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Purpose of review This article summarises current understanding of the genetic architecture underpinning left ventricular noncompaction (LVNC) and highlights the difficulty in differentiating LVNC from hypertrabeculation seen in normal, healthy individuals, that caused by physiological adaptation or that seen in association with cardiomyopathy phenotypes. Recent findings Progress has been made in better defining the LVNC phenotype and those patients who may benefit from genetic testing. Yield of diagnostic genetic testing may be low in the absence of syndromic features, systolic dysfunction and a family history of cardiomyopathy. Sarcomeric gene variants are most commonly identified but a wide-range of genes are implicated, emphasising the high degree of heterogeneity of studied cohorts. Summary More accurate phenotyping and genotype-phenotype correlation are required to better characterise the genetic architecture of LVNC.

Current diagnostic strategies fail to illuminate the presence of rare disease in the heart failure population. One-third of heart failure patients are categorised as suffering an idiopathic dilated cardiomyopathy, while others are labelled only as heart failure with preserved ejection fraction. Those affected frequently suffer from delays in diagnosis, which can have a significant impact on quality of life and prognosis. Traditional rhetoric argues that delineation of this patient population is superfluous to treatment, as elucidation of aetiology will not lead to a deviation from standard management protocols. This article emphasises the importance of identifying genetic, inflammatory and infiltrative causes of heart failure to enable patients to access tailored management strategies.

Background Dilated cardiomyopathy (DCM) has an estimated population prevalence of 1/250 and is the underlying diagnosis in a third of heart failure patients. A substantial proportion of patients have familial disease caused by dominant mutations in one of more than 50 genes, but clinical practice guidelines recommend genetic testing in young patients with idiopathic DCM. There is an absence of robust data on the influence of age on the diagnostic yield of genetic testing. Methods The study cohort comprised 825 consecutive and unrelated patients (524 male (63.5%)) with DCM who underwent genetic testing from 2015 to 2019. Genetic variants were classified using American College of Medical Genetics (ACMG) criteria. Analyses were stratified by age and sex. Results 173 (20.1%) patients had a positive genetic test (“pathogenic” or “likely pathogenic” variant); 292 (34.4%) had a variant of unknown significance. Mean age at genetic testing was 49.9±14.4 years. Mean age of patients with a positive test was 47.6±13.6 years. 99 (18.9%) men and 67 (22.3%) women had a positive test (p=0.246). Mutations in the TTN gene, encoding for titin, accounted for 46.1% of positive results. 13.8% of mutations were in DSP, 8.4% in RBM20, 6% in FLNC, 4.2% in LMNA, 3.6% in BAG3 and 3.6% in MYH7. There was a trend to declining yield with age (likelihood ratio chi-square p value = 0.047). The yield was 17.2% in the 56–65 year age group and 11.5% above 66 years of age (figure 1). Conclusions Approximately 1 in 5 patients with DCM had a positive genetic test. The yield declined in patients over 66 years but remained above 11%, suggesting that genetic testing should not be confined to younger patients with DCM. Figure 1. Yield of Genetic Testing by Age Funding Acknowledgement Type of funding source: None

The Deformable Mirror Demonstration Mission (DeMi) is a 6U CubeSat that will operate and characterize the on-orbit performance of a Microelectromechanical Systems (MEMS) deformable mirror (DM) with both an image plane and a Shack-Hartmann wavefront sensor (SHWFS). Coronagraphs on future space telescopes will require precise wavefront control to detect and characterize Earth-like exoplanets. High-actuator count MEMS deformable mirrors can provide wavefront control with low size, weight, and power. The DeMi payload will characterize the on-orbit performance of a 140 actuator MEMS DM with 5.5 μm maximum stroke, with a goal of measuring individual actuator wavefront displacement contributions to a precision of 12 nm. The payload is designed to measure low order aberrations to λ/10 accuracy and λ/50 precision, and correct static and dynamic wavefront phase errors to less than 100 nm RMS. The thermal stability of the payload is key to maintaining the errors below that threshold. To decrease mismatches between coefficients of thermal expansion, the payload structure is made out of a single material, aluminum 7075. The gap between the structural components of the payload was filled with a thermal gap filler to increase the temperature homogeneity of the payload. The fixture that holds the payload into the bus is a set of three titanium flexures, which decrease the thermal conductivity between the bus and the payload while providing flexibility for the payload to expand without being deformed. The mounts for the optical components are attached to the main optical bench through kinematic coupling to allow precision assembly and location repeatability. The MEMS DM is controlled by miniaturized high-voltage driver electronics. Two cross-strapped Raspberry Pi 3 payload computers interface with the DM drive electronics. Each Raspberry Pi is paired to read out one of the wavefront sensor cameras. The DeMi payload is ~4.5U in volume, 2.5 kg in mass, and is flying on a 6U spacecraft built by Blue Canyon Technologies. The satellite launch was on February15,2020 onboard a Northrop Grumman Antares rocket, lifting off from the NASA Wallops Flight Facility. We present the mechanical design of the payload, the thermal considerations and decisions taken into the design, the manufacturing process of the flight hardware, and the environmental testing results.

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument., Comment: Full report: 498 pages. Executive Summary: 14 pages. More information about HabEx can be found here: https://www.jpl.nasa.gov/habex/

We present the detailed design of a Laser Guide Star small satellite that would formation fly with a large space observatory or fly with respect to a ground telescope that use adaptive optics (AO) for wavefront sensing and control. Using the CubeSat form factor for the Laser Guide Star small satellite, we develop a 12U system to accommodate a propulsion system. The propulsion system enables the LGS satellite to formation fly near the targets in the telescope boresight and to meet mission requirements on number of targets and duration. We simulate the formation flight at L2 to assess the precision required to enable the wavefront sensing and control during observation. We describe a design reference mission (DRM) for deploying 18 Laser Guide Stars to L2 to assist the Large Ultraviolet, Optical, Infrared Surveyor (LUVOIR). The L2 LGS DRM covers over 250 exoplanet target systems with 5 or more revisits to each system over a 5-year mission using eighteen 12U CubeSats. We present a design reference mission for a laser guide star satellite to geostationary orbit for use with 6.5+ meter ground telescopes with AO to look at HD 50281, HD 180617, and other near-equatorial targets. We assess simulations on the maximum level of thruster noise permitted during the observations to maintain precision formation flying with the observatories.

The Deformable Mirror Demonstration Mission (DeMi) is a 6U CubeSat that will operate and characterize the on-orbit performance of a Microelectromechanical Systems (MEMS) deformable mirror (DM) with both an image plane and a Shack-Hartmann wavefront sensor (SHWFS). Coronagraphs on future space telescopes will require precise wavefront control to detect and characterize Earth-like exoplanets. High-actuator count MEMS deformable mirrors can provide wavefront control with low size, weight, and power. The DeMi payload will characterize the on-orbit performance of a 140 actuator MEMS DM with 5.5 _m maximum stroke, with a goal of measuring individual actuator wavefront displacement contributions to a precision of 12 nm. The payload will be able to measure low order aberrations to l/10 accuracy and l/50 precision, and will correct static and dynamic wavefront phase errors to less than 100 nm RMS. The DeMi team developed miniaturized DM driver boards to fit within the CubeSat form factor, and two cross-strapped Raspberry Pi 3 boards are used as payload computers. We present an overview of the payload design, the assembly, integration and test progress, and the miniaturized DM driver characterization process. Launch is planned for late 2019.

CubeSats have the potential to expand astrophysical discovery space, complementing ground-based electromagnetic and gravitational-wave observatories. The CubeSat design specifications help streamline delivery of instrument payloads to space. CubeSat planners have more options for tailoring orbits to fit observational needs and may have more flexibility in rapidly rescheduling observations to respond to transients. With over 1000 CubeSats launched, there has been a corresponding increase in the availability and performance of commercial-off-the-shelf (COTS) components compatible with the CubeSat standards, from solar panels and power systems to reaction wheels for three axis stabilization and precision attitude control. Commercially available components can reduce cost CubeSat missions, allowing more resources to be directed toward scientific instrument payload development and technology demonstrations., 6 pages, 0 figures. APC white paper submitted to the Astro2020 Decadal Survey with minor typographical edits

Cold debris disks (T$, Comment: 8 pages, with 3 figures. White Paper submitted in response to Astro 2020 Science White paper call. Co-signers on this work are: Vanessa Bailey (JPL), William C. Danchi (GSFC), Laurent Pueyo (STScI), Marshall Perrin (STScI), Bin Ren (STScI), Aki Roberge (GSFC), Glenn Schneider (U. of Arizona), Jordan Steckloff (PSI)

The challenges of high contrast imaging (HCI) for detecting exoplanets for both ground and space applications can be met with extreme adaptive optics (ExAO), a high-order adaptive optics system that performs wavefront sensing (WFS) and correction at high speed. We describe two ExAO optical system designs, one each for ground-based telescopes and space-based missions, and examine them using the angular spectrum Fresnel propagation module within the Physical Optics Propagation in Python (POPPY) package. We present an end-to-end (E2E) simulation of the MagAO-X instrument, an ExAO system capable of delivering 6$\times10^{-5}$ visible-light raw contrast for static, noncommon path aberrations without atmosphere. We present a laser guidestar (LGS) companion spacecraft testbed demonstration, which uses a remote beacon to increase the signal available for WFS and control of the primary aperture segments of a future large space telescope, providing on order of a factor of ten factor improvement for relaxing observatory stability requirements. The LGS E2E simulation provides an easily adjustable model to explore parameters, limits, and trade-offs on testbed design and characterization., 11 pages, 12 figures, SPIE Astronomical Telescopes and Instrumentation 2018

Coronagraphs on future space telescopes will require precise wavefront correction to detect Earth-like exoplanets near their host stars. High-actuator count microelectromechanical system (MEMS) deformable mirrors provide wavefront control with low size, weight, and power. The Deformable Mirror Demonstration Mission (DeMi) payload will demonstrate a 140 actuator MEMS deformable mirror (DM) with \SI{5.5}{\micro\meter} maximum stroke. We present the flight optomechanical design, lab tests of the flight wavefront sensor and wavefront reconstructor, and simulations of closed-loop control of wavefront aberrations. We also present the compact flight DM controller, capable of driving up to 192 actuator channels at 0-250V with 14-bit resolution. Two embedded Raspberry Pi 3 compute modules are used for task management and wavefront reconstruction. The spacecraft is a 6U CubeSat (30 cm x 20 cm x 10 cm) and launch is planned for 2019., Comment: 15 pages, 10 figues. Presented at SPIE Astronomical Telescopes + Instrumentation, Austin, Texas, USA

MagAO-X is an entirely new "extreme" adaptive optics system for the Magellan Clay 6.5 m telescope, funded by the NSF MRI program starting in Sep 2016. The key science goal of MagAO-X is high-contrast imaging of accreting protoplanets at H$\alpha$. With 2040 actuators operating at up to 3630 Hz, MagAO-X will deliver high Strehls (>70%), high resolution (19 mas), and high contrast ($< 1\times10^{-4}$) at H$\alpha$ (656 nm). We present an overview of the MagAO-X system, review the system design, and discuss the current project status., Comment: Presented at SPIE Astronomical Telescopes and Instrumentation 2018

For the first time in human history, technologies have matured sufficiently to enable a mission capable of discovering and characterizing habitable planets like Earth orbiting sunlike stars other than the Sun. At the same time, such a platform would enable unique science not possible from ground-based facilities. This science is broad and exciting, ranging from new investigations of our own solar system to a full range of astrophysics disciplines. The Habitable Exoplanet Observatory, or HabEx, is one of four studies currently being undertaken by NASA in preparation for the 2020 Astrophysics Decadal Survey. HabEx has been designed to be the Great Observatory of the 2030s, with community involvement through a competed and funded Guest Observer (GO) program. This interim report describes the HabEx baseline concept, which is a space-based 4-meter diameter telescope mission concept with ultraviolet (UV), optical, and near-infrared (near-IR) imaging and spectroscopy capabilities. More information on HabEx can be found at https://www.jpl.nasa.gov/habex, Comment: 212 Pages

We test the utility of the OII 83.4 nm emission feature as a measure of ionospheric parameters. Observed with the Remote Atmospheric and Ionospheric Detection System (RAIDS) Extreme Ultraviolet Spectrograph on the International Space Station (ISS), limb profiles of 83.4 nm emissions are compared to predicted dayglow emission profiles from a theoretical model incorporating ground-based electron density profiles measured by the Millstone Hill radar and parameterized by a best-fit Chapman-{\alpha} function. Observations and models are compared for periods of conjunction between Millstone Hill and the RAIDS fields-of-view. These RAIDS observations show distinct differences in topside morphology between two days, 15 January and 10 March 2010, closely matching the forward model morphology and demonstrating that 83.4 nm emission is sensitive to changes in the ionospheric density profile from the 340 km altitude of the ISS during solar minimum. We find no significant difference between 83.4 nm emission profiles modeled assuming a constant scale height Chapman-{\alpha} best-fit to the ISR measurements and those assuming varying scale height.

A NASA sounding rocket for high contrast imaging with a visible nulling coronagraph, the Planet Imaging Coronagraphic Technology Using a Reconfigurable Experimental Base (PICTURE-B) payload has made two suborbital attempts to observe the warm dust disk inferred around Epsilon Eridani. We present results from the November 2015 launch demonstrating active wavefront sensing in space with a piezoelectric mirror stage and a micromachine deformable mirror along with precision pointing and lightweight optics in space., Presented at SPIE Astronomical Telescopes + Instrumentation

The PICTURE-C mission will fly a 60 cm off-axis unobscured telescope and two high-contrast coronagraphs in successive high-altitude balloon flights with the goal of directly imaging and spectrally characterizing visible scattered light from exozodiacal dust in the interior 1-10 AU of nearby exoplanetary systems. The first flight in 2017 will use a 10^(-4) visible nulling coronagraph (previously flown on the PICTURE sounding rocket) and the second flight in 2019 will use a 10^(-7) vector vortex coronagraph. A low-order wavefront corrector (LOWC) will be used in both flights to remove time-varying aberrations from the coronagraph wavefront. The LOWC actuator is a 76-channel high-stroke deformable mirror packaged on top of a tip-tilt stage. This paper will detail the selection of a complementary high-speed, low-order wavefront sensor (LOWFS) for the mission. The relative performance and feasibility of several LOWFS designs will be compared including the Shack-Hartmann, Lyot LOWFS, and the curvature sensor. To test the different sensors, a model of the time-varying wavefront is constructed using measured pointing data and inertial dynamics models to simulate optical alignment perturbations and surface deformation in the balloon environment.

There is currently a large amount of literature to provide guidance on the areas that should be considered when developing a reporting system. However there is no current methodology of monitoring the performance and compliance of a reporting system.This paper outlines the development process for a Self-Assessment Tool (SAT) assessing the effectiveness of safety reporting within safety critical activities. The paper outlines the need for such a self-assessment tool, the areas that will be assessed (and the rationale be-hind their selection), selection of the platform and finally the planned validation exercises for the paper

Develop a best-practice model based on literature and industrial experience • Industrial Case Studies to allow a cross industrial comparison • Develop a suite of techniques that can be used cross-industry to assess the effectiveness of a reporting system • Propose a theoretical framework for the effective implementation of risk and hazard reporting as an input for safety management

Cardiovascular diseases (CVD) are becoming a major problem all over the world. Normal cardiac contraction requires generation and propagation of an action potential and the sequential opening and closing of a number of ion channels in the cell membrane. Cardiac arrhythmias result from disturbances in the activation or closing of ion channels or problems with impulse propagation. Antiarrhythmic drugs act on various ion channels but many of them have potential risk of causing arrhythmias through multiple pathways. Drug-induced long QT syndrome is caused by many drugs and is due to slowing of repolarization and blockade of the potassium currents. Many newer antiarrhythmic drugs can cause arrhythmias. Beta blockers and calcium channel blockers induce various cardiac effects, as discussed in the chapter. Early signs of digoxin toxicity is premature ventricular contractions, and hyperkalemia can increase the risk of arrhythmias. Diuretics cause dyselectrolytemia, which can induce arrhythmias. Adenosine suppresses most ventricular arrhythmias but is associated with sympathetic activation. Phosphodiesterase inhibitors are inodilators and in long-term use have the potential to cause hypotension and arrhythmias. Statins have beneficial effects on cardiovascular mortality but may predispose to new-onset diabetes. Warfarin interacts with a number of drugs and herbs increasing the risk of bleeding. Ranolazine, a new drug, may possess both antianginal and antiarrhythmic properties. Much work is going on toward predicting cardiovascular toxicity during drug development.

Develop a best-practice model based on literature and industrial experience • Industrial Case Studies to allow a cross industrial comparison • Develop a suite of techniques that can be used cross-industry to assess the effectiveness of a reporting system • Propose a theoretical framework for the effective implementation of risk and hazard reporting as an input for safety management

This paper describes the assessment criteria that have been identified for use within a self-assessment tool for risk reporting within an industrial context. An in-depth review of the available literature was carried out exposing the criteria discussed within this paper. The criteria target all areas of reporting from the design of the reporting interface to the cultural considerations and initiatives. These criteria will be refined and weighted using industrial case study experience and then developed into the full self-assessment tool.

Research shows that there are many factors that can influence the operation of a “Reporting Culture” within organisations, ranging from the attitudes to the workers, to the methodology implemented, to the managerial attitudes within the organisation (Reason, 1998). Understanding and modelling these factors may help develop an optimum reporting system. Historically, research has focused on the concept of “Near Miss Reporting” which is based on the idea of identifying the “bottom” of the safety triangle concept put forward in Heinrich (1941) which suggests that for each accident there are dozens of near misses, and identifying these near misses will hopefully allow faults, errors, design problems to be assessed and mitigated before they can allow an accident to develop. Reporting near misses is a key factor in a proactive Reporting Culture. Before any improvement strategy for the reporting culture or system can be developed an organization should be able to understand its current practices and the key influencing factors around them. Therefore in the current paper we start by presenting a model based on a real world case study developed to highlight areas where improvements can be made. Concurrently, a model of best practice is also to be developed as a terms of comparison with the current practice to help generate recommendations to improve reporting. The model could also potentially allow any new practice to be assessed before it is tested in the real world. The mapping of current practices was based on a number of semi-structured interviews with both managerial staff and the day-to-day staff in a pharmaceutical company. This was undertaken to determine the culture within the organisation, the reporting process, the factors that influence the reporting culture, etc. The data from these interviews allowed the drafting of a model detailing the reporting process and structure within the organisation. In modelling these processes a software tool called SCOPE was used to create a visual model of the main reporting tasks and the actors and equipment involved. The tool also facilitated the mapping out of relationships between actors, managers, resources, information systems, KPIs etc. Those relationships and the factors that than can influence these entities can then be analysed using a preliminary hazard analysis and an information-mapping module within the tool. The expected benefit of the work is the improvement of reporting practices in the organisation and the validation of the factors influencing reporting.

International audience; Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between individuals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of individuals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family; eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.