Explore the vast range of titles available.

The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

This retrospective study developed an automated algorithm for 3D segmentation of adipose tissue and paravertebral muscle on chest CT using artificial intelligence (AI) and assessed its feasibility. The study included patients from the Boston Lung Cancer Study (2000–2011). For adipose tissue quantification, 77 patients were included, while 245 were used for muscle quantification. The data were split into training and test sets, with manual segmentation as the ground truth. Subcutaneous and visceral adipose tissues (SAT and VAT) were segmented separately. Muscle area, mean attenuation value, and intermuscular adipose tissue percentage (IMAT%) were calculated in the paravertebral muscle segmentation. The AI algorithm was trained on the training sets, and its performance was evaluated on the test sets. The AI achieved Dice scores above 0.87 and showed excellent correlations for VAT/SAT ratios, muscle attenuation value, and IMAT% (correlation coefficients > 0.98, p  < 0.001). The mean differences between the AI and ground truth were minimal (VAT/SAT ratio: 0.7%; muscle attenuation value: 1 HU; IMAT%: <1%). In conclusion, we developed a feasible AI algorithm for automated 3D segmentation of adipose tissue and paravertebral muscle on chest CT.

To assess changes in right heart flow and pulmonary artery hemodynamics in patients with repaired Tetralogy of Fallot (rTOF) we used whole heart, four dimensional (4D) velocity mapping (VM) cardiovascular magnetic resonance (CMR). CMR studies were performed in 11 subjects with rTOF (5M/6F; 20.1 ± 12.4 years) and 10 normal volunteers (6M/4F; 34.2 ± 13.4 years) on clinical 1.5T and 3.0T MR scanners. 4D VM-CMR was performed using PC VIPR (Phase Contrast Vastly undersampled Isotropic Projection Reconstruction). Interactive streamline and particle trace visualizations of the superior and inferior vena cava (IVC and SVC, respectively), right atrium (RA), right ventricle (RV), and pulmonary artery (PA) were generated and reviewed by three experienced readers. Main PA net flow, retrograde flow, peak flow, time-to-peak flow, peak acceleration, resistance index and mean wall shear stress were quantified. Differences in flow patterns between the two groups were tested using Fisher’s exact test. Differences in quantitative parameters were analyzed with the Kruskal-Wallis rank sum test. 4D VM-CMR was successfully performed in all volunteers and subjects with TOF. Right heart flow patterns in rTOF subjects were characterized by (a) greater SVC/IVC flow during diastole than systole, (b) increased vortical flow patterns in the RA and in the RV during diastole, and (c) increased helical or vortical flow features in the PA's. Differences in main PA retrograde flow, resistance index, peak flow, time-to-peak flow, peak acceleration and mean wall shear stress were statistically significant. Whole heart 4D VM-CMR with PC VIPR enables detection of both normal and abnormal right heart flow patterns, which may allow for comprehensive studies to evaluate interdependencies of post-surgically altered geometries and hemodynamics.

ObjectivesRecent studies with lung MRI (MRI) have shown high sensitivity (Sn) and specificity (Sp) for lung nodule detection and characterization relative to low-dose CT (LDCT). Using this background data, we sought to compare the potential screening performance of MRI vs. LDCT using a Markov model of lung cancer screening.MethodsWe created a Markov cohort model of lung cancer screening which incorporated lung cancer incidence, progression, and mortality based on gender, age, and smoking burden. Sensitivity (Sn) and Sp for LDCT were taken from the MISCAN Lung Microsimulation and Sn/Sp for MRI was estimated from a published substudy of the German Lung Cancer Screening and Intervention Trial. Screening, work-up, and treatment costs were estimated from published data. Screening with MRI and LDCT was simulated for a cohort of male and female smokers (2 packs per day; 36 pack/years of smoking history) starting at age 60. We calculated the screening performance and cost-effectiveness of MRI screening and performed a sensitivity analysis on MRI Sn/Sp and cost.ResultsThere was no difference in life expectancy between MRI and LDCT screening (males 13.28 vs. 13.29 life-years; females 14.22 vs. 14.22 life-years). MRI had a favorable cost-effectiveness ratio of$258,169 in men and $ 403,888 in women driven by fewer false-positive screens. On sensitivity analysis, MRI remained cost effective at screening costs <$396 dollars and Sp > 81%.ConclusionsIn this Markov model of lung cancer screening, MRI has a near-equivalent life expectancy benefit and has superior cost-effectiveness relative to LDCT.Key Points• In this Markov model of lung cancer screening, there is no difference in mortality between yearly screening with MRI and low-dose CT.• Compared to low-dose CT, screening with MRI led to a reduction in false-positive studies from 26 to 2.8% in men and 26 to 2.6% in women.• Due to similar life-expectancy and reduced false-positive rate, we found a favorable cost-effectiveness ratio of $ 258,169 in men and $403,888 in women of MRI relative to low-dose CT.

Abstract Background: Four computed tomography (CT) imaging-based clusters have been identified in a study of the Severe Asthma Research Program (SARP) cohort and have been significantly correlated with clinical and demographic metrics (J Allergy Clin Immunol 2017; 140:690–700.e8). We used a computational fluid dynamics (CFD) model to investigate air flow and aerosol deposition within imaging archetypes representative of the four clusters. Methods: CFD simulations for air flow and 1–8 μm particle transport were performed using CT-based airway models from two healthy subjects and eight asthma subjects. The subject selection criterion was based on the discriminant imaging-based flow-related variables of J(Total) (average local volume expansion in the total lung) and Dh*(sLLL) (normalized airway hydraulic diameter in the left lower lobe), where reduced J(Total) and Dh*(sLLL) indicate reduced regional ventilation and airway constriction, respectively. The analysis focused on the comparisons between all clusters with respect to healthy subjects, between cluster 2 and cluster 4 (nonsevere and severe asthma clusters with airway constriction) and between cluster 3 and cluster 4 (two severe asthma clusters characterized by normal and constricted airways, respectively). Results: Nonsevere asthma cluster 2 and severe asthma cluster 4 subjects characterized by airway constriction had an increase in the deposition fraction (DF) in the left lower lobe. Constricted flows impinged on distal bifurcations resulting in large depositions. Although both cluster 3 (without constriction) and cluster 4 (with constriction) were severe asthma, they exhibited different particle deposition patterns with increasing particle size. The statistical analysis showed that Dh*(sLLL) plays a more important role in particle deposition than J(Total), and regional flow fraction is correlated with DF among lobes for smaller particles. Conclusions: We demonstrated particle deposition characteristics associated with cluster-specific imaging-based metrics such as airway constriction, which could pertain to the design of future drug delivery improvements.

Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell‐based screening of FDA‐approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum , while in mice infected with a highly virulent multidrug‐resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR‐independent pathway controlled by cellular depletion of myo‐inositol. While strain‐specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug‐resistant mycobacterial infection. Synopsis Carbamazepine reveals a novel mechanism of mTOR‐independent control of autophagy that may be manipulated pharmacologically and provides proof of principle that therapeutic autophagy stimulation can be an effective strategy to treat multidrug‐resistant tuberculosis. Functional screening of FDA‐approved drugs identified two anticonvulsants, carbamazepine and valproic acid, capable of enhancing autophagic killing of mycobacteria from primary human monocyte derived and alveolar macrophages. In vivo , carbamazepine enhanced clearance of M. marinum from zebrafish and multidrug‐resistant M. tuberculosis from mice at drug concentrations achievable in man during therapeutic dosing. Carbamazepine stimulates autophagy by blocking myo‐inositol uptake in macrophages, leading to decreased phosphatidylinositol, inositol trisphosphate, and cellular ATP but activation of AMP kinase. Graphical Abstract Carbamazepine reveals a novel mechanism of mTOR‐independent control of autophagy that may be manipulated pharmacologically and provides proof of principle that therapeutic autophagy stimulation can be an effective strategy to treat multidrug‐resistant tuberculosis.

Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum , mycobacterium-induced STAT activity triggered by unpaired -family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila . Cytokines and their associated pathways can affect survival of Mycobacterium tuberculosis in macrophages, representing potential targets for host-directed therapies. Here, Péan et al . show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplet homeostasis.

Bronchoscopy is not conventionally guided by prior knowledge of segmental airway obstruction. Hyperpolarized gas magnetic resonance imaging (MRI) ventilation abnormalities and computed tomography (CT) air trapping are related to lung function and asthma severity but have not been used to target segmental inflammation and remodeling. We evaluate the feasibility of using bronchoscopy guided by 3He MRI and CT to reveal differences in inflammatory response, morphology, and cellular activity in poorly‐ (defect) versus well‐ventilated (control) lung regions. Eleven participants (5 female; age, 22.8 ± 3.4 years; 9 asthma) who experienced a cold with increased lower airway symptoms underwent 3He MRI and/or CT at least 6 weeks after recovery. Differences between defect and control regions were compared. In defect as compared to control sites, bronchoalveolar lavage neutrophils (p = 0.06) and granulocytes (p = 0.08) trended towards an increase; inflammatory mediators (i.e., 15‐epi‐LXA4, LXA4) were also significantly different (p < 0.05) between sites. Correlations were observed between macrophages, neutrophils, and eosinophils with inflammatory mediators (i.e., 15‐epi‐LXA4, LXA4, LTB4). Correlations were observed for macrophages and neutrophils with 15‐epi‐LXA4, and eosinophils with LXA4 and leukotriene B4. Basement membrane wall thickness was similar for defect versus control sites (p = 0.9). These results support the feasibility of image‐guided methods to identify airway obstruction phenotypes. Image guided bronchoscopy using MRI and CT (Methods, left) can identify regions of airway injury (Results, right) to evaluate cellular and molecular phenotypes of asthma.

BackgroundHyperpolarized helium 3 magnetic resonance imaging (3He MRI) is useful for investigating pulmonary physiology of pediatric asthma, but a detailed assessment of the safety profile of this agent has not been performed in children.ObjectiveTo evaluate the safety of 3He MRI in children and adolescents with asthma.Materials and methodsThis was a retrospective observational study. 3He MRI was performed in 66 pediatric patients (mean age 12.9 years, range 8–18 years, 38 male, 28 female) between 2007 and 2017. Fifty-five patients received a single repeated examination and five received two repeated examinations. We assessed a total of 127 3He MRI exams. Heart rate, respiratory rate and pulse oximetry measured oxygen saturation (SpO2) were recorded before, during (2 min and 5 min after gas inhalation) and 1 h after MRI. Blood pressure was obtained before and after MRI. Any subjective symptoms were also noted. Changes in vital signs were tested for significance during the exam and divided into three subject age groups (8–12 years, 13–15 years, 16–18 years) using linear mixed-effects models.ResultsThere were no serious adverse events, but three minor adverse events (2.3%; headache, dizziness and mild hypoxia) were reported. We found statistically significant increases in heart rate and SpO2 after 3He MRI. The youngest age group (8–12 years) had an increased heart rate and a decreased respiratory rate at 2 min and 5 min after 3H inhalation, and an increased SpO2 post MRI.ConclusionThe use of 3He MRI is safe in children and adolescents with asthma.

Our aim was to validate the previously published claim of a positive relationship between low blood hemoglobin level (anemia) and pulmonary embolism (PE). This was a retrospective study of patients undergoing cross-sectional imaging to evaluate for PE at an academic medical center. Patients were identified using billing records for charges attributed to either magnetic resonance angiography or computed tomography angiography of the chest from 2008 to 2013. The main outcome measure was mean hemoglobin levels among those with and without PE. Our reference standard for PE status included index imaging results and a 6-month clinical follow-up for the presence of interval venous thromboembolism, conducted via review of the electronic medical record. Secondarily, we performed a subgroup analysis of only those patients who were seen in the emergency department. Finally, we again compared mean hemoglobin levels when limiting our control population to an age- and sex-matched cohort of the included cases. There were 1294 potentially eligible patients identified, of whom 121 were excluded. Of the remaining 1173 patients, 921 had hemoglobin levels analyzed within 24 hours of their index scan and thus were included in the main analysis. Of those 921 patients, 107 (11.6%; 107/921) were positive for PE. We found no significant difference in mean hemoglobin level between those with and without PE regardless of the control group used (12.4 ± 2.1 g/dL and 12.3 ± 2.0 g/dL [P = .85], respectively). Our data demonstrated no relationship between anemia and PE.