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Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity
No full textAimTo identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi).Materials and MethodsAnalysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC).ResultsAmong 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints.ConclusionsOur method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models.<br/
Observer reactions to witnessed mistreatment at work: It’s a matter of perspective
No full textWorkplace mistreatment regularly occurs in the presence of others (i.e., observers). The reactions of observers toward those involved in the mistreatment episode have wide-reaching implications. In the current set of studies, we draw on theories of perspective-taking to consider how this form of interpersonal sensemaking influences observer reactions toward those involved in a witnessed incident of workplace mistreatment. We find blame attributions and empathic concern for the individual whose perspective is taken explain the positive effects of perspective-taking on observer attitudes toward and performance evaluations of both the target and instigator of a witnessed incident of mistreatment. We also find that the effect of perspective-taking on observer reactions is stronger when the witnessed mistreatment is more severe. Finally, we find that although observer perspective-taking in the context of mistreatment can be encouraged performance . Implications for targets, instigators, and organizations are discussed
Cut-and-project quasicrystals, lattices, and dense forests
No full textDense forests are discrete subsets of Euclidean space which are uniformly close to all sufficiently long line segments. The degree of density of a dense forest is measured by its visibility function. We show that cut-and-project quasicrystals are never dense forests, but their finite unions could be uniformly discrete dense forests. On the other hand, we show that finite unions of lattices typically are dense forests, and give a bound on their visibility function, which is close to optimal. We also construct an explicit finite union of lattices which is a uniformly discrete dense forest with an explicit bound on its visibility
Views of practitioners and researchers on the use of virtual reality in treatments for substance use disorders
No full textPerspectives on glucocorticoid usage in patients with adult inflammatory myopathy
No full textObjective: To describe the patient perspective on glucocorticoid (GC) treatment and adverse effects (AEs) in idiopathic inflammatory myopathy (IIM). Methods: An online survey was distributed to patients with adult-onset IIM using the Myositis UK page on Healthunlocked.com, an online social network for health. Respondents were asked to rate the severity of AEs they attributed to GCs on a Likert scale (0-5), and to report concerns and overall experience of GC treatment. Results: The survey was completed by 122 respondents. The median reported current daily dose of prednisolone was 15 mg (interquartile range [IQR] 8, 25) and median treatment duration 5.3 years (IQR 3.4, 8.0) at the time of survey completion. Only 54% of respondents “agreed” or “strongly agreed” that the information provided to them about GC treatment was adequate. AEs rated most severe by respondents were weight gain, moon face, sleep disturbances, increased hunger. The duration of GC treatment weakly correlated with the mean number of reported AEs (p=0.004) and mean severity of AEs (p=0.017). There was an inverse relationship between age and acne, stretch marks, hair loss, facial hair, nausea, and heartburn (p<0.05). Conclusion: In this first study of patient-reported experiences of GCs specifically in IIM, we describe the burden of treatment and highlight the unmet need for safe and well tolerated treatments. We report that patients with IIM often remain on long-term GC treatment at moderate doses, and that AEs are common. The reported data will be useful in planning discussions with patients regarding adherence to their treatment options
CO2-plume geothermal processes: A parametric study of salt precipitation influenced by capillary-driven back flow
No full textOrientation-selective and Frequency-correlated Light-induced Pulsed Dipolar Spectroscopy
No full textWe explore the potential of orientation-resolved pulsed dipolar spectroscopy (PDS) in light-induced versions of the experiment. The use of triplets as spin-active moieties for PDS offers an attractive tool for studying biochemical systems containing optically-active cofactors. Cofactors are often rigidly bound within the protein structure, providing an accurate positional marker. The rigidity leads to orientation selection effects in PDS, which can be analyzed to give both distance and mutual orientation information. Here we present a comprehensive analysis of the orientation selection of a full set of light-induced PDS experiments. We exploit the complementary information provided by the different light-induced techniques to yield atomic-level structural information. For the first time, we measure a 2D frequency-correlated laser-induced magnetic dipolar spectrum and we were able to monitor the complete orientation dependence of the system in a single experiment. Alternatively, the summed spectrum enables an orientation independent analysis to determine the distance distribution
Physical, cognitive, and mental health impacts of COVID-19 following hospitalisation – a multi-centre prospective cohort study
No full textBackground The impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood. Methods PHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function. Findings We report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity. Interpretation We identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services
NERO: A Biomedical Named-entity (Recognition) Ontology with a Large, Annotated Corpus Reveals Meaningful Associations Through Text Embedding
No full textMachine reading is essential for unlocking valuable knowledge contained in millions of existing biomedical documents. Over the last two decades, the most dramatic advances in machine-reading have followed in the wake of critical corpus development1 Large, well-annotated corpora have been associated with punctuated advances in machine reading methodology and automated knowledge extraction systems in the same way that ImageNet 2 was fundamental for developing machine vision techniques. This study contributes six components to an advanced, named-entity analysis tool for biomedicine: (a) a new, Named Entity Recognition Ontology (NERO) developed specifically for describing textual entities in biomedical texts, which accounts for diverse levels of ambiguity, bridging the scientific sublanguages of molecular biology, genetics, biochemistry, and medicine; (b) detailed guidelines for human experts annotating hundreds of named-entity classes; (c) pictographs for all named entities, to simplify the burden of annotation for curators; (d) an original, annotated corpus comprising 35,865 sentences, which encapsulate 190,679 named entities and 43,438 events connecting two or more entities; (e) validated, off-the-shelf, named entity recognition automated extraction, and; (f) embedding models that demonstrate the promise of biomedical associations embedded within this corpus
High-order simulations of isothermal flows using the local anisotropic basis function method (LABFM)
No full textMesh-free methods have significant potential for simulations of flows in complex geometries, with the difficulties of domain discretisation greatly reduced. However, many mesh-free methods are limited to low order accuracy. In order to compete with conventional mesh-based methods, high order accuracy is essential. The Local Anisotropic Basis Function Method (LABFM) is a meshfree method introduced in King et al., J. Comput. Phys. 415:109549 (2020), which enables the construction of highly accurate difference operators on disordered node discretisations. Here, we introduce a number of developments to LABFM, in the areas of basis function construction, stencil optimisation, stabilisation, variable resolution, and high order boundary conditions. With these developments, direct numerical simulations of the Navier Stokes equations are possible at extremely high order (up to 10th order in characteristic node spacing internally). We numerically solve the isothermal compressible Navier Stokes equations for a range of geometries: periodic and channel flows, flows past a cylinder, and porous media. Excellent agreement is seen with analytical solutions, published numerical results (using a spectral element method), and experiments. The potential of the method for direct numerical simulations in complex geometries is demonstrated with simulations of subsonic and transonic flows through an inhomogeneous porous media at pore Reynolds numbers up to Rep = 968