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Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.Objective: To identify common genetic variants affecting susceptibility to severe asthma.Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study. [ABSTRACT FROM AUTHOR]

Background: Functionally relevant polymorphisms of the beta2-adrenoceptor gene (ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the ADRB2 gene.Methods: The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses.Findings: Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36.3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44.6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16-Gln27 haplotype at these loci, 19.3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11.9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1.5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies.Interpretation: ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population. [ABSTRACT FROM AUTHOR]

Spirometry is underutilised and can be difficult to access. This study assessed the accuracy and feasibility of home spirometry compared to gold standard. Findings suggest home spirometry is accurate and feasible across many respiratory disease groups. https://bit.ly/42TLoYd., Competing Interests: Conflict of interest: C.L. Wilson was awarded the Margaret Lowman-Hall honours scholarship stipend to undertake this project. She has no other conflicts of interest to declare. Conflict of interest: C. McLaughlin is the recipient of the Bendat Family Foundation Clinical Researcher Fellowship. She has no other conflicts of interest to declare. Conflict of interest: A. Cairncross has no conflict of interest to declare. Conflict of interest: E. Gabbay has no conflict of interest to declare. Conflict of interest: P.B. Noble has no conflict of interest to declare. Conflict of interest: J.D. Blakey was awarded an investigator-initiated grant from Novartis. He has no other conflict of interest to declare. Conflict of interest: A.L. Crawford was awarded the Charlies Foundation for Research 2022/23 Bright Idea Grant Program. She has no other conflict of interest to declare., (Copyright ©The authors 2024.)

Definitions and measures of asthma control used in clinical trials and practice often vary, as highlighted in the manuscript, "Is asthma control more than just an absence of symptoms? An expert consensus statement". Furthermore, the authors discussed differences between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma. Given these disparities, there is a need for consensus regarding what constitutes well-controlled asthma and, especially, how best it can be measured and recorded. In the current work, we describe our data and provide more detail on the methodology from a two-stage Delphi survey and a structured literature review, which were designed to reach a consensus definition of asthma control and alleviate misalignments between patients and HCPs. Survey data were collected using a two-stage Delphi technique; a method used to collate expert opinions over a series of sequential questionnaires to reach a consensus. The collated Delphi survey data were compared with results from a comprehensive, structured literature review of 216 publications, to assess if there was a correlation between existing guidance and measures of asthma control used in clinical trials and standard clinical practice. In order to collate and interpret findings from the Delphi survey, responses from 82 panelists (73 HCPs and 9 authors) were qualitatively analyzed, quantitatively categorized, and presented as percentages or counts in Excel databases, which are detailed in the current work. Searches conducted using PubMed and Cochrane identified 664 manuscripts, and Embase was used to identify 89 congress abstracts. After applying a stringent screening method using predefined key words, the structured literature review consisted of 185 peer-reviewed manuscripts and 31 congress abstracts, and assessed existing guidance and measures of asthma control used in clinical trials. In this publication, we provide further insight into the predefined keywords, search strings, and strategy applied to identify manuscripts and congress abstracts for inclusion/exclusion, and detail methods for data extraction. Together, the data from the Delphi survey and structured literature review aimed to provide greater insights into challenges and approaches in achieving asthma control in clinical practice, with the potential for results to be used to guide a universally accepted definition and measure of asthma control that can be used and understood by patients, HCPs, and researchers. Qualitative and quantitative methodology and analysis from the Delphi survey and literature review search strategy can potentially be used to identify disparities and explore expert opinion and relevant literature in other therapeutic areas to guide a consensus where disparities exist., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. Spanevello reports consulting fees from GSK; payment or honoraria from AstraZeneca, Chiesi, and GSK; and participation on a data safety monitoring board or advisory board for GSK. L. Pérez de Llano reports grants or contracts from AstraZeneca, Esteve, FAES Pharma, and Teva, consulting fees from AstraZeneca, GEBRO, Gilead, GSK, MSD, Novartis, and Sanofi; payment or honoraria from AstraZeneca, Chiesi, Esteve, GSK, LEO Pharma, MSD, Novartis, and Sanofi; support for attending meetings and/or travel from AstraZeneca, Chiesi, FAES Pharma, GSK, and Novartis; and participation on a data safety monitoring board or advisory board for AstraZeneca. C. Domingo Ribas has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GSK, Menarini, Novartis, Pfizer, and Stallergenes, and declares no specific conflicts of interest to report regarding this paper. J.D. Blakey reports grants or contracts from AstraZeneca, GSK, and Novartis; consulting fees from Boehringer Ingelheim, Chiesi, and GSK; payment or honoraria from AstraZeneca, Chiesi, and GSK; support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, and GSK; receipt of medical writing support from GSK and Teva; payment to their institution for advisory work from Asthma Australia; and unpaid advisory work from Asthma WA. H. Inoue declares research grants from Boehringer Ingelheim, payment or honoraria for lectures and advisory committees from AstraZeneca, Boehringer Ingelheim, GSK, Kyorin, Novartis, and Sanofi. G.W. Canonica declares no conflict of interest for the current paper, and reports having received research grants as well as being lecturer or having received advisory board fees from A.Menarini, Allergy Therapeutics, Anallergo, AstraZeneca, Chiesi, FAES Pharma, Firma, Genentech, GSK, Guidotti-Malesci, Hal Allergy, Innovacaremd, Novartis, OmPharma, RedMaple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, ThermoFisher, Uriach Pharma, and Valeas. D. Yang, and M. Dalcolmo declare that they have no disclosures of interest. G. Garcia declares participation in advisory boards for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi; participation in sponsored activities for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Sanofi, and Phoenix; principal investigator for AstraZeneca, Boehringer Ingelheim, Chiesi, Covance, GSK, Iqvia, Novartis, Parexel, PPD, Sanofi, and Zambon. S. Mokashi, A. Kurne, and A. Butta were GSK employees at the time of study conduct and hold shares in GSK., (© 2023 Published by Elsevier Inc.)

Background: Several million inhalers are used annually by the millions of Australians with respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). Prescriptions in primary care tend to be for pressurised metered-dose inhalers (pMDIs), and consumers can purchase pMDI salbutamol over the counter. These inhalers contain potent greenhouse gases., Objective: This article briefly summarises the scale of the problem caused by pMDI propellants before discussing options available to general practitioners to mitigate their environmental impact while maintaining high-quality patient care., Discussion: The best inhaler for any patient is one that they can and will use as prescribed. However, for many people with chronic airways diseases, the environmental impact of their inhalers can be considered when doctors make prescribing choices, at least until newer, more climate-friendly propellants are introduced. Other aspects of asthma and COPD management that minimise environmental impact are also important.

Paroxysms of dyspnoea in the general population are commonly reported and are frequently assumed to be asthma-related, especially if this diagnostic label has been previously applied. Often, this is not the case. Inducible Laryngeal Obstruction (ILO) and Dysfunctional Breathing (DB) are common comorbid conditions that go unrecognised in many difficult-to-treat asthmatics. On average, these patients have a delay in diagnosis of almost 5 years. This delay, along with ineffective, inappropriate escalation of asthma therapy, frequent hospital presentations for uncontrolled symptoms, and even intensive care admissions, magnifies patient morbidity and poor quality of life. ILO and DB have similar presentations and triggers to asthma. Differentiating between them can be challenging, especially in centres that do not have access to multidisciplinary subspecialty asthma services. Objectively confirming the diagnosis can likewise be challenging as symptoms fluctuate, and gold-standard investigations require extensive experience. This mini-review will summarise the clinical features of ILO and DB, with particular focus in the context of individuals treated for asthma. This narrative review will define each condition, highlight poignant aspects of the history and describe elements of the diagnostic pathway to gain objective confirmation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Crawford, Blakey and Baumwol.)

Purpose: Definitions and measures of asthma control used in clinical trials and in clinical practice vary considerably. There is also misalignment between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma control. This study aimed to progress towards a consensus definition of asthma control, and evaluate disparities between HCP and patient perspectives., Basic Procedures: A two-stage Delphi questionnaire involving asthma specialists sought to identify areas of consensus on aspects of asthma control in clinical practice. Results were compared with those of a structured literature review to assess if existing guidance and measures of asthma control used in studies correlated with practice. Eighty-two panelists took part in the Delphi questionnaire. The structured literature review included 185 manuscripts and 31 abstracts., Main Findings: Panelists agreed that there was no standard definition of asthma control, confirmed by a total of 19 different composite consensus/guideline definitions and/or validated measures of control being identified across the Delphi study and literature review. Panelists agreed on the positive associations of well-controlled asthma with patient outcomes, but not on the components or thresholds of a working definition of control., Principal Conclusions: A universally accepted definition and measure of asthma control that is utilized and understood by patients, HCPs, and researchers is required., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced., Methods: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with >800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities., Results: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43-2.66) and sleep apnoea (OR 1.78, 95% CI 1.30-2.46)., Conclusion: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition., Competing Interests: Kerry L. Hancock has received speakers’ fees, consulting honoraria and/or travel grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Menarini Australia, Mylan and Novartis. Sinthia Bosnic-Anticevich has received honorarium for participation in expert advisory boards and given lectures for Teva Pharmaceuticals, AstraZeneca, GSK, Meda, Mundipharma, Sanofi, Mylan and received unrestricted research grants from Mylan, AstraZeneca, Teva and Mundipharma International. John D. Blakey has received speaker fees and/or consulting fees from Chiesi, Sanofi Boehringer Ingelheim and GSK, and his institution has received income from his activity from AstraZeneca and GSK all for unrelated projects. He has received investigator-initiated research funding from Novartis, and research support-in-kind from GSK, Boehringer Ingelheim and Teva. He is a medical advisor for Asthma Australia for which his institution receives income. Li Ping Chung has received speaker and consultancy fees and conference expenses from AstraZeneca, Novartis, GSK, Boehringer Ingelheim and Menarini. Claude Farah has received honoraria from Boehringer Ingelheim, AstraZeneca, GSK, and Sanofi for attending and speaking at educational meetings and advisory boards. Biljana Cvetkovski has received honorarium for participation in expert advisory boards and given presentations for Sanofi and GSK. Mark Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, and Seqirus, for unrelated projects. Anita Sharma is a practising Primary Care Physician and Senior Lecturer, School of Clinical Medicine-Primary Care Clinical Unit, University of Queensland. She supervises clinical training of primary care doctors and serves on advisory boards for Diabetes, Heart Failure and Osteoporosis for Novartis, Merck Sharp & Dohme and Boehringer Ingelheim, Eli Lilley and Amgen. Peter K Smith has advisory board membership with Meda, Nestle Nutrition Institute and Sanofi. He has an unrestricted funding for investigator-initiated studies with Meda. He does not have stock options. Philip J Thompson served on advisory boards & provided consultancies for Astra Zeneca, CSL Behring, Boehringer Ingelheim, Grifols, GSK, and Novartis. In the last 12 months, he received honoraria from GSK for presentations. Russell Wiseman has received consulting honoraria and travel grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Menarini Australia, and Novartis. John W. Upham has received speaker fees and consulting fees from Novartis, AstraZeneca, GSK, Sanofi, and Boehringer Ingelheim. Kwok Y Yan has received honoraria for participation in expert advisory boards and presentations for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and StallergenesGreer. Scott Claxton, Eve Denton, Joe Doan, Peter Del Fante, Lucy Morgan, Kanchanamala Ranasinghe, and Deb Stewart declare no conflict of interest. Victoria Carter is an employee of Optimum Patient Care Global and has 5% shareholding of Optimum Patient Care Australia, who is a part-funder of the ACAER Asthma program initiative and this study. Kiranjeet Dhillon, Florian Heraud, Thao Le and Rebecca Vella are employees of Optimum Patient Care Australia, who is a part-funder of the ACAER Asthma program initiative and this study. David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L, Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; 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 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2022 Hancock et al.)

Background: There is a high burden of asthma morbidity and mortality in Latin America. It has been proposed that this relates to limited access to diagnostic tests, asthma medications and specialised doctors. However, little is known of what caregivers of asthmatic children and healthcare professionals (HCPs) perceive as barriers and facilitators to adequate care. We aimed to explore the barriers and facilitators to asthma care access from caregivers' and HCP's perspective in an Ecuadorian low-resource setting., Methods: In 2017, we conducted 5 focus group discussions (FGD) with 20 caregivers of asthmatic children and 12 in-depth interviews with 3 paediatricians, 6 general doctors and 3 respiratory therapists in Esmeraldas city, Ecuador. FGDs and interviews were digitally recorded, transcribed, open-coded in QDA Miner, categorised using an interpretative phenomenological approach and analysed thematically. Barriers and facilitators were classified into availability, accessibility, acceptability and contact of healthcare services, based on Tanahashi model of health service access., Results: Limited resources, use of alternative medicines, fear of medication side-effects and lack of specific training for doctors and knowledge in families were common barriers for both caregivers and HCPs. Caregivers and HCPs proposed the implementation of public health asthma-focused programmes that would include close community-based follow-up of people with asthma, educational sessions for their families and public engagement activities. HCPs also suggested implementing training programmes on asthma management for general doctors., Conclusion: Multiple barriers identified by caregivers and HCPs referred to economic and health service organisational issues, fear of side effects of medication or ineffective self-management. Increasing caregivers and HCPs' asthma knowledge, as well as HCPs' communication skills to establish a patient-centred approach with a shared decision-making process could improve asthma care in this setting., Competing Interests: Competing interests: CA-G received a fellowship from the Wellcome Trust for this manuscript. JDB received grants or contracts from AZ, Novartis and GSK; consulting fees from GSK, Chiesi and Boehringer Ingelheim; payments or honoraria from AZ, Chiesi and GSK; support for meetings or travel from GSK, Boehringer Ingelheim and AZ; received equipment or materials from GSK and Teva; leadership or fiduciary roles for TSANZ, Asthma Australia and Asthma WA; other financial or non-financial interests from Optimum Patient Care Australia. PJC and NR-S have nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent worldwide, and major sources of morbidity. Key barriers to reduce the harm from these conditions are the widespread and related issues of low use of prescribed inhaled therapy, use of medicines differently from that prescribed, suboptimal inhaler technique, and lack of adherence are the action plans. Connected smart inhalers show great potential to improve these issues, and thus outcomes from airways disease. In this mini-review, we considered the published evidence that the use of smart inhalers leads to more doses of preventative treatment being taken on time and with appropriate techniques. We found multiple trials across a variety of settings and age groups where smart inhalers were used with audio-visual reminders and healthcare professional feedback, which substantially improved the number of doses of preventative treatment taken. Trial evidence also supports the use of feedback from smart inhalers in improving true concordance (doses taken correctly and on time), though only for a single type of smart device. The relative lack of study is in contrast with the potential impact of smart inhalers. Major research questions remain unresolved, as who might fund future large-scale studies, how guideline committees may consider them, and how to implement effective solutions., Competing Interests: In the last 3 years, JB has undertaken educational presentations and advisory boards for companies that manufacture inhaled medicines, with fees going to charitable accounts (Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK). He has benefitted from travel and accommodation relating to conference and educational meeting attendance (Boehringer Ingelheim, GSK). He has investigator initiated grants or involvement in research collaborations with “in kind” benefit (GSK, Novartis, Teva). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zabczyk and Blakey.)

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown., Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function., Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs., Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV 1 , FEV 1 /forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function., Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

Background: Clinical prediction models are widely used to guide medical advice and therapeutic interventions. Asthma is one of the most common chronic diseases globally and is characterised by acute deteriorations. These exacerbations are largely preventable, so there is interest in using clinical prediction models in this area. The objective of this review was to identify studies which have developed such models, determine whether consistent and appropriate methodology was used and whether statistically reliable prognostic models exist., Methods: We searched online databases MEDLINE (1948 onwards), CINAHL Plus (1937 onwards), The Cochrane Library, Web of Science (1898 onwards) and ClinicalTrials.gov, using index terms relating to asthma and prognosis. Data was extracted and assessment of quality was based on GRADE and an early version of PROBAST (Prediction study Risk of Bias Assessment Tool). A meta-analysis of the discrimination and calibration measures was carried out to determine overall performance across models., Results: Ten unique prognostic models were identified. GRADE identified moderate risk of bias in two of the studies, but more detailed quality assessment via PROBAST highlighted that most models were developed using highly selected and small datasets, incompletely recorded predictors and outcomes, and incomplete methodology. None of the identified models modelled recurrent exacerbations, instead favouring either presence/absence of an event, or time to first or specified event. Preferred methodologies were logistic regression and Cox proportional hazards regression. The overall pooled c-statistic was 0.77 (95% confidence interval 0.73 to 0.80), though individually some models performed no better than chance. The meta-analysis had an I 2 value of 99.75% indicating a high amount of heterogeneity between studies. The majority of studies were small and did not include internal or external validation, therefore the individual performance measures are likely to be optimistic., Conclusions: Current prognostic models for asthma exacerbations are heterogeneous in methodology, but reported c-statistics suggest a clinically useful model could be created. Studies were consistent in lacking robust validation and in not modelling serial events. Further research is required with respect to incorporating recurrent events, and to externally validate tools in large representative populations to demonstrate the generalizability of published results.

Objectives: This study aimed to estimate how many patients with asthma in England met the referral eligibility criteria using national asthma guidelines, identify what proportion were referred and determine the average waiting time to referral., Design: This is an observational cohort study., Setting/data Sources: Routinely collected healthcare data were provided by Clinical Practice Research Datalink records and Hospital Episode Statistics records from January 2007 to December 2015., Participants: Patients with asthma aged 18-80 years participated in this study., Main Outcome Measures: Eligibility for referral by the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) 2016 guidelines, determined after a 3-month pharmacological therapy exposure assessment, was classed by either 'high-dose therapies', 'continuous or frequent use of oral steroids' or 'incident eligibility' during follow-up (continuous oral corticosteroids for more than 3 months, or ≥800 µg/day inhaled corticosteroids/long-acting β 2 -agonist (or three controllers) and ≥2 asthma attacks/year)., Results: From the final cohort (n=23293), 19837 patients were eligible for specialist referral during follow-up based on the BTS/SIGN guideline recommendations. Among eligible patients without any previously recorded referral, 4% were referred during follow-up, with a median waiting time of 880 days (IQR=1428 days) between eligibility and referral., Conclusions: A large number of patients with asthma were eligible for specialist referral, of which a small proportion were referred, and many experienced a long waiting time before referral. The results indicate a major unmet need in asthma referral, which is a potential source of preventable harm and are likely to have implications regarding how services are organised to address this unmet need., Competing Interests: Competing interests: In the last three years, JDB has received personal fees and non-financial support from Napp, AstraZeneca and Boehringer Ingelheim, and personal fees from Novartis and Teva, outside the submitted work. GHJ has received personal fees from Pfizer, AstraZeneca, Chiesi and GlaxoSmithKline, and non-financial support from Napp, outside the submitted work. AG was an employee of Boehringer Ingelheim at the time the study was carried out. MGS and MB are employees of Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Asthma is a common cause of emergency care attendance in low- and middle-income countries (LMICs). While few prospective studies of predictors for emergency care attendance have been undertaken in high-income countries, none have been performed in a LMIC.We followed a cohort of 5-15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City, Ecuador. We collected blood and nasal wash samples, and performed spirometry and exhaled nitric oxide fraction measurements. We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months' follow-up.We recruited 283 children of whom 264 (93%) were followed-up for ≥6 months or until their next asthma attack. Almost half (46%) had a subsequent severe asthma attack requiring emergency care. Predictors of recurrence in adjusted analyses were (adjusted OR, 95% CI) younger age (0.87, 0.79-0.96 per year), previous asthma diagnosis (2.2, 1.2-3.9), number of parenteral corticosteroid courses in previous year (1.3, 1.1-1.5), food triggers (2.0, 1.1-3.6) and eczema diagnosis (4.2, 1.02-17.6). A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor (adjusted hazard ratio 0.69, 95% CI 0.50-0.95). Laboratory and lung function tests did not predict recurrence.Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-resource LMIC setting. This study suggests that a simple risk-assessment tool could potentially be created for emergency rooms in similar settings to identify higher-risk children on whom limited resources might be better focused., Competing Interests: Conflict of interest: C. Ardura-Garcia has nothing to disclose. Conflict of interest: E. Arias has nothing to disclose. Conflict of interest: P. Hurtado has nothing to disclose. Conflict of interest: L.J. Bonnett has nothing to disclose. Conflict of interest: C. Sandoval has nothing to disclose. Conflict of interest: A. Maldonado has nothing to disclose. Conflict of interest: L.J. Workman has nothing to disclose. Conflict of interest: T.A.E. Platts-Mills has nothing to disclose. Conflict of interest: P.J. Cooper reports grants from PATH Vaccines and National Institutes of Health Research, outside the submitted work. Conflict of interest: J.D. Blakey reports personal fees and non-financial support from Astra Zeneca, Boehringer Ingelheim and Napp, personal fees from Teva and non-financial support from Novartis, outside the submitted work., (Copyright ©ERS 2019.)

Introduction: Antibiotics are routinely given to people with chronic obstructive pulmonary disease (COPD) presenting with lower respiratory tract infection (LRTI) symptoms in primary care. Population prescribing habits and their consequences have not been well-described., Methods: We conducted a retrospective analysis of antibiotic prescriptions for non-pneumonic exacerbations of COPD from 2010 to 2015 using the UK primary care Optimum Patient Care Research Database. As a proxy of initial treatment failure, second antibiotic prescriptions for LRTI or all indications within 14 days were the primary and secondary outcomes, respectively. We derived a model for repeat courses using univariable and multivariable logistic regression analysis., Results: A total of 8.4% of the 9042 incident events received further antibiotics for LRTI, 15.5% further courses for any indication. Amoxicillin and doxycycline were the most common index and second-line drugs, respectively (58.7% and 28.7%), mostly given for 7 days. Index drugs other than amoxicillin, cardiovascular disease, pneumococcal vaccination and more primary care consultations were statistically significantly associated with repeat prescriptions for LRTI (p<0.05). The ORs and 95% CIs were: OR 1.28, 95% CI 1.10 to 1.49; OR 1.37, 95% CI 1.13 to 1.66; OR 1.33, 95% CI 1.14 to 1.55 and OR 1.05, 95% CI 1.02 to 1.07, respectively. Index duration, inhaled steroid use and exacerbation frequency were not statistically significant. The derived model had an area under the curve of 0.61, 95% CI 0.59 to 0.63., Discussion: The prescription of multiple antibiotic courses for COPD exacerbations was relatively common-one in twelve patients receiving antibiotics for LRTI had a further course within 2 weeks. The findings support the current preference for amoxicillin as index drug within the limitations of this observational study. Further clinical trials to determine best practice in this common clinical situation appear required., Competing Interests: Competing interests: JDB reports personal fees from Novartis and Teva, personal fees and non-financial support from AstraZeneca and Boehringer Ingelheim, and non-financial support from Virginia Commonwealth University and Respiratory Effectiveness Group, outside the submitted work. However, none of these relates to the topic of this submission., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Asthma and pneumonia are common respiratory conditions globally, affecting individuals of all ages. Streptococcus pneumoniae is the predominant bacterial cause of pneumonia, with nasopharyngeal carriage an important step towards invasive and pulmonary disease. Vaccines provide individual protection, and also prevent nasopharyngeal carriage, providing herd immunity. Asthma is associated with an increased risk of pneumonia, but there is limited information on the underlying mechanism of this predisposition. Both asthma and its treatment may conceivably alter propensity to, and density of, carriage through an altered epithelial microenvironment driven by disease-related inflammation or treatment-related immunomodulation, for example with inhaled corticosteroids. The relative importance of these factors could impact the efficacy of vaccines in this vulnerable patient population. In this review, we summarize the evidence for an increased risk of pneumonia in asthma, and discuss factors affecting nasopharyngeal carriage in the context of current guidelines for pneumococcal vaccination., (© 2019 Asian Pacific Society of Respirology.)

Background: Patients with asthma who present with lower respiratory tract infections (LRTIs) often receive antibiotics. There is uncertainty about the need for and consequences of antibiotic administration., Objective: To describe the demographic characteristics of and antibiotic prescriptions for adult patients with asthma with LRTI and investigate factors associated with repeat antibiotic courses., Methods: We analyzed prescriptions of antibiotics for LRTIs in UK primary care from 2010 to 2015 using the Optimum Care Database. The primary outcome was a second antibiotic prescription for an LRTI code within 14 days of index prescription, as a proxy of initial treatment failure. A model for repeat prescriptions was derived using univariable and multivariable logistic regression analyses., Results: We assessed 28,289 cases with complete data sets, 6.5% of which received a second antibiotic course. Amoxicillin and clarithromycin respectively were used most commonly as index and second agents. The most frequent course length was 7 days for both index and repeat prescriptions. Multivariable analysis demonstrated that age, index antibiotic and duration, smoking status, location, and number of consultations and oral steroid courses in the previous year were significantly associated with repeat prescriptions. The derived model predicted the binary outcome adequately (Cox-Snell R 2 , 0.012; area under curve, 0.62; 95% CI, 0.61-0.63). Comorbidities, vaccinations, asthma treatment, and number of exacerbations were significant only in the univariable analysis., Conclusions: The current index prescribing preference of 7 days of amoxicillin correlated to fewer repeat courses. Baseline asthma treatment was not associated with risk of further prescriptions. Antibiotic administration in older patients with a smoking history could be a target for future studies., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma., Methods: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10 -6 in stage 1. We set genome-wide significance at p less than 5 × 10 -8 . For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls., Findings: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10 -10 ), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10 -8 ), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10 -9 ). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10 -5 ) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022)., Interpretation: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population., Funding: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust., (Copyright © 2019 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.)

Antibiotic prescriptions for lower respiratory tract infections occur commonly in primary care but there is uncertainty about the most effective initial treatment strategy. Both increasing antimicrobial resistance and awareness of preventable harm from medicines make resolving this uncertainty a priority. Pragmatic, real-life epidemiological investigations are needed to inform future interventional studies. In this cross-sectional database study we analysed antibiotic prescriptions for non-pneumonic, lower respiratory tract infections (LRTI) in primary care as captured in the Optimum Care Database from 1984 to 2017. The primary outcome was a second antibiotic prescription for a LRTI code within 14 days of index prescription, the secondary outcome further antibiotic prescription for any indication. Only individuals without chronic respiratory diseases were included. We conducted univariable analysis to identify factors associated with repeat prescriptions and generate hypotheses for forthcoming projects. We analysed 367,188 index prescriptions for LRTI. Amoxicillin was the commonest used index drug (65.1%). In 6% a second antibiotic course coded for a further LRTI was prescribed (11.2% without this coding restriction). Further antibiotic prescriptions for LRTI were significantly associated with older age, previous smoking, seven day index courses and not using amoxicillin initially. The largest effect size was seen when amoxicillin was not used as index drug (odds ratio (OR) 1.15, p  < 0.001). This would support current prescribing practice for amoxicillin as index drug in those without respiratory disease. Prospective studies are needed to explore the observed differences.

Background: Asthma attacks are common and have significant physical, psychological, and financial consequences. Improving the assessment of a child's risk of subsequent asthma attacks could support front-line clinicians' decisions on augmenting chronic treatment or specialist referral. We aimed to identify predictors for emergency department (ED) or hospital readmission for asthma from the published literature., Methods: We searched MEDLINE, EMBASE, AMED, PsycINFO, and CINAHL with no language, location, or time restrictions. We retrieved observational studies and randomized controlled trials (RCT) assessing factors (personal and family history, and biomarkers) associated with the risk of ED re-attendance or hospital readmission for acute childhood asthma., Results: Three RCTs and 33 observational studies were included, 31 from Anglophone countries and none from Asia or Africa. There was an unclear or high risk of bias in 14 of the studies, including 2 of the RCTs. Previous history of emergency or hospital admissions for asthma, younger age, African-American ethnicity, and low socioeconomic status increased risk of subsequent ED and hospital readmissions for acute asthma. Female sex and concomitant allergic diseases also predicted hospital readmission., Conclusion: Despite the global importance of this issue, there are relatively few high quality studies or studies from outside North America. Factors other than symptoms are associated with the risk of emergency re-attendance for acute asthma among children. Further research is required to better quantify the risk of future attacks and to assess the role of commonly used biomarkers., (© 2018 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.)

Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide, primarily through exacerbations. Exacerbations are often treated with antibiotics but their optimal course duration is uncertain. Reducing antibiotic duration may influence antimicrobial resistance but risks treatment failure. The objective of this article is to review published literature to investigate whether shorter antibiotic therapy duration affects clinical outcomes in the treatment of asthma and COPD exacerbations. We systematically searched electronic databases (MEDLINE, EMBASE, CINAHL, World Health Organisation International Clinical Trial Registry Platform, the Cochrane library, and ISRCTN) with no language, location, or time restrictions. We retrieved observational and controlled trials comparing different durations of the same oral antibiotic therapy in the treatment of acute exacerbations of asthma or COPD in adults. We found no applicable studies for asthma exacerbations. We included 10 randomized, placebo-controlled trials for COPD patients, all from high-income countries. The commonest studied antibiotic class was fluoroquinolones. Antibiotic courses shorter than 6 days were associated with significantly fewer overall adverse events (risk ratio (RR): 0.84, 95% confidence interval (CI): 0.75-0.93, p = 0.001) when compared with those of 7 or more days. There was no statistically significant difference for clinical success or bacteriological eradication in sputum (RR: 1.00, 95% CI: 0.88-1.13 and RR: 1.06, 95% CI: 0.79-1.44, respectively). Shorter durations of antibiotics for COPD exacerbations do not seem to confer a higher risk of treatment failure but are associated with fewer adverse events. This is in keeping with previous studies in community acquired pneumonia, but studies were heterogeneous and differed from usual clinical practice. Further observational and prospective work is needed to explore the significance of antibiotic duration in the treatment of asthma and COPD exacerbations.

Background: Healthcare systems are under increasing strain, predominantly due to chronic non-communicable diseases. Connected healthcare technologies are becoming ever more capable and their components cheaper. These innovations could facilitate both self-management and more efficient use of healthcare resources for common respiratory diseases such as asthma and chronic obstructive pulmonary disease. However, newer technologies can only facilitate major changes in practice, and cannot accomplish them in isolation., Focus of Review: There are now large numbers of devices and software offerings available. However, the potential of such technologies is not being realised due to limited engagement with the public, clinicians and providers, and a relative paucity of evidence describing elements of best practice in this complex and evolving environment. Indeed, there are clear examples of wasted resources and potential harm. We therefore call on interested parties to work collaboratively to begin to realize the potential benefits and reduce the risks of connected technologies through change in practice. We highlight key areas where such partnership can facilitate the effective and safe use of technology in chronic respiratory care: developing data standards and fostering inter-operability, making collaborative testing facilities available at scale for small to medium enterprises, developing and promoting new adaptive trial designs, developing robust health economic models, agreeing expedited approval pathways, and detailed planning of dissemination to use., Conclusion: The increasing capability and availability of connected technologies in respiratory care offers great opportunities and significant risks. A co-ordinated collaborative approach is needed to realize these benefits at scale. Using newer technologies to revolutionize practice relies on widespread engagement and cannot be delivered by a minority of interested specialists. Failure to engage risks a costly and inefficient chapter in respiratory care., Competing Interests: Disclosure RWC has a patent on the use of acoustic analysis to assess inhaler use. DP has previously had research funding to develop software to assess inhaler technique. The other authors report no conflicts of interest in this work.

Background: Asthma attacks are common, serious, and costly. Individual factors associated with attacks, such as poor symptom control, are not robust predictors., Objective: We investigated whether the rich data available in UK electronic medical records could identify patients at risk of recurrent attacks., Methods: We analyzed anonymized, longitudinal medical records of 118,981 patients with actively treated asthma (ages 12-80 years) and 3 or more years of data. Potential risk factors during 1 baseline year were evaluated using univariable (simple) logistic regression for outcomes of 2 or more and 4 or more attacks during the following 2-year period. Predictors with significant univariable association (P < .05) were entered into multiple logistic regression analysis with backward stepwise selection of the model including all significant independent predictors. The predictive accuracy of the multivariable models was assessed., Results: Independent predictors associated with future attacks included baseline-year markers of attacks (acute oral corticosteroid courses, emergency visits), more frequent reliever use and health care utilization, worse lung function, current smoking, blood eosinophilia, rhinitis, nasal polyps, eczema, gastroesophageal reflux disease, obesity, older age, and being female. The number of oral corticosteroid courses had the strongest association. The final cross-validated models incorporated 19 and 16 risk factors for 2 or more and 4 or more attacks over 2 years, respectively, with areas under the curve of 0.785 (95% CI, 0.780-0.789) and 0.867 (95% CI, 0.860-0.873), respectively., Conclusions: Routinely collected data could be used proactively via automated searches to identify individuals at risk of recurrent asthma attacks. Further research is needed to assess the impact of such knowledge on clinical prognosis., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: : Pandemic influenza has potential to overwhelm healthcare resources. There is uncertainty over performance of existing triage tools for hospital admission and discharge decisions., Aim: : Our aim was to identify clinical criteria that predict safe discharge from hospital and develop a pragmatic triage tool to guide physician decision-making., Design: : We retrospectively examined an existing database of patients who presented to the Royal Liverpool University Hospital during the 2010-11 influenza pandemic., Methods: Inclusion criteria: patients ≥18 years, with PCR confirmed H1N1 influenza. Exclusion criteria: died in the emergency department or case notes unavailable. Successful discharge was defined as discharge within 24 h of presentation and no readmission within 7 days., Results: Eighty-six patients were included and 16 were successfully discharged. Estimated P/F ratio and C-reactive protein predicted safe discharge in a multivariable logistic regression model (AUC 0.883). A composite univariate predictor (estimated P/F minus C-reactive protein, AUC 0.877) was created to calculate specific cut off points for sensitivity and specificity. A pragmatic decision tool was created to incorporate these thresholds and relevant guidelines. Discharge: SpO 2 (in air)   ≥ 94% and CRP <50. Observe: SpO 2  ≥   94% and CRP >50 or SpO 2  ≤   93% and CRP <50. Admit: SpO 2  ≤   93% and CRP >50., Conclusions: We identified that oxygen exchange and CRP, a marker of acute inflammation, were the most important predictors of safe discharge. Our proposed simple triage model requires validation but has the potential to aid clinical decisions in the event of a future pandemic, and potentially for seasonal influenza., (© The Author 2016. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Introduction: Antimicrobial resistance threatens to undermine treatment of severe infection; new therapeutic strategies are urgently needed. Preclinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection., Methods: We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (≥3 months postdischarge). Blood samples were taken in early (≤48 h postdiagnosis, n = 54), latent (7 days postdiagnosis, n = 39), and convalescent (3-6 months postdiagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonized Streptococcus pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads., Results: P4 peptide increased neutrophil killing of opsonized pneumococci by 8.6% (confidence interval 6.35-10.76, P < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared with unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source., Conclusions: We have extended preclinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis.

Objectives: Ploidy assessment is often required for the diagnosis of partial molar pregnancy. While fluorescence in situ hybridization has been shown to be effective, it is not available in many laboratories. We validated chromogenic in situ hybridization (CISH) for this purpose., Methods: CISH using probes to chromosomes 17 and 10 was performed on 20 POC cases with known cytogenetics to establish a reference percentage. This was then used to classify a randomized set of abnormal and normal cases., Results: An abnormal CISH cutoff of greater than 7% was established. All abnormal cases (six triploid and three tetraploid), 11 "normal" (46, XX or XY or undetectable abnormalities), and one trisomy 10 were all correctly classified by the assay., Conclusions: CISH is a useful ancillary technique for the diagnosis of molar pregnancy. Its greater accessibility and ability to score even rare placental tissue in a background of maternal tissue offer advantages over other methods., (© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is growing evidence of greater rates of morbidity and mortality in hospitals during out-of-hours shifts, which appears to be exacerbated during the period in which newly qualified doctors commence work. In order to combat this issue, an online simulation of a night shift was developed and trialled in order to improve the non-technical skills of newly qualified doctors and, ultimately, improve clinical outcomes. A randomised feasibility trial of the electronic training simulation was performed with medical students (n=30) at the end of their training and in the initial weeks of working at a large teaching hospital. The study showed that participants in the intervention group completed their non-urgent tasks more rapidly than the control group: mean (SD) time to complete a non-urgent task of 85.1 (50.1) versus 157.6 (90.4) minutes, p=0.027. This difference persisted using linear regression analysis, which was undertaken using rota and task volume as independent cofactors (p=0.028). This study shows the potential for simulation technologies to improve non-technical skills.

Background: Junior doctors commonly prescribe inhaled medication for patients admitted to hospitals, and this may be a potential source of prescription error. Objective To determine the potential type, frequency and cost of prescription errors for inhaled medication, and ascertain if a simple educational intervention can improve junior doctors' knowledge and reduce these., Methods: We carried out a prospective study looking at the types and cost of inhaled prescription errors. Simultaneously we tested knowledge of junior doctors' using a quiz. Both the studies were carried out before and after the introduction of inhaler flash cards (pictures of devices with, instructions on use and the medication they contain) on specific wards. This was followed by an electronic feedback survey., Results: Error rates varied greatly (p = 6.8 × 10(-8)) by device, with 23 % of Evohaler and Accuhaler prescriptions being incorrect. The average cost of an erroneously prescribed medication was £45.50. There were 14 % incorrect prescriptions before the intervention. There was no significant improvement in junior doctors' knowledge of inhalers or the rate of prescription error after the intervention., Conclusion: Prescription errors of inhaled medication are common and costly to rectify. There is a need for improved teaching and training of junior doctors and medical students.

Background: The "weekend effect" describes an increase in adverse outcomes for patients admitted at the weekend. Critical care units have moved to higher intensity working patterns to address this with some improved outcomes. However, support services have persisted with traditional working patterns. Blood cultures are an essential diagnostic tool for patients with sepsis but yield is dependent on sampling technique and processing. We therefore used blood culture yield as a surrogate for the quality of support service provision. We hypothesized that blood culture yields would be lower over the weekend as a consequence of reduced support services., Methods: We performed a retrospective observational study examining 1575 blood culture samples in a university hospital critical care unit over a one-year period., Results: Patients with positive cultures had, on average, higher APACHE II scores (p = 0.015), longer durations of stay (p = 0.03), required more renal replacement therapy (p<0.001) and had higher mortality (p = 0.024). Blood culture yield decreased with repeated sampling with an increased proportion of contaminants. Blood cultures were 26.7% less likely to be positive if taken at the weekend (p = 0.0402). This effect size is the equivalent to the impact of sampling before and after antibiotic administration., Conclusions: Our study demonstrates that blood culture yield is lower at the weekend. This is likely caused by delays or errors in incubation and processing, reflecting the reduced provision of support services at the weekend. Reorganization of services to address the "weekend effect" should acknowledge the interdependent nature of healthcare service delivery.

Asthma attacks are a major global source of morbidity and cost. The incidence and impact of asthma attacks have not improved despite widespread adoption of effective universal treatment guidelines. Consequently, there is increasing interest in managing asthma based on specific assessments of both current symptoms and future risk. In this review, we consider 'risk' in asthma, and how it might be assessed from the patient's history and objective measurements. We also discuss the potential for encouraging shared decision-making and improving medical consensus through explicit communication of risk and highlight the potential opportunities and challenges in risk assessment to improve asthma management through individualised treatment strategies., (© 2014 John Wiley & Sons Ltd.)

Background: The Hospital at Night system has been widely adopted to manage Out-of-Hours workload. However, it has the potential to introduce delays and corruption of information. The introduction of newer technologies to replace landlines, pagers and paper may ameliorate these issues., Aim: To establish if the introduction of a Hospital at Night system supported by a wireless taskflow system affected the escalation of high Early Warning Scores (EWSs) to medical attention, and the time taken to medical review., Design: Prospective 'pre and post' observational study in a teaching hospital in the UK., Methods: Review of observation charts and medical records, and data extraction from the electronic taskflow system., Results: The implementation of a technology-supported Hospital at Night system was associated with a significant decrease in time to documentation of initial review in those who were reviewed. However, there was no change in the proportion of those with a high EWS that were reviewed, and throughout the study a majority of patients with high EWSs were not reviewed in accordance with guidelines., Conclusion: Introduction of a Hospital at Night system supported by mobile technology appeared to improve the transfer of information, but did not affect the nursing decision whether to escalate abnormal findings.

Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks.