Improvements in electron-optical picosecond photography

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The predictive role of symptoms in COVID-19 diagnostic models : A longitudinal insight

Acknowledgements 2019nCoV-302 Study Group Members: The NVX-CoV2373-2019nCoV-302 clinical trial was a collective group effort across multiple institutions and locations. Below is a list of sites and staff that significantly contributed to the implementation and conduct of the NVX-CoV2373-2019nCoV-302 clinical trial.Peer reviewe

The association between weekly hours of physical activity and mental health: A three-year follow-up study of 15–16-year-old students in the city of Oslo, Norway

<p>Abstract</p> <p>Background</p> <p>Mental health problems are a worldwide public health burden. The literature concerning the mental health benefits from physical activity among adults has grown. Adolescents are less studied, and especially longitudinal studies are lacking. This paper investigates the associations between weekly hours of physical activity at age 15–16 and mental health three years later.</p> <p>Methods</p> <p>Longitudinal self-reported health survey. The baseline study consisted of participants from the youth section of the Oslo Health Study, carried out in schools in 2000–2001 (<it>n </it>= 3811). The follow-up in 2003–2004 was conducted partly at school and partly through mail. A total of 2489 (1112 boys and 1377 girls) participated in the follow-up. Mental health was measured by the Strengths and Difficulties Questionnaire with an impact supplement. Physical activity was measured by a question on weekly hours of physical activity outside of school, defined as exertion 'to an extent that made you sweat and/or out of breath'. Adjustments were made for well-documented confounders and mental health at baseline.</p> <p>Results</p> <p>In boys, the number of hours spent on physical activity per week at age 15–16 was negatively associated with emotional symptoms [B (95%CI) = -0.09 (-0.15, -0.03)] and peer problems [B (95%CI) = -0.08 (-0.14, -0.03)] at age 18–19 after adjustments. In girls, there were no significant differences in SDQ subscales at age 18–19 according to weekly hours of physical activity at age 15–16 after adjustments. Boys and girls with five to seven hours of physical activity per week at age 15–16 had the lowest mean scores for total difficulties and the lowest percentage with high impact score at age 18–19, but the differences were not statistically significant after adjustments.</p> <p>Conclusion</p> <p>Weekly hours of physical activity at age 15–16 years was weakly associated with mental health at three-year follow-up in boys. Results encourage a search for further knowledge about physical activity as a possible protective factor in relation to mental health problems in adolescence.</p

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

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

Optimal primary care management of clinical osteoarthritis and joint pain in older people: a mixed-methods programme of systematic reviews, observational and qualitative studies, and randomised controlled trials

Background Osteoarthritis (OA) is the most common long-term condition managed in UK general practice. However, care is suboptimal despite evidence that primary care and community-based interventions can reduce OA pain and disability. Objectives The overall aim was to improve primary care management of OA and the health of patients with OA. Four parallel linked workstreams aimed to (1) develop a health economic decision model for estimating the potential for cost-effective delivery of primary care OA interventions to improve population health, (2) develop and evaluate new health-care models for delivery of core treatments and support for self-management among primary care consulters with OA, and to investigate prioritisation and implementation of OA care among the public, patients, doctors, health-care professionals and NHS trusts, (3) determine the effectiveness of strategies to optimise specific components of core OA treatment using the example of exercise and (4) investigate the effect of interventions to tackle barriers to core OA treatment, using the example of comorbid anxiety and depression in persons with OA. Data sources The North Staffordshire Osteoarthritis Project database, held by Keele University, was the source of data for secondary analyses in workstream 1. Methods Workstream 1 used meta-analysis and synthesis of published evidence about effectiveness of primary care treatments, combined with secondary analysis of existing longitudinal population-based cohort data, to identify predictors of poor long-term outcome (prognostic factors) and design a health economic decision model to estimate cost-effectiveness of different hypothetical strategies for implementing optimal primary care for patients with OA. Workstream 2 used mixed methods to (1) develop and test a ‘model OA consultation’ for primary care health-care professionals (qualitative interviews, consensus, training and evaluation) and (2) evaluate the combined effect of a computerised ‘pop-up’ guideline for general practitioners (GPs) in the consultation and implementing the model OA consultation on practice and patient outcomes (parallel group intervention study). Workstream 3 developed and investigated in a randomised controlled trial (RCT) how to optimise the effect of exercise in persons with knee OA by tailoring it to the individual and improving adherence. Workstream 4 developed and investigated in a cluster RCT the extent to which screening patients for comorbid anxiety and depression can improve OA outcomes. Public and patient involvement included proposal development, project steering and analysis. An OA forum involved public, patient, health professional, social care and researcher representatives to debate the results and formulate proposals for wider implementation and dissemination. Results This programme provides evidence (1) that economic modelling can be used in OA to extrapolate findings of cost-effectiveness beyond the short-term outcomes of clinical trials, (2) about ways of implementing support for self-management and models of optimal primary care informed by National Institute for Health and Care Excellence recommendations, including the beneficial effects of training in a model OA consultation on GP behaviour and of pop-up screens in GP consultations on the quality of prescribing, (3) against adding enhanced interventions to current effective physiotherapy-led exercise for knee OA and (4) against screening for anxiety and depression in patients with musculoskeletal pain as an addition to current best practice for OA. Conclusions Implementation of evidence-based care for patients with OA is feasible in general practice and has an immediate impact on improving the quality of care delivered to patients. However, improved levels of quality of care, changes to current best practice physiotherapy and successful introduction of psychological screening, as achieved by this programme, did not substantially reduce patients’ pain and disability. This poses important challenges for clinical practice and OA research. Limitations The key limitation in this work is the lack of improvement in patient-reported pain and disability despite clear evidence of enhanced delivery of evidence-based care. Future work recommendations (1) New thinking and research is needed into the achievable and desirable long-term goals of care for people with OA, (2) continuing investigation into the resources needed to properly implement clinical guidelines for management of OA as a long-term condition, such as regular monitoring to maintain exercise and physical activity and (3) new research to identify subgroups of patients with OA as a basis for stratified primary care including (i) those with good prognosis who can self-manage with minimal investigation or specialist treatment, (ii) those who will respond to, and benefit from, specific interventions in primary care, such as physiotherapy-led exercise, and (iii) develop research into effective identification and treatment of clinically important anxiety and depression in patients with OA and into the effects of pain management on psychological outcomes in patients with OA. Trial registration Current Controlled Trials ISRCTN06984617, ISRCTN93634563 and ISRCTN40721988. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme and will be published in full in Programme Grants for Applied Research Programme; Vol. 6, No. 4. See the NIHR Journals Library website for further project information. </jats:sec