Showing papers by "Keele University published in 2021"

COVID-19 vaccination intention in the UK: results from the COVID-19 vaccination acceptability study (CoVAccS), a nationally representative cross-sectional survey.

Abstract: To investigate factors associated with intention to be vaccinated against COVID-19 we conducted a cross-sectional survey of 1,500 UK adults, recruited from an existing online research panel. Data were collected between 14th and 17th July 2020. We used linear regression analyses to investigate associations between intention to be vaccinated for COVID-19 "when a vaccine becomes available to you" and sociodemographic factors, previous influenza vaccination, general vaccine attitudes and beliefs, attitudes and beliefs about COVID-19, and attitudes and beliefs about a COVID-19 vaccination. 64% of participants reported being very likely to be vaccinated against COVID-19, 27% were unsure, and 9% reported being very unlikely to be vaccinated. Personal and clinical characteristics, previous influenza vaccination, general vaccination beliefs, and beliefs and attitudes about COVID-19 and a COVID-19 vaccination explained 76% of the variance in vaccination intention. Intention to be vaccinated was associated with more positive general COVID-19 vaccination beliefs and attitudes, weaker beliefs that the vaccination would cause side effects or be unsafe, greater perceived information sufficiency to make an informed decision about COVID-19 vaccination, greater perceived risk of COVID-19 to others (but not risk to oneself), older age, and having been vaccinated for influenza last winter (2019/20). Despite uncertainty around the details of a COVID-19 vaccination, most participants reported intending to be vaccinated for COVID-19. Actual uptake may be lower. Vaccination intention reflects general vaccine beliefs and attitudes. Campaigns and messaging about a COVID-19 vaccination could consider emphasizing the risk of COVID-19 to others and necessity for everyone to be vaccinated.

Psychology for Musicians : Understanding and Acquiring the Skills

Abstract: PART I: MUSICAL LEARNING 1. Science and Musical Skills 2. Development 3. Motivation 4. Practice SECTION II: MUSICAL SKILLS 5. Expression and Interpretation 6. Reading or Listening and Remembering 7. Composition and Improvisation 8. Managing Performance Anxiety SECTION III: MUSICAL ROLES 9. The Performer 10. The Teacher 11. The Listener 12. The User

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes.

Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15542. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Protocol for development of a reporting guideline (TRIPOD-AI) and risk of bias tool (PROBAST-AI) for diagnostic and prognostic prediction model studies based on artificial intelligence.

Abstract: Introduction The Transparent Reporting of a multivariable prediction model of Individual Prognosis Or Diagnosis (TRIPOD) statement and the Prediction model Risk Of Bias ASsessment Tool (PROBAST) were both published to improve the reporting and critical appraisal of prediction model studies for diagnosis and prognosis. This paper describes the processes and methods that will be used to develop an extension to the TRIPOD statement (TRIPOD-artificial intelligence, AI) and the PROBAST (PROBAST-AI) tool for prediction model studies that applied machine learning techniques. Methods and analysis TRIPOD-AI and PROBAST-AI will be developed following published guidance from the EQUATOR Network, and will comprise five stages. Stage 1 will comprise two systematic reviews (across all medical fields and specifically in oncology) to examine the quality of reporting in published machine-learning-based prediction model studies. In stage 2, we will consult a diverse group of key stakeholders using a Delphi process to identify items to be considered for inclusion in TRIPOD-AI and PROBAST-AI. Stage 3 will be virtual consensus meetings to consolidate and prioritise key items to be included in TRIPOD-AI and PROBAST-AI. Stage 4 will involve developing the TRIPOD-AI checklist and the PROBAST-AI tool, and writing the accompanying explanation and elaboration papers. In the final stage, stage 5, we will disseminate TRIPOD-AI and PROBAST-AI via journals, conferences, blogs, websites (including TRIPOD, PROBAST and EQUATOR Network) and social media. TRIPOD-AI will provide researchers working on prediction model studies based on machine learning with a reporting guideline that can help them report key details that readers need to evaluate the study quality and interpret its findings, potentially reducing research waste. We anticipate PROBAST-AI will help researchers, clinicians, systematic reviewers and policymakers critically appraise the design, conduct and analysis of machine learning based prediction model studies, with a robust standardised tool for bias evaluation. Ethics and dissemination Ethical approval has been granted by the Central University Research Ethics Committee, University of Oxford on 10-December-2020 (R73034/RE001). Findings from this study will be disseminated through peer-review publications. PROSPERO registration number CRD42019140361 and CRD42019161764.

Burden of heart failure and underlying causes in 195 countries and territories from 1990 to 2017.

Abstract: Aims To provide the first systematic analysis of the burden and underlying causes of heart failure (HF) in 195 countries and territories from 1990 to 2017. Methods and results We collected detailed information on prevalence, years lived with disability (YLDs), and underlying causes of HF from the Global Burden of Disease study 2017. Numbers and age-standardized rates of HF prevalence and YLDs were compared by age, sex, socio-demographic index (SDI), and location. The proportions of HF age-standardized prevalence rates due to 23 underlying causes were also presented. Globally, the age-standardized prevalence and YLD rates of HF in 2017 were 831.0 and 128.2 per 100 000 people, a decrease of -7.2% and -0.9% from 1990, respectively. Nevertheless, the absolute numbers of HF prevalent cases and YLDs have increased by 91.9% and 106.0% from 1990, respectively. There is significant geographic and socio-demographic variation in the levels and trends of HF burden from 1990 to 2017. Among all causes of HF, ischaemic heart disease accounted for the highest proportion (26.5%) of age-standardized prevalence rate of HF in 2017, followed by hypertensive heart disease (26.2%), chronic obstructive pulmonary disease (23.4%). Conclusion HF remains a serious public health problem worldwide, with increasing age-standardized prevalence and YLD rates in countries with relatively low SDI. More geo-specific strategies aimed at preventing underlying causes and improving medical care for HF are warranted to reduce the future burden of this condition.

Effects of the COVID-19 pandemic on primary care-recorded mental illness and self-harm episodes in the UK: a population-based cohort study.

Abstract: Summary Background The COVID-19 pandemic has adversely affected population mental health. We aimed to assess temporal trends in primary care-recorded common mental illness, episodes of self-harm, psychotropic medication prescribing, and general practitioner (GP) referrals to mental health services during the COVID-19 emergency in the UK. Methods We did a population-based cohort study using primary care electronic health records from general practices registered on the UK Clinical Practice Research Datalink (CPRD). We included patient records from Jan 1, 2010, to Sept 10, 2020, to establish long-term trends and patterns of seasonality, but focused primarily on the period January, 2019–September, 2020. We extracted data on clinical codes entered into patient records to estimate the incidence of depression and anxiety disorders, self-harm, prescriptions for antidepressants and benzodiazepines, and GP referrals to mental health services, and assessed event rates of all psychotropic prescriptions and self-harm. We used mean-dispersion negative binomial regression models to predict expected monthly incidence and overall event rates, which were then compared with observed rates to assess the percentage reduction in incidence and event rates after March, 2020. We also stratified analyses by sex, age group, and practice-level Index of Multiple Deprivation quintiles. Findings We identified 14 210 507 patients from 1697 UK general practices registered in the CPRD databases. In April, 2020, compared with expected rates, the incidence of primary care-recorded depression had reduced by 43·0% (95% CI 38·3–47·4), anxiety disorders by 47·8% (44·3–51·2), and first antidepressant prescribing by 36·4% (33·9–38·8) in English general practices. Reductions in first diagnoses of depression and anxiety disorders were largest for adults of working age (18–44 and 45–64 years) and for patients registered at practices in more deprived areas. The incidence of self-harm was 37·6% (34·8–40·3%) lower than expected in April, 2020, and the reduction was greatest for women and individuals aged younger than 45 years. By September, 2020, rates of incident depression, anxiety disorder, and self-harm were similar to expected levels. In Northern Ireland, Scotland, and Wales, rates of incident depression and anxiety disorder remained around a third lower than expected to September, 2020. In April, 2020, the rate of referral to mental health services was less than a quarter of the expected rate for the time of year (75·3% reduction [74·0–76·4]). Interpretation Consequences of the considerable reductions in primary care-recorded mental illness and self-harm could include more patients subsequently presenting with greater severity of mental illness and increasing incidence of non-fatal self-harm and suicide. Addressing the effects of future lockdowns and longer-term impacts of economic instability on mental health should be prioritised. Funding National Institute for Health Research and Medical Research Council.

Place and causes of acute cardiovascular mortality during the COVID-19 pandemic.

Abstract: Objective To describe the place and causes of acute cardiovascular death during the COVID-19 pandemic. Methods Retrospective cohort of adult (age ≥18 years) acute cardiovascular deaths (n=5 87 225) in England and Wales, from 1 January 2014 to 30 June 2020. The exposure was the COVID-19 pandemic (from onset of the first COVID-19 death in England, 2 March 2020). The main outcome was acute cardiovascular events directly contributing to death. Results After 2 March 2020, there were 28 969 acute cardiovascular deaths of which 5.1% related to COVID-19, and an excess acute cardiovascular mortality of 2085 (+8%). Deaths in the community accounted for nearly half of all deaths during this period. Death at home had the greatest excess acute cardiovascular deaths (2279, +35%), followed by deaths at care homes and hospices (1095, +32%) and in hospital (50, +0%). The most frequent cause of acute cardiovascular death during this period was stroke (10 318, 35.6%), followed by acute coronary syndrome (ACS) (7 098, 24.5%), heart failure (6 770, 23.4%), pulmonary embolism (2 689, 9.3%) and cardiac arrest (1 328, 4.6%). The greatest cause of excess cardiovascular death in care homes and hospices was stroke (715, +39%), compared with ACS (768, +41%) at home and cardiogenic shock (55, +15%) in hospital. Conclusions and relevance The COVID-19 pandemic has resulted in an inflation in acute cardiovascular deaths, nearly half of which occurred in the community and most did not relate to COVID-19 infection suggesting there were delays to seeking help or likely the result of undiagnosed COVID-19.

An update on developments in medical education in response to the COVID-19 pandemic: A BEME scoping review: BEME Guide No. 64.

Abstract: COVID-19 has fundamentally altered how education is delivered. Gordon et al. previously conducted a review of medical education developments in response to COVID-19; however, the field has rapidly ...

SARS/MERS/SARS-CoV-2 Outbreaks and Burnout Syndrome among Healthcare Workers. An Umbrella Systematic Review.

Abstract: The coronavirus-19 (COVID-19) pandemic is putting a severe strain on all healthcare systems. Several occupational risk factors are challenging healthcare workers (HCWs) who are at high risk of mental health outcomes, including Burnout Syndrome (BOS). BOS is a psychological syndrome characterized by emotional exhaustion, depersonalization, and low personal accomplishment. An umbrella review of systematic reviews and meta-analyses concerning BOS and coronavirus (SARS/MERS/SARS-CoV-2) outbreaks was carried out on PubMed Central/Medline, Cochrane Library, PROSPERO, and Epistemonikos databases. Data relating to COVID-19 is insufficient, but in previous SARS and MERS outbreaks about one-third of HCWs manifested BOS. This prevalence rate is similar to the figure recorded in some categories of HCWs exposed to chronic occupational stress and poor work organization during non-epidemic periods. Inadequate organization and worsening working conditions during an epidemic appear to be the most likely causes of BOS. Preventive care and workplace health promotion programs could be useful for protecting healthcare workers during pandemics, as well as during regular health activities.

Global, regional, and national prevalence, incidence, mortality, and risk factors for atrial fibrillation, 1990-2017: results from the Global Burden of Disease Study 2017.

Abstract: Aims To estimate the prevalence, incidence, mortality, and risk factors for atrial fibrillation (AF) in 195 countries and territories from 1990 to 2017. Methods and results Following the methodologies used in the Global Burden of Disease study 2017, the prevalence, incidence, and mortality of AF were analyzed by age, sex, year, socio-demographic index (SDI), and location. The percentage contributions of major risk factors to age-standardised AF deaths were measured by population attributable fractions. In 2017, there were 37.57 million [95% uncertainty interval (UI) 32.55 to 42.59] prevalent cases and 3.05 million (95% UI 2.61 to 3.51) incident cases of AF globally, contributing to 287,241 (95% UI 276,355 to 304,759) deaths. The age-standardised rates of prevalent cases, incident cases, and deaths of AF in 2017 and their temporal trends from 1990 to 2017 varied significantly by SDI quintile and location. High systolic blood pressure was the leading risk factor for AF age-standardised deaths [34.3% (95% UI 27.4 to 41.5)] in 2017, followed by high body-mass index [20.7% (95% UI 11.5 to 32.2)] and alcohol use [9.4% (95% UI 7.0 to 12.2)]. Conclusion Our study has systematically and globally assessed the temporal trends of AF, which remains a major public heath challenge. Although AF mainly occurred in developed countries, the unfavorable trend in countries with lower SDI also deserves particular attention. More effective prevention and treatment strategies aimed at counteracting the increase in AF burden should be established in some countries.

International Collaboration to Ensure Equitable Access to Vaccines for COVID-19: The ACT-Accelerator and the COVAX Facility.

Abstract: Policy Points Equitable access to a COVID-19 vaccine in all countries remains a key policy objective, but experience of previous pandemics suggests access will be limited in developing countries, despite the rapid development of three successful vaccine candidates. The COVAX Facility seeks to address this important issue, but the prevalence of vaccine nationalism threatens to limit the ability of the facility to meet both its funding targets and its ambitious goals for vaccine procurement. A failure to adequately address the underlying lack of infrastructure in developing countries threatens to further limit the success of the COVAX Facility. Context Significant effort has been directed toward developing a COVID-19 vaccine, which is viewed as the route out of the pandemic. Much of this effort has coalesced around COVAX, the multilateral initiative aimed at accelerating the development of COVID-19 vaccines, and ensuring they are equitably available in low- and middle-income countries (LMICs). This paper represents the first significant analysis of COVAX, and the extent to which it can be said to have successfully met these aims. Methods This paper draws on the publicly available policy documents made available by the COVAX initiatives, as well as position papers and public statements from governments around the world with respect to COVID-19 vaccines and equitable access. We analyze the academic literature regarding access to vaccines during the H1N1 pandemic. Finally, we consider the WHO Global Allocation System, and its principles, which are intended to guide COVAX vaccine deployment. Findings We argue that the funding mechanism deployed by the COVAX Pillar appears to be effective at fostering at-risk investments in research and development and the production of doses in advance of confirmation of clinical efficacy, but caution that this represents a win-win situation for vaccine manufacturers, providing them with opportunity to benefit regardless of whether their vaccine candidate ever goes on to gain regulatory approval. We also argue that the success of the COVAX Facility with respect to equitable access to vaccine is likely to be limited, primarily as a result of the prevalence of vaccine nationalism, whereby countries adopt policies which heavily prioritize their own public health needs at the expense of others. Conclusions Current efforts through COVAX have greatly accelerated the development of vaccines against COVID-19, but these benefits are unlikely to flow to LMICs, largely due to the threat of vaccine nationalism.

Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles.

Abstract: Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP's plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.

Suicide, self-harm and suicidal ideation during COVID-19: A systematic review.

Abstract: We aimed to do a systematic review and meta-analysis of studies describing suicidal ideation, suicide attempts and suicide and associated risk factors during COVID-19 pandemic. We searched following electronic databases using relevant search terms: Medline, Embase, PsycInfo and CINAHL and systematically reviewed the evidence following PRISMA guidelines. The meta-analysis of prevalence of suicidal ideation was done using random effect model. The search returned 972 records, we examined 106 in full text and included 38 studies describing 120,076 participants. Nineteen studies described suicide or attempted self-harm, mostly in case reports. Out of 19 studies describing suicidal ideations, 12 provided appropriate data for meta-analysis. The pooled prevalence of suicidal ideation in these studies was 12.1% (CI 9.3-15.2). Main risk factors for suicidal ideations were: low social support, high physical and mental exhaustion and poorer self-reported physical health in frontline medical workers, sleep disturbances, quarantine and exhaustion, loneliness, and mental health difficulties. We provide first meta-analytic estimate of suicidal ideation based on large sample from different countries and populations. The rate of suicidal ideations during COVID pandemic is higher than that reported in studies on general population prior to pandemic and may result in higher suicide rates in future.

Patient response, treatments and mortality for acute myocardial infarction during the COVID-19 pandemic.

Abstract: Aims COVID-19 might have affected the care and outcomes of hospitalized acute myocardial infarction (AMI). We aimed to determine whether the COVID-19 pandemic changed patient response, hospital treatment, and mortality from AMI. Methods and results Admission was classified as non-ST-elevation myocardial infarction (NSTEMI) or STEMI at 99 hospitals in England through live feeding from the Myocardial Ischaemia National Audit Project between 1 January 2019 and 22 May 2020. Time series plots were estimated using a 7-day simple moving average, adjusted for seasonality. From 23 March 2020 (UK lockdown), median daily hospitalizations decreased more for NSTEMI [69 to 35; incidence risk ratios (IRR) 0.51, 95% confidence interval (CI) 0.47-0.54] than STEMI (35 to 25; IRR 0.74, 95% CI 0.69-0.80) to a nadir on 19 April 2020. During lockdown, patients were younger (mean age 68.7 vs. 66.9 years), less frequently diabetic (24.6% vs. 28.1%), or had cerebrovascular disease (7.0% vs. 8.6%). ST-elevation myocardial infarction more frequently received primary percutaneous coronary intervention (81.8% vs. 78.8%), thrombolysis was negligible (0.5% vs. 0.3%), median admission-to-coronary angiography duration for NSTEMI decreased (26.2 vs. 64.0 h), median duration of hospitalization decreased (4 to 2 days), secondary prevention pharmacotherapy prescription remained unchanged (each > 94.7%). Mortality at 30 days increased for NSTEMI [from 5.4% to 7.5%; odds ratio (OR) 1.41, 95% CI 1.08-1.80], but decreased for STEMI (from 10.2% to 7.7%; OR 0.73, 95% CI 0.54-0.97). Conclusion During COVID-19, there was a substantial decline in admissions with AMI. Those who presented to hospital were younger, less comorbid and, for NSTEMI, had higher 30-day mortality.

Sleep Quality and Physical Activity as Predictors of Mental Wellbeing Variance in Older Adults during COVID-19 Lockdown: ECLB COVID-19 International Online Survey.

Abstract: Background. The COVID-19 lockdown could engender disruption to lifestyle behaviors, thus impairing mental wellbeing in the general population. This study investigated whether sociodemographic variables, changes in physical activity, and sleep quality from pre- to during lockdown were predictors of change in mental wellbeing in quarantined older adults. Methods. A 12-week international online survey was launched in 14 languages on 6 April 2020. Forty-one research institutions from Europe, Western-Asia, North-Africa, and the Americas, promoted the survey. The survey was presented in a differential format with questions related to responses “pre” and “during” the lockdown period. Participants responded to the Short Warwick–Edinburgh Mental Wellbeing Scale, the Pittsburgh Sleep Quality Index (PSQI) questionnaire, and the short form of the International Physical Activity Questionnaire. Results. Replies from older adults (aged >55 years, n = 517), mainly from Europe (50.1%), Western-Asia (6.8%), America (30%), and North-Africa (9.3%) were analyzed. The COVID-19 lockdown led to significantly decreased mental wellbeing, sleep quality, and total physical activity energy expenditure levels (all p < 0.001). Regression analysis showed that the change in total PSQI score and total physical activity energy expenditure (F(2, 514) = 66.41 p < 0.001) were significant predictors of the decrease in mental wellbeing from pre- to during lockdown (p < 0.001, R2: 0.20). Conclusion. COVID-19 lockdown deleteriously affected physical activity and sleep patterns. Furthermore, change in the total PSQI score and total physical activity energy expenditure were significant predictors for the decrease in mental wellbeing.

Barriers and facilitators of the uptake of digital health technology in cardiovascular care: a systematic scoping review.

Abstract: Digital health technology (DHT) has the potential to revolutionize healthcare delivery but its uptake has been low in clinical and research settings. The factors that contribute to the limited adoption of DHT, particularly in cardiovascular settings, are unclear. The objective of this review was to determine the barriers and facilitators of DHT uptake from the perspective of patients, clinicians, and researchers. We searched MEDLINE, EMBASE, and CINAHL databases for studies published from inception to May 2020 that reported barriers and/or facilitators of DHT adoption in cardiovascular care. We extracted data on study design, setting, cardiovascular condition, and type of DHT. We conducted a thematic analysis to identify barriers and facilitators of DHT uptake. The search identified 3075 unique studies, of which 29 studies met eligibility criteria. Studies employed: qualitative methods (n = 13), which included interviews and focus groups; quantitative methods (n = 5), which included surveys; or a combination of qualitative and quantitative methods (n = 11). Twenty-five studies reported patient-level barriers, most common of which were difficult-to-use technology (n=7) and a poor internet connection (n=7). Six studies reported clinician-level barriers, which included increased workload (n=4) and a lack of integration with electronic medical records (n=3).Twenty-four studies reported patient-level facilitators, which included improved communication with clinicians (n=10) and personalized technology (n=6). Four studies reported clinician-level facilitators, which included approval and organizational support from cardiology departments and/or hospitals (n=3) and technologies that improved efficiency (n=3). No studies reported researcher-level barriers or facilitators. In summary, internet access, user-friendliness, organizational support, workflow efficiency, and data integration were reported as important factors in the uptake of DHT by patients and clinicians. These factors can be considered when selecting and implementing DHTs in cardiovascular clinical settings.

Six transiting planets and a chain of Laplace resonances in TOI-178

Abstract: Determining the architecture of multi-planetary systems is one of the cornerstones of understanding planet formation and evolution. Resonant systems are especially important as the fragility of their orbital configuration ensures that no significant scattering or collisional event has taken place since the earliest formation phase when the parent protoplanetary disc was still present. In this context, TOI-178 has been the subject of particular attention since the first TESS observations hinted at the possible presence of a near 2:3:3 resonant chain. Here we report the results of observations from CHEOPS, ESPRESSO, NGTS, and SPECULOOS with the aim of deciphering the peculiar orbital architecture of the system. We show that TOI-178 harbours at least six planets in the super-Earth to mini-Neptune regimes, with radii ranging from to Earth radii and periods of 1.91, 3.24, 6.56, 9.96, 15.23, and 20.71 days. All planets but the innermost one form a 2:4:6:9:12 chain of Laplace resonances, and the planetary densities show important variations from planet to planet, jumping from to times the Earth’s density between planets c and d . Using Bayesian interior structure retrieval models, we show that the amount of gas in the planets does not vary in a monotonous way, contrary to what one would expect from simple formation and evolution models and unlike other known systems in a chain of Laplace resonances. The brightness of TOI-178 (H = 8.76 mag, J = 9.37 mag, V = 11.95 mag) allows for a precise characterisation of its orbital architecture as well as of the physical nature of the six presently known transiting planets it harbours. The peculiar orbital configuration and the diversity in average density among the planets in the system will enable the study of interior planetary structures and atmospheric evolution, providing important clues on the formation of super-Earths and mini-Neptunes.

Unfractionated heparin inhibits live wild-type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations.

Abstract: Background and purpose Currently, there are no licensed vaccines and limited antivirals for the treatment of COVID-19. Heparin (delivered systemically) is currently used to treat anticoagulant anomalies in COVID-19 patients. Additionally, in the United Kingdom, Brazil and Australia, nebulised unfractionated heparin (UFH) is being trialled in COVID-19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild type SARS-CoV-2, in vitro, is needed. Experimental approach Seven different heparin preparations including UFH and low MW heparins (LMWH) of porcine or bovine origin were screened for antiviral activity against live SARS-CoV-2 (Australia/VIC01/2020) using a plaque inhibition assay with Vero E6 cells. Interaction of heparin with spike protein RBD was studied using differential scanning fluorimetry and the inhibition of RBD binding to human ACE2 protein using elisa assays was examined. Key results All the UFH preparations had potent antiviral effects, with IC50 values ranging between 25 and 41 μg·ml-1 , whereas LMWHs were less inhibitory by ~150-fold (IC50 range 3.4-7.8 mg·ml-1 ). Mechanistically, we observed that heparin binds and destabilizes the RBD protein and furthermore, we show heparin directly inhibits the binding of RBD to the human ACE2 protein receptor. Conclusion and implications This comparison of clinically relevant heparins shows that UFH has significantly stronger SARS-CoV-2 antiviral activity compared to LMWHs. UFH acts to directly inhibit binding of spike protein to the human ACE2 protein receptor. Overall, the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID-19.

Risk of bias in studies on prediction models developed using supervised machine learning techniques: systematic review

Abstract: Objective To assess the methodological quality of studies on prediction models developed using machine learning techniques across all medical specialties. Design Systematic review. Data sources PubMed from 1 January 2018 to 31 December 2019. Eligibility criteria Articles reporting on the development, with or without external validation, of a multivariable prediction model (diagnostic or prognostic) developed using supervised machine learning for individualised predictions. No restrictions applied for study design, data source, or predicted patient related health outcomes. Review methods Methodological quality of the studies was determined and risk of bias evaluated using the prediction risk of bias assessment tool (PROBAST). This tool contains 21 signalling questions tailored to identify potential biases in four domains. Risk of bias was measured for each domain (participants, predictors, outcome, and analysis) and each study (overall). Results 152 studies were included: 58 (38%) included a diagnostic prediction model and 94 (62%) a prognostic prediction model. PROBAST was applied to 152 developed models and 19 external validations. Of these 171 analyses, 148 (87%, 95% confidence interval 81% to 91%) were rated at high risk of bias. The analysis domain was most frequently rated at high risk of bias. Of the 152 models, 85 (56%, 48% to 64%) were developed with an inadequate number of events per candidate predictor, 62 handled missing data inadequately (41%, 33% to 49%), and 59 assessed overfitting improperly (39%, 31% to 47%). Most models used appropriate data sources to develop (73%, 66% to 79%) and externally validate the machine learning based prediction models (74%, 51% to 88%). Information about blinding of outcome and blinding of predictors was, however, absent in 60 (40%, 32% to 47%) and 79 (52%, 44% to 60%) of the developed models, respectively. Conclusion Most studies on machine learning based prediction models show poor methodological quality and are at high risk of bias. Factors contributing to risk of bias include small study size, poor handling of missing data, and failure to deal with overfitting. Efforts to improve the design, conduct, reporting, and validation of such studies are necessary to boost the application of machine learning based prediction models in clinical practice. Systematic review registration PROSPERO CRD42019161764.

Minimum sample size for external validation of a clinical prediction model with a continuous outcome

Abstract: In prediction model research, external validation is needed to examine an existing model's performance using data independent to that for model development. Current external validation studies often suffer from small sample sizes and consequently imprecise predictive performance estimates. To address this, we propose how to determine the minimum sample size needed for a new external validation study of a prediction model for a binary outcome. Our calculations aim to precisely estimate calibration (Observed/Expected and calibration slope), discrimination (C-statistic), and clinical utility (net benefit). For each measure, we propose closed-form and iterative solutions for calculating the minimum sample size required. These require specifying: (i) target SEs (confidence interval widths) for each estimate of interest, (ii) the anticipated outcome event proportion in the validation population, (iii) the prediction model's anticipated (mis)calibration and variance of linear predictor values in the validation population, and (iv) potential risk thresholds for clinical decision-making. The calculations can also be used to inform whether the sample size of an existing (already collected) dataset is adequate for external validation. We illustrate our proposal for external validation of a prediction model for mechanical heart valve failure with an expected outcome event proportion of 0.018. Calculations suggest at least 9835 participants (177 events) are required to precisely estimate the calibration and discrimination measures, with this number driven by the calibration slope criterion, which we anticipate will often be the case. Also, 6443 participants (116 events) are required to precisely estimate net benefit at a risk threshold of 8%. Software code is provided.

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart ‘OMics’ in AGEing (HOMAGE) randomized clinical trial

Abstract: Aims: To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results: Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P < 0.0001) were reduced in those assigned spironolactone. Conclusions: Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

Stress and worry in the 2020 coronavirus pandemic: relationships to trust and compliance with preventive measures across 48 countries in the COVIDiSTRESS global survey

Abstract: The COVIDiSTRESS global survey collects data on early human responses to the 2020 COVID-19 pandemic from 173 429 respondents in 48 countries. The open science study was co-designed by an international consortium of researchers to investigate how psychological responses differ across countries and cultures, and how this has impacted behaviour, coping and trust in government efforts to slow the spread of the virus. Starting in March 2020, COVIDiSTRESS leveraged the convenience of unpaid online recruitment to generate public data. The objective of the present analysis is to understand relationships between psychological responses in the early months of global coronavirus restrictions and help understand how different government measures succeed or fail in changing public behaviour. There were variations between and within countries. Although Western Europeans registered as more concerned over COVID-19, more stressed, and having slightly more trust in the governments' efforts, there was no clear geographical pattern in compliance with behavioural measures. Detailed plots illustrating between-countries differences are provided. Using both traditional and Bayesian analyses, we found that individuals who worried about getting sick worked harder to protect themselves and others. However, concern about the coronavirus itself did not account for all of the variances in experienced stress during the early months of COVID-19 restrictions. More alarmingly, such stress was associated with less compliance. Further, those most concerned over the coronavirus trusted in government measures primarily where policies were strict. While concern over a disease is a source of mental distress, other factors including strictness of protective measures, social support and personal lockdown conditions must also be taken into consideration to fully appreciate the psychological impact of COVID-19 and to understand why some people fail to follow behavioural guidelines intended to protect themselves and others from infection. The Stage 1 manuscript associated with this submission received in-principle acceptance (IPA) on 18 May 2020. Following IPA, the accepted Stage 1 version of the manuscript was preregistered on the Open Science Framework at https://osf.io/g2t3b. This preregistration was performed prior to data analysis.

Determining sample size for progression criteria for pragmatic pilot RCTs: the hypothesis test strikes back!

Abstract: The current CONSORT guidelines for reporting pilot trials do not recommend hypothesis testing of clinical outcomes on the basis that a pilot trial is under-powered to detect such differences and this is the aim of the main trial. It states that primary evaluation should focus on descriptive analysis of feasibility/process outcomes (e.g. recruitment, adherence, treatment fidelity). Whilst the argument for not testing clinical outcomes is justifiable, the same does not necessarily apply to feasibility/process outcomes, where differences may be large and detectable with small samples. Moreover, there remains much ambiguity around sample size for pilot trials. Many pilot trials adopt a ‘traffic light’ system for evaluating progression to the main trial determined by a set of criteria set up a priori. We construct a hypothesis testing approach for binary feasibility outcomes focused around this system that tests against being in the RED zone (unacceptable outcome) based on an expectation of being in the GREEN zone (acceptable outcome) and choose the sample size to give high power to reject being in the RED zone if the GREEN zone holds true. Pilot point estimates falling in the RED zone will be statistically non-significant and in the GREEN zone will be significant; the AMBER zone designates potentially acceptable outcome and statistical tests may be significant or non-significant. For example, in relation to treatment fidelity, if we assume the upper boundary of the RED zone is 50% and the lower boundary of the GREEN zone is 75% (designating unacceptable and acceptable treatment fidelity, respectively), the sample size required for analysis given 90% power and one-sided 5% alpha would be around n = 34 (intervention group alone). Observed treatment fidelity in the range of 0–17 participants (0–50%) will fall into the RED zone and be statistically non-significant, 18–25 (51–74%) fall into AMBER and may or may not be significant and 26–34 (75–100%) fall into GREEN and will be significant indicating acceptable fidelity. In general, several key process outcomes are assessed for progression to a main trial; a composite approach would require appraising the rules of progression across all these outcomes. This methodology provides a formal framework for hypothesis testing and sample size indication around process outcome evaluation for pilot RCTs.