Dual bronchodilators in Bronchiectasis study (DIBS): protocol for a pragmatic, multicentre, placebo-controlled, three-arm, double-blinded, randomised controlled trial studying bronchodilators in preventing exacerbations of bronchiectasis

INTRODUCTION: Bronchiectasis is a long-term lung condition, with dilated bronchi, chronic inflammation, chronic infection and acute exacerbations. Recurrent exacerbations are associated with poorer clinical outcomes such as increased severity of lung disease, further exacerbations, hospitalisations, reduced quality of life and increased risk of death. Despite an increasing prevalence of bronchiectasis, there is a critical lack of high-quality studies into the disease and no treatments specifically approved for its treatment. This trial aims to establish whether inhaled dual bronchodilators (long acting beta agonist (LABA) and long acting muscarinic antagonist (LAMA)) taken as either a stand-alone therapy or in combination with inhaled corticosteroid (ICS) reduce the number of exacerbations of bronchiectasis requiring treatment with antibiotics during a 12 month treatment period. METHODS: This is a multicentre, pragmatic, double-blind, randomised controlled trial, incorporating an internal pilot and embedded economic evaluation. 600 adult patients (≥18 years) with CT confirmed bronchiectasis will be recruited and randomised to either inhaled dual therapy (LABA+LAMA), triple therapy (LABA+LAMA+ICS) or matched placebo, in a 2:2:1 ratio (respectively). The primary outcome is the number of protocol defined exacerbations requiring treatment with antibiotics during the 12 month treatment period. ETHICS AND DISSEMINATION: Favourable ethical opinion was received from the North East-Newcastle and North Tyneside 2 Research Ethics Committee (reference: 21/NE/0020). Results will be disseminated in peer-reviewed publications, at national and international conferences, in the NIHR Health Technology Assessments journal and to participants and the public (using lay language). TRIAL REGISTRATION NUMBER: ISRCTN15988757

Partnering in oncogenetic research – the INHERIT BRCAs experience : opportunities and challenges

Today it is common to conduct research in collaboration with colleagues from different disciplines and institutions. The INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility (INHERIT BRCAs), involves Canadian and international experts from diverse fields working with health service providers, patients and collaborators from the World Health Organization and other European networks. Evidence-based information and knowledge transfer drive our efforts to advance genomic research to understand the genetic basis of cancer susceptibility and treatment response. Several goals reveal the interdisciplinary team approach: (a) to estimate the prevalence and penetrance of BRCA1 and BRCA2 mutations and their deleterious impact upon different populations; (b) to pinpoint novel breast cancer susceptibility loci; (c) to assess the efficacy of clinical interventions; (d) to address changes in quality of life and health-related behaviour from the decision to undergo genetics testing and during follow-up; (e) to evaluate legal, social and ethical implications; and, finally; (f) to promote professional and public education by facilitating the transfer of research findings to clinical practice and informing policy makers. The lessons learned by the INHERIT research team and future challenges are presented

Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe

Background Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. Methods Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final “bacterial” or “viral” phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. Results Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the “Watch” category. Conclusions Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results

Raising AWaRe-ness of antimicrobial stewardship challenges in pediatric emergency care: results from the PERFORM study assessing consistency and appropriateness of antibiotic prescribing across Europe.

OBJECTIVES Optimization of antimicrobial stewardship (AMS) is key to tackling antimicrobial resistance (AMR), which is exacerbated by over-prescription of antibiotics in pediatric Emergency Departments (EDs). We described patterns of empiric antibiotic use in European EDs, and characterized appropriateness and consistency of prescribing. METHODS Between August 2016 and December 2019 febrile children attending the ED in nine European countries with suspected infection were recruited into the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management) study. Empiric systemic antibiotic use was determined in view of assigned final 'bacterial' or 'viral' phenotype. Antibiotics were classified according to WHO AWaRe. RESULTS Of 2130 febrile episodes (excluding children with non-bacterial/non-viral phenotypes), 1549 (72.7%) were assigned a 'bacterial' and 581 (27.3%) a 'viral' phenotype. A total of 1318/1549 (85.1%) episodes with a 'bacterial' and 269/581 (46.3%) with a 'viral' phenotype received empiric systemic antibiotics (first two days of admission). Of those, the majority (87.8% in 'bacterial' and 87.0% in 'viral' group) received parenteral antibiotics. The top three antibiotics prescribed were third-generation cephalosporins, penicillins and penicillin/beta-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the 'viral' group 216/269 (80.3%) received ≥ one Watch antibiotic. CONCLUSIONS Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial over-prescription of antibiotics. A significant proportion of patients with a 'viral' phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology, could significantly improve AMS

The Perioperative Quality Improvement Programme (PQIP patient study): protocol for a UK multicentre, prospective cohort study to measure quality of care and outcomes after major surgery

INTRODUCTION: Major surgery accounts for a substantial proportion of health service activity, due not only to the primary procedure, but the longer-term health implications of poor short-term outcome. Data from small studies or from outside the UK indicate that rates of complications and failure to rescue vary between hospitals, as does compliance with best practice processes. Within the UK, there is currently no system for monitoring postoperative complications (other than short-term mortality) in major non-cardiac surgery. Further, there is variation between national audit programmes, in the emphasis placed on quality assurance versus quality improvement, and therefore the principles of measurement and reporting which are used to design such programmes. METHODS AND ANALYSIS: The PQIP patient study is a multi-centre prospective cohort study which recruits patients undergoing major surgery. Patient provide informed consent and contribute baseline and outcome data from their perspective using a suite of patient-reported outcome tools. Research and clinical staff complete data on patient risk factors and outcomes in-hospital, including two measures of complications. Longer-term outcome data are collected through patient feedback and linkage to national administrative datasets (mortality and readmissions). As well as providing a uniquely granular dataset for research, PQIP provides feedback to participating sites on their compliance with evidence-based processes and their patients' outcomes, with the aim of supporting local quality improvement. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Health Research Authority in the UK. Dissemination of interim findings (non-inferential) will form a part of the improvement methodology and will be provided to participating centres at regular intervals, including near-real time feedback of key process measures. Inferential analyses will be published in the peer-reviewed literature, supported by a comprehensive multi-modal communications strategy including to patients, policy makers and academic audiences as well as clinicians

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Dual bronchodilators in Bronchiectasis study (DIBS): protocol for a pragmatic, multicentre, placebo-controlled, three-arm, double-blinded, randomised controlled trial studying bronchodilators in preventing exacerbations of bronchiectasis

Introduction: Bronchiectasis is a long-term lung condition, with dilated bronchi, chronic inflammation, chronic infection and acute exacerbations. Recurrent exacerbations are associated with poorer clinical outcomes such as increased severity of lung disease, further exacerbations, hospitalisations, reduced quality of life and increased risk of death. Despite an increasing prevalence of bronchiectasis, there is a critical lack of high-quality studies into the disease and no treatments specifically approved for its treatment. This trial aims to establish whether inhaled dual bronchodilators (long acting beta agonist (LABA) and long acting muscarinic antagonist (LAMA)) taken as either a stand-alone therapy or in combination with inhaled corticosteroid (ICS) reduce the number of exacerbations of bronchiectasis requiring treatment with antibiotics during a 12 month treatment period. Methods: This is a multicentre, pragmatic, double-blind, randomised controlled trial, incorporating an internal pilot and embedded economic evaluation. 600 adult patients (≥18 years) with CT confirmed bronchiectasis will be recruited and randomised to either inhaled dual therapy (LABA+LAMA), triple therapy (LABA+LAMA+ICS) or matched placebo, in a 2:2:1 ratio (respectively). The primary outcome is the number of protocol defined exacerbations requiring treatment with antibiotics during the 12 month treatment period. Ethics and dissemination: Favourable ethical opinion was received from the North East—Newcastle and North Tyneside 2 Research Ethics Committee (reference: 21/NE/0020). Results will be disseminated in peer-reviewed publications, at national and international conferences, in the NIHR Health Technology Assessments journal and to participants and the public (using lay language). Trial registration number: ISRCTN15988757

The LifeCycle Project-EU Child Cohort Network : a federated analysis infrastructure and harmonized data of more than 250,000 children and parents

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.Peer reviewe