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Background: Cardiovascular outcomes for people with familial hypercholesterolaemia can be improved with diagnosis and medical management. However, 90% of individuals with familial hypercholesterolaemia remain undiagnosed in the USA. We aimed to accelerate early diagnosis and timely intervention for more than 1·3 million undiagnosed individuals with familial hypercholesterolaemia at high risk for early heart attacks and strokes by applying machine learning to large health-care encounter datasets., Methods: We trained the FIND FH machine learning model using deidentified health-care encounter data, including procedure and diagnostic codes, prescriptions, and laboratory findings, from 939 clinically diagnosed individuals with familial hypercholesterolaemia (395 of whom had a molecular diagnosis) and 83 136 individuals presumed free of familial hypercholesterolaemia, sampled from four US institutions. The model was then applied to a national health-care encounter database (170 million individuals) and an integrated health-care delivery system dataset (174 000 individuals). Individuals used in model training and those evaluated by the model were required to have at least one cardiovascular disease risk factor (eg, hypertension, hypercholesterolaemia, or hyperlipidemia). A Health Insurance Portability and Accountability Act of 1996-compliant programme was developed to allow providers to receive identification of individuals likely to have familial hypercholesterolaemia in their practice., Findings: Using a model with a measured precision (positive predictive value) of 0·85, recall (sensitivity) of 0·45, area under the precision-recall curve of 0·55, and area under the receiver operating characteristic curve of 0·89, we flagged 1 331 759 of 170 416 201 patients in the national database and 866 of 173 733 individuals in the health-care delivery system dataset as likely to have familial hypercholesterolaemia. Familial hypercholesterolaemia experts reviewed a sample of flagged individuals (45 from the national database and 103 from the health-care delivery system dataset) and applied clinical familial hypercholesterolaemia diagnostic criteria. Of those reviewed, 87% (95% Cl 73-100) in the national database and 77% (68-86) in the health-care delivery system dataset were categorised as having a high enough clinical suspicion of familial hypercholesterolaemia to warrant guideline-based clinical evaluation and treatment., Interpretation: The FIND FH model successfully scans large, diverse, and disparate health-care encounter databases to identify individuals with familial hypercholesterolaemia., Funding: The FH Foundation funded this study. Support was received from Amgen, Sanofi, and Regeneron., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Bioluminescent copepods are often the most abundant marine zooplankton and play critical roles in oceanic food webs. Metridia copepods exhibit particularly bright bioluminescence, and the molecular basis of their light production has just recently begun to be explored. Here we add to this body of work by transcriptomically profiling Metridia lucens , a common species found in temperate, northern, and southern latitudes. In this previously molecularly-uncharacterized species, we find the typical luciferase paralog gene set found in Metridia . More surprisingly, we recover noteworthy putative luciferase sequences that had not been described from Metridia species, indicating that bioluminescence produced by these copepods may be more complex than previously known. This includes another copepod luciferase, as well as one from a shrimp. Furthermore, feeding experiments using mass spectrometry and 13 C labelled L-tyrosine and L-phenylalanine firmly establish that M. lucens produces its own coelenterazine luciferin rather than acquiring it through diet. This coelenterazine synthesis has only been directly confirmed in one other copepod species., Competing Interests: The authors declare there are no competing interests.

As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world., (© 2016 WILEY PERIODICALS, INC.)

The gene cluster responsible for synthesis of the unknown molecule "colibactin" has been identified in mutualistic and pathogenic Escherichia coli. The pathway endows its producer with a long-term persistence phenotype in the human bowel, a probiotic activity used in the treatment of ulcerative colitis, and a carcinogenic activity under host inflammatory conditions. To date, functional small molecules from this pathway have not been reported. Here we implemented a comparative metabolomics and targeted structural network analyses approach to identify a catalog of small molecules dependent on the colibactin pathway from the meningitis isolate E. coli IHE3034 and the probiotic E. coli Nissle 1917. The structures of 10 pathway-dependent small molecules are proposed based on structural characterizations and network relationships. The network will provide a roadmap for the structural and functional elucidation of a variety of other small molecules encoded by the pathway. From the characterized small molecule set, in vitro bacterial growth inhibitory and mammalian CNS receptor antagonist activities are presented.

The use of azobenzene photoswitches has become a dependable method for rapid and exact modulation of biological processes and material science systems. The requirement of ultraviolet light for azobenzene isomerization is not ideal for biological systems due to poor tissue penetration and potentially damaging effects. While modified azobenzene cores with a red-shifted cis-to-trans isomerization have been previously described, they have not yet been incorporated into a powerful method to control protein function: the photoswitchable tethered ligand (PTL) approach. We report the synthesis and characterization of a red-shifted PTL, L-MAG0460, for the light-gated ionotropic glutamate receptor LiGluR. In cultured mammalian cells, the LiGluR+L-MAG0460 system is activated rapidly by illumination with 400-520 nm light to generate a large ionic current. The current rapidly turns off in the dark as the PTL relaxes thermally back to the trans configuration. The visible light excitation and single-wavelength behavior considerably simplify use and should improve utilization in tissue.

Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.

This research was conducted to define viewing distance characteristics of individuals engaged in ordinary reading tasks. Specific attention was directed to assessing the potential relationship between observed distance and individual resting point accommodation. Consistent, statistically significant differences were observed across variable handheld and structurally-fixed hardcopy display configuration conditions. Relationships between observed viewing distance and resting point accommodation were not apparent. These findings suggest that simple eye-to-display viewing distance is fundamentally different for handheld text presentations and for the same text presented in a configuration similar to that of a video display terminal.

A clinical study was conducted to determine if the systolic spike often observed in an invasive blood pressure display originates in the measurement system. The clinical system consisted of a catheter, stopcocks, 4 ft of tubing, an amplifier (containing a 12-Hz low-pass filter), and a continuous flush device. A second transducer was connected directly to the patient's catheter, in parallel with the clinical system. Its output was conditioned by an amplifier modified to exclude the low-pass filter. Simultaneous measurements were taken from both transducers, recorded, and later analyzed. A comparison of the traces in the time domain, as well as an analysis of the signals in the frequency domain, suggests that the systolic spike did not originate in the pressure tubing or in the amplifier system.

A prototype anesthesia delivery system has been developed to test the appropriateness of new technological design approaches. The objectives were to eliminate human-factors problems associated with present anesthesia apparatus and to lay a suitable technical foundation for the development of new techniques in anesthesia management. This prototype performs all the functions of a conventional anesthesia machine, as well as many monitoring and surveillance tasks. Eventual incorporation of new teaching functions, and additional monitoring and record-keeping activities, are intended. The system is fundamentally electronic with few moving parts. Reliability, safety, and clarity of operation were the primary criteria in selection and application of the specific technologies employed. The result is a promising first step in the development of a system oriented toward supporting rather than preoccupying the anesthestist.

According to conventional theory the product of the transport flowrate and the mean transit time of a tracer through a system yields the equilibrium volume of distribution for the tracer, regardless of tracer kinetics or space geometry. Experimental results do not support this notion. The influence of measurement time on the volume measured with a bolus technique is addressed using systems theory to analyze a tissue-impedance form of the Sangren-Sheppard model. Assymptotic solutions show that the volume estimates are governed by a time constant, tau, related to diffusion in the tissue, to tissue capacity, and to wall permeability, and by a dimensionless ratio, f, describing a relation of tau to vascular transport time. A third parameter, g, describing the relative contributions to overall resistance to diffusion of effective permeability and of limited diffusivity in the tissue, is shown to be of less importance. The derived tau is similar to but not equivalent to the often cited "characteristic time". The "equilibrium" volume of distribution is defined as that which would be measured if equilibrium were allowed to establish. The "non-equilibrium" volume of distribution is defined as that which would be measured given finite times and is shown to approach the "equilibrium" volume as such times increase. Tracer equilibration is not required to accurately measure the "equilibrium" volume. When there is no flow limitation (f much less than 1) a measurement time of tau (plus vascular transit time) would yield a "non-equilibrium" volume only 33% of the "equilibrium" volume; a time of 2 tau would yield 55%; a time of 10 tau would yield effectively the total equilibrium volume. Finite diffusivity in tissue and permeability restrictions can have significant effects on the proportion of the volume measured.