WILL (When to Induce Labour to Limit risk in pregnancy hypertension): a multicentre randomised controlled trial - adaptations to deliver a timing-of-birth trial during the COVID-19 international pandemic.

BACKGROUND: As a pragmatic randomised timing-of-birth trial, WILL adapted its trial procedures in response to the COVID-19 pandemic. These are reviewed here to inform post-pandemic trial methodology. METHODS: The trial (internal pilot) paused in March 2020, re-opened in July 2020, and is currently recruiting in 37 UK NHS consultant-led maternity units. We evaluated pandemic adaptations made to WILL processes and surveyed sites for their views of these changes (20 sites, videoconference). RESULTS: Despite 88% of sites favouring an electronic investigator site file (ISF), information technology requirements and clinical trial unit (CTU) operating procedures mandated the ongoing use of paper ISFs; site start-up delays resulted from restricted access to the CTU. Site initiation visits (SIVs) were conducted remotely; 50% of sites preferred remote SIVs and 44% felt that it was trial-dependent, while few preferred SIVs in-person as standard procedure. The Central team felt remote SIVs provided scheduling and attendance flexibility (for sites and trial staff), the option of recording discussions for missing or future staff, improved efficiency by having multiple sites attend, and time and cost savings; the negative impact on rapport-building and interaction was partially mitigated over time with more familiarity with technology and new ways-of-working. Two methods of remote consent were developed and used by 30/37 sites and for 54/156 recruits. Most (86%) sites using remote consenting felt it improved recruitment. For remote data monitoring (5 sites), advantages were primarily for the monitor (e.g. flexibility, no time constraints, reduced cost), and disadvantages primarily for the sites (e.g. document and access preparation, attendance at a follow-up meeting), but 81% of sites desired having the option of remote monitoring post-pandemic. CONCLUSIONS: COVID adaptations to WILL trial processes improved the flexibility of trial delivery, for Central and site staff, and participants. Flexibility to use these strategies should be retained post-pandemic. TRIAL REGISTRATION: ISRCTN77258279. Registered on 05 December 2018

Interventions to increase physical activity and reduce sedentary behaviour in severe mental ill health: How effective are they?’- A systematic review.

Background People with severe mental ill health experience a mortality gap of 15–20 years and one of the main reasons for this is due to preventable physical health conditions. Physical activity can reduce the risk of developing physical health conditions such as diabetes and cardiovascular disease yet people with severe mental ill health are less physically active and more sedentary than the general population. Methods A systematic review was conducted to investigate the effectiveness of interventions aimed at increasing physical activity and reducing sedentary behaviour in people with severe mental ill health. The protocol was published with PROSPERO (CRD42021277579). Randomised controlled trials conducted in any country in any setting and published in English with an aim of increasing physical activity or reducing sedentary behaviour were included. Results Eleven unique studies were identified for inclusion. Due to the variability between interventions, outcome measures, and time points, it was not possible to conduct a meta-analysis. Effect estimates suggested that three of the interventions were effective at increasing physical activity. However, the certainty of the evidence was rated as low using the GRADE approach. Conclusions The evidence on interventions to increase activity shows promise but is insufficiently robust for an intervention to be recommended in clinical guidelines. More high-quality and statistically powered trials are needed to guide best practice and policy

Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery A Randomized Clinical Trial and Systematic Review

Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm.Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm.Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014.Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366).Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay.Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]).Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rate

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

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space

The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL; https://anvilproject.org) was developed to address a widespread community need for a unified computing environment for genomics data storage, management, and analysis. In this perspective, we present AnVIL, describe its ecosystem and interoperability with other platforms, and highlight how this platform and associated initiatives contribute to improved genomic data sharing efforts. The AnVIL is a federated cloud platform designed to manage and store genomics and related data, enable population-scale analysis, and facilitate collaboration through the sharing of data, code, and analysis results. By inverting the traditional model of data sharing, the AnVIL eliminates the need for data movement while also adding security measures for active threat detection and monitoring and provides scalable, shared computing resources for any researcher. We describe the core data management and analysis components of the AnVIL, which currently consists of Terra, Gen3, Galaxy, RStudio/Bioconductor, Dockstore, and Jupyter, and describe several flagship genomics datasets available within the AnVIL. We continue to extend and innovate the AnVIL ecosystem by implementing new capabilities, including mechanisms for interoperability and responsible data sharing, while streamlining access management. The AnVIL opens many new opportunities for analysis, collaboration, and data sharing that are needed to drive research and to make discoveries through the joint analysis of hundreds of thousands to millions of genomes along with associated clinical and molecular data types

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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Protracted eclogite-facies metamorphism of the Dulan area, North Qaidam ultrahigh-pressure terrane: Insights on zircon growth during continental subduction and collision

Continental subduction and collision are recorded by ultrahigh-pressure (UHP) terranes; UHP terranes that form at early stages of an orogeny tend to be small and experience short residence at eclogite-facies depths, whereas terranes that form at mature stages of an orogeny tend to be larger and experience longer residence at these depths, but accurately determining eclogite-facies residence time requires a large geochronologic dataset tied to metamorphic conditions (via trace elements and/or inclusions). In the Dulan area, North Qaidam UHP terrane, China, it remains unclear whether the terrane experienced a long residence at eclogite-facies depths, marking the mature stage of an orogeny or two distinct (ultra)high pressure ([U]HP) events (with short residence times), interpreted as the transition from oceanic subduction to continental collision, where one (U)HP event is related to the former and second (U)HP event to the latter. To address this issue, we report new zircon U–Pb ages and trace-element data from eclogite and host paragneiss from the Dulan area and show that this terrane records ~42 Myr of eclogite-facies metamorphism at (U)HP conditions, similar to other large UHP terranes. Zircon from 11 eclogite and 2 gneiss samples yields weighted mean ages of 463–425 Ma, flat heavy rare earth element (HREE) patterns without negative Eu anomalies, and eclogitic mineral inclusions, indicating eclogite-facies conditions. Paragneiss metamorphic ages overlap with ages from eclogite but are generally younger, suggesting that a lack of internally generated fluids may have inhibited zircon growth and/or recrystallization until early decompression and white mica consumption in felsic gneiss generated fluids; thus, we interpret that these felsic rocks record the later stages of continental collision. Dataset patterns from all new and previously published analyses for the Dulan area (34 eclogite and 14 gneiss) suggest that metamorphic zircon in eclogite records prograde, peak and possibly early retrograde conditions, in contrast to the prediction from mass balance models that metamorphic zircon should only grow during exhumation and cooling. We reconcile our observations with these model predictions by recognizing that differential solubility can lead to grain-scale zircon growth or recrystallization over a large segment of the pressure–temperature (P–T) path even where zircon abundance decreases at the whole-rock scale

WILL (when to induce labour to limit risk in pregnancy hypertension): protocol for a multicentre randomised trial

Objectives: to address optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. Study design: Pragmatic, non-masked randomised trial. Inclusion: maternal age ≥16 years, chronic or gestational hypertension, singleton pregnancy, live fetus, 36+0–37+6 weeks’ gestation, and able to give documented informed consent. Exclusion: contraindication to either trial arm (e.g., pre-eclampsia or another indication for birth at term), blood pressure (BP) ≥ 160/110 mmHg until controlled, major fetal anomaly anticipated to require neonatal care unit admission, or participation in another timing of birth trial. Randomisation (1:1 ratio, minimised for key prognostic variables: site, hypertension type, and prior Caesarean) to ‘planned early term birth at 38+0-3 weeks’ or ‘usual care at term’ (revised from ‘expectant care until at least 40+0 weeks’, Aug 2022).Outcomes: maternal co-primary: composite of ‘poor maternal outcome’ (severe hypertension, maternal death, or maternal morbidity). Neonatal co-primary: neonatal care unit admission for ≥4 h. Each co-primary is measured until primary hospital discharge or 28 days post-birth (whichever is earlier). Key secondary: Caesarean birth.Analysis: sample of 1080 participants (540/arm) will detect an 8% reduction in the maternal co-primary (90% power, superiority hypothesis), and give 94% power for a between-group non-inferiority margin of difference of 9% in the neonatal co-primary. Analysis will be by intention-to-treat. Ethics approval has been obtained (NHS Health Research Authority London Fulham Research Ethics Committee, 18/LO/2033). Conclusions: The study will provide data for women to make informed choices about their care and allow health systems to plan services.</p