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In this instalment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With 6 biologics now approved for use in this area comprising 4 different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data. We use 4 variations of a case of severe uncontrolled asthma to develop concepts and considerations introduced in the previous installment ("Workup of Severe Asthma") and discuss pregnancy-related, biomarker-related, comorbidity-related, and corticosteroid dependency-related considerations when choosing a biologic. The related questions of deciding when, why, and how to switch from one biologic to another also are discussed. Overall, we consider that the choice of biologics should be based on the available clinical trial data for the desired efficacy outcomes, the biomarker profile of the patient, safety profiles (eg, when pregnancy is considered), and opportunities to target 2 comorbidities with 1 biologic. Using systemic and airway biomarkers (blood eosinophils and exhaled nitric oxide) and other phenotypic characteristics, we suggest a framework to facilitate therapeutic decision-making. Post hoc studies and new comparative studies are needed urgently to test this framework and to determine whether it allows us to make other clinically useful predictions., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. C. reports nonrestricted research grants from the NIHR Oxford BRC, the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire, AstraZeneca, bioMérieux, and Sanofi-Genyme-Regeneron; support as the Association Pulmonaire du Québec’s Research Chair in Respiratory Medicine and as a clinical research scholar of the Fonds de Recherche du Québec; speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Valeo Pharma; consultancy fees from FirstThought, AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, Access Biotechnology, and Access Industries; and sponsorship to attend or speak at international scientific meetings by or for AstraZeneca and Sanofi-Regeneron. He is an advisory board member and will have stock options for Biometry, Inc., a company that is developing an Feno device (myBiometry). He advised the Institut National d’Excellence en Santé et Services Sociaux for an update of the asthma general practice information booklet for general practitioners. D. J. J. has received advisory board and speaker’s fees from AstraZeneca, Boehringer Ingelheim, Novartis, Teva, GSK, Sanofi/Regeneron, and Chiesi outside of the submitted work. I. D. P. has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine AB, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini, and GSK in the last 5 years and has received payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp and has received payments to support Food and Drug Administration approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva, and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. He is copatent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer, and Insmed. In 2014-2015 he was an expert witness for a patent dispute involving AstraZeneca and Teva. M. E. W. reports grants and personal fees from Novartis, Sanofi, GSK, and Cohero Health; personal fees from Regeneron, Genentech, Sentien, Restorbio, Equillium, and Genzyme; grants, personal fees, and nonfinancial support from Teva; personal fees and nonfinancial support from Boehringer Ingelheim; and grants, personal fees, and nonfinancial support from AstraZeneca., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Uncontrolled asthma is associated with an increased risk of adverse perinatal outcomes. Asthma biologics reduce exacerbation frequency, are steroid sparing, and improve quality of life in people with severe asthma. However, evidence for the use and safety of asthma biologics during pregnancy is scarce, largely because pregnant women were excluded from clinical trials. To help to support clinical teams, we conducted an international modified Delphi study. 141 panellists from 32 countries who were involved in the care of people with severe asthma completed two rounds of online surveys covering key areas surrounding the use of asthma biologics in pregnancy. The results from this international Delphi study emphasise risk versus benefit discussions and shared clinical decision making, with consensus among panellists that asthma biologics can be used during conception and throughout pregnancy, initiated during pregnancy in line with prescribing criteria for non-pregnant people, and initiated or continued during breastfeeding. Collating data through international registries remains essential to inform clinical guidelines., Competing Interests: Declaration of interests JN and MC declare no competing interests. DJJ has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi and research grant funding to his institution from AstraZeneca. GdA has received grants from AstraZeneca, GSK, and Chiesi; consulting fees and payment for educational events from AstraZeneca, GSK, Sanofi, and Chiesi; and support to attend meetings from Chiesi and Sanofi. LGH has received research grant funding to his institution from GSK, AstraZeneca, and Roche/Genentech; lectures fees from AstraZeneca, Novartis, Roche, Genentech, Sanofi, Circassia, GSK, Chiesi, and Teva; and travel funding from AstraZeneca and GSK. LGH has sat on Novartis, Roche/Genentech, GSK, Teva, and Celltrion monitoring and advisory boards. PD has received advisory board fees, speaker fees, and congress travel support from AstraZeneca, GSK, Chiesi, and Sanofi. AB has received research grant funding to his institution from AstraZeneca and lecture fees from Chiesi. HR has received advisory board and speaker fees from GSK, Chiesi, AstraZeneca, Sanofi, and Boehringer Ingelheim; conference support from AstraZeneca; and grant funding to her institution from AstraZeneca and GSK., (Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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.)

Competing Interests: ML reports grants for research or clinical trials, paid to his institution, from AstraZeneca, Deutsche Forschungsgemeinschaft (DFG), and GSK; and consulting fees, travel expenses, or honoraria for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, Stallergenes, and Teva. RB reports grants, paid to his institution, from Boehringer Ingelheim, GSK, Novartis, and Roche; speaker fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva; and payment for advisory board participation from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva. GWC reports research or clinical trial grants, paid to his institution, from Menarini, AstraZeneca, GSK, Sandi, and Genzyme; and personal fees for lectures and advisory board participation from Menarini, AstraZeneca, Chiesi, Faes Farma, Genentech, Guidotti-Malesci, GSK, HAL Allergy, Innovacaremed, Novartis, OM Pharma, Red Maple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes, and Uriach Pharma. CDR reports funding for travel and speaker fees from Novartis, Sanofi, GSK, TEVA, MSD, Almirall, AstraZeneca, Chiesi, Menarini, Stallergens, ALK-Abello, Allergy Therapeutics, HAL Allergy, Immunotek, and Royal. HN reports grants from GSK and personal fees from AstraZeneca, GSK, Kyorin Pharmaceutical, Novartis, and Sanofi; he is a scientific advisor for GSK. GGB reports personal fees for advisory board participation and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi, outside of the submitted work. DJJ has received an investigator-initiated research grant from AstraZeneca and reports fees for advisory board participation and lectures from AstraZeneca, Sanofi, and GSK. In the past 5 years, IDP has received honoraria for speaking at sponsored meetings from AstraZeneca, Aerocrine, Chiesi, Sanofi/Regeneron, Menarini, and GSK; payments for organising educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva; honoraria for advisory panel participation from Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp; and sponsorship to attend international scientific meetings from GSK, AstraZeneca, Teva, and Chiesi. SK reports consulting fees and speaker fees from AstraZeneca, GSK, Chiesi, Sanofi, and Novartis. KM reports consulting fees and speaker frees from AstraZeneca, GSK, and Sanofi; and speaker fees from Chiesi and Novartis. JCV reports research grants from DFG, Land Mecklenburg-Vorpommern, GSK, and MSD; he has given independent lectures for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Lupin, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Regeneron, Revotar, Sandoz-Hexal, Sanofi-Aventis, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila; and participated on advisory boards and provided independent advice for AstraZeneca, Avontec, Bayer, Bencard, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, and UCB/Schwarz-Pharma. CT declares no competing interests.

Background: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists., Methods: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519., Findings: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study., Interpretation: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control., Funding: AstraZeneca., Competing Interests: Declaration of interests DJJ has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi. LGH has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Evelo Biosciences, GSK, Hoffmann-La Roche, Novartis, Sanofi, Teva, and Theravance; he has received grants from Aerocrine, Amgen, AstraZeneca, Genentech/Hoffman-La Roche, GSK, MedImmune, Novartis UK, Roche/Genentech, and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, GSK, and Hoffmann-La Roche, for which his institution received remuneration; he 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, GSK, Hoffmann-La Roche, and Janssen. MH has received consulting fees from AstraZeneca, Chiesi, GSK, Novartis, and Sanofi. BDK has participated in advisory boards or received speaker fees from AstraZeneca, Chiesi, GSK, Novartis, and Teva; has received educational travel bursaries from Boehringer Ingelheim, Chiesi, and Napp Pharmaceuticals; and has received research funding from Itamar Medical. AS was an employee of AstraZeneca at the time of this study and may own stock. LH was an employee of AstraZeneca at the time of this study and may own stock. LO is an employee of Cytel and was on contract to AstraZeneca at the time of this study. DC was an employee of AstraZeneca at the time of this study and may own stock. AM-G was an employee of AstraZeneca at the time of this study and may own stock; has attended advisory boards for AstraZeneca, GSK, Novartis, Regeneron, Sanofi, and Teva; has received speaker fees from AstraZeneca, Novartis, Sanofi, and Teva; has participated in research with AstraZeneca, for which his institution was remunerated; and has had consultancy agreements with AstraZeneca and Sanofi. SK has received grants and personal fees for lectures and advisory boards from AstraZeneca, GSK, Novartis, Sanofi-Genzyme, and Teva., (Copyright © 2024 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: Dupilumab efficacy and safety in children aged 6-11 years with uncontrolled, moderate-to-severe asthma were shown in the VOYAGE study-a 52-week, multinational, multicentre, phase 3 randomised, double-blind, placebo-controlled trial. We aimed to evaluate the long-term safety and efficacy of dupilumab in children with moderate-to-severe asthma who previously participated in the VOYAGE study., Methods: 365 of 408 children with moderate-to-severe asthma from VOYAGE enrolled in EXCURSION, a 52 week, open-label extension study conducted at 70 centres across 17 countries. 240 children continued with add-on dupilumab (dosed according to bodyweight: 100 mg for those weighing ≤30 kg and 200 mg for those weighing more than 30 kg at EXCURSION baseline) once every 2 weeks administered by subcutaneous injection (dupilumab/dupilumab group) and 125 children on placebo during VOYAGE initiated dupilumab (100 or 200 mg, according to bodyweight), once every 2 weeks administered by subcutaneous injection (placebo/dupilumab group). Following a protocol amendment, for a subset of children weighing 30 kg or less, the dose was changed to 300 mg once every 4 weeks. The primary endpoint for the open-label extension study was the number and proportion of patients with any treatment-emergent adverse event (TEAE) during the 52-week study period in the overall population (defined as children aged 6-11 years old with moderate-to-severe asthma who previously completed VOYAGE). Statistical analyses were descriptive. This study is registered with ClinicalTrials.gov (NCT03560466; EXCURSION)., Findings: Children who completed VOYAGE were eligible to enrol in EXCURSION between June 21, 2018 and Aug 18, 2020. During EXCURSION, the safety profile and proportion of patients reporting TEAEs were consistent with those observed during the parent study (VOYAGE). In the overall population, 232 (63·6%) of 365 patients experienced at least one TEAE (dupilumab/dupilumab: 147 [61·3%]; placebo/dupilumab: 85 [68·0%]). The most frequently reported TEAEs were nasopharyngitis, pharyngitis, and upper respiratory tract infections., Interpretation: In EXCURSION, long-term treatment with dupilumab was well tolerated with an acceptable safety profile., Funding: Sanofi and Regeneron Pharmaceuticals., Competing Interests: Declaration of interests LBB has received speaker fees from AstraZeneca, GSK, Regeneron Pharmaceuticals, and Sanofi; is a member of the data and safety monitoring board for DBV Technologies and Cystic Fibrosis Foundation; and has received research support from the US National Institutes of Health, Sanofi, and Vectura. JFM is a consultant for AstraZeneca and Sanofi; has received speaker fees from GSK, Menarini, Novartis, and Uriach; and reports research grants from Novartis. CHK reports honoraria for presentations; and was a principal investigator of the dupilumab asthma phase 2b (NCT01854047) and phase 3 (NCT02414854) studies for Regeneron Pharmaceuticals and Sanofi. AGF is a member of the advisory boards for Abbott, Danone, DBV Technologies, HiPP Organic, Novartis, and Stallergenes Greer; and reports currently sponsoring research from Danone, Ferrero, HiPP Organic, and Sanofi. RG reports research grants from ALK, AstraZeneca, BioCryst, DBV Technologies, Genentech, Greencross, Novartis, Regeneron Pharmaceuticals, Sanofi, and Shire; is a consultant for ALK, AstraZeneca, Pfizer, and Sanofi; and has received speaker fees from Novartis. IdM reports personal fees for lectures and boards from GSK and Sanofi; conference registration and travel fees from Novartis; and conference registration fees from Aldo-Unión. TWG reports grants from NIH and GSK; grants and consulting fees from Sanofi, Regeneron Pharmaceuticals, Amgen, and AstraZeneca; consulting fees from Novartis, Genentech, Polarean, OM Pharma, AiCME, and Best Pharmaceuticals for Children Act; and royalties from UpToDate. DJJ is a consultant for AstraZeneca, Avillion, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Vifor Pharma; and is a member of the data and safety monitoring board for Pfizer. HWS, NL, EL, LPM, KT, MH, RMA, and LBR are employees of Sanofi, and might hold stock or stock options in the company. BA, JM, FAK, and DJL are employees and shareholders of Regeneron Pharmaceuticals., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1), and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterised by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis and produced greater amounts of IL-1α/β, IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Spatial localizing of skeletal proteins in biogenic minerals remains a challenge in biomineralization research. To address this goal, we developed a novel in situ mapping technique based on molecular recognition measurements via atomic force microscopy (AFM), which requires three steps: (1) the development and purification of a polyclonal antibody elicited against the target protein, (2) its covalent coupling to a silicon nitride AFM tip ('functionalization'), and (3) scanning of an appropriately prepared biomineral surface. We applied this approach to a soluble shell protein - accripin11 - recently identified as a major component of the calcitic prisms of the fan mussel Pinna nobilis [1]. Multiple tests reveal that accripin11 is evenly distributed at the surface of the prisms and also present in the organic sheaths surrounding the calcitic prisms, indicating that this protein is both intra- and inter-crystalline. We observed that the adhesion force in transverse sections is about twice higher than in longitudinal sections, suggesting that accripin11 may exhibit preferred orientation in the biomineral. To our knowledge, this is the first time that a protein is localized by molecular recognition atomic force microscopy with antibody-functionalized tips in a biogenic mineral. The 'pros' and 'cons' of this methodology are discussed in comparison with more 'classical' approaches like immunogold. This technique, which leaves the surface to analyze clean, might prove useful for clinical tests on non-pathological (bone, teeth) or pathological (kidney stone) biomineralizations. Studies using implants with protein-doped calcium phosphate coating can also benefit from this technology. STATEMENT OF SIGNIFICANCE: Our paper deals with an unconventional technical approach for localizing proteins that are occluded in biominerals. This technique relies on the use of molecular recognition atomic force microscopy with antibody-functionalized tips. Although such approach has been employed in other system, this is the very first time that it is developed for biominerals. In comparison to more classical approaches (such as immunogold), AFM microscopy with antibody-functionalized tips allows higher magnification and keeps the scanned surface clean for other biophysical characterizations. Our method has a general scope as it can be applied in human health, for non-pathological (bone, teeth) and pathological (kidney stone) biomineralizations as well as for bone implants coated with protein-doped calcium phosphate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods., Methods: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete., Findings: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA., Interpretation: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden., Funding: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline., Competing Interests: Declaration of interests DJJ reports grants from AstraZeneca and personal fees from Sanofi Regeneron, AstraZeneca, and GlaxoSmithKline. BDK report personal fees from AstraZeneca and GlaxoSmithKline. GG reports patents to quantify adherence and to predict exacerbations. CH reports fees from Alphabet, granted as part of employment by Google. DMM reports personal fees from AstraZeneca, Teva, GlaxoSmithKline, Sanofi, and Novartis. RBR reports a patent for the use of acoustics to assess inhaler adherence. JFMvB reports institutional grants from Aardex, AstraZeneca, Chiesi, European Commission COST Action 19132 ENABLE, Lung Alliance Netherlands, Novartis, Trudell Medical and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Teva, Trudell Medical, and Vertex. LGH was academic lead for the UK MRC Consortium for Stratified Medicine in Severe Asthma—Industrial Pharma partners Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche–Genentech, GlaxoSmithKline, and Boehringer Ingelheim; grants or contracts from GlaxoSmithKline, Schering Plough, Synairgen, Novartis and Roche–Genentech MedImmune, Novartis UK, Roche–Genentech and GlaxoSmithKline; and lectures supported by AstraZeneca, Novartis, Roche–Genentech, Sanofi, Circassia, GlaxoSmithKline, Chiesi, and Teva. RWC reports institutional grants from GlaxoSmithKline, Aerogen, and Enterprise Ireland; personal fees from AstraZeneca, Teva, GlaxoSmithKline, PMD solutions, and Novartis; and a patent for the use of acoustics to assess inhaler adherence, to quantify adherence and to predict exacerbations. EM, CM, MCM, BC, IS, VB, PJK, MB, IC, JF, JH, MK, RC, LL, JW, SP, TAM, and AMNK declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone., Methods: This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588., Findings: Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab., Interpretation: Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations., Funding: US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline., Competing Interests: Declaration of interests All authors, with the exceptions of PMB, LG, and PJG, report grants from the US National Institutes of Health (NIH)–NIAID during the study. CMV, AC, SW, LG, PJG, and PMB have nothing to disclose outside of the submitted work. LBB reports personal fees from GlaxoSmithKline, Genentech–Novartis, Teva, Boehringer Ingelheim, AstraZeneca, WebMD–Medscape, Merck, DBV Technologies, Circassia, Sanofi–Regeneron, and Vectura, all outside the submitted work. GTO reports personal fees from AstraZeneca and grant funding from Janssen Pharmaceuticals, outside the submitted work. CMD reports personal fees from Horizon Therapeutics and Enzyvant Therapeutics, outside the submitted work. MCA reports personal fees from Sanofi–Regeneron, outside the submitted work. WWB reports personal fees from Boston Scientific, Novartis, GlaxoSmithKline, Genentech, Sanofi–Genzyme, AstraZeneca, Teva, Regeneron, and Elsevier, outside the submitted work. MAG reports an honorarium for and support for travel to the 2017 American Academy of Allergy, Asthma & Immunology meeting during this study and monetary compensation from the American Academy of Pediatrics for her work teaching the biannual Pediatrics board review course: PREP The Course. GKKH reports grants from Adare during the study. DJJ reports personal fees from Novartis, Pfizer, Regeneron, AstraZeneca, Sanofi, and Vifor Pharma; grants and personal fees from GlaxoSmithKline; and grants from NIH–US National Heart, Lung, and Blood Institute (NHLBI), all outside the submitted work. MK reports personal fees from Regeneron, outside the submitted work. RSG reports government employment from the Center for Biologics Evaluation and Research and personal fees from Consulting Massachusetts Medical Society, outside the submitted work. AHL reports personal fees from Phadia ThermoFisher as consulting honoraria; grants and non-financial support from ResMed–Propeller Health; non-financial support from Revenio; grants and personal fees from Avillion; and personal fees from Labcorp, all outside the submitted work. SJT reports grants from NIH–Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH–NHLBI, and EJF Philanthropies and personal fees from Uptodate, all outside the submitted work. JAP reports provision of study drug for another asthma research study from GlaxoSmithKline and Boehringer Ingelheim and provision of study drug for another asthma research study and for food allergy research studies from Genentech–Novartis, all outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of interests ML has received consulting fees or honoraria, or both for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, and TEVA; and grants for research or clinical trials, or both from Deutsche Forschungsgemeinschaft, AstraZeneca, and GSK. GGB has received honoraria for lectures from AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Chiesi, and Sanofi. GWC has received consulting fees or honoraria, or both for lectures from AstraZeneca, Chiesi, Novartis, Sanofi, Menarini, Stallergenes Greer, GSK, and HAL Allergy. DJJ has received consulting fees or honoraria or both for lectures from AstraZeneca, GSK, and Sanofi; and grants for research from AstraZeneca. PN has received personal fees or grants, or both from AstraZeneca, TEVA, Sanofi, Equillium, Foresee, Arrowhead Pharma, Cyclomedica, and GSK. RB has received consulting fees or honoraria, or both for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, HAL Allergy, Leti, Novartis, Roche, Sanofi, and TEVA; and grants for research or clinical trials, or both from Boehringer Ingelheim, GSK, Novartis, and Roche. JCV has received consulting fees or honoraria, or both for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Genzyme, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed (Altana), Pfizer, Regeneron, Revotar, Sanofi, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, and Cadila; and received grants for research or clinical trials, or both from Deutsche Forschungsgemeinschaft, GSK, and MSD.

Background: No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation., Methods: This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1-5 mg every 1-4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307., Findings: Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86-66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62-84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2-3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations., Interpretation: Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm., Funding: AstraZeneca., Competing Interests: Declaration of interests AM-G has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, and Teva, and is a steering committee member for the AstraZeneca PONENTE study; has received speakers’ fees from AstraZeneca, Novartis, Roche, and Teva; has participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva; and has made consultancy agreements with AstraZeneca, Sanofi, and Vectura. MG is a steering committee member for the AstraZeneca PONENTE study and has received speakers’ fees from AstraZeneca, Novartis, and Teva. LGH is a steering committee member for the AstraZeneca PONENTE study and has received research funding, consulting fees, and speakers’ fees from AstraZeneca. LGH has also received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; lecture fees from Novartis, Hoffmann-La Roche and Genentech, Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia; and institutional grant funding from Medimmune, Novartis, Hoffman-La Roche and Genentech, and GlaxoSmithKline. He is academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with Amgen, Hoffman-La Roche and Genentech, AstraZeneca, Medimmune, GlaxoSmithKline, Aerocrine, and Vitalograph. JC has received grants from AstraZeneca in addition to grants and personal fees from Genentech, Novartis, Regeneron Pharmaceuticals, and Sanofi. EHB reports non-financial support, grants, and personal fees from GlaxoSmithKline; grants and personal fees from AstraZeneca; grants from Roche, personal fees from Chiesi and Sanofi and Regeneron; and grants and personal fees from Teva. EHB is also a steering committee member for the AstraZeneca PONENTE study, Novartis, Sterna, and Teva. JM has consulted for AstraZeneca, Sanofi, and Teva; was a speaker for GlaxoSmithKline, Menarini, Novartis, and Uriach; and has received research grants from Novartis. TH reports grants from AstraZeneca and the National Institute for Health Research, UK; and personal fees and non-financial support from AstraZeneca. TH is also a steering committee member for the AstraZeneca PONENTE study, GlaxoSmithKline, Vectura, Boehringer Ingelheim, Chiesi, and Synairgen. During the study's completion, he also became an employee of AstraZeneca. DJJ has received speakers’ honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva, and honoraria for attending advisory panels with AstraZeneca, GlaxoSmithKline, Novartis, Chiesi, Sanofi and Regeneron, and Teva. DP has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, and Thermo Fisher Scientific; consultancy agreements with Amgen and AstraZeneca; and is a steering committee member for the AstraZeneca PONENTE study, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance. DP has also received grants and unrestricted funding for investigator-initiated studies (done through the Observational and Pragmatic Research Institute) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, and the UK National Health Service; payment for lectures or speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel, accommodation, or meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, and Thermo Fisher Scientific; and funding for patient enrolment or completion of research from Novartis; stock or stock options from AKL Research and Development. He owns 74% of the social enterprise Optimum Patient Care (Australia and UK) and 74% of Observational and Pragmatic Research Institute (Singapore); and 5% shareholding in Timestamp. He is a peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme and Health Technology Assessment (both National Institute of Health Research programmes); and was an expert witness for GlaxoSmithKline. NL has received consulting fees from AstraZeneca and is a steering committee member for the AstraZeneca PONENTE study and Teva; has participated in advisory boards for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, and Sanofi; and has received grants for clinical trials from AstraZeneca, Genentech, GlaxoSmithKline, and Sanofi. JK, AdG-M, KP, UJM, and EGG are full time employees of and stockholders in AstraZeneca. AB is a contract employee of AstraZeneca., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A 56-year-old man has difficult-to-control asthma and a history of four exacerbations in the prior 12 months despite high-dose inhaled corticosteroids (ICS) and additional controller therapies. Is he suitable for more advanced therapeutic options? To address this query, we herein review the clinical assessment of a patient with suspected severe asthma and discuss factors contributing to poor asthma control and how biomarkers assist in disease investigation and stratification. The key components of our multidisciplinary approach are to confirm an asthma diagnosis and adherence to treatment, to assess any contributing comorbidities or confounding factors, and to stratify what type of asthma the patient has. The combination of spirometry and repeated measures of key biomarkers of type 2 airway inflammation-the blood eosinophil count and fractional exhaled nitric oxide-identifies whether poor disease control is driven by uncontrolled, ICS-resistant type 2 airway inflammation or ongoing airflow obstruction. A failure to elicit evidence of either suggests an alternative driver for the patient's symptoms, including chronic airway infection and non-asthma causes. Each phenotype represents a treatable trait that requires a specific targeted approach. Critically, steroids can cause harm, and their use should be guided by objective evidence of inflammation rather than symptoms alone. To conclude, after assessment of treatment adherence and exclusion of relevant comorbidities, the patient was found to have severe asthma with ICS-resistant type 2 airway inflammation. We will consider additional treatment options at our next appointment in part 2/2 of this How I Do It series., (Copyright © 2021. Published by Elsevier Inc.)

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/aims: When conducting clinical trials comparing over-the-counter (OTC) medications, the wide availability of these treatments are a potential challenge to maintaining study integrity. We seek to describe adherence to a study protocol involving widely available OTC medications., Methods: To prospectively evaluate associations between acetaminophen use and asthma in 300 children aged 1-5 years, we conducted a double blind, randomized, controlled trial where parents administered blinded forms of either acetaminophen or ibuprofen as needed to their children over a 48 week period. Written and verbal instructions encouraged the exclusive use of the blinded study medication and discouraged OTC use. Adherence was determined by evaluating the frequency of use of per-protocol blinded study medication compared to off-protocol use of OTC medications., Results: 4195 doses of acetaminophen or ibuprofen were received by children during the study which included 3664 doses (87.3%) of blinded study medication adhering to the protocol and 531 doses (12.7%) of OTC products deviating from the protocol with better adherence among those randomized to ibuprofen as compared to acetaminophen (89.5% vs. 85.5% of doses, p < 0.01). Individually, 227 participants (75.7%) remained fully adherent by not receiving any OTC medications. Pre-study preference for either acetaminophen or ibuprofen by the participants' families was not associated with differential rates of adherence to the blinded medication., Conclusion: This parallel study demonstrated greater than 85% of acetaminophen or ibuprofen doses were blinded study medications adhering to the protocol while less than 15% were OTC deviations from the protocol. This successfully implemented study design provides a template to comparatively evaluate these and other OTC medications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation rates and maintenance oral corticosteroids (mOCSs)., Research Question: What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy?, Study Design and Methods: We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma., Results: One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 [56.9%]), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV 1 . Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients., Interpretation: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Asthma is a common condition that causes episodic expiratory airflow limitation due to bronchial smooth muscle constriction and airways inflammation resulting in increased respiratory symptoms and acute asthma exacerbations. Patients with severe asthma have relied on either recurrent courses or daily use of oral corticosteroids (OCS) to control their disease. However a high level of OCS exposure is associated with significant morbidity and mortality. In recent years the elucidation of the role of T2 inflammation underpinning asthma pathogenesis has led to the development of monoclonal antibody (mAb) therapies targeting this pathway. Established therapies now include omalizumab targeting IgE, mepolizumab and reslizumab targeting IL-5, benralizumab targeting the IL-5R and dupilumab targeting IL-4R. For many patients these therapies have been transformative and their use has additionally advanced our understanding of the immunology that underpins the disease. This article reviews the biologic therapies currently available for the treatment of severe asthma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Mepolizumab was the first licensed anti-IL5 monoclonal antibody for severe eosinophilic asthma (SEA). To date there are few data to confirm its efficacy in the real-world setting or assessment of baseline characteristics associated with response., Research Question: How do patients with severe eosinophilic asthma respond to mepolizumab in the real world setting and which characteristics are associated with a super-response to this therapy?, Study Design and Methods: We conducted a retrospective review of all patients who received at least 16 weeks of treatment with mepolizumab (100 mg subcutaneously) for SEA at our regional asthma center in the United Kingdom. Clinical data were collected at each 4-week visit. At 16, 24, and 52 weeks, patients were classified as "responders" or "nonresponders." A response was defined as ≥50% reduction in exacerbations; for patients whose condition requires maintenance oral corticosteroids (mOCS), a response was defined as ≥50% reduction in prednisolone dose. Super responders were defined as exacerbation-free and off mOCS at one year., Results: Ninety-nine patients were included in the analysis. Asthma exacerbations decreased from a baseline of 4.04 ± 2.57 to 1.86 ± 2.17 per year at one year (54% reduction; P < .001). Sixty-eight patients were receiving mOCS at the time of commencing mepolizumab. By one year, the daily median dose fell from 10 mg (interquartile range, 10 to 15) to 0 mg (interquartile range, 0 to 10; P < .001). Fifty-seven percent of them were able to discontinue mOCS; 72.7% (95% CI, 63.0 to 80.7) of the patients were classified as responders, and 28.3% (95% CI, 20.2 to 38.0) of the patients were classified as super responders. Baseline characteristics associated with responder and super responder status included the presence of nasal polyposis (P = .012), lower baseline Asthma Control Questionnaire 6 (P = .006), a lower BMI (P = .014), and, in those patients receiving mOCS, a significantly lower prednisolone dose at baseline (P = .005). At 16 weeks, the one-year responder status was correctly identified in 80.8% patients; by 24 weeks, this status rose to 92.9%., Interpretation: In a real-world SEA cohort, treatment with mepolizumab reduced exacerbation frequency and mOCS requirements. Nasal polyposis, a lower BMI, and a lower maintenance prednisolone requirement at baseline were associated with better outcomes. Twelve-month response was identifiable in >90% of patients by week 24., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus., Methods: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA)., Findings: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480&#95;G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131&#95;A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15-1·44], p<0·0001)., Interpretation: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus., Funding: National Institutes of Health, Office of the Director., (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.)

Biomineralization processes in bivalve molluscs are still poorly understood. Here we provide an analysis of specifically expressed sequences from a mantle transcriptome of the blue mussel, Mytilus edulis. We then developed a novel, integrative shell injury assay to test, whether biomineralization candidate genes highly expressed in marginal and pallial mantle could be induced in central mantle tissue underlying the damaged shell areas. This experimental approach makes it possible to identify gene products that control the chemical micro-environment during calcification as well as organic matrix components. This is unlike existing methodological approaches that work retroactively to characterize calcification relevant molecules and are just able to examine organic matrix components that are present in completed shells. In our assay an orthogonal array of nine 1mm holes was drilled into the left valve, and mussels were suspended in net cages for 20, 29 and 36days to regenerate. Structural observations using stereo-microscopy, SEM and Raman spectroscopy revealed organic sheet synthesis (day 20) as the first step of shell-repair followed by the deposition of calcite crystals (days 20 and 29) and aragonite tablets (day 36). The regeneration period was characterized by time-dependent shifts in gene expression in left central mantle tissue underlying the injured shell, (i) increased expression of two tyrosinase isoforms (TYR3: 29-fold and TYR6: 5-fold) at day 20 with a decline thereafter, (ii) an increase in expression of a gene encoding a nacrein-like protein (max. 100-fold) on day 29. The expression of an acidic Asp-Ser-rich protein was enhanced during the entire regeneration process. This proof-of-principle study demonstrates that genes that are specifically expressed in pallial and marginal mantle tissue can be induced (4 out of 10 genes) in central mantle following experimental injury of the overlying shell. Our findings suggest that regeneration assays can be used systematically to better characterize gene products that are essential for distinct phases of the shell formation process, particularly those that are not incorporated into the organic shell matrix., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

Since the discovery of interleukin 33 as the adopted ligand for the then orphan ST2 receptor, many studies have implicated this cytokine in the pathogenesis of respiratory allergy and asthma. Although some extracellular functions of interleukin 33 have been well defined, many aspects of the regulation and secretion of this cytokine need clarification. Interleukin 33 has been identified as a trigger of T-helper-type-2 cell differentiation, which by interacting with both the innate and the adaptive immune systems, can drive allergy and asthma pathogenesis. However, induction of interleukin 33 by both environmental and endogenous triggers implies a possible role during infection and tissue damage. Further understanding of the biology of interleukin 33 will clarify its possible role in future therapeutic interventions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Data from a prospective multisite cohort study were used to examine the effect of HIV exposure, untreated HIV infection, and single-dose nevirapine on infant growth velocity. The 2009 WHO growth velocity standards constitute a new tool for this type of investigation and are in need of functional validation. In period 1 (3-24 wk), 65 HIV-infected, 502 HIV-exposed uninfected (HEU), and 216 HIV-unexposed infants were included. In period 2 (25-36 wk), 31 infants moved from the HEU group to the HIV-infected group. We compared weight velocity Z-scores (WVZ) and length velocity Z-scores (LVZ) by HIV group and assessed their independent influences. In period 1, mean WVZ (95% CI) was significantly (P < 0.001) lower in infected [-0.87 (-1.77, 0.04)] than HEU [0.81 (0.67, 0.94)] and unexposed [0.55 (0.33, 0.78)] infants. LVZ showed similar associations. In both periods, sick infants and those exposed to higher maternal viral loads had lower WVZ. Higher mean LVZ was associated with low birth weight. Infants that had received nevirapine had higher LVZ. In conclusion, HIV infection and not exposure was associated with low WVZ and LVZ in period 1. Eliminating infant HIV infection is a critical component in averting HIV-related poor growth patterns in infants in the first 6 mo of life.

Background: Presently, there is insufficient information to compare the value of daily diaries vs retrospective questionnaires for assessing symptoms in relationship to asthma control in clinical trials. Daily symptom diaries are often burdensome to gather, incomplete, susceptible to fabrication, and of questionable reliability. There is also concern that retrospective symptom questionnaires may be subject to poor recall and may be insensitive., Methods: To compare these two methods of assessing symptoms reporting, we analyzed data collected during the Best Add-on Therapy Giving Effective Responses (BADGER) trial. During the trial, asthma control in 182 children aged 6 to 17 years was assessed in two ways: (1) by asthma control days (ACDs) determined by manually recorded daily diary symptom and rescue medication use scores and (2) by monthly retrospective report of symptoms embedded within the age-appropriate version of the Asthma Control Test (ACT). Correlations between ACDs and ACT scores were analyzed, and the sensitivity of each method for measuring asthma control and determining the differential response among the three BADGER treatments was evaluated., Results: Although validated using a 4-week recall period, ACT correlated better with daily diary information from the last 2 weeks of the 4-week recall (r = 0.46) than from the first 2 weeks (r = 0.34). In addition, clinically significant differential treatment responses were detected using ACDs but not ACT scores ., Conclusions: The results of this study indicate that daily diaries used to determine ACDs can be a more sensitive tool than ACT for assessing differential treatment responses with respect to asthma control.

The field of mother to child transmission of human-immunodeficiency virus is rapidly evolving. In the United States, prevention focuses on implementation of universal human-immunodeficiency virus testing to assure compliance with recommended treatment regimens and infant-feeding strategies. In most cases, this is the avoidance of all breastfeeding. In developing countries, avoidance of breastfeeding places infants at higher risk of morbidity and mortality. Current World Health Organization recommendations require individualized counseling to determine the best feeding method for each woman.

Objective: Very high-frequency ultrasound (VHFU; >35 megahertz [MHz]) allows imaging of anterior segment structures of the eye with a resolution of less than 40 microm. The low focal ratio of VHFU transducers, however, results in a depth of field (DOF) of less than 1 mm. The aim was to develop a high-frequency annular array transducer for ocular imaging with improved DOF, sensitivity, and resolution compared with conventional transducers., Design: Experimental study., Participants: Cadaver eyes, ex vivo cow eyes, in vivo rabbit eyes., Methods: A spherically curved annular array ultrasound transducer was fabricated. The array consisted of 5 concentric rings of equal area, had an overall aperture of 6 mm, and a geometric focus of 12 mm. The nominal center frequency of all array elements was 40 MHz. An experimental system was designed in which a single array element was pulsed and echo data were recorded from all elements. By sequentially pulsing each element, echo data were acquired for all 25 transmit-and-receive annuli combinations. The echo data then were focused synthetically and composite images were produced. Transducer operation was tested by scanning a test object consisting of a series of 25-microm diameter wires spaced at increasing range from the transducer. Imaging capabilities of the annular array were demonstrated in ex vivo bovine, in vivo rabbit, and human cadaver eyes., Main Outcome Measures: Depth of field, resolution, and sensitivity., Results: The wire scans verified the operation of the array and demonstrated a 6.0-mm DOF, compared with the 1.0-mm DOF of a conventional single-element transducer of comparable frequency, aperture, and focal length. B-mode images of ex vivo bovine, in vivo rabbit, and cadaver eyes showed that although the single-element transducer had high sensitivity and resolution within 1 to 2 mm of its focus, the array with synthetic focusing maintained this quality over a 6-mm DOF., Conclusions: An annular array for high-resolution ocular imaging has been demonstrated. This technology offers improved DOF, sensitivity, and lateral resolution compared with single-element fixed focus transducers currently used for VHFU imaging of the eye.

Risk assessment of the overweight and obese patient is an important and necessary first step in the treatment process. Risk classification begins with determination of body mass index (BMI), waist circumference for those with a BMI of 35 or less, and presence of comorbid conditions. With the exception of measuring a fasting blood glucose and lipid panel on all patients, other diagnostic laboratory tests are selected based on the patient's risk factor status. Understanding the reasons leading to and sustaining the patient's overweight and obesity is the next major step and is paramount to designing individualized and targeted treatment. This information is ascertained by having the patient graph his or her weight pattern with associated life events and by assessing detailed dietary and physical activity histories. Calculating estimated energy balance has both benefits and limitations in clinical practice. Pediatric and geriatric patients represent special populations that require additional focus. Improvement in the assessment process will likely be achieved by using a team approach along with future developments in practical measurement of body composition and energy expenditure.

Cells were isolated from human term placentae by trypsinisation of fragments of chorionic villi and fractionation of cells on a Percoll density gradient into six layers. A panel of 10 monoclonal antibodies to antigens on or in trophoblast cells (placental alkaline phosphatase (PLAP), cytokeratin-7, beta-human chorionic gonadotrophin (beta-hCG), human leucocyte antigen-G (HLA-G)), leucocytes (CD45), monocytes, macrophages, dendritic cells, B cells (HLA class II), mesenchyme cells (vimentin), fibroblasts (fibroblast antigen) and nucleated cells excluding villous trophoblast (HLA class I, CD9) was used to characterise the cells by flow cytometry. For staining intracellular antigens (cytokeratin, vimentin, beta-hCG) the cells were first fixed and permeabilised. The upper two layers from the gradient (density 1.013-1.039 g/ml) contained predominantly PLAP-positive cells or fragments, probably derived from the syncytiotrophoblast. Cytokeratin-positive cells accumulated mainly in the layer of density 1.039-1.052 g/ml and comprised the majority of the cell types identified in this fraction. Few or no cells reactive with antibodies to beta-hCG or HLA-G were identified in any layer. Non-trophoblast cells were heavier, being present mainly at densities 1.052-1.079 g/ml (CD45, HLA class I, vimentin) and 1.066-1.092 g/ml (fibroblast). Fewer than 10% of cells in any layer were HLA class II- or CD9-positive. Further purification of trophoblast cells was by negative immunomagnetic separation with removal of CD45-positive cells and HLA class II-positive cells to less than 1%. On culture of the cells from each layer, those of density 1.039-1.066 g/ml exhibited characteristics of cytotrophoblast cells; they secreted high levels of human chorionic gonadotrophin and formed adherent multinucleate cells. This procedure enabled the selection and enrichment of cytotrophoblast cells and/or syncytiotrophoblast fragments that are suitable for cellular and molecular studies.

Purpose: Conventional ophthalmic ultrasonography is performed using 10-megahertz (MHz) transducers. Our aim was to explore the use of higher frequency ultrasound to provide improved resolution of the posterior pole., Design: Prospective case series., Participants: One normal subject and 5 subjects with pathologies affecting the posterior coats, including nevii, small melanomas, and macular hole., Methods: We modeled the frequency-dependent attenuation of ultrasound across the eye to develop an understanding of the range of frequencies that might be practically applied for imaging of the posterior pole. We compared images of the posterior coats made at 10, 15, and 20 MHz, and 20-MHz ultrasound images of pathologies with 10-MHz ultrasound and optical coherence tomography (OCT)., Main Outcome Measures: Ability to resolve normal and pathologic structures affecting posterior coats of the eye., Results: Modeling showed that frequencies of 20 to 25 MHz might be used for posterior pole imaging. Twenty-megahertz images allowed differentiation of the retina, choroid, and sclera. In addition, at 20 MHz the retina showed banding patterns suggesting an internal structure comparable in many respects to that seen in OCT and histology. Images of ocular pathology provided much improved detail relative to 10-MHz images and deeper penetration than OCT., Conclusions: Twenty-megahertz ultrasound can be practically employed for imaging of the posterior pole of the eye, providing a 2-fold improvement in resolution relative to conventional 10-MHz instruments. Although not providing the resolution of OCT, ultrasound can be used in the presence of optical opacities and allows evaluation of deeper tissue structures.

Purpose: Primary malignant melanoma of the choroid and ciliary body has traditionally been treated without histologic staging, using purely clinical indicators. The presence of extravascular matrix patterns (EMP) in histologic sections of uveal melanoma has been shown to be an independent indicator of metastatic risk. These patterns are of a dimension and physical composition that are likely to be detected with ultrasound backscatter analysis. Our aim was to determine whether ultrasound parameter imaging could detect the presence of EMP at a diagnostically significant level for treatment staging and for planning investigational studies of therapeutic modalities., Design: Prospective, masked ultrasound-pathologic correlative study., Participants: One hundred seventeen patients diagnosed with previously untreated choroidal melanoma were scanned within 2 weeks before enucleation., Methods: Tumors were evaluated histologically and divided into high-risk and low-risk groups on the basis of the presence of 2% or more histologic cross-sectional area composed of EMP patterns. Digital ultrasound data were processed to generate parameter images representing the size and concentration of ultrasound scatterers. Histologic and ultrasound images and data were correlated, and linear and nonlinear statistical methods were used to create multivariate models for noninvasive differentiation of high-risk and low-risk tumors., Main Outcome Measures: Presence or absence of high-risk EMP and associated ultrasound parameter classification models., Results: Of the 117 tumors, 69 were classified as low risk, and 48 were classified as high-risk with histologic analysis. A classification that used ultrasound parameter image features with linear discriminant analysis could correctly identify 79.5% of cases retrospectively and 75.2% of cases by use of cross-validation, an estimate of prospective classification ability. By use of a more powerful classification technique (support vector machine), 93.1% of cases were correctly classified retrospectively. With a cross-validation procedure, 80.10% of cases were correctly classified., Conclusions: Ultrasound can be used noninvasively to classify tumors into high-risk and low-risk groups by detecting the presence of EMP patterns. By the use of previous studies that compared the histologic presence of EMP patterns with patient survival, estimates of hazard rates associated with ultrasound risk groups can be made. The noninvasive ultrasound classification is potentially useful as a prognostic variable and as a tool for stratification of patient populations for tumor treatment evaluation.

Objective: This study compared the effects of early admission in labor and perinatal care provider on delivery method. Higher spontaneous vaginal delivery rates for certified nurse midwives as compared with physicians have been reported in observational studies and randomized clinical trials. Certified nurse midwives, with their more expectant approach to labor management, would be expected to admit women later in labor than obstetricians., Methods: Prospective cohort study of 2,196 low-risk pregnancies, with singleton, vertex infants admitted in spontaneous labor. Independent and joint effects of perinatal care provider and cervical dilation at admission on delivery method were evaluated. Confounding was addressed using restriction and multiple regression., Results: Fewer (23.4%) women in collaborative care were admitted in early labor (< 4 cm cervical dilation) than women managed by obstetricians (95% CI = -27.6 to -19.2). Obstetrician care had 9% to 30% fewer spontaneous vaginal deliveries. Women admitted early in labor also had 6% to 34% fewer spontaneous vaginal deliveries. Evaluation of joint effects suggested that interaction between obstetrician provider and earlier admission increased the risk of operative delivery., Conclusion: Later admission in labor (at 4 cm or greater cervical dilation) and management of perinatal care by certified nurse midwives in collaboration with obstetricians increased the rate of spontaneous vaginal delivery in low-risk women.

Women in developed countries who are human immunodeficiency virus (HIV)-positive generally feed their infants formula to avoid virus transmission via breastfeeding. However, for most of the world's women who are HIV positive, the choice of infant feeding method is not so clear. Poor socioeconomic and living conditions place infants on breast milk substitutes at higher risk of non-HIV infectious diseases as compared with breastfed infants. Mothers in these settings who are HIV positive must weigh the risks and benefits of breastfeeding to choose the best infant feeding option.

Current literature on the safety and efficacy of freestanding birth centers suggests that these centers are safe and have reduced costs for delivery of low-risk women compared with hospitals. Despite these findings, birth centers continue to arouse controversy and remain limited in number. Potential inequality of birth center and hospital subjects as to perinatal risk is cited as the major methodologic flaw in the current research on birth centers. Defining an appropriate comparison group is arguably the most important methodologic issue encountered in these investigations. Defining women as "low risk" according to standard perinatal risk tools is not an adequate measure of comparability, as these criteria are generally not equivalent to those defining birth center eligibility. The key is to identify groups for comparison that, at baseline, would be expected to have similar outcomes. To address this concern, a tool based on the American College of Nurse-Midwives' Nurse-Midwifery Clinical Data Set was developed to identify valid comparison subjects for birth center research. This tool focuses on birth center eligibility as opposed to traditionally defined risk. This article reviews the issues of population comparability in birth center research and presents the results of a validation study using this newly developed tool.

The BirthPlace program in San Diego, California, is an example of a successfully "mainstreamed" alternative maternity care program. It was developed to address an access to prenatal care problem in the county, and it has successfully integrated four systems of care: 1) a private practice of nurse-midwives and obstetricians, 2) the public community clinic system, 3) the tertiary university hospital, and 4) a freestanding birth center. It provides a model of care that, if replicated, could be an answer for ensuring universal access to maternity care in the United States. The BirthPlace program primarily serves a public-funded, Hispanic population, with certified nurse-midwives as the primary providers. The program's greatest challenge has been to maintain a personalized, family-centered focus, which has been the hallmark of freestanding birth centers to date, in the face of large numbers of clients and low reimbursement for care. The program has addressed the challenge of increasing access and cost-effectiveness while ensuring family-centered care through decentralized clinic management, informed consent, culturally sensitive care, and appropriate use of technology. However, in the face of an ever-changing health care system, balancing these issues will remain a constant challenge as we reshape our maternity care services.