at lower pacing frequencies. Consequentially, frequency‐dependence of Ca 2+ transients is less in Rad −/− , and the frequency dependence of relaxation is also blunted. In isolated working hearts, similar results were obtained; chiefly, + dP /dt was elevated at baseline and developed pressure was relatively nonresponsive to acute β‐adrenergic receptor stimulation. In single cells, at subphysiological frequencies, nonstimulated calmodulin‐dependent protein kinase–sensitive calcium release is observed. Remarkably, Rad −/− hearts did not show hypertrophic growth despite elevated levels of diastolic calcium. Conclusions This study demonstrates that the depletion of Rad GTP ase is equivalent to sympathomimetic β‐adrenergic receptor, without stimulating cardiac hypertrophy. Thus, targeting Rad GTP ase is a novel potential therapeutic target for Ca 2+ ‐homeostasis–driven positive inotropic support of the heart.

Background: Rad is a small GTPase that regulates inward calcium current in excitable cells. In human heart failure, calcium dysregulation is accompanied by lowered levels of Rad expression, and dampened responsiveness to beta-adrenergic stimulation. However, the effects of Rad ablation on calcium cycling in the heart have yet to be examined. Hypothesis: Loss of Rad emulates beta-adrenergic stimulation in cardiac myocytes, elevating calcium levels, and promoting after depolarizations. Methods: The role of Rad was evaluated using knockout mice (RadKO)at several levels of biological organization. Inward calcium current, action potentials, fractional shortening, and calcium transients were measured in isolated ventricular myocytes. Functional parameters were recorded in the isolated working heart, and telemetry was used to monitor ECGs in intact freely-roaming mice. Results: Isolated ventricular myoctyes from Rad null mice display increased ICaL density, greater inward current at low voltages, and after depolarizations at low frequencies. Isolated cells exhibit increased diastolic calcium levels and increased dynamic calcium changes in transient amplitude during pacing. Further, RadKO cardiomyocytes develop a significantly greater number of spontaneous calcium transients than wildtype cohorts. Ventricular myocytes and intact working hearts from RadKO mice fail to respond to beta-adrenergic stimulation at the level of channel activation, calcium transient kinetics, and exhibit a significantly dampened change in +dP/dt in the isolated heart. Consistent with these effects, PKA substrates are phosphorylated at baseline in RadKO cardiomyocytes, suggesting tonic PKA activation. Conclusion: These data suggest the new provocative hypothesis that beta-adrenergic-mediated changes in excitation, calcium handling, and heart contraction involve relief of Rad-dependent negative regulation of channel function.

Background Mitochondrial disorders are difficult to diagnose due to extreme genetic and phenotypic heterogeneities. Methods We explored the utility of targeted next-generation sequencing for the diagnosis of mitochondrial disorders in 148 patients submitted for clinical testing. A panel of 447 nuclear genes encoding mitochondrial respiratory chain complexes, and other genes inducing secondary mitochondrial dysfunction or that cause diseases which mimic mitochondrial disorders were tested. Results We identified variants considered to be possibly disease-causing based on family segregation data and/or variants already known to cause disease in twelve genes in thirteen patients. Rare or novel variants of unknown significance were identified in 45 additional genes for various metabolic, genetic or neurogenetic disorders. Conclusions Primary mitochondrial defects were confirmed only in four patients indicating that majority of patients with suspected mitochondrial disorders are presumably not the result of direct impairment of energy production. Our results support that clinical and routine laboratory ascertainment for mitochondrial disorders are challenging due to significant overlapping non-specific clinical symptoms and lack of specific biomarkers. While next-generation sequencing shows promise for diagnosing suspected mitochondrial disorders, the challenges remain as the underlying genetic heterogeneity may be greater than suspected and it is further confounded by the similarity of symptoms with other conditions as we report here.

High-speed electronic circuits are needed for Army systems in communications, wireless sensors, imaging, and other systems. Gallium nitride (GaN) technology offers the highest power densities for radio frequency (RF) and wireless integrated circuits. Several GaN broadband high power efficient power amplifier designs for high frequency operation, such as satellite communications (SATCOM), were recently designed and submitted for fabrication using a proprietary 0.15-micrometer GaN process under development at TriQuint Semiconductor. These monolithic microwave integrated circuits (MMICs) are being fabricated by TriQuint as part of a recent cooperative research and development agreement (CRADA) with the U.S. Army Research Laboratory (ARL).

High-performance microwave and radio frequency integrated circuits are of interest to the Army. Several monolithic microwave integrated circuits (MMICs) were designed to enhance the performance of commercial-off-the-shelf (COTS) RF integrated circuits (RFICs) used in many wireless systems. This report is a summary of the steps and documentation delivered to TriQuint for their Prototype Development Quickturn (PDQ) Option for a set of MMIC designs fabricated for the U.S. Army Research Laboratory (ARL). This is an optimized set of designs based on some previous work. In this design submission, there are 10 separate MMIC designs on the 5 x 10 mm quarter tile.

We are interested in the remote determination of materials. That is, we desire to irradiate a material from a distance using efficient antenna systems and infer from the scattered signal the nature of the irradiated material. To accomplish this task we require a library of material properties as related to electromagnetic scattering and we require signal features that permit materials to be discriminated from a distance using scattered signals. This technical report provides a significant first step in the direction of providing the needed capability. A small materials library is presented along with signal properties of interest.

Development of fast electromagnetic switches, power sources and antennas is resulting in the generation of short, high-energy electromagnetic pulses.1,2 Understanding how such pulses propagate through living tissue is of interest to basic biology and of particular interest to the field of occupational medicine which is concerned to establish safe exposure levels for humans.

The MMlC designer has several options available to verify the performance and simulation agreement of his circuits. They can be divided into two basic categories: calibration reference plane at the probe tips or on the MMIC chip at the coplanar interface to the device under test (DUT). The calibration technique used determines the reference plane of the measurements. Several on-wafei and off-wafer calibration techniques were used to obtain measurements of GaAs MMICs. A Wafer Probe station and a vector network analyzer were used to obtain LRM, SOLT, and TRL calibrated measurements of GaAs devices. In order to use on wafer calibration, an open, a short, a load, a "short" microstrip line, and a "long" microstrip line were designed and included on the GaAs wafer. An SOLT and a TRL calibration was performed with these on-wafer calibration standards. For off-wafer calibration, the Cascade Microtech Impedance Standard Substrate (ISS) was used to obtain an LRM calibration for a third set of measurements. To equalize the reference plane of the LRM measurements with the on-wafer TRL and SOLT calibration measurements, the MMlC launches which transition from the coplanar probe to the microstrip were subtracted out, i.e. deembeded to equalize the reference plane. A numerical technique was used to extract the approximate s-parameters of the MMIC launch from LRM measured data. Device measurements with all three calibration techniques closely agreed and were repeatable. These deembeded measurements compared favorably to foundry supplied device models.

Diabetes is one of the leading health problems in the United States today, particularly among Native Americans. For those diagnosed with non-insulin dependent (Type II) diabetes mellitus, control of the disease involves significant changes in life style. A number of cultural factors affecting an individual's ability to control diabetes have been investigated. Rarely, however, has the variable of cultural identity been studied in this regard. The exploratory study reported in this article describes the development of a scale designed to measure cultural identity among diabetic members of the Omaha Tribe of Nebraska. The 19-item scale was subsequently used to test the hypothesis that high cultural identity would be positively correlated with measures of diabetes control. Control of diabetes was measured using both behavioral self-report, and fasting blood sugar levels. Support for the hypothesis was found with regard to fasting blood sugar levels, but not behavioral self-reports.

Electrical resistivity and Seebeck coefficients were determined for NiSb and CoSb as a function of composition. The results indicate that clustering of defects occurs for large deviations from the stoichiometric composition in CoSb, and that these compounds cannot be classified as electron compounds.

This thesis is an investigation of the effect of welding heat on the properties of hardened concrete. In precast concrete structures, where the bearing plates are embedded in the concrete, the welding heat on these plates, generated by the electric arc, penetrates into the concrete. It has been known for many years that high temperatures will lower the modulus of elasticity and the ultimate strength. This thesis is concerned with the “critical” temperatures at which losses begin and the arc energy required to develop this temperature at a reasonable depth into the concrete. In the investigation, the “critical” temperature, using limestone aggregate concrete that might be typical for precast construction, was found to be between 900°F and 1,000°F. The investigation, to determine the arc energy required to develop this temperature, was halted when under severe heating, where the arc burned through both plates, the maximum temperature at a point one half inch from the bearing plate was 710°F. Although cracking was severe in the immediate vicinity of the plate, the moduli of elasticity were lowered only slightly and the welding heat was not high enough to affect the ultimate strength. Master of Science

A wide range of patient health data is recorded in Electronic Health Records (EHR). This data includes diagnosis, surgical procedures, clinical laboratory measurements, and medication information. Together this information reflects the patient's medical history. Many studies have efficiently used this data from the EHR to find associations that are clinically relevant, either by utilizing International Classification of Diseases, version 9 (ICD-9) codes or laboratory measurements, or by designing phenotype algorithms to extract case and control status with accuracy from the EHR. Here we developed a strategy to utilize longitudinal quantitative trait data from the EHR at Geisinger Health System focusing on outpatient metabolic and complete blood panel data as a starting point. Comprehensive Metabolic Panel (CMP) as well as Complete Blood Counts (CBC) are parts of routine care and provide a comprehensive picture from high level screening of patients' overall health and disease. We randomly split our data into two datasets to allow for discovery and replication. We first conducted a genome-wide association study (GWAS) with median values of 25 different clinical laboratory measurements to identify variants from Human Omni Express Exome beadchip data that are associated with these measurements. We identified 687 variants that associated and replicated with the tested clinical measurements at p

Numerical research is reported on the propagation of short microwave pulses into living, biological materials. These materials are dispersive, and data on the dielectric constant and conductivity for these materials follow a Debye model. A Fourier-series calculation is presented that predicts the occurrence of Brillouin precursors when the incident pulses have sufficiently short rise times. These transients are attenuated with increasing propagation distance but are attenuated more slowly than the carrier frequency of the pulse, which is attenuated exponentially with distance. An analysis of the numerical error resulting from truncation of the Fourier series is given. Upper-bound estimates of truncation error show good series convergence.