A regression based transmission/disequilibrium test for binary traits: the power of joint tests for linkage and association

BACKGROUND: In this analysis we applied a regression based transmission disequilibrium test to the binary trait presence or absence of Kofendred Personality Disorder in the Genetic Analysis Workshop 14 (GAW14) simulated dataset and determined the power and type I error rate of the method at varying map densities and sample sizes. To conduct this transmission disequilibrium test, the logit transformation was applied to a binary outcome and regressed on an indicator variable for the transmitted allele from informative matings. All 100 replicates from chromosomes 1, 3, 5, and 9 for the Aipotu and the combined Aipotu, Karangar, and Danacaa populations were used at densities of 3, 1, and 0.3 cM. Power and type I error were determined by the number of replicates significant at the 0.05 level. RESULTS: The maximum power to detect linkage and association with the Aipotu population was 93% for chromosome 3 using a 0.3-cM map. For chromosomes 1, 5, and 9 the power was less than 10% at the 3-cM scan and less than 22% for the 0.3-cM map. With the larger sample size, power increased to 38% for chromosome 1, 100% for chromosome 3, 31% for chromosome 5, and 23% for chromosome 9. Type I error was approximately 7%. CONCLUSION: The power of this method is highly dependent on the amount of information in a region. This study suggests that single-point methods are not particularly effective in narrowing a fine-mapping region, particularly when using single-nucleotide polymorphism data and when linkage disequilibrium in the region is variable

How Flies Are Flirting on the Fly

Background  Flies have some of the most elaborate visual systems in the Insecta, often featuring large, sexually dimorphic eyes with specialized “bright zones” that may have a functional role during mate-seeking behavior. The fast visual system of flies is considered to be an adaptation in support of their advanced flight abilities. Here, we show that the immense processing speed of the flies’ photoreceptors plays a crucial role in mate recognition. Results  Video-recording wing movements of abdomen-mounted common green bottle flies, Lucilia sericata, under direct light at 15,000 frames per second revealed that wing movements produce a single, reflected light flash per wing beat. Such light flashes were not evident when we video-recorded wing movements under diffuse light. Males of L. sericata are strongly attracted to wing flash frequencies of 178 Hz, which are characteristic of free-flying young females (prospective mates), significantly more than to 212, 235, or 266 Hz, characteristic of young males, old females, and old males, respectively. In the absence of phenotypic traits of female flies, and when given a choice between light emitting diodes that emitted either constant light or light pulsed at a frequency of 110, 178, 250, or 290 Hz, males show a strong preference for the 178-Hz pulsed light, which most closely approximates the wing beat frequency of prospective mates. Conclusions  We describe a previously unrecognized visual mate recognition system in L. sericata. The system depends upon the sex- and age-specific frequencies of light flashes reflecting off moving wings, and the ability of male flies to distinguish between the frequency of light flashes produced by rival males and prospective mates. Our findings imply that insect photoreceptors with fast processing speed may not only support agile flight with advanced maneuverability but may also play a supreme role in mate recognition. The low mating propensity of L. sericata males on cloudy days, when light flashes from the wings of flying females are absent, seems to indicate that these flies synchronize sexual communication with environmental conditions that optimize the conspicuousness of their communication signals, as predicted by sensory drive theory

Variability of Dosing and Number of Medications Needed to Achieve Adequate Sedation in Mechanically Ventilated Pediatric Intensive Care Patients.

Children admitted to the pediatric intensive care unit (PICU) often require multiple medications to achieve comfort and sedation. Although starting doses are available, these medications are typically titrated to the desired effect. Both oversedation and undersedation are associated with adverse events. The aim of this retrospective study was to evaluate cumulative medication burden necessary to achieve comfort in patients in the PICU and determine relevant predictors of medication needs. In order to account for all of the sedative medications, z-scores were used to assess the population average dose of each medication and compare each patient day to this population average. Sedation regimens for 130 patients in the PICU were evaluated. Mean overall infusion rates of fentanyl, morphine, and hydromorphone were 1.67 ± 0.81 µg/kg/hour, 0.12 ± 0.08 mg/kg/hour, and 17.84 ± 13.4 µg/kg/hour, respectively. The mean infusion rate of dexmedetomidine was 0.59 ± 0.28 µg/kg/hour, and midazolam was 0.14 ± 0.1 mg/kg/hour. Summation z-sores were used to rank the amount of sedation medication needed to achieve comfort for each individual patient for his/her PICU stay in relation to the entire sample. Patient age, weight, and length of mechanical ventilation were all significant predictors of sedation requirement. This study will provide data necessary to develop a model of cumulative medication burden needed to achieve appropriate sedation in this population. This descriptive model in appropriately ranking patients based on sedative needs is the first step in exploring potential genetic factors that may provide an insight into homing in on the appropriate sedation regimen

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.This work was supported by: UK Medical Research Council Project Grants [MR/M00046X/1], [MR/R026440/1] and Project grant from National Institute of Health Research Biomedical Research Centre at Addenbrooke's Hospital (to E.R.), Fondazione Bambino Gesù (Vite Coraggiose) and Italian Ministry of Health (CCR-2017-23669081) (to M.T.), National Institute for Health Research (NIHR) for the Cambridge Biomedical Research Centre and NIHR BioResource (Grant Number RG65966) (to F.L.R.), and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 216370/Z/19/Z) (to J.E.). CIMR was supported by a Wellcome Trust Strategic Award [100140] and Equipment Grant [093026]. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support

The association of quantitative PSMA PET parameters with pathologic ISUP grade: an international multicenter analysis.

PURPOSE To assess if PSMA PET quantitative parameters are associated with pathologic ISUP grade group (GG) and upgrading/downgrading. METHODS PCa patients undergoing radical prostatectomy with or without pelvic lymph node dissection staged with preoperative PSMA PET at seven referral centres worldwide were evaluated. PSMA PET parameters which included SUVmax, PSMAvolume, and total PSMA accumulation (PSMAtotal) were collected. Multivariable logistic regression evaluated the association between PSMA PET quantified parameters and surgical ISUP GG. Decision-tree analysis was performed to identify discriminative thresholds for all three parameters related to the five ISUP GGs The ROC-derived AUC was used to determine whether the inclusion of PSMA quantified parameters improved the ability of multivariable models to predict ISUP GG ≥ 4. RESULTS A total of 605 patients were included. Overall, 2%, 37%, 37%, 10% and 13% patients had pathologic ISUP GG1, 2, 3, 4, and 5, respectively. At multivariable analyses, all three parameters SUVmax, PSMAvolume and PSMAtotal were associated with GG ≥ 4 at surgical pathology after accounting for PSA and clinical T stage based on DRE, hospital and radioligand (all p  28, PSMAvol 0-2, 2-9, 9-20 and > 20 and PSMAtotal 0-12, 12-98 and > 98). PSMAvolume was significantly associated with GG upgrading (OR 1.03 95%CI 1.01 - 1.05). In patients with biopsy GG1-3, PSMAvolume ≥ 2 was significantly associated with higher odds for upgrading to ISUP GG ≥ 4, compared to PSMAvolume < 2 (OR 6.36, 95%CI 1.47 - 27.6). CONCLUSION Quantitative PSMA PET parameters are associated with surgical ISUP GG and upgrading. We propose clinically relevant thresholds of these parameters which can improve in PCa risk stratification in daily clinical practice

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Background: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. // Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. // Results: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. // Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing

Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic Star Formation Rate Density 300 Myr after the Big Bang

© 2024 The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/We characterize the earliest galaxy population in the JADES Origins Field, the deepest imaging field observed with JWST. We make use of ancillary Hubble Space Telescope optical images (five filters spanning 0.4–0.9 μm) and novel JWST images with 14 filters spanning 0.8−5 μm, including seven medium-band filters, and reaching total exposure times of up to 46 hr per filter. We combine all our data at >2.3 μm to construct an ultradeep image, reaching as deep as ≈31.4 AB mag in the stack and 30.3–31.0 AB mag (5σ, r = 0.″1 circular aperture) in individual filters. We measure photometric redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts z = 11.5−15. These objects show compact half-light radii of R 1/2 ∼ 50−200 pc, stellar masses of M ⋆ ∼ 107−108 M ☉, and star formation rates ∼ 0.1−1 M ☉ yr−1. Our search finds no candidates at 15 < z < 20, placing upper limits at these redshifts. We develop a forward-modeling approach to infer the properties of the evolving luminosity function without binning in redshift or luminosity that marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the impact of nondetections. We find a z = 12 luminosity function in good agreement with prior results, and that the luminosity function normalization and UV luminosity density decline by a factor of ∼2.5 from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical models for evolution of the dark matter halo mass function.Peer reviewe

The Gender Congruence and Life Satisfaction Scale (GCLS): development and validation of a scale to measure outcomes from transgender health services

Background: It is vital that the treatment offered at transgender health services can be evaluated to ensure a high quality of care. However, the tools currently used to evaluate treatment at transgender health services are limited by mainly focusing on mental health or because they have been developed for binary transgender people only. This study therefore aimed to develop and validate a tool that addresses these limitations. The Gender Congruence and Life Satisfaction Scale (GCLS) was developed through reviewing the literature, conducting interviews with transgender people, and holding discussions with experts working in transgender healthcare. An initial pool of items was developed and feedback on these was obtained. The tool was then validated. Method: For the validation of the tool a total of 789 participants (451 transgender [171 transgender females, 147 transgender males, 133 non-binary identifying people], and 338 cisgender [254 females, 84 males]) were recruited from the United Kingdom to test the factor structure and validity of the GCLS. Results: Exploratory factor analysis retained 38 items which formed seven subscales (psychological functioning; genitalia; social gender role recognition; physical and emotional intimacy; chest; other secondary sex characteristics; and life satisfaction). These seven subscales were found to have good internal consistency and convergent validity. The GCLS was also found to be capable of discriminating between groups (e.g., people who have and have not undergone gender affirming medical interventions). Transgender and cisgender subscale norms are provided for the GCLS. Conclusion: The GCLS is a suitable tool to use with the transgender population to measure health-related outcomes for both clinical and research purposes

Stability and detectability of exomoons orbiting HIP 41378 f, a temperate Jovian planet with an anomalously low apparent density

Moons orbiting exoplanets (“exomoons”) may hold clues about planet formation, migration, and habitability. In this work, we investigate the plausibility of exomoons orbiting the temperate (T eq = 294 K) giant (R = 9.2 R ⊕) planet HIP 41378 f, which has been shown to have a low apparent bulk density of 0.09 g cm−3 and a flat near-infrared transmission spectrum, hinting that it may possess circumplanetary rings. Given this planet’s long orbital period (P ≈ 1.5 yr), it has been suggested that it may also host a large exomoon. Here, we analyze the orbital stability of a hypothetical exomoon with a satellite-to-planet mass ratio of 0.0123 orbiting HIP 41378 f. Combining a new software package, astroQTpy, with REBOUND and EqTide, we conduct a series of N-body and tidal migration simulations, demonstrating that satellites up to this size are largely stable against dynamical escape and collisions. We simulate the expected transit signal from this hypothetical exomoon and show that current transit observations likely cannot constrain the presence of exomoons orbiting HIP 41378 f, though future observations may be capable of detecting exomoons in other systems. Finally, we model the combined transmission spectrum of HIP 41378 f and a hypothetical moon with a low-metallicity atmosphere and show that the total effective spectrum would be contaminated at the ∼10 ppm level. Our work not only demonstrates the feasibility of exomoons orbiting HIP 41378 f but also shows that large exomoons may be a source of uncertainty in future high-precision measurements of exoplanet systems

The First Near-infrared Transmission Spectrum of HIP 41378 f, A Low-mass Temperate Jovian World in a Multiplanet System

Abstract: We present a near-infrared transmission spectrum of the long-period (P = 542 days), temperate (T eq = 294 K) giant planet HIP 41378 f obtained with the Wide-Field Camera 3 instrument aboard the Hubble Space Telescope (HST). With a measured mass of 12 ± 3 M ⊕ and a radius of 9.2 ± 0.1 R ⊕, HIP 41378 f has an extremely low bulk density (0.09 ± 0.02 g cm−3). We measure the transit depth with a median precision of 84 ppm in 30 spectrophotometric channels with uniformly sized widths of 0.018 μm. Within this level of precision, the spectrum shows no evidence of absorption from gaseous molecular features between 1.1 and 1.7 μm. Comparing the observed transmission spectrum to a suite of 1D radiative-convective-thermochemical-equilibrium forward models, we rule out clear, low-metallicity atmospheres and find that the data prefer high-metallicity atmospheres or models with an additional opacity source, such as high-altitude hazes and/or circumplanetary rings. We explore the ringed scenario for HIP 41378 f further by jointly fitting the K2 and HST light curves to constrain the properties of putative rings. We also assess the possibility of distinguishing between hazy, ringed, and high-metallicity scenarios at longer wavelengths with the James Webb Space Telescope. HIP 41378 f provides a rare opportunity to probe the atmospheric composition of a cool giant planet spanning the gap in temperature, orbital separation, and stellar irradiation between the solar system giants, directly imaged planets, and the highly irradiated hot Jupiters traditionally studied via transit spectroscopy