The masses, radii and luminosities of the components of U Geminorum

We present a phase-resolved spectroscopic study of the secondary star in the cataclysmic variable U Gem. We use our data to measure the radial velocity semi-amplitude, systemic velocity and rotational velocity of the secondary star. Combining this with literature data allows us to determine masses and radii for both the secondary star and white dwarf which are independent of any assumptions about their structure. We use these to compare their properties with those of field stars and find that both components follow field mass-radius relationships. The secondary star has the mass, radius, luminosity and photometric temperature of an M2 star, but a spectroscopic temperature of M4. The latter may well be due to a high metallicity. There is a troubling inconsistency between the radius of the white dwarf inferred from its gravitational redshift and inclination and that inferred from its temperature, flux, and astrometric distance. We find that there are two fundamental limits to the accuracy of the parameters we can derive. First the radial velocity curve of the secondary star deviates from a sinusoid, in part because of its asphericity (which can be modelled) and in part because the line flux is not evenly distributed over its surface. Second we cannot be certain which spectral type is the best match for the lines of the secondary star, and the derived rotational velocity is a function of the spectral type of the template star used.Comment: 12 pages, 10 figures. Accepted for MNRA

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Supported and valued? A survey of Early Career Researchers’ experiences and perceptions of youth and adult involvement in mental health, self-harm and suicide research

BackgroundPatient and public involvement (PPI) in mental health research, including self-harm and suicide research, is desirable (as with other health topics) but may involve specific challenges given the perceived sensitivity of the topic. This is particularly so when involving young people. We explore the experiences and perceptions of Early Career Researchers (ECRs) undertaking youth and adult involvement work in mental health, self-harm and/or suicide research. We consider current practice, barriers and facilitators.MethodsAn online survey of a convenience sample of ECRs (N = 41) undertaking research on mental health, self-harm and/or suicide. Questions examined the perceived value of involvement work, involvement methods used, funding availability and the extent to which researchers felt knowledgeable, supported and confident in their involvement activities. Descriptive statistics are presented with appropriate tests. Open-ended questions, related to barriers and facilitators for involvement work, were subjected to an inductive thematic analysis.ResultsYouth and adult involvement work were valued to a similar extent, though institutions were reported to value youth involvement to a lesser extent. Researchers’ knowledge, confidence and support ratings were comparable for youth and adult involvement. The involvement methods used with young people and adults were also similar, with analysing data being the least popular method used and developing resources (e.g. information sheets) being the most popular method used. Less than a third of participants reported that funding was available for their research involvement activities. Barriers to involvement in research on mental health, self-harm and suicide were: ethical issues and perceived risk; real costs (in terms of money/time) versus perceived value; and the challenge of recruiting people. Facilitators to involvement work were: expert examples, expertise and guidelines; and investment in involvement work.ConclusionsECRs in the fields of mental health, self-harm and suicide are engaged in youth and adult involvement work. They value (find worthwhile) youth and adult involvement work to a similarly high extent, but feel their institutions may regard youth involvement slightly less highly than adult involvement. ECRs rate themselves as feeling similarly knowledgeable, confident and supported when doing involvement activities with both age groups. Nonetheless, significant barriers to involvement work on these topics are reported and are generally issues that need to be tackled at an institutional level (ethical/governance issues and lack of funding)

Report of the Lancet Commission on the Value of Death: bringing death back into life

The story of dying in the 21st century is a story of paradox. While many people are overtreated in hospitals with families and communities relegated to the margins, still more remain undertreated, dying of preventable conditions and without access to basic pain relief. The unbalanced and contradictory picture of death and dying is the basis for this Commission

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture

© 2020, The Author(s). Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer’s disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD

Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome

BACKGROUND: Cerebral ischaemia initiates an inflammatory response in the brain and periphery. We assessed the relationship between peak values of plasma interleukin-6 (IL-6) in the first week after ischaemic stroke, with measures of stroke severity and outcome. METHODS: Thirty-seven patients with ischaemic stroke were prospectively recruited. Plasma IL-6, and other markers of peripheral inflammation, were measured at pre-determined timepoints in the first week after stroke onset. Primary analyses were the association between peak plasma IL-6 concentration with both modified Rankin score (mRS) at 3 months and computed tomography (CT) brain infarct volume. RESULTS: Peak plasma IL-6 concentration correlated significantly (p < 0.001) with CT brain infarct volume (r = 0.75) and mRS at 3 months (r = 0.72). It correlated similarly with clinical outcome at 12 months or stroke severity. Strong associations were also noted between either peak plasma C-reactive protein (CRP) concentration or white blood cell (WBC) count, and all outcome measures. CONCLUSIONS: These data provide evidence that the magnitude of the peripheral inflammatory response is related to the severity of acute ischaemic stroke, and clinical outcome

Artificial intelligence for diagnosis and Gleason grading of prostate cancer: The PANDA challenge

Through a community-driven competition, the PANDA challenge provides a curated diverse dataset and a catalog of models for prostate cancer pathology, and represents a blueprint for evaluating AI algorithms in digital pathology. Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted kappa, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.KWF Kankerbestrijding ; Netherlands Organization for Scientific Research (NWO) ; Swedish Research Council European Commission ; Swedish Cancer Society ; Swedish eScience Research Center ; Ake Wiberg Foundation ; Prostatacancerforbundet ; Academy of Finland ; Cancer Foundation Finland ; Google Incorporated ; MICCAI board challenge working group ; Verily Life Sciences ; EIT Health ; Karolinska Institutet ; MICCAI 2020 satellite event team ; ERAPerMe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice