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Competing Interests: Financial/Nonfinancial Disclosures None declared.

Airway mucus is a hydrogel with unique biophysical properties due to its primary water composition and a small proportion of large anionic glycoproteins or mucins. The predominant mucins in human mucus, MUC5AC and MUC5B, are secreted by specialized cells within the airway epithelium both in normal conditions and in response to various stimuli. Their relative proportions are correlated with specific inflammatory responses and disease mechanisms. The dysregulation of mucin expression is implicated in numerous respiratory diseases, including asthma, COPD, and cystic fibrosis, where the pathogenic role of mucus has been extensively described yet often overlooked. In airway diseases, excessive mucus production or impaired mucus clearance leads to mucus plugging, with secondary airway occlusion that contribute to airflow obstruction, asthma severity and poor control. Eosinophils and Charcot Leyden crystals in sputum contribute to the mucus burden and tenacity. Mucin may also contribute to eosinophil survival. Other mechanisms, including eosinophil-independent IL-13 release, mast-cell activation and non-type-2 (T2) cytokines, are also likely to participate in mucus pathobiology. An accurate assessment of mucus and its clinical and functional consequences require a thorough approach that includes evaluation of cellular predominance in sputum, airway cytokines and other inflammatory markers, mucus characteristics and composition and structural and functional impact measured by advanced lung imaging. This review, illustrated with clinical scenarios, provides an overview of current methods to assess mucus and its relevance to the choice of biologics to treat patients with severe asthma., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Airway wall thickening and excess airway mucus occur in asthma and chronic obstructive pulmonary disease (COPD), but few studies have investigated the relationship between them. Our objective was to determine the association between computed tomography (CT) airway wall thickening in segmental airways proximal to airways with or without mucus plugging in patients with asthma and COPD., Methods: Mucus plugging was scored using a CT bronchopulmonary segment-based scoring system in asthma and COPD patients. For each of the 19 segmental airways, a mucus plug was defined as complete occlusion of one or more of the daughter branches (sub-segmental airways) by mucus. CT airway measurements were generated for each of the 19 segmental airways: wall-area-percentage (WA%), lumen area (LA), and total airway count (TAC) (VIDA Diagnostics Inc.). Multivariable logistic regression models were constructed for the presence of mucus plugs with corresponding CT measurement and adjusted by covariates; each of the 19 segments was treated as a nested variable., Results: A total of 33 participants were evaluated. Participants had a mean age of 60 ± 15yrs and there were n = 14 (42%) males. There were 16 (48%) participants with a diagnosis of asthma and 17 (52%) with a COPD diagnosis. The mean FEV 1 was 53 ± 21%pred and FEV 1 /FVC was 54 ± 15%. The mean mucus score in all participants was 15 ± 4 (min = 0, max = 19). Multivariable logistic regression analysis showed the presence of airway mucus was significantly associated with increased CT WA% (β = 7.30, p = 0.004) and reduced TAC (β = -0.06, p = 0.045)., Conclusions: There was increased airway wall thickness and reduced airway counts on CT in segments where there was a distal mucus plug compared to segments without mucus plugs in asthma and COPD., Competing Interests: Declaration of competing interest TH reports grants from Fisher and Paykel and personal fees from Sanofi, outside the submitted work. PN reports grants from AstraZeneca, Teva, Roche, Novartis, Sanofi and Foresee, and personal fees from AstraZeneca, Teva, Roche, Novartis, Merck and Equillium, outside the submitted work. SS reports grants from Cyclomedica and personal fees from AstraZeneca, Novartis, Polarean, and Arrowhead Pharmaceuticals, all outside the submitted work. All other authors do not have any potential conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Patients with eosinophilic asthma often report poor symptomatic control and quality of life. Anti-IL-5 therapy, including anti-IL-5Rα (benralizumab), rapidly depletes eosinophils in the blood and airways and also reduces asthma exacerbations and improves quality of life scores. In patients with severe asthma, eosinophilic inflammation-driven airway mucus occlusions have been measured using thoracic x-ray CT imaging. Pulmonary 129 Xe MRI ventilation defect percentage (VDP) also sensitively measures asthma airway dysfunction caused by airway hyperresponsiveness, remodeling, and luminal mucus occlusions. Using 129 Xe MRI and CT imaging together, it is feasible to measure both airway luminal occlusions and airway ventilation in relationship to anti-IL-5 therapy to ascertain the direct impact of therapy-induced eosinophil depletion on airway function., Research Question: Does 129 Xe MRI detect airway functional responses to eosinophil depletion after a single benralizumab dose and do airway mucus occlusions mediate this response?, Study Design and Methods: MRI, eosinophil count, spirometry, oscillometry, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and St. George's Respiratory Questionnaire were completed on day 0 and 28 days after a single 30-mg subcutaneous benralizumab dose. CT scan mucus plugs were scored on day 0, and MRI VDP was quantified on days 0 and 28., Results: Twenty-nine participants (27 with baseline CT imaging) completed day 0 and day 28 visits. On day 28 after a single benralizumab dose, significantly improved blood eosinophil counts, VDP, ACQ 6 scores, AQLQ scores (all P < .001), and peripheral airway resistance (P = .04) were found in all participants. On day 28, significantly improved VDP and ACQ 6 scores also were found in the subgroup of nine participants with five or more mucus plugs, but not in the subgroup (n = 18) with fewer than five mucus plugs. Based on univariate relationships for change in ACQ 6 score, multivariate models were generated and showed that day 0 VDP (P < .001) and day 0 CT scan mucus score (P < .001) were significant variables for change in ACQ 6 score on day 28 after benralizumab injection., Interpretation: 129 Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab., Trial Registry: ClinicalTrials.gov; No.: NCT03733535; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum eosinophilia and may be due to eosinophil-driven airway pathology that is responsive to "anti-T2" therapy., Research Question: Do anti-T2 therapies that clear eosinophils from the airway lumen decrease ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma?, Study Design and Methods: Inhaled hyperpolarized gas MRI was performed before and after bronchodilation in 10 prednisone-dependent patients with asthma with uncontrolled eosinophilic bronchitis (sputum eosinophils ≥3%) at baseline and 558 (100-995) days later when their eosinophilic bronchitis had been controlled (sputum eosinophils <3%) by additional anti-T2 therapy. The effect of anti-T2 therapy on ventilation defects, quantified as the MRI ventilation-defect-percent (VDP), was evaluated before and after bronchodilation for all patients and compared between patients dichotomized based on the median percentage of sputum eosinophils at baseline (15.8%)., Results: MRI VDP was improved pre- (ΔVDP +anti-T2 : -3% ± 4%, P = .02) and post-bronchodilator (ΔVDP +anti-T2 : -3% ± 4%; P = .04) after additional anti-T2 therapy that controlled eosinophilic bronchitis (n = 2 mepolizumab, n = 2 reslizumab, n = 3 benralizumab, n = 1 dupilumab, n = 2 increased daily prednisone). A greater post-bronchodilator ΔVDP +anti-T2 was observed in those patients with median or higher percentage of sputum eosinophils at baseline (≥15.8%; P = .01). In 7 of 10 patients with asthma, residual ventilation defects persisted despite bronchodilator and anti-T2 therapy., Interpretation: Controlling sputum eosinophilia with anti-T2 therapies improves ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Recent pulmonary functional MRI findings of spatially and temporally persistent ventilation abnormalities in patients with asthma contrast with previous in silico modeling studies that suggest that in asthma, ventilation defects may be randomly distributed. In a case study that used pulmonary MRI, CT imaging, and pulmonary function tests, we prospectively evaluated over the course of 7 years, nonidentical female adult twins, each with a lifelong history of asthma. We evaluated pulmonary function and MRI ventilation heterogeneity at baseline and follow-up after 7 years. In both twins, there was a spatially identical MRI ventilation defect and an abnormal subsegmental left-sided upper lobe airway that persisted in the same spatial location after 7 years. If ventilation defects are randomly distributed, this bears a probability of approximately one per 130,000 people. Our MRI observations in related patients with asthma suggest that ventilation abnormalities may not be randomly distributed in patients with asthma and persist distal to airway abnormalities for long periods of time., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Intraluminal contributor(s) to airflow obstruction in severe asthma are patient-specific and must be evaluated to personalize treatment. The occurrence and functional consequence of airway mucus in the presence or absence of airway eosinophils remain undetermined., Objective: The objective of this study was to understand the functional consequence of airway mucus in the presence or absence of eosinophils and to identify biomarkers of mucus-related airflow obstruction., Methods: Mucus plugs were quantified on CT scans, and their contribution to ventilation heterogeneity (using MRI ventilation defect percent [VDP]) was evaluated in 27 patients with severe asthma. Patients were dichotomized based on sputum eosinophilia such that the relationship between mucus, eosinophilia, and ventilation heterogeneity could be investigated. Fractional exhaled nitric oxide (Feno) and related cytokines in sputum were measured., Results: Mucus plugging was present in 100% of asthma patients with sputum eosinophils and 36% of those without sputum eosinophils (P = .0006) and was correlated with MRI VDP prebronchodilator (r = 0.68; P = .0001) and postbronchodilator (r = 0.72; P < .0001). In a multivariable regression, both mucus and eosinophils contributed to the prediction of postbronchodilator MRI VDP (R 2  = 0.75; P < .0001). Patients with asthma in whom the mucus score was high had raised Feno (P = .03) and IL-4 (P = .02) values. Mucus plugging correlated with Feno (r = 0.63; P = .005)., Conclusions: Both airway eosinophils and mucus can contribute to ventilation heterogeneity in patients with severe asthma. Patients in whom mucus is the dominant cause of airway obstruction have evidence of an upregulated IL-4/IL-13 pathway that could be identified according to increased Feno level., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Pulmonary imaging using hyperpolarized (3)He/(129)Xe gas is emerging as a new way to understand the regional nature of pulmonary ventilation abnormalities in obstructive lung diseases. However, the quantitative information derived is completely dependent on robust methods to segment both functional and structural/anatomical data. Here, we propose an approach to jointly segment the lung cavity from (1)H and (3)He pulmonary magnetic resonance images (MRI) by constraining the spatial consistency of the two segmentation regions, which simultaneously employs the image features from both modalities. We formulated the proposed co-segmentation problem as a coupled continuous min-cut model and showed that this combinatorial optimization problem can be solved globally and exactly by means of convex relaxation. In particular, we introduced a dual coupled continuous max-flow model to study the convex relaxed coupled continuous min-cut model under a primal and dual perspective. This gave rise to an efficient duality-based convex optimization algorithm. We implemented the proposed algorithm in parallel using general-purpose programming on graphics processing unit (GPGPU), which substantially increased its computational efficiency. Our experiments explored a clinical dataset of 25 subjects with chronic obstructive pulmonary disease (COPD) across a wide range of disease severity. The results showed that the proposed co-segmentation approach yielded superior performance compared to single-channel image segmentation in terms of precision, accuracy and robustness., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We have examined expression of the lambdacI operon in single cells via a rex Colon, two colons gfp substitution. Although average fluorescence agreed with expectations for expression of lambda-repressor, fluorescence fluctuated greatly from cell-to-cell. Fluctuations in repressor concentration are not predicted by previous models and are tolerated in part by a regulatory response to DNA damage.