Dimensionless Groups by Entropic Similarity: II-Wave Phenomena and Information-Theoretic Flow Regimes.

The aim of this study is to explore the insights of the information-theoretic definition of similarity for a multitude of flow systems with wave propagation. This provides dimensionless groups of the form Πinfo=U/c, where U is a characteristic flow velocity and c is a signal velocity or wave celerity, to distinguish different information-theoretic flow regimes. Traditionally, dimensionless groups in science and engineering are defined by geometric similarity, based on ratios of length scales; kinematic similarity, based on ratios of velocities or accelerations; and dynamic similarity, based on ratios of forces. In Part I, an additional category of entropic similarity was proposed based on ratios of (i) entropy production terms; (ii) entropy flow rates or fluxes; or (iii) information flow rates or fluxes. In this Part II, the information-theoretic definition is applied to a number of flow systems with wave phenomena, including acoustic waves, blast waves, pressure waves, surface or internal gravity waves, capillary waves, inertial waves and electromagnetic waves. These are used to define the appropriate Mach, Euler, Froude, Rossby or other dimensionless number(s)-including new groups for internal gravity, inertial and electromagnetic waves-to classify their flow regimes. For flows with wave dispersion, the coexistence of different celerities for individual waves and wave groups-each with a distinct information-theoretic group-is shown to imply the existence of more than two information-theoretic flow regimes, including for some acoustic wave systems (subsonic/mesosonic/supersonic flow) and most systems with gravity, capillary or inertial waves (subcritical/mesocritical/supercritical flow). For electromagnetic wave systems, the additional vacuum celerity implies the existence of four regimes (subluminal/mesoluminal/transluminal/superluminal flow). In addition, entropic analyses are shown to provide a more complete understanding of frictional behavior and sharp transitions in compressible and open channel flows, as well as the transport of entropy by electromagnetic radiation. The analyses significantly extend the applications of entropic similarity for the analysis of flow systems with wave propagation.

Dimensionless Groups by Entropic Similarity: I - Diffusion, Chemical Reaction and Dispersion Processes.

Since the time of Buckingham in 1914, dimensional analysis and similarity arguments based on dimensionless groups have served as powerful tools for the analysis of systems in all branches of science and engineering. Dimensionless groups are generally classified into those arising from geometric similarity, based on ratios of length scales; kinematic similarity, based on ratios of velocities or accelerations; and dynamic similarity, based on ratios of forces. We propose an additional category of dimensionless groups based on entropic similarity, defined by ratios of (i) entropy production terms; (ii) entropy flow rates or fluxes; or (iii) information flow rates or fluxes. Since all processes involving work against friction, dissipation, diffusion, dispersion, mixing, separation, chemical reaction, gain of information or other irreversible changes are driven by (or must overcome) the second law of thermodynamics, it is appropriate to analyze them directly in terms of competing entropy-producing and transporting phenomena and the dominant entropic regime, rather than indirectly in terms of forces. In this study, entropic groups are derived for a wide variety of diffusion, chemical reaction and dispersion processes relevant to fluid mechanics, chemical engineering and environmental engineering. It is shown that many dimensionless groups traditionally derived by kinematic or dynamic similarity (including the Reynolds number) can also be recovered by entropic similarity-with a different entropic interpretation-while many new dimensionless groups can also be identified. The analyses significantly expand the scope of dimensional analysis and similarity arguments for the resolution of new and existing problems in science and engineering.

Kinetic model of PFAS removal by semi-batch foam fractionation and validation by experimental data for K-PFOS.

Adsorptive bubble separation techniques such as foam fractionation have recently been applied for the extraction of per- and polyfluoroalkyl substances (PFAS) from waters at both laboratory and operational scales. However, few authors have developed mathematical models of their removal of PFAS. This study presents a theoretical framework for the kinetics of PFAS removal from fresh and monovalent saline waters by a semi-batch foam fractionation process, by the mechanisms of adsorption, entrainment and volatilization, as a function of pertinent parameters including PFAS air-water adsorption, bubble radius, electrolyte concentration and ionic strength, PFAS volatility, and flow and geometric parameters. The freshwater model is validated for the removal of potassium perfluorooctane sulfonate (K-PFOS) using published experimental data (Meng, P. et al., Chemosphere, 2018, 203, 263-270). The proposed models provide quantitative tools for process design and the optimization of individual PFAS removal by semi-batch adsorptive bubble separation techniques such as foam fractionation.

Comparison of DRASTIC and DRASTICL groundwater vulnerability assessments of the Burdekin Basin, Queensland, Australia.

In the Burdekin Basin, Queensland, Australia, groundwater contamination due to agricultural activities has led to concerns over its impacts on globally significant ecosystems such as the Great Barrier Reef. An appropriate method for groundwater vulnerability assessment is essential for the sustainable use of this groundwater resource and its longer-term environmental management. The aim of this study is to apply and assess the suitability of the standard DRASTIC index-based method for groundwater vulnerability assessment of the Burdekin Basin. The intrinsic groundwater vulnerability is calculated in ArcGIS, using data for the period 2010 to 2021. The results are compared to available water quality data. The calculated DRASTIC scores are found to be only weakly correlated with water quality parameters, including the nitrate concentration (R = 0.07), which should behave as a proxy measure of groundwater vulnerability. To address this, a modified DRASTICL method containing a land use parameter is also implemented, to assess the specific groundwater vulnerability. The correlation between DRASTICL scores and nitrate levels (R = 0.2) is more significant but is still relatively weak. From this study, it is recommended that alternative methods be developed to assess groundwater vulnerability in the Burdekin Basin, and other comparable aquifer systems.

Long-term effectiveness and safety of omalizumab in pediatric and adult patients with moderate-to-severe inadequately controlled allergic asthma.

Omalizumab is recommended as an add-on therapy in patients aged ≥6 years with inadequately controlled, moderate-to-severe persistent allergic asthma. The efficacy and safety of omalizumab treatment in allergic asthma clinical trials and its effectiveness in the real world have been reported in numerous studies. In this review, we examine clinical evidence in pediatric and adult patients with allergic asthma who received omalizumab treatment for at least 2 years, to assess its effectiveness, durability, and trajectory of response over time as well as safety. We performed a literature search from inception until March 2022 in PubMed using the keywords "omalizumab" and "allergic asthma" to retrieve articles examining the effects of omalizumab in patients with allergic asthma, aged ≥6 years. Only articles that evaluated the effectiveness of omalizumab for at least 2 years were included. Data from case reports were excluded. Our review confirmed the long-term effectiveness and safety of omalizumab, demonstrating reduced rate of exacerbations, improved lung function, asthma control, and quality of life, decreased health care resource utilization, and use of corticosteroids (oral/inhaled) with a favorable safety and tolerability profile for up to 9 years in adult patients with moderate-to-severe allergic asthma. Similar results were also observed in the pediatric population with up to 7.5 years of omalizumab treatment. This review highlights and confirms the sustained clinical benefits of omalizumab over long periods of treatment in pediatric and adult populations with allergic asthma.

Groundwater vulnerability assessment: A review including new statistical and hybrid methods.

The concept of groundwater vulnerability was first introduced in the 1970s in France to recognize sensitive areas in which surface pollution could affect groundwater, and to enable others to develop management methods for groundwater protection against surface pollutants. Since this time, numerous methods have been developed for groundwater vulnerability assessment (GVA). These can be categorized into four groups: (i) overlay and index-based methods, (ii) process-based simulation models, (iii) statistical methods, and (iv) hybrid methods. This work provides a comprehensive review of modern GVA methods, which in contrast to previous reviews, examines the last two categories in detail. First, the concept of groundwater vulnerability is defined, then the major GVA methods are introduced and classified. This includes detailed accounts of statistical methods, which can be subdivided into orthodox statistical, data-driven and Bayesian methods, and their advantages and disadvantages, as well as modern hybrid methods. It is concluded that Bayesian inference offers many advantages compared with other GVA methods. It combines theory and data to give the posterior probabilities of different models, which can be continually updated with new data. Furthermore, using the Bayesian approach, it is possible to calculate the probability of a proposition, which is exactly what is needed to make decisions. However, despite the advantages of Bayesian inference, its applications to date have been very limited.

A Hierarchy of Probability, Fluid and Generalized Densities for the Eulerian Velocivolumetric Description of Fluid Flow, for New Families of Conservation Laws.

The Reynolds transport theorem occupies a central place in continuum mechanics, providing a generalized integral conservation equation for the transport of any conserved quantity within a fluid or material volume, which can be connected to its corresponding differential equation. Recently, a more generalized framework was presented for this theorem, enabling parametric transformations between positions on a manifold or in any generalized coordinate space, exploiting the underlying continuous multivariate (Lie) symmetries of a vector or tensor field associated with a conserved quantity. We explore the implications of this framework for fluid flow systems, based on an Eulerian velocivolumetric (position-velocity) description of fluid flow. The analysis invokes a hierarchy of five probability density functions, which by convolution are used to define five fluid densities and generalized densities relevant to this description. We derive 11 formulations of the generalized Reynolds transport theorem for different choices of the coordinate space, parameter space and density, only the first of which is commonly known. These are used to generate a table of integral and differential conservation laws applicable to each formulation, for eight important conserved quantities (fluid mass, species mass, linear momentum, angular momentum, energy, charge, entropy and probability). The findings substantially expand the set of conservation laws for the analysis of fluid flow and dynamical systems.

Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma.

BACKGROUND: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.

Bronchial Thermoplasty Global Registry (BTGR): 2-year results.

OBJECTIVES: Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. DESIGN: The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. SETTING: Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia PARTICIPANTS: One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator's opinion, made them inappropriate for BT treatment were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. RESULTS: Subjects' baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ and ACT). CONCLUSIONS: The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT. TRIAL REGISTRATION NUMBER: NCT02104856.

Invariance Properties of the Entropy Production, and the Entropic Pairing of Inertial Frames of Reference by Shear-Flow Systems.

This study examines the invariance properties of the thermodynamic entropy production in its global (integral), local (differential), bilinear, and macroscopic formulations, including dimensional scaling, invariance to fixed displacements, rotations or reflections of the coordinates, time antisymmetry, Galilean invariance, and Lie point symmetry. The Lie invariance is shown to be the most general, encompassing the other invariances. In a shear-flow system involving fluid flow relative to a solid boundary at steady state, the Galilean invariance property is then shown to preference a unique pair of inertial frames of reference-here termed an entropic pair-respectively moving with the solid or the mean fluid flow. This challenges the Newtonian viewpoint that all inertial frames of reference are equivalent. Furthermore, the existence of a shear flow subsystem with an entropic pair different to that of the surrounding system, or a subsystem with one or more changing entropic pair(s), requires a source of negentropy-a power source scaled by an absolute temperature-to drive the subsystem. Through the analysis of different shear flow subsystems, we present a series of governing principles to describe their entropic pairing properties and sources of negentropy. These are unaffected by Galilean transformations, and so can be understood to "lie above" the Galilean inertial framework of Newtonian mechanics. The analyses provide a new perspective into the field of entropic mechanics, the study of the relative motions of objects with friction.

Recommendations following a modified UK-Delphi consensus study on best practice for referral and management of severe asthma.

INTRODUCTION: Severe asthma affects an estimated 3%-5% of people with asthma and is associated with frequent exacerbations, poor symptom control and significant morbidity from the disease itself, as well as high dose of inhaled and systemic steroids used to treat it. The introduction of specialist asthma services across the UK has attempted to improve quality of care and ensure that patients undergo a full systematic assessment prior to initiation of advanced biological therapies. However, improvements are required in the patient pathway to minimise avoidable harm. OBJECTIVES: To define standards of care in areas where the evidence base is lacking through patient and healthcare professional (HCP) consensus. METHODS: The precision UK National Working Group of asthma experts identified 42 statements formed from 7 key themes. An online four-point Likert scale questionnaire was sent to HCPs working in asthma throughout the UK to assess agreement (consensus) with these statements; a subset of the statements formed a patient questionnaire. Consensus was defined as high if ≥75% and very high if ≥90% of respondents agreed with a statement. RESULTS: A total of 117/197 responses (59.3% response rate) were received from severe asthma patients (n=15) and HCPs (n=102) including respiratory physicians, respiratory nurse specialists, respiratory pharmacists, specialist physiotherapists and general practitioners. Consensus was very high in 25 (60%) statements, high in 12 (29%) statements and was not achieved in 5 (12%) statements. Based on the consensus scores, the precision UK National Working Group derived 10 key recommendations. These focus on referrals from primary and secondary care, accessing specialist asthma services, homecare provision for severe asthma patients and outcome measures. CONCLUSIONS: Implementation of these 10 recommendations across the severe asthma pathway in the UK has the potential to improve outcomes for patients by reducing delays to assessment and initiation of advanced phenotype-specific therapies.

Serum Inhaled Corticosteroid Detection for Monitoring Adherence in Severe Asthma.

BACKGROUND: Daily inhaled corticosteroids (ICSs) are fundamental to asthma management, but adherence is low. OBJECTIVES: To investigate (1) whether LC-MS/MS could be used to detect ICSs in serum and (2) whether serum levels related to markers of disease severity. METHODS: We collected blood samples over an 8-hour period from patients with severe asthma prescribed at least 1000 µg daily of beclomethasone dipropionate equivalent. Following baseline sampling, patients were observed taking their usual morning dose. Subsequent blood samples were obtained 1, 2, 4, and 8 hours postinhalation and analyzed by LC-MS/MS. Correlations between serum ICS levels and severity markers were investigated. RESULTS: A total of 60 patients were recruited (41 females; 39 prescribed maintenance prednisolone; mean age, 49 ± 12 years; FEV1, 63 ± 20 %predicted). Eight hours postinhalation, all patients using budesonide (n = 10) and beclomethasone dipropionate (15), and all but 1 using fluticasone propionate (28), had detectable serum drug levels. Fluticasone furorate was detected in 2 patients (of 4), ciclesonide in none (of 7). Low adherence by repeat prescription records (<80%) was identified in 43%. Blood ICS levels correlated negatively with exacerbation rate, and (for fluticasone propionate only) positively with FEV1 %predicted. CONCLUSIONS: Commonly used ICSs can be reliably detected in the blood at least 8 hours after dosing, and could therefore be used as a measure of adherence in severe asthma. Higher exacerbation rates and poorer lung function (for fluticasone propionate) were associated with lower blood levels.

Unification of surface tension isotherms of PFOA or GenX salts in electrolyte solutions by mean ionic activity.

The surface tension isotherms of soluble salts of per- and polyfluoroalkyl substances (PFAS) in electrolyte solutions are typically reported as functions of the PFAS concentration. However, for univalent salts and electrolytes, the Langmuir-Szyszkowski equation is a function of the mean ionic activity a*. Using previously reported data, we show that for salts of perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide dimer acid (GenX™), use of a* rather than concentration provides a unified surface tension isotherm, independent of the electrolyte concentration. This suggests that the electrolyte dependence of the isotherm arises purely from its effect on PFAS activity, rather than an intrinsic surface property. This finding has important implications for the understanding of PFAS retention in saline unsaturated soils, and for PFAS extraction from saline waters by foam fractionation.

Safety and effectiveness of bronchial thermoplasty after 10 years in patients with persistent asthma (BT10+): a follow-up of three randomised controlled trials.

BACKGROUND: Bronchial thermoplasty is an endoscopic treatment for uncontrolled asthma. Previous randomised clinical trials have shown that bronchial thermoplasty reduces severe exacerbations in people with asthma. However, the long-term efficacy and safety of bronchial thermoplasty beyond 5 years is unknown. The BT10+ study aimed to investigate the efficacy and safety of bronchial thermoplasty after 10 or more years of follow-up. METHODS: BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric high-resolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. FINDINGS: The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10·8-15·6 years (median 12·1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0·6%, 95% CI -9·7 to 10·8) and 5 years (28 [22%] of 130 participants; difference 3·5%, -6·7% to 13·6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. INTERPRETATION: Our findings suggest that efficacy of bronchial thermoplasty is sustained for 10 years or more, with an acceptable safety profile. Therefore, bronchial thermoplasty is a long-acting therapeutic option for patients with asthma that remains uncontrolled despite optimised medical treatment. FUNDING: Boston Scientific.

Factors Associated with Frequent Exacerbations in the UK Severe Asthma Registry.

BACKGROUND: Frequent exacerbations are an important cause of morbidity in patients with severe asthma. OBJECTIVE: Our aim was to identify factors associated with frequent exacerbations in a large well-characterized severe asthma population and determine whether factors differed in patients treated with and without maintenance oral corticosteroids (OCS). METHODS: Adults with severe asthma from specialized asthma centers across the United Kingdom were recruited to the UK Severe Asthma Registry. Demography, comorbidities and physiological measurements were collected. We conducted univariable and multivariable logistic regression analyses to identify factors associated with frequent exacerbations, defined as 3 or more exacerbations treated with high-dose systemic corticosteroids in the past year. RESULTS: Of 1,592 patients with severe asthma from the UK Severe Asthma Registry, 1,137 (71%) were frequent exacerbators and 833 (52%) were on maintenance OCS. The frequent exacerbators were more likely to be ex-smokers, have gastroesophageal reflux disease, higher Asthma Control Questionnaire-6 (ACQ-6) score, and higher blood eosinophilia. Multivariable regression analyses showed ACQ-6 score greater than 1.5 (odds ratio [OR] 4.25; P < .001), past smoking history (OR 1.55; P = .024), and fractional exhaled nitric oxide greater than 50ppb (OR 1.54; P = .044) were independently associated with frequent exacerbations. Past smoking history correlated with frequent exacerbations only in patients on maintenance OCS (OR 2.25; P = .004), whereas ACQ-6 score greater than 1.5 was independently associated with frequent exacerbations in those treated with and without maintenance OCS (OR 2.74; P = .017 and OR 6.42; P < .001, respectively). CONCLUSIONS: Several factors were associated with frequent exacerbations in a large UK severe asthma registry population. High ACQ-6 score had the strongest association with frequent exacerbations irrespective of maintenance OCS status.

Phenotypic and functional translation of IL33 genetics in asthma.

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 FEV1, FEV1/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.

Attack, flare-up, or exacerbation? The terminology preferences of patients with severe asthma.

Background: People with severe asthma experience frequent life-threatening acute asthma events. A Lancet commission recently highlighted that terms "exacerbations" and "flare-ups" are seen to trivialize these episodes and recommended use of the term "attacks." Clinicians however, preferentially use the term "exacerbation" and some guidelines recommend the use of "exacerbation" with patients.Objective: This descriptive qualitative study aimed to understand the patient's experience and perspectives of these events and language used to describe them.Methods: Semi-structured one-on-one interviews were conducted in Australia and the UK in 18 people with severe asthma and 10 with mild-moderate asthma regarding their usage and preferences for such terminologies. Additionally, nine people with severe asthma participated in two focus groups in which use of preferred terminology was explored.Results: Mean age of participants was 57 ± 14.03 yr and 65% were female. A total 67 quotes were recorded in which 16 participants with severe asthma spontaneously used either the term "attack," "flare-up" and/or "exacerbation." Of these quotes, all 16 participants used "attack," one used all three terms and two used both "exacerbation" and "attack." The term "attack" was used to describe frightening events having major impacts on participant's lives, whereas "exacerbation" and "flare-up" were used to refer to both severe and mild, transient asthma-related events.Conclusion: Usage of the term "attack" was preferred by patients with severe asthma. Adoption of this language may assist in patient-clinician communication and disease management and outcomes. Wider stakeholder engagement is needed to confirm this suggestion. AbbreviationsFEV1forced expiratory volume in 1 secondATSAmerican Thoracic SocietyERSEuropean Respiratory SocietyACQAsthma Control QuestionnaireICSinhaled corticosteroidsOCSoral corticosteroidsBTSBritish Thoracic SocietySIGNScottish Intercollegiate Guidelines NetworkWAPwritten action plan.

Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.

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

Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings.

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened three forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to: (i) identify areas of consensus among experts; (ii) define activities and resources required for the implementation of findings into practice; and (iii) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma.