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Background: Exacerbation frequency strongly influences treatment choices in patients with severe asthma., Research Question: What is the extent of the variability of exacerbation rate across countries and its implications in disease management?, Study Design and Methods: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables., Results: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39)., Interpretation: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. P. has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, and Thermofisher; has consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; has grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, and UK National Health Service; has received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals; has received payment for the development of educational materials from Mundipharma and Novartis; has received payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, and Thermofisher; has received funding for patient enrollment or completion of research from Novartis; has stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); has 5% shareholding in Timestamp, which develops adherence monitoring technology; is a peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. E. W. has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech; and has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva Pharmaceuticals, for which her institution has received funding. M. E. W. reports grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Cohero Health, Teva Pharmaceuticals, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound biologic, Incyte, and Kinaset. D. J. J. has received speaker fees and consultancy fees from AZ, GSK, Sanofi Regeneron, and BI; and research funding from AstraZeneca. J. B. has received research grants from AstraZeneca and personnel fees from NuvoAir, outside the submitted work. L. G. H. has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva Pharmaceuticals; has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, Amgen, Genentech/Hoffman la Roche, AstraZeneca, MedImmune, Glaxo Smith Kline, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, and Napp Pharmaceuticals; has taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; and is the academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. P. E. P. has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. D.-W. P. received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. B. G. C. declares grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva Pharmaceuticals, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca, outside the submitted work. L. P.-L. reports grants, personal fees, and nonfinancial support from AstraZeneca, Teva Pharmaceuticals, Sanofi, and FAES; personal fees and nonfinancial support from GlaxoSmithKline and Chiesi; personal fees from MSD, TECHDOW PHARMA, and Leo-Pharma; grants and personal fees from GEBRO; and personal fees from GILEAD, outside the submitted work. R. A.-L. has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi; and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbot. D. L.-L. reports personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, and Carnot; and grants from Abbvie, Bayer, Lilly, Sanofi, Astrazeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline, outside the submitted work. M. A.-A. has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline; and received a grant from Kuwait Foundation for the Advancement of Sciences (KFAS). C. K. R. received consulting/lecture fees from MSD, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva Pharmaceuticals, Sanofi, and Bayer. T. I. received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, and AstraZeneca. E. H. declares personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes, and Circassia. G. W. C. has received research grants and lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva Pharmaceuticals, Thermo Fisher, and Valeas. R. C. has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva Pharmaceuticals; is a member of advisory boards for GlaxoSmithKline and Novartis; has received grant support from GlaxoSmithKline and Aerogen; and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence, and prediction of exacerbations. N. G. P. has been a speaker and/or advisory board member for Abbott, Abbvie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GSK, HAL, Faes Farma, Medscape, Menarini, MSD, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. A. I. P. has received fees and honoraria from Menarini, GSK, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. C. M. P. has attended advisory boards for AstraZeneca, Novartis, Teva Pharmaceuticals, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, Teva Pharmaceuticals, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, Teva Pharmaceuticals, GlaxoSmithKline, ALK, and Sanofi-Genzyme. C. A. T.-D. has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. T. A. P. declares relevant research support from Novartis and Chiesi Pharma. M. H. declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva Pharmaceuticals, and Seqirus, for unrelated projects. M. P. declares personal fees and nonfinancial support from AstraZeneca and GlaxoSmithKline. P. G. G. has received speaker fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. J. M. reports speaker fees, grants, or advisory boards for AstraZeneca, Sanofi, GSK, Novartis, Inmunotek, Menarini, and Noucor. C. B. reports advisory boards participation for Sanofi, AstraZeneca, Takeda, and ValeoPharma; honorarium for presentations for GlaxoSmithKline, AstraZeneca, Amgen, Grifols, Sanofi, Regeneron, and ValeoPharma; and clinical trials paid to University of British Columbia sponsored by AstraZeneza, GlaxoSmithKline, BioHaven, and Sanofi. S. C. declares receiving conference fees from Novartis S.A de C.V, Glaxosmithkline Mexico, AstraZeneca Mexico, and Sanofi Mexico. M. S. has received honoraria from AstraZeneca, Boehringer Ingelheim, Teva Pharmaceuticals, and GlaxoSmithKline for purposes unrelated to the content of this manuscript; and has received research funding from AstraZeneza and Boehringer Ingelheim directly into his research account from AstraZeneza for unrelated projects. None declared (T. Y. L., C. P. Y., R. R., L. H. M. L., B. M., G. C. C., E. A. C.-C., W. C.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A recent epidemiological study systematically screened 250 prescription medications for associations with oesophageal cancer risk, using Scottish data, and identified an increased risk with use of prednisolone and warfarin. We investigated whether oral prednisolone or warfarin use was associated with increased oesophageal cancer risk., Methods: A case-control study was conducted within the Clinical Practice Research Datalink. In the primary analysis oesophageal cancer cases were identified from linked cancer registry records. Up to 5 cancer-free controls were matched to each case (based upon sex, birth year, GP practice and year of GP registration). Prednisolone and warfarin medications were identified from prescribing records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression after adjusting for covariates including demographics, comorbidities and medication use., Results: There were 4552 oesophageal cancer cases and 22,601 matched control participants. Overall, there was no evidence of an increased risk of oesophageal cancer with oral prednisolone use (unadjusted OR=1.16 95% CI 1.06, 1.27 and adjusted OR=0.99 95% CI 0.89, 1.11) or warfarin use (unadjusted OR=1.12 95% CI 0.99, 1.28 and adjusted OR=1.08 95% CI 0.92, 1.27)., Conclusions: In this large population-based study, oral prednisolone and warfarin were not associated with oesophageal cancer risk., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab., Methods: This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230., Findings: Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SE HIGH ) with exacerbations with a low sputum eosinophil count (<2%; SE LOW ), the SE HIGH exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV 1 percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV 1 to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per μL [20 to 70]; p=0·0009). By contrast, SE LOW exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related., Interpretation: Exacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab., Funding: UK Medical Research council., Competing Interests: Declaration of interests PJM has received speaker's fees from Glaxo Smith Kline, outside the submitted work. FY has received personal fees and non-financial support from AstraZeneca and non-financial support from GlaxoSmithKline, outside the submitted work. CEB has received grants and personal fees from GlaxoSmithKline, AstraZeneca, Sanofi, Novartis, Chiesi, Genentech, Gossamer, Mologic, and 4DPharma for services outside the submitted work. RC has received grants, personal fees, and non-financial support from AstraZeneca; personal fees from GlaxoSmithKline and Novartis; personal fees and non-financial support from Teva and Chiesi; and non-financial support from Napp Pharmaceuticals, all outside the submitted work. IDP has received financial support for research from Sanofi and Regeneron Pharmaceuticals, and non-financial support from Excerpta Medica, during the conduct of the study. IDP has also received speaker's fees from Aerocrine AB; speaker's fees and consultant fees from Almirall and Novartis; speaker's fees, payments for organisation of educational events, consultant fees, and international scientific meeting scholarship from AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals, Sanofi, and Teva; speaker's fees, consultant fees, and international scientific meeting sponsorship from Boehringer Ingelheim; speaker's fees, consultant fees, international scientific meeting sponsorship, and a research grant from Chiesi; consultant fees from Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, Merck Sharp & Dohme, RespiVert, and Schering-Plough; and consultant fees and international scientific meeting sponsorship from Napp Pharmaceuticals, all outside the submitted work. LGH has received non-financial support from GlaxoSmithKline during the conduct of the study; has received grants from Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline, Boehringer Ingelheim, Aerocrine, and Vitalograph; is the lead for the UK MRC Consortium for Stratified Medicine in Severe Asthma in partnership with Novartis, Hoffman la Roche/Genentech, Evelo Biosciences, Sanofi, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia; has received travel funding support for international respiratory meetings (institution remunerated) from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceutical; has received project grant funding from Medimmune, Novartis UK, Roche/Genentech, and GlaxoSmithKline; and has received funding for clinical trials (institution remunerated) from AstraZeneca, GlaxoSmithKline, Schering Plough, Synairgen, Novartis, and Roche/Genentech, all outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts., Research Question: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables?, Study Design and Methods: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC)., Results: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV 1 , 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy., Interpretation: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control)., Methods: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed., Findings: Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose., Interpretation: Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low., Funding: This study was funded, in part, by the Medical Research Council UK., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Several studies have investigated the physiological effect of OCS in stable asthma, however these have included heterogeneous populations and outcomes. This paper is the first to combine their results., Methods: We searched Medline, Embase and Web of Science databases for studies reporting the impact of OCS on FEV 1 , FVC, blood eosinophils, fractional exhaled nitric oxide (FeNO), Asthma Control Questionnaire (ACQ) score or Asthma Quality Of Life Questionnaire (AQLQ) score in stable asthma. We extracted data on the correlates of OCS response., Results: 61 studies, comprising 1608 patients, were included. FEV 1 was improved by 9% (95% CI: 7, 11). There were stronger increases in FEV 1 among those with a mean baseline FEV 1 <60% predicted (19%, 95% CI: 13, 24). Despite these improvements, substantial residual impairment remained after treatment. Blood eosinophils were reduced by 76% (95% CI: 63, 88) with larger decreases in studies of corticosteroid-naïve patients (93%, 95% CI: 73,100). Sputum eosinophils were reduced by 89% (95% CI: 79, 98) while FeNO was decreased by 35% (95% CI: 28, 41). ACQ scores were reduced by 20% (95% CI: 11, 29). Patients with higher baseline lung function impairment, sputum eosinophils, blood eosinophils and FeNO had improved OCS response., Interpretation: OCS consistently improves lung function, reduces markers of type-2 inflammation, and alleviates asthma symptoms. However, substantial residual impairment remained following treatment and mean improvements were below the minimally important clinically difference. Patients with increased markers of type-2 inflammation are more responsive to treatment, suggesting these should be used to better target OCS use., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Clinical characteristics of the international population with severe asthma are unknown. Intercountry comparisons are hindered by variable data collection within regional and national severe asthma registries. We aimed to describe demographic and clinical characteristics of patients treated in severe asthma services in the United States, Europe, and the Asia-Pacific region., Methods: The International Severe Asthma Registry retrospectively and prospectively collected data in patients with severe asthma (≥ 18 years old), receiving Global Initiative for Asthma (GINA) Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4. Baseline demographic and clinical data were collected from the United States, United Kingdom, South Korea, Italy, and the Severe Asthma Web-based Database registry (including Australia, Singapore, and New Zealand) from December 2014 to December 2017., Results: We included 4,990 patients. Mean (SD) age was 55.0 (15.9) years, and mean (SD) age at asthma onset was 30.7 (17.7) years. Patients were predominantly female (59.3%) and white (72.6%), had never smoked (60.5%), and were overweight or obese (70.4%); 34.9% were at GINA Step 5; and 57.2% had poorly controlled disease. A total of 51.1% of patients were receiving regular intermittent oral corticosteroids, and 25.4% were receiving biologics (72.6% for those at GINA Step 5). Mean (SD) exacerbation rate was 1.7 (2.7) per year. Intercountry variation was observed in clinical characteristics, prescribed treatments, and biomarker profiles., Conclusions: Using a common data set and definitions, this study describes severe asthma characteristics of a large patient cohort included in multiple severe asthma registries and identifies country differences. Whether these are related to underlying epidemiological factors, environmental factors, phenotypes, asthma management systems, treatment access, and/or cultural factors requires further study., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To estimate the cost-effectiveness of a two-step clinical rule using symptoms, signs and dipstick testing to guide the diagnosis and antibiotic treatment of urinary tract infection (UTI) in acutely unwell young children presenting to primary care., Methods: Decision analytic model synthesising data from a multicentre, prospective cohort study (DUTY) and the wider literature to estimate the short-term and lifetime costs and healthcare outcomes (symptomatic days, recurrent UTI, quality adjusted life years) of eight diagnostic strategies. We compared GP clinical judgement with three strategies based on a 'coefficient score' combining seven symptoms and signs independently associated with UTI and four strategies based on weighted scores according to the presence/absence of five symptoms and signs. We compared dipstick testing versus laboratory culture in children at intermediate risk of UTI., Results: Sampling, culture and antibiotic costs were lowest in high-specificity DUTY strategies (£1.22 and £1.08) compared to clinical judgement (£1.99). These strategies also approximately halved urine sampling (4.8% versus 9.1% in clinical judgement) without reducing sensitivity (58.2% versus 56.4%). Outcomes were very similar across all diagnostic strategies. High-specificity DUTY strategies were more cost-effective than clinical judgement in the short- (iNMB = £0.78 and £0.84) and long-term (iNMB =£2.31 and £2.50). Dipstick tests had poorer cost-effectiveness than laboratory culture in children at intermediate risk of UTI (iNMB = £-1.41)., Conclusions: Compared to GPs' clinical judgement, high specificity clinical rules from the DUTY study could substantially reduce urine sampling, achieving lower costs and equivalent patient outcomes. Dipstick testing children for UTI is not cost-effective., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, application across a large cell panel representing various non-Hodgkin's lymphoma (NHL) subtypes, and their efficacy in EZH2mutant-containing GCB-DLBCL xenograft models. Surprisingly, our EZH2 inhibitors selectively affect the turnover of trimethylated, but not monomethylated histone H3 lysine 27 at pharmacologically relevant doses. Importantly, we find that these inhibitors are broadly efficacious also in NHL models with wild-type EZH2.

The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) is a candidate oncogene due to its prevalent overexpression in malignant diseases, including late stage prostate and breast cancers. The dependency of cancer cells on EZH2 activity is also predicated by recurrent missense mutations residing in the catalytic domain of EZH2 that have been identified in subtypes of diffuse large B cell lymphoma, follicular lymphoma and melanoma. Herein, we report the identification of a highly selective small molecule inhibitor series of EZH2 and EZH1. These compounds inhibit wild-type and mutant versions of EZH2 with nanomolar potency, suppress global histone H3-lysine 27 methylation, affect gene expression, and cause selective proliferation defects. These compounds represent a structurally distinct EZH2 inhibitor chemotype for the exploration of the role of Polycomb Repressive Complex 2-mediated H3K27 methylation in various biological contexts., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: We report the uptake, length of stay and vascular readmission rates of carotid endarterectomy (CEA) and CAS among patients with symptomatic or asymptomatic carotid artery disease in the English National Health Service (NHS)., Methods: Retrospective cohort study based on routinely collected Hospital Episode Statistics (HES) inpatient data. We identified individual admissions for CEA (n = 15996) or CAS (n = 632) between 2006 and 2009. Summary data were used to describe procedure volumes between 2009 and 2012. We analysed trends in procedure use over time and used ordinary least squares regression to evaluate patient, clinical and organisational characteristics associated with longer length of stay for revascularisation., Results: CAS made up less than 5% of carotid revascularisation procedures; there was no trend for increasing use between 2006 and 2012. Patients treated with CAS were on average younger, lived in areas of higher deprivation and were more likely to have amaurosis fugax or a comorbidity of heart disease. CAS patients had a 19% (95% CI 14-24) shorter stay in hospital than CEA patients., Conclusion: Despite the early promise of CAS and numerous randomised controlled trials evaluating efficacy, it has not been rapidly adopted in England. Cautious adoption may be appropriate given the higher periprocedural risk of stroke or death after CAS, particularly in recently symptomatic patients., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Malonyl-CoA decarboxylase (MCD) catalyzes the conversion of malonyl-CoA to acetyl-CoA and thereby regulates malonyl-CoA levels in cells. Malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase-1, a key enzyme involved in the mitochondrial uptake of fatty acids for oxidation. Abnormally high rates of fatty acid oxidation contribute to ischemic damage. Inhibition of MCD leads to increased malonyl-CoA and therefore decreases fatty acid oxidation, representing a novel approach for the treatment of ischemic heart injury. The commonly used MCD assay monitors the production of NADH fluorometrically, which is not ideal for library screening due to potential fluorescent interference by certain compounds. Here we report a luminescence assay for MCD activity. This assay is less susceptible to fluorescent interference by compounds. Furthermore, it is 150-fold more sensitive, with a detection limit of 20 nM acetyl-CoA, compared to 3 muM in the fluorescence assay. This assay is also amenable to automation for high-throughput screening and yields excellent assay statistics (Z' > 0.8). In addition, it can be applied to the screening for inhibitors of any other enzymes that generate acetyl-CoA.

A persisting complication in the development of well-resolved two-dimensional PAGE maps of halophilic proteins is their natural incompatibility with isoelectric focusing (IEF). The complete desalting of samples, which is necessary for IEF, tends to aggregate halophilic proteins, often requires relatively large amounts of starting material due to significant loss of sample, and is relatively time-consuming. Here, we describe a method of preparing protein samples from the haloarchaeon Haloferax volcanii that not only desalts the samples thoroughly but also drastically reduces the amount of protein loss associated with previous sample preparation methods and prevents protein aggregation during the removal of salt. This method of sample preparation, which incorporates Trizol (phenol/guanidine isothiocyanate), can easily be extended to analyze halophilic proteins from other organisms.

Cases of malignant fibrous histiocytoma arising from the aorta are rare and have a dismal outlook despite treatment. The longest reported survival period following resection is only 28 months. A patient with malignant fibrous histiocytoma of the descending thoracic aorta was successfully treated with resection and reconstruction with a prosthetic graft. The patient developed metastatic disease eight months postoperatively. With aggressive triple regimen chemotherapy, complete remission has been obtained. The patient is alive and free of disease six years postoperatively.