INTEGRATE: Gene fusion discovery using whole genome and transcriptome data

While next-generation sequencing (NGS) has become the primary technology for discovering gene fusions, we are still faced with the challenge of ensuring that causative mutations are not missed while minimizing false positives. Currently, there are many computational tools that predict structural variations (SV) and gene fusions using whole genome (WGS) and transcriptome sequencing (RNA-seq) data separately. However, as both WGS and RNA-seq have their limitations when used independently, we hypothesize that the orthogonal validation from integrating both data could generate a sensitive and specific approach for detecting high-confidence gene fusion predictions. Fortunately, decreasing NGS costs have resulted in a growing quantity of patients with both data available. Therefore, we developed a gene fusion discovery tool, INTEGRATE, that leverages both RNA-seq and WGS data to reconstruct gene fusion junctions and genomic breakpoints by split-read mapping. To evaluate INTEGRATE, we compared it with eight additional gene fusion discovery tools using the well-characterized breast cell line HCC1395 and peripheral blood lymphocytes derived from the same patient (HCC1395BL). The predictions subsequently underwent a targeted validation leading to the discovery of 131 novel fusions in addition to the seven previously reported fusions. Overall, INTEGRATE only missed six out of the 138 validated fusions and had the highest accuracy of the nine tools evaluated. Additionally, we applied INTEGRATE to 62 breast cancer patients from The Cancer Genome Atlas (TCGA) and found multiple recurrent gene fusions including a subset involving estrogen receptor. Taken together, INTEGRATE is a highly sensitive and accurate tool that is freely available for academic use

Robotic Versus Laparoscopic Ventral Hernia Repair: Two-Year Results From a Prospective, Multicenter, Blinded Randomized Clinical Trial

OBJECTIVE: Report the 2-year outcomes of a multicenter randomized controlled trial comparing robotic versus laparoscopic intraperitoneal onlay mesh ventral hernia repair. BACKGROUND: Ventral hernia repair is one of the most common operations performed by general surgeons. To our knowledge, no studies have been published to date comparing long-term outcomes of laparoscopic versus robotic ventral hernia repair. METHODS: The trial was registered at clinicaltrials.gov (NCT03490266). Clinical outcomes included surgical site infection, surgical site occurrence, hernia occurrence, readmission, reoperation, and mortality. RESULTS: A total of 175 consecutive patients were approached that were deemed eligible for elective minimally invasive ventral hernia repair. In all, 124 were randomized and 101 completed follow-up at 2 years. Two-year follow-up was completed in 54 patients (83%) in the robotic arm and 47 patients (80%) in the laparoscopic arm. No differences were seen in surgical site infection or surgical site occurrence. Hernia recurrence occurred in 2 patients (4%) receiving robotic repair versus in 6 patients (13%) receiving laparoscopic repair (relative risk: 0.3, 95% CI: 0.06-1.39; P =0.12). No patients (0%) required reoperation in the robotic arm whereas 5 patients (11%) underwent reoperation in the laparoscopic arm ( P =0.019, relative risk not calculatable due to null outcome). CONCLUSIONS: Robotic ventral hernia repair demonstrated at least similar if not improved outcomes at 2 years compared with laparoscopy. There is potential benefit with robotic repair; however, additional multi-center trials and longer follow-up are needed to validate the hypothesis-generating findings of this study

The cryomechanical design of MUSIC: a novel imaging instrument for millimeter-wave astrophysics at the Caltech Submillimeter Observatory

MUSIC (Multicolor Submillimeter kinetic Inductance Camera) is a new facility instrument for the Caltech Submillimeter Observatory (Mauna Kea, Hawaii) developed as a collaborative effect of Caltech, JPL, the University of Colorado at Boulder and UC Santa Barbara, and is due for initial commissioning in early 2011. MUSIC utilizes a new class of superconducting photon detectors known as microwave kinetic inductance detectors (MKIDs), an emergent technology that offers considerable advantages over current types of detectors for submillimeter and millimeter direct detection. MUSIC will operate a focal plane of 576 spatial pixels, where each pixel is a slot line antenna coupled to multiple detectors through on-chip, lumped-element filters, allowing simultaneously imaging in four bands at 0.86, 1.02, 1.33 and 2.00 mm. The MUSIC instrument is designed for closed-cycle operation, combining a pulse tube cooler with a two-stage Helium-3 adsorption refrigerator, providing a focal plane temperature of 0.25 K with intermediate temperature stages at approximately 50, 4 and 0.4 K for buffering heat loads and heat sinking of optical filters. Detector readout is achieved using semi-rigid coaxial cables from room temperature to the focal plane, with cryogenic HEMT amplifiers operating at 4 K. Several hundred detectors may be multiplexed in frequency space through one signal line and amplifier. This paper discusses the design of the instrument cryogenic hardware, including a number of features unique to the implementation of superconducting detectors. Predicted performance data for the instrument system will also be presented and discussed

Using the Galactic Dynamics of M7 Dwarfs to Infer the Evolution of Their Magnetic Activity

We present a spectroscopic study and dynamical analysis of ~2600 M7 dwarfs. We confirm our previous finding that the fraction of magnetically active stars decreases with vertical distance from the Galactic plane. We also show that the mean luminosity of the H-alpha emission has a small but statistically significant decrease with distance. Using space motions for ~1300 stars and a simple one-dimensional dynamical simulation, we demonstrate that the drop in the activity fraction of M7 dwarfs can be explained by thin disk dynamical heating and a rapid decrease of magnetic activity at a mean stellar age of ~6-7 Gyr.Comment: 6 pages, accepted for publication in A

Cost-effectiveness of exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: Protocol for an economic evaluation alongside the SITLESS three-armed pragmatic randomised controlled trial

Introduction: Promoting physical activity (PA) and reducing sedentary behaviour (SB) may exert beneficial effects on the older adult population, improving behavioural, functional, health and psychosocial outcomes in addition to reducing health, social care and personal costs. This paper describes the planned economic evaluation of SITLESS, a multicountry three-armed pragmatic randomised controlled trial (RCT) which aims to assess the short-term and long-term effectiveness and cost-effectiveness of a complex intervention on SB and PA in community-dwelling older adults, based on exercise referral schemes enhanced by a group intervention providing self-management strategies to encourage lifestyle change. Methods and analysis: A within-trial economic evaluation and long-term model from both a National Health Service/personal social services perspective and a broader societal perspective will be undertaken alongside the SITLESS multinational RCT. Healthcare costs (hospitalisations, accident and emergency visits, appointment with health professionals) and social care costs (eg, community care) will be included in the economic evaluation. For the cost-utility analysis, quality-adjusted life-years will be measured using the EQ-5D-5L and capability well-being measured using the ICEpop CAPability measure for Older people (ICECAP-O) questionnaire. Other effectiveness outcomes (health related, behavioural, functional) will be incorporated into a cost-effectiveness analysis and cost-consequence analysis. The multinational nature of this RCT implies a hierarchical structure of the data and unobserved heterogeneity between clusters that needs to be adequately modelled with appropriate statistical and econometric techniques. In addition, a long-term population health economic model will be developed and will synthesise and extrapolate within-trial data with additional data extracted from the literature linking PA and SB outcomes with longer term health states. Methods guidance for population health economic evaluation will be adopted including the use of a long-time horizon, 1.5% discount rate for costs and benefits, cost consequence analysis framework and a multisector perspective. Ethics and dissemination: The study design was approved by the ethics and research committee of each intervention site: the Ethics and Research Committee of Ramon Llull University (reference number: 1314001P) (Fundació Blanquerna, Spain), the Regional Committees on Health Research Ethics for Southern Denmark (reference number: S-20150186) (University of Southern Denmark, Denmark), Office for Research Ethics Committees in Northern Ireland (ORECNI reference number: 16/NI/0185) (Queen’s University of Belfast) and the Ethical Review Board of Ulm University (reference number: 354/15) (Ulm, Germany). Participation is voluntary and all participants will be asked to sign informed consent before the start of the study. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement number 634 270. This article reflects only the authors' view and the Commission is not responsible for any use that may be made of the information it contains. The findings of the study will be disseminated to different target groups (academia, policymakers, end users) through different means following the national ethical guidelines and the dissemination regulation of the Horizon 2020 funding agency. Use of the EuroQol was registered with the EuroQol Group in 2016. Use of the ICECAP-O was registered with the University of Birmingham in March 2017. Trial registration number: NCT02629666; Pre-results

Status of MUSIC, the MUltiwavelength Sub/millimeter Inductance Camera

We present the status of MUSIC, the MUltiwavelength Sub/millimeter Inductance Camera, a new instrument for the Caltech Submillimeter Observatory. MUSIC is designed to have a 14', diffraction-limited field-of-view instrumented with 2304 detectors in 576 spatial pixels and four spectral bands at 0.87, 1.04, 1.33, and 1.98 mm. MUSIC will be used to study dusty star-forming galaxies, galaxy clusters via the Sunyaev-Zeldovich effect, and star formation in our own and nearby galaxies. MUSIC uses broadband superconducting phased-array slot-dipole antennas to form beams, lumpedelement on-chip bandpass filters to define spectral bands, and microwave kinetic inductance detectors to sense incoming light. The focal plane is fabricated in 8 tiles consisting of 72 spatial pixels each. It is coupled to the telescope via an ambient-temperature ellipsoidal mirror and a cold reimaging lens. A cold Lyot stop sits at the image of the primary mirror formed by the ellipsoidal mirror. Dielectric and metal-mesh filters are used to block thermal infrared and out-ofband radiation. The instrument uses a pulse tube cooler and ^(3)He/^(3)He/^(4)He closed-cycle cooler to cool the focal plane to below 250 mK. A multilayer shield attenuates Earth's magnetic field. Each focal plane tile is read out by a single pair of coaxes and a HEMT amplifier. The readout system consists of 16 copies of custom-designed ADC/DAC and IF boards coupled to the CASPER ROACH platform. We focus on recent updates on the instrument design and results from the commissioning of the full camera in 2012

Identification of a Wide, Low-Mass Multiple System Containing the Brown Dwarf 2MASS J0850359+105716

We report our discovery of NLTT 20346 as an M5+M6 companion system to the tight binary (or triple) L dwarf 2MASS J0850359+105716. This nearby (~31 pc), widely separated (~7700 AU) quadruple system was identified through a cross-match of proper motion catalogs. Follow-up imaging and spectroscopy of NLTT 20346 revealed it to be a magnetically active M5+M6 binary with components separated by ~2" (50-80 AU). Optical spectroscopy of the components show only moderate Halpha emission corresponding to a statistical age of ~5 - 7 Gyr for both M dwarfs. However NLTT 20346 is associated with the XMM-Newton source J085018.9+105644, and based on X-ray activity the age of NLTT 20346 is between 250-450 Myr. Strong Li absorption in the optical spectrum of 2MASS J0850+1057 indicates an upper age limit of 0.8 - 1.5 Gyr favoring the younger age for the primary. Using evolutionary models in combination with an adopted system age of 0.25-1.5 Gyr indicates a total mass for 2MASS J0850+1057 of 0.07+/-0.02 Msun if it is a binary. NLTT 20346/2MASS J0850+1057 joins a growing list of hierarchical systems containing brown dwarf binaries and is among the lowest binding energy associations found in the field. Formation simulations via gravitational fragmentation of massive extended disks have successfully produced a specific analog to this system.Comment: 13 pages, accepted for publication to A

MKID multicolor array status and results from DemoCam

We present the results of the latest multicolor Microwave Kinetic Inductance Detector (MKID) focal plane arrays in the submillimeter. The new detectors on the arrays are superconducting resonators which combine a coplanar waveguide section with an interdigitated capacitor, or IDC. To avoid out-of-band pickup by the capacitor, a stepped-impedance filter is used to prevent radiation from reaching the absorptive aluminum section of the resonator. These arrays are tested in the preliminary demonstration instrument, DemoCam, a precursor to the Multicolor Submillimeter Inductance Camera, MUSIC. We present laboratory results of the responsivity to light both in the laboratory and at the Caltech Submillimeter Observatory. We assess the performance of the detectors in filtering out-of-band radiation, and find the level of excess load and its effect on detector performance. We also look at the array design characteristics, and the implications for the optimization of sensitivities expected by MUSIC