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Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: a genome-wide cross-trait analysis
No full textLittle is known regarding the shared genetic architecture or causality underlying the phenotypic association observed for uterine leiomyoma (UL) and breast cancer (BC). Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) conducted in each trait, we investigated the genetic overlap and causal associations of UL with BC overall, as well as with its subtypes defined by the status of estrogen receptor (ER). We observed a positive genetic correlation between UL and BC overall (r_g = 0.09, P = 6.00×10-3), which was consistent in ER+ subtype (r_g = 0.06, P = 0.01) but not in ER subtype (r_g = 0.06, P = 0.08). Partitioning the whole genome into 1,703 independent regions, local genetic correlation was identified at 22q13.1 for UL with BC overall and with ER+ subtype. Significant genetic correlation was further discovered in 9 out of 14 functional categories, with the highest estimates observed in coding, H3K9ac, and repressed regions. Cross-trait meta-analysis identified 9 novel loci shared between UL and BC. Mendelian randomization demonstrated a significantly increased risk of BC overall (OR = 1.09, 95% CI = 1.01-1.18) and ER+ subtype (OR = 1.09, 95% CI = 1.01-1.17) for genetic liability to UL. No reverse causality was found. Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a putative causal relationship between UL and BC, highlighting an intrinsic link underlying these two complex female diseases
Expensive Optimization with Production-Graph Resource Constraints: A First Look at a New Problem Class
No full textWe consider a new class of expensive, resource-constrained optimization problems (here arising from molecular discovery) where costs are associated with the experiments (or evaluations) to be carried out during the optimization process. In the molecular discovery problem, candidate compounds to be optimized must be synthesized in an iterative process that starts from a set of purchasable items and builds up to larger molecules. To produce target molecules, their required resources are either used from alreadysynthesized items in storage or produced themselves on-demand at an additional cost. Any remaining resources from the production process are stored for reuse for the next evaluations.We model these resource dependencies with a directed acyclic production graph describing the development process from granular purchasableitems to evaluable target compounds. Moreover, we develop several resource-efficient algorithms to address this problem. In particular, we develop resource-aware variants of Random Search heuristics and of Bayesian Optimization and analyze their performance in terms of anytime behavior. The experimental results were obtained from a real-world molecular optimization problem. Our results suggest that algorithms that encourage exploitation by reusing existing resources achieve satisfactory results while using fewer resources overall.CCS CONCEPTS• Theory of computation→Random search heuristics; • Mathematics of computing→Probabilistic algorithms.KEYWORDSmolecular discovery, production costs, resource constraints, expensive optimization<br/
Heart rate variability biofeedback in Long COVID (HEARTLOC)
No full textIntroduction: Long COVID (LC) refers to symptoms persisting 12 weeks after SARS-COV-2 infection. It affects over 50 million people worldwide, causing varied symptoms including fatigue, breathlessness and palpitations Many of these symptoms can be linked to autonomic nervous system dysregulation (dysautonomia). This proof-of-concept study tests feasibility, and estimates efficacy, of a heart rate variability biofeedback (HRV-B) intervention using a standardised diaphragmatic breathing technique in LC patients.Methods and Analysis: 30 adult LC patients with symptoms of palpitations or dizziness and abnormal NASA Lean Test (NLT) are recruited from a UK COVID-19 rehabilitation service. They undertake an active 4-week HRV-B intervention using a chest strap linked to a HRV phone application while undertaking the breathing technique for 10-min twice daily. Quantitative data including HRV are gathered during the study period using Fitbit, the modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm), Composite Autonomic Symptom Score (COMPASS 31), World Health Organisation Disability Assessment Schedule (WHODAS 2.0) and EQ-5D-5L health related quality of life measure. Quantitative data will be analysed using standard statistical tests.Results: This study is ongoing; we have preliminary data for 3 completed participants. They demonstrated mean improvement of 3.7 points (from 16.7 pre-intervention to 13 post-intervention) on C19-YRS symptom severity scale, 1.3 (from 5.3 to 4.0) on C19-YRS functional scale, and 0.6 (from 4.7 to 5.3) on C19-YRS overall health score. Average autonomic score improved by 9.6 (from 47.0 to 37.4). Mean WHODAS score improvement was 4.3 (from 28.5 to 24.2) There was improvement in HRV score and reduction in resting heart rate. Further data will be presented at conference.Conclusion: These preliminary data demonstrate that HRV-B can improve LC symptoms, autonomic symptoms, reduce disability and improve HRV
ESBMC-CHERI: Towards Verification of C Programs for CHERI Platforms with ESBMC
No full textIn this paper we present ESBMC-CHERI – first bounded model checker capable of formally verifying C programs for CHERI-enabled platforms. CHERI provides run-time protection for the memory unsafe programming languages such as C/C++ at the hardware level. At the same time, it introduces new semantics to C programs, making some safe C programs cause hardware exceptions on CHERI-extended platforms. Hence, it is crucial to detect memory safety violations and compatibility issues ahead of compilation. However, there are no verification tools currently available for reasoning over CHERI-C programs. We demonstrate the work undertaken towards implementing support for CHERI-C in our state-of-the-art bounded model checker ESBMC and the plans for future work and extensive evaluation of ESBMC-CHERI. The ESBMC-CHERI demonstration and the source code are available at https://github.com/esbmc/esbmc/tree/cheri-clang
Staff training to improve participant recruitment into surgical randomised controlled trials: a feasibility Study Within A Trial (SWAT) across four host randomised controlled trials simultaneously
No full textObjectiveTo test the feasibility of undertaking a simultaneous Study Within A Trial (SWAT) to train staff who recruit participants into surgical randomised controlled trials (RCTs), by assessing key uncertainties around recruitment, randomisation, intervention delivery and data collection. Study design and settingTwelve surgical RCTs were eligible. Interested sites (clusters) were randomised 1:1, with recruiting staff (surgeons and nurses) offered training or no training. The primary outcome was the feasibility of recruiting sites across multiple surgical trials simultaneously. Secondary outcomes included numbers/types of staff enrolled, attendance at training, training acceptability, confidence in recruiting and participant recruitment rates six months later. ResultsFour RCTs (33%) comprising 91 sites participated. Of these, 29 sites agreed to participate (32%) and were randomised to intervention (15 sites, 29 staff) or control (14 sites, 29 staff). Research nurses attended and found the training to be acceptable; no surgeons attended. In the intervention group, there was evidence of increased confidence when pre and post training scores were compared (mean difference in change 1.42; 95% CI 0.56, 2.27; p = 0.002) – there was no effect on recruitment rate. ConclusionIt was feasible to randomise sites across four surgical RCTs in a simultaneous SWAT design. However, as small numbers of trials and sites participated, and no surgeons attended training, strategies to improve these aspects are needed for future evaluations. Trial registrationISRCTN registry: DISC (ISRCTN18254597), registered on 4th April 2017; PROFHER 2 (ISRCTN76296703), registered on 5th April 2018; IntAct (ISRCTN13334746), registered on 10th April 2017; and START:REACTS (ISRCTN17825590), registered on 5th March 2018. The training SWAT has been submitted to the MRC SWAT repository (SWAT111) <br/
Definition, diagnosis, and clinical management of nonobstructive kidney dysplasia: A consensus statement by the ERKNet working group on Kidney Malformations
No full textKidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term “kidney dysplasia” is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professional and with patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological, and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment.We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field
Approximation of Wave Packets on the Real Line
No full textIn this paper we compare three different orthogonal systems in L2(R) which can be used in the construction of a spectral method for solving the semi-classically scaled time dependent Schrödinger equation on the real line, specifically, stretched Fourier functions, Hermite functions and Malmquist–Takenaka functions. All three have banded skew-Hermitian differentiation matrices, which greatly simplifies their implementation in a spectral method, while ensuring that the numerical solution is unitary – this is essential in order to respect the Born interpretation in quantum mechanics and, as a byproduct, ensures numerical stability with respect to the L2(R) norm. We derive asymptotic approximations of the coefficients for a wave packet in each of these bases, which are extremely accurate in the high frequency regime. We show that the Malmquist–Takenaka basis is superior, in a practical sense, to the more commonly used Hermite functions and stretched Fourier expansions for approximating wave packets
Applications of Immersive Technologies for Occupational Safety and Health Management in the Construction Industry: A Systematic Review
No full textThe construction industry contributes significantly to workplace fatalities and injuries despite multiple interventions implemented by governments and construction companies. Recently, immersive technologies as part of a suite of industry 4.0 technologies have also strongly emerged as a viable pathway to help address poor construction occupational safety and health (OSH) performance. A review of literature on the application of immersive technologies for construction OSH management is conducted with the aim of gaining a broader view of different construction OSH areas using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) approach. The evaluation of 79 relevant articles were carried out, selected from Scopus database. The review revealed that literature have focused on the application of various immersive technologies for hazard identification and visualisation, safety training, design for safety, risk perception and assessment in various construction works. This review identified several limitations regarding the use of immersive technologies, which include the low level of adoption of developed immersive technologies for OSH management, very limited research works on the application of immersive technologies for health hazards and limited focus on the effectiveness of various immersive technologies for construction OSH management. Future research should identify possible reasons for the low level knowledge transfer from research to practice and proffer ways of addressing the identified reasons. The effectiveness of the use of immersive technologies for addressing health hazards should also be investigated
ADBSat: Methodology of a novel panel method tool for aerodynamic analysis of satellites
No full textADBSat is a novel software that determines the aerodynamic properties of any body in free-molecular flow. Its main advantage is the fast approximation of the aerodynamics of spacecraft in the lower end of the low-Earth orbit altitude range. It is a novel implementation of a panel method, where the body is represented as a set of fundamental elements and the sum of their individual aerodynamic properties makes up the properties of the whole. ADBSat’s approach treats the shape as a set of flat triangular plates. These are read from a CAD geometry file in the Wavefront format, which can be created with most common CAD programs. A choice of gas-surface interaction models is available to represent the physics of free-molecular flow under different conditions. Its modular design means that other models can be easily and quickly implemented. It also benefits from a new shading algorithm for fast determination of elemental flow exposure. An example case is presented to show the capability and functionality of the program
