Knowledge Hidden in Nuances: From Molecules to Society

The Goal: We have discussed the theme of reintegrating biology several times at the national level over several decades (ex. A New Biology for the 21st Century, National Academy of Sciences, 2009). While these discussions are fruitful and certainly the topic may require an adaptive framework, we suggest a fundamental change in how the scientific community approaches this topic. In particular, we propose that biology can only be integrated when the structural, societal and methodological barriers to participation in biology are alleviated. A focus on the average or most prevalent approach or system - whether it is the structure of a protein, a biological process or pathway, or the average scientist - they all end up excluding observations, people, and ideas. In contrast, we propose a focus on and inclusion of nuances will enable us to examine the boundaries and rarer instances whether of topic or of people, enable us to explore, and learn from diversity that is currently unnoticed and may provide new perspectives, insights about the range of possibilities, and solutions to current challenges. By extending this paradigm to our society, including diverse perspectives and experiences may shed light on how we can learn about new ideas, tools, and resources to enhance our collective toolkits and approach solutions for problems we are addressing. The paper will compare the benefits of applying a nuanced approach at a molecular, cellular, organismal, and population levels and then extend this thinking to science and society. We think that including individuals and perspectives that are beyond the current majority/mainstream will enhance our understanding and ability to approach/address problems. Adding nuance to our understanding of science can come from better inclusion and integration. The intended audience for our Vision paper includes the National Science Foundation (NSF), academic and research institutions, and society at large. We hope that NSF has the potential to create and support opportunities for multiscale scientific explorations at the edge of the boundary (outside the averages). Knowledge derived from these observations and analyses can inspire new perspectives and/or solutions that are universally usable. Additionally, other Vision groups in the Reintegrating Biology meetings include topics that could benefit from the vision presented here (space, time, resilience, modelling, communication/signalling, networks, animal learning, biocomplexity). Academic and research institutions may utilize the proposed framework to review their institutional policies that directly or indirectly (via access to resources, opportunities etc.,) restrict collaborations based on interests and expertise. Our hope for society at large is to consider including, sharing, and respecting diverse perspectives and experiences

Lifestyle Matters for maintenance of health and wellbeing in people aged 65 years and over: study protocol for a randomised controlled trial

Background Healthy, active ageing is strongly associated with good mental wellbeing which in turn helps to prevent mental illness. However, more investment has been made into research into interventions to prevent mental illness than into those designed to improve mental wellbeing. This applied research programme will provide high quality evidence for an intervention designed to improve and sustain mental wellbeing in older adults. Methods/Design This study was a multi-centre, pragmatic, two-arm, parallel group, individually randomised controlled trial to determine the population benefit of an occupational therapy based intervention for community living people aged 65 years or older. Participants (n = 268) will be identified in one city in the North of England and in North Wales through GP mail-outs, signposting by local authority, primary care staff and voluntary sector organisations and through community engagement. Participants will be randomised to one of two treatment arms: an intervention (Lifestyle Matters programme); or control (routine access to health and social care). All participants will be assessed at baseline, 6 and 24 months post-randomisation. The primary outcome, which is a person reported outcome, is the SF-36 Mental Health dimension at six months post randomisation. Secondary outcome measures have been selected to measure psychosocial, physical and mental health outcomes. They include other dimensions of the SF36, EQ-5D-3L, Brief Resilience Scale, General Perceived Self Efficacy Scale, PHQ-9, de Jong Gierveld Loneliness Scale, Health and Social Care Resource Use and the wellbeing question of the Integrated Household Survey 2011. A cost effectiveness analysis will investigate the incremental cost per Quality Adjusted Life Years (QALYs) of the Lifestyle Matters intervention compared with treatment as usual. Discussion The questions being posed through this research are important given the increasing numbers of older people, pressure on the public purse and the associated need to support good health in the extended lifespan. The proposed trial will determine the clinical and cost effectiveness of the intervention delivered in a UK context. The results will support commissioners and providers with decisions about implementation.</p

ORCA-EFCD consensus report on clinical recommendation for caries diagnosis. Paper I:caries lesion detection and depth assessment

OBJECTIVES: The aim of the present consensus paper was to provide recommendations for clinical practice considering the use of visual examination, dental radiography and adjunct methods for primary caries detection.MATERIALS AND METHODS: The executive councils of the European Organisation for Caries Research (ORCA) and the European Federation of Conservative Dentistry (EFCD) nominated ten experts each to join the expert panel. The steering committee formed three work groups that were asked to provide recommendations on (1) caries detection and diagnostic methods, (2) caries activity assessment and (3) forming individualised caries diagnoses. The experts responsible for "caries detection and diagnostic methods" searched and evaluated the relevant literature, drafted this manuscript and made provisional consensus recommendations. These recommendations were discussed and refined during the structured process in the whole work group. Finally, the agreement for each recommendation was determined using an anonymous Delphi survey.RESULTS: Recommendations (N = 8) were approved and agreed upon by the whole expert panel: visual examination (N = 3), dental radiography (N = 3) and additional diagnostic methods (N = 2). While the quality of evidence was found to be heterogeneous, all recommendations were agreed upon by the expert panel.CONCLUSION: Visual examination is recommended as the first-choice method for the detection and assessment of caries lesions on accessible surfaces. Intraoral radiography, preferably bitewing, is recommended as an additional method. Adjunct, non-ionising radiation methods might also be useful in certain clinical situations.CLINICAL RELEVANCE: The expert panel merged evidence from the scientific literature with practical considerations and provided recommendations for their use in daily dental practice.</p

ORCA-EFCD consensus report on clinical recommendation for caries diagnosis. Paper I:caries lesion detection and depth assessment

OBJECTIVES: The aim of the present consensus paper was to provide recommendations for clinical practice considering the use of visual examination, dental radiography and adjunct methods for primary caries detection.MATERIALS AND METHODS: The executive councils of the European Organisation for Caries Research (ORCA) and the European Federation of Conservative Dentistry (EFCD) nominated ten experts each to join the expert panel. The steering committee formed three work groups that were asked to provide recommendations on (1) caries detection and diagnostic methods, (2) caries activity assessment and (3) forming individualised caries diagnoses. The experts responsible for "caries detection and diagnostic methods" searched and evaluated the relevant literature, drafted this manuscript and made provisional consensus recommendations. These recommendations were discussed and refined during the structured process in the whole work group. Finally, the agreement for each recommendation was determined using an anonymous Delphi survey.RESULTS: Recommendations (N = 8) were approved and agreed upon by the whole expert panel: visual examination (N = 3), dental radiography (N = 3) and additional diagnostic methods (N = 2). While the quality of evidence was found to be heterogeneous, all recommendations were agreed upon by the expert panel.CONCLUSION: Visual examination is recommended as the first-choice method for the detection and assessment of caries lesions on accessible surfaces. Intraoral radiography, preferably bitewing, is recommended as an additional method. Adjunct, non-ionising radiation methods might also be useful in certain clinical situations.CLINICAL RELEVANCE: The expert panel merged evidence from the scientific literature with practical considerations and provided recommendations for their use in daily dental practice.</p

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

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

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication