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Background: This study evaluated the prevalence of Helicobacter pylori infection and the risk factors associated with H. pylori transmission among spouses.Methods: We assessed the spousal concurrence of H. pylori infection using the Campylobacter-like organism (CLO) test under gastro-endoscopy in 132 couples. Based on the CLO test results, participants were categorized into H. pylori concurrent and independent groups. The chi-square test and Student t-test were performed for demographic comparisons between the concurrent and independent H. pylori groups. In addition, multivariate logistic regression analysis was performed to identify factors associated with concurrent H. pylori infection.Results: The study revealed that the concurrence rate of H. pylori infection was 42.4% in married Korean couples. The odds ratio (OR) derived from the concurrence of H. pylori infection tended to decrease in older couples (OR, 0.975; 95% confidence interval [CI], 0.949–1.002; P=0.072). Gastric erosion was also associated with a decreased OR for concurrent infection (OR, 0.488; 95% CI, 0.295–0.808; P=0.005). Conversely, active duodenal ulcers were associated with an increased OR for concurrent infections (OR, 6.501; 95% CI, 1.267–33.346; P=0.025). Duodenal ulcer scars tended to increase the OR of concurrent infections (OR, 1.392; 95% CI, 0.815–2.380; P=0.226).Conclusion: Spousal transmission and concurrence of H. pylori infection were negatively associated with gastric erosion; however, they were positively associated with active duodenal ulcers. Further studies are warranted to elucidate the mechanisms underlying these findings.

Image registration-based local displacement analysis enables evaluation of respiratory motion between two computed tomography-captured lung volumes. The objective of this study was to compare diaphragm movement among emphysema, idiopathic pulmonary fibrosis (IPF) and normal subjects. 29 normal, 50 emphysema, and 51 IPF subjects were included. A mass preserving image registration technique was used to compute displacement vectors of local lung regions at an acinar scale. Movement of the diaphragm was assumed to be equivalent to movement of the basal lung within 5 mm from the diaphragm. Magnitudes and directions of displacement vectors were compared between the groups. Three-dimensional (3D) and apico-basal displacements were smaller in emphysema than normal subjects (P = 0.003, P = 0.002). Low lung attenuation area on expiration scan showed significant correlations with decreased 3D and apico-basal displacements (r = − 0.546, P P P P

In vivo presentation of airway hyper-responsiveness (AHR) at the different time points of the allergic reaction is not clearly understood. The purpose of this study was to investigate how AHR manifests in the airway and the lung parenchyma in vivo following exposure to different stimuli and in the early and late phases of asthma after allergen exposure. Ovalbumin (OVA)-induced allergic asthma model was established using 6-week female BALB/c mice. Enhanced pause was measured with a non-invasive method to assess AHR. The dynamic changes of the airway and lung parenchyma were evaluated with ultra-high-resolution computed tomography (128 multi-detector, 1024 × 1024 matrix) for 10 h. While the methacholine challenge showed no grossly visible changes in the proximal airway and lung parenchyma despite provoking AHR, the OVA challenge induced significant immediate changes manifesting as peribronchial ground glass opacities, consolidations, air-trapping, and paradoxical proximal airway dilatations. After resolution of immediate response, multiple episodes of AHRs occurred with paradoxical proximal airway dilatation and peripheral air-trapping in late phase over a prolonged time period in vivo. Understanding of airflow limitation based on the structural changes of asthmatic airway would be helpful to make an appropriate drug delivery strategy for the treatment of asthma.

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 D(h)*(sLLL) (normalized airway hydraulic diameter in the left lower lobe), where reduced J(Total) and D(h)*(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 D(h)*(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.

Background Previous studies suggested that the prone position (PP) improves oxygenation and reduces mortality among patients with acute respiratory distress syndrome (ARDS). However, the mechanism of this clinical benefit of PP is not completely understood. The aim of the present study was to quantitatively compare regional characteristics of lung functions in the PP with those in the supine position (SP) using inspiratory and expiratory computed tomography (CT) scans. Methods Ninety subjects with normal pulmonary function and inspiration and expiration CT images were included in the study. Thirty-four subjects were scanned in PP, and 56 subjects were scanned in SP. Non-rigid image registration-based inspiratory-expiratory image matching assessment was used for regional lung function analysis. Tissue fractions (TF) were computed based on the CT density and compared on a lobar basis. Three registration-derived functional variables, relative regional air volume change (RRAVC), volumetric expansion ratio (J), and three-dimensional relative regional displacement (s*) were used to evaluate regional ventilation and deformation characteristics. Results J was greater in PP than in SP in the right middle lobe (P = 0 .025), and RRAVC was increased in the upper and right middle lobes (P J, and RRAVC at the upper lobes to those at the middle and lower lobes and that ratio at the upper and middle lobes to those at the lower lobes of were all near unity in PP, and significantly higher than those in SP (0.98–1.06 vs 0.61–0.94, P Conclusion We visually and quantitatively observed that PP not only induced more uniform contributions of regional lung ventilation along the ventral-dorsal axis but also minimized the lobar differences of lung functions in comparison with SP. This may help in the clinician’s search for an understanding of the benefits of the application of PP to the patients with ARDS or other gravitationally dependent pathologic lung diseases. Trial registration Retrospectively registered.

Multiple combination therapies with chemotherapeutic drugs and inhibitors of drug resistance have been effective in the clinical cases, but concerns have been raised about the severe toxicity of these chemotherapeutic drugs. Herein, we report a potent and safe combination strategy of cancer-specific doxorubicin (DOX) prodrug nanoparticles (PNPs) and B-cell lymphoma-2 (Bcl-2) anti-apoptotic inhibitor, Navitoclax, to overcome acquired drug resistance during chemotherapy. The cancer-specific PNPs were constructed by conjugating cathepsin B-specific cleavable peptide (Phe-Arg-Arg-Gly; FRRG) to DOX, resulting in FRRG-DOX that self-assembled into nanoparticles and the FRRG-DOX nanoparticles were further stabilized with the FDA-approved pharmaceutical excipient, Pluronic F68. The resulting PNPs are specifically cleaved and metabolized to free DOX in cathepsin B-overexpressing cancer cells, but they exhibited minimal cytotoxicity in cathepsin B-deficient normal cells. As expected, free DOX and PNPs induced overexpression of Bcl-2 in MDA-MB-231 cells, due to acquired drug resistance in a cell culture system. However, combination therapy with PNPs and Navitoclax showed the outstanding synergetic cytotoxicity by decreasing the expression level of Bcl-2. In MDA-MB231 breast tumor-bearing mice, intravenously injected PNPs efficiently accumulated in targeted tumor tissues via enhanced permeability and retention (EPR) effect. When combined with orally administered Navitoclax, PNPs exhibited more potent therapeutic efficacy in aquired drug resistant models than free DOX plus Navitoclax, whereas PNPs greatly reduced systemic toxic side effects in normal organs. Our cancer-specific PNP-based combination therapy with Bcl-2 inhibitor may provide a promising approach for the potent and safe treatment of acquired drug-resistant cancers.

Background Dust exposure has been reported as a risk factor of pulmonary disease, leading to alterations of segmental airways and parenchymal lungs. This study aims to investigate alterations of quantitative computed tomography (QCT)-based airway structural and functional metrics due to cement-dust exposure. Methods To reduce confounding factors, subjects with normal spirometry without fibrosis, asthma and pneumonia histories were only selected, and a propensity score matching was applied to match age, sex, height, smoking status, and pack-years. Thus, from a larger data set (N = 609), only 41 cement dust-exposed subjects were compared with 164 non-cement dust-exposed subjects. QCT imaging metrics of airway hydraulic diameter (Dh), wall thickness (WT), and bifurcation angle (θ) were extracted at total lung capacity (TLC) and functional residual capacity (FRC), along with their deformation ratios between TLC and FRC. Results In TLC scan, dust-exposed subjects showed a decrease of Dh (airway narrowing) especially at lower-lobes (p p θ at most of the central airways (p p θ at the right main bronchi and left main bronchi (p Conclusions Dust-exposed subjects with normal spirometry demonstrated airway narrowing at lower-lobes, wall thickening at all segmental airways, a different bifurcation angle at central airways, and a loss of airway wall elasticity at lower-lobes. The airway structural alterations may indicate different airway pathophysiology due to cement dusts.

Background Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. Methods Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. Results Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. Conclusions Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.

Objectives The purpose of this study was to investigate regional air volume changes at the acinar scale of the lung in chronic obstructive pulmonary disease (COPD) patients using an image registration technique. Materials and Methods Thirty-four emphysema patients and 24 subjects with normal chest CT and pulmonary function test (PFT) results were included in this retrospective study for which informed consent was waived by the institutional review board. After lung segmentation, a mass-preserving image registration technique was used to compute relative regional air volume changes (RRAVCs) between inspiration and expiration CT scans. After determining the appropriate thresholds of RRAVCs for low ventilation areas (LVAs), they were displayed and analyzed using color maps on the background inspiration CT image, and compared with the low attenuation area (LAA) map. Correlations between quantitative CT parameters and PFTs were assessed using Pearson's correlation test, and parameters were compared between emphysema and normal-CT patients using the Student's t-test. Results LVA percentage with an RRAVC threshold of 0.5 (%LVA0.5) showed the strongest correlations with FEV1/FVC (r = −0.566), FEV1 (r = −0.534), %LAA-950insp (r = 0.712), and %LAA-856exp (r = 0.775). %LVA0.5 was significantly higher (P Conclusion RRAVC-based %LVA0.5 correlated well with FEV1/FVC, FEV1, %LAA-950insp and %LAA-856exp. RRAVC holds the potential for providing additional acinar scale functional information for emphysematous LAAs in inspiratory CT images, providing the basis for a novel set for emphysematous phenotypes.

Intraperitoneal (IP) chemotherapy has shown promising efficacy in ovarian cancer with peritoneal carcinomatosis (PC), but in vivo rapid clearance and severe toxicity of free anticancer drugs hinder the effective treatment. Herein, we propose the safe and effective IP chemotherapy with cathepsin B-specific doxorubicin prodrug nanoparticles (PNPs) in ovarian cancer with PC. The PNPs are prepared by self-assembling cathepsin B-specific cleavable peptide (FRRG) and doxorubicin (DOX) conjugates, which are further formulated with pluronic F68. The PNPs exhibit stable spherical structure and cytotoxic DOX is specifically released from PNPs via sequential enzymatic degradation by cathepsin B and intracellular proteases. The PNPs induce cytotoxicity in cathepsin B-overexpressing ovarian (SKOV-3 and HeyA8) and colon (MC38 and CT26) cancer cells, but not in cathepsin B-deficient normal cells in cultured condition. With enhanced cancer-specificity and in vivo residence time, IP injected PNPs efficiently accumulate within PC through two targeting mechanisms of direct penetration (circulation independent) and systemic blood vessel-associated accumulation (circulation dependent). As a result, IP chemotherapy with PNPs efficiently inhibit tumor progression with minimal side effects in peritoneal human ovarian tumor-bearing xenograft (POX) and patient derived xenograft (PDX) models. These results demonstrate that PNPs effectively inhibit progression of ovarian cancer with peritoneal carcinomatosis with minimal local and systemic toxicities by high cancer-specificity and favorable in vivo PK/PD profiles enhancing PC accumulation.

The effective chemotherapeutic drug, doxorubicin (DOX), elicits immunogenic cell death (ICD) and additional anticancer immune responses during chemotherapy. However, it also induces severe side effects and systemic immunosuppression, hampering its wide clinical application. Herein, we constructed cancer-activated DOX prodrug by conjugating the cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in FRRG-DOX that self-assembled into cancer-activated DOX prodrug nanoparticles (CAP-NPs). The resulting CAP-NPs were further stabilized with the FDA-approved compound, Pluronic F68. CAP-NPs formed stable prodrug nanoparticles and they were specifically cleaved to cytotoxic DOX molecules only in cathepsin B-overexpressing cancer cells, inducing a cancer cell-specific cytotoxicity. In particular, the CAP-NPs induced ICD through cathepsin B-cleavage mechanism only in targeted cancer cells in vitro. In colon tumor-bearing mice, selectively accumulated CAP-NPs at tumors enhanced antitumor immunity without DOX-related severe toxicity, inflammatory response and systemic immunosuppression. Moreover, cytotoxicity against immune cells infiltrated into tumor microenvironment was significantly reduced compared to free DOX, leading to increased response to checkpoint inhibitor immunotherapy. The combinatorial treatment of CAP-NPs with anti-PD-L1 exhibited high rate of complete tumor regression (50%) compared to free DOX with anti-PD-L1. Concurrently, DOX-related side effects were greatly reduced during chemoimmunotherapy. Collectively, our results suggest that cancer-activated DOX prodrug nanoparticles provide a promising approach to increase clinical benefit by inducing an immune response preferentially only to targeted cancer cells, not to normal cells and immune cells, and potentiates checkpoint inhibitor immunotherapy.

With the help of quantitative computed tomography (QCT), it is possible to identify smoking-associated airway remodeling. However, there is currently little information on whether QCT-based airway metrics are sensitive to early airway wall remodeling in subclinical phases of smoking-associated airway disease. This study aimed to evaluate a predictive model that normalized airway parameters and investigate structural airway alterations in smokers with normal-looking CT using the normalization scheme.In this retrospective analysis, 222 non-smokers (male 97, female 125) and 69 smokers (male 66, female 3) from January 2014 to December 2016 were included, and airway parameters were quantitatively analyzed. To control inter-subject variability, multiple linear regressions of tracheal wall thickness (WT), diameter (D), and luminal area (LA) were performed, adjusted for age, sex, and height. Using this normalization scheme, airway parameters with matched generation were compared between smokers and non-smokers.Using the normalization scheme, it was possible to assess generation-based structural alterations of the airways in subclinical smokers. Smokers showed diffuse luminal narrowing of airways for most generations (P 0.05, except 3rd generation), no change in wall thickness of the proximal bronchi (1st-3rd generation), and a thinning of distal airways (P0.05, ≥4th generation).QCT assessment for subclinical smokers can help identify minimal structural changes in airways induced by smoking.

The purpose of this study was to explore new insights in non-linearity, hysteresis and ventilation heterogeneity of asthmatic human lungs using four-dimensional computed tomography (4D-CT) image data acquired during tidal breathing. Volumetric image data were acquired for 5 non-severe and one severe asthmatic volunteers. Besides 4D-CT image data, function residual capacity and total lung capacity image data during breath-hold were acquired for comparison with dynamic scans. Quantitative results were compared with the previously reported analysis of five healthy human lungs. Using an image registration technique, local variables such as regional ventilation and anisotropic deformation index (ADI) were estimated. Regional ventilation characteristics of non-severe asthmatic subjects were similar to those of healthy subjects, but different from the severe asthmatic subject. Lobar airflow fractions were also well correlated between static and dynamic scans (R2>0.84). However, local ventilation heterogeneity significantly increased during tidal breathing in both healthy and asthmatic subjects relative to that of breath-hold perhaps because of airway resistance present only in dynamic breathing. ADI was used to quantify non-linearity and hysteresis of lung motion during tidal breathing. Non-linearity was greater on inhalation than exhalation among all subjects. However, exhalation non-linearity among asthmatic subjects was greater than healthy subjects and the difference diminished during inhalation. An increase of non-linearity during exhalation in asthmatic subjects accounted for lower hysteresis relative to that of healthy ones. Thus, assessment of non-linearity differences between healthy and asthmatic lungs during exhalation may provide quantitative metrics for subject identification and outcome assessment of new interventions.

This study numerically investigates the effect of hygroscopicity on transport and deposition of particles in severe asthmatic lungs with distinct airway structures. The study human subjects were selected from two imaging-based severe asthmatic clusters with one characterized by non-constricted airways and the other by constricted airways in the lower left lobe (LLL). We compared the deposition fractions of sodium chloride (NaCl) particles with a range of aerodynamic diameters (1–8 μm) in cluster archetypes under conditions with and without hygroscopic growth. The temperature and water vapor distributions in the airways were simulated with an airway wall boundary condition that accounts for variable temperature and water vapor evaporation at the interface between the lumen and the airway surface liquid layer. On average, the deposition fraction increased by about 6% due to hygroscopic particle growth in the cluster subjects with constricted airways, while it increased by only about 0.5% in those with non-constricted airways. The effect of particle growth was most significant for particles with an initial diameter of 2 μm in the cluster subjects with constricted airways. The effect diminished with increasing particle size, especially for particles with an initial diameter larger than 4 μm. This suggests the necessity to differentiate asthmatic subjects by cluster in engineering the aerosol size for tailored treatment. Specifically, the treatment of severe asthmatic subjects who have constricted airways with inhalation aerosols may need submicron-sized hygroscopic particles to compensate for particle growth, if one targets for delivering to the peripheral region. These results could potentially inform the choice of particle size for inhalational drug delivery in a cluster-specific manner.

Background Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. Methods An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. Results We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. Conclusions QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes. Electronic supplementary material The online version of this article (10.1186/s12931-019-1121-z) contains supplementary material, which is available to authorized users.

Direct local delivery of immunogenic cell death (ICD) inducers to a tumor site is an attractive approach for leading ICD effectively, due to enabling the concentrated delivery of ICD inducers to the tumor site. Herein, we prepared doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using different molecular weight PLGA (7000 g/mol and 12,000 g/mol), showing different drug release kinetics. The different release kinetics of DOX might differently stimulate a tumor cell-specific immune response by releasing damage-associated molecular patterns (DAMPs), resulting in showing a different antitumor response in the living body. DOX-PLGA7K NPs showed faster DOX release kinetics than DOX-PLGA12K NPs in the physiological condition. DOX-PLGA7K NPs and DOX-PLGA12K NPs were successfully taken up by the CT-26 tumor cells, subsequently showing different DOX localization times at the nucleus. Released DOX successfully lead to cytotoxicity and HMGB1 release in vitro. Although the DOX-PLGA7K NPs and DOX-PLGA12K NPs showed different sustained DOX release kinetics in vitro, tumor growth of the CT-26 tumor was similarly inhibited for 28 days post-direct tumor injection. Furthermore, the immunological memory effect was successfully established by the ICD-based tumor-specific immune responses, including DC maturation and tumor infiltration of cytotoxic T lymphocytes (CTLs). We expect that the controlled release of ICD-inducible chemotherapeutic agents, using different types of nanomedicines, can provide potential in precision cancer immunotherapy by controlling the tumor-specific immune responses, thus improving the therapeutic efficacy.

This study aims to assess regional ventilation, nonlinearity, and hysteresis of human lungs during dynamic breathing via image registration of four-dimensional computed tomography (4D-CT) scans. Six healthy adult humans were studied by spiral multidetector-row CT during controlled tidal breathing as well as during total lung capacity and functional residual capacity breath holds. Static images were utilized to contrast static vs. dynamic (deep vs. tidal) breathing. A rolling-seal piston system was employed to maintain consistent tidal breathing during 4D-CT spiral image acquisition, providing required between-breath consistency for physiologically meaningful reconstructed respiratory motion. Registration-derived variables including local air volume and anisotropic deformation index (ADI, an indicator of preferential deformation in response to local force) were employed to assess regional ventilation and lung deformation. Lobar distributions of air volume change during tidal breathing were correlated with those of deep breathing ( R2 ≈ 0.84). Small discrepancies between tidal and deep breathing were shown to be likely due to different distributions of air volume change in the left and the right lungs. We also demonstrated an asymmetric characteristic of flow rate between inhalation and exhalation. With ADI, we were able to quantify nonlinearity and hysteresis of lung deformation that can only be captured in dynamic images. Nonlinearity quantified by ADI is greater during inhalation, and it is stronger in the lower lobes ( P < 0.05). Lung hysteresis estimated by the difference of ADI between inhalation and exhalation is more significant in the right lungs than that in the left lungs.

Introduction Quantitative CT (QCT) imaging-based metrics have quantified disease alterations in asthma and chronic obstructive pulmonary disease (COPD), respectively. We seek to characterise the similarity and disparity between these groups using QCT-derived airway and parenchymal metrics. Methods Asthma and COPD subjects (former-smoker status) were selected with a criterion of post-bronchodilator FEV1

Methacholine challenge tests are used to measure changes in pulmonary function that indicate symptoms of asthma. In addition to pulmonary function tests, which measure global changes in pulmonary function, computed tomography images taken at full inspiration before and after administration of methacholine provide local air volume changes (hyper-inflation post methacholine) at individual acinar units, indicating local airway hyperresponsiveness. Some of the acini may have extreme air volume changes relative to the global average, indicating hyperresponsiveness, and those extreme values may occur in clusters. We propose a Gaussian mixture model with a spatial smoothness penalty to improve prediction of hyperresponsive locations that occur in spatial clusters. A simulation study provides evidence that the spatial smoothness penalty improves prediction under different data-generating mechanisms. We apply this method to computed tomography data from Seoul National University Hospital on five healthy and ten asthmatic subjects. Copyright © 2017 John Wiley & Sons, Ltd.

ObjectivesExtra-thoracic tumors send out pilot cells that attach to the pulmonary endothelium. We hypothesized that this could alter regional lung mechanics (tissue stiffening or accumulation of fluid and inflammatory cells) through interactions with host cells. We explored this with serial inspiratory computed tomography (CT) and image matching to assess regional changes in lung expansion.Materials and methodsWe retrospectively assessed 44 pairs of two serial CT scans on 21 sarcoma patients: 12 without lung metastases and 9 with lung metastases. For each subject, two or more serial inspiratory clinically-derived CT scans were retrospectively collected. Two research-derived control groups were included: 7 normal nonsmokers and 12 asymptomatic smokers with two inspiratory scans taken the same day or one year apart respectively. We performed image registration for local-to-local matching scans to baseline, and derived local expansion and density changes at an acinar scale. Welch two sample t test was used for comparison between groups. Statistical significance was determined with a p value < 0.05.ResultsLung regions of metastatic sarcoma patients (but not the normal control group) demonstrated an increased proportion of normalized lung expansion between the first and second CT. These hyper-expanded regions were associated with, but not limited to, visible metastatic lung lesions. Compared with the normal control group, the percent of increased normalized hyper-expanded lung in sarcoma subjects was significantly increased (p < 0.05). There was also evidence of increased lung "tissue" volume (non-air components) in the hyper-expanded regions of the cancer subjects relative to non-hyper-expanded regions. "Tissue" volume increase was present in the hyper-expanded regions of metastatic and non-metastatic sarcoma subjects. This putatively could represent regional inflammation related to the presence of tumor pilot cell-host related interactions.ConclusionsThis new quantitative CT (QCT) method for linking serial acquired inspiratory CT images may provide a diagnostic and prognostic means to objectively characterize regional responses in the lung following oncological treatment and monitoring for lung metastases.

Objective Considering the different prevalence rates of diseases such as asthma and chronic obstructive pulmonary disease in Asians relative to other races, Koreans may have unique airway structure and lung function. This study aimed to investigate unique features of airway structure and lung function based on quantitative computed tomography (QCT)-imaging metrics in the Korean Asian population (Koreans) as compared with the White American population (Whites). Materials and Methods QCT data of healthy non-smokers (223 Koreans vs. 70 Whites) were collected, including QCT structural variables of wall thickness (WT) and hydraulic diameter (Dh) and functional variables of air volume, total air volume change in the lung (ΔVair), percent emphysema-like lung (Emph%), and percent functional small airway disease-like lung (fSAD%). Mann-Whitney U tests were performed to compare the two groups. Results As compared with Whites, Koreans had smaller volume at inspiration, ΔVair between inspiration and expiration (p < 0.001), and Emph% at inspiration (p < 0.001). Especially, Korean females had a decrease of ΔVair in the lower lobes (p < 0.001), associated with fSAD% at the lower lobes (p < 0.05). In addition, Koreans had smaller Dh and WT of the trachea (both, p < 0.05), correlated with the forced expiratory volume in 1 second (R = 0.49, 0.39; all p < 0.001) and forced vital capacity (R = 0.55, 0.45; all p < 0.001). Conclusion Koreans had unique features of airway structure and lung function as compared with Whites, and the difference was clearer in female individuals. Discriminating structural and functional features between Koreans and Whites enables exploration of inter-racial differences of pulmonary disease in terms of severity, distribution, and phenotype.

A novel algorithm is presented that links local structural variables (regional ventilation and deforming central airways) to global function (total lung volume) in the lung over three imaged lung volumes, to derive a breathing lung model for computational fluid dynamics simulation. The algorithm constitutes the core of an integrative, image-based computational framework for subject-specific simulation of the breathing lung. For the first time, the algorithm is applied to three multi-detector row computed tomography (MDCT) volumetric lung images of the same individual. A key technique in linking global and local variables over multiple images is an in-house mass-preserving image registration method. Throughout breathing cycles, cubic interpolation is employed to ensure C"1 continuity in constructing time-varying regional ventilation at the whole lung level, flow rate fractions exiting the terminal airways, and airway deformation. The imaged exit airway flow rate fractions are derived from regional ventilation with the aid of a three-dimensional (3D) and one-dimensional (1D) coupled airway tree that connects the airways to the alveolar tissue. An in-house parallel large-eddy simulation (LES) technique is adopted to capture turbulent-transitional-laminar flows in both normal and deep breathing conditions. The results obtained by the proposed algorithm when using three lung volume images are compared with those using only one or two volume images. The three-volume-based lung model produces physiologically-consistent time-varying pressure and ventilation distribution. The one-volume-based lung model under-predicts pressure drop and yields un-physiological lobar ventilation. The two-volume-based model can account for airway deformation and non-uniform regional ventilation to some extent, but does not capture the non-linear features of the lung.

Objectives/Hypothesis Obstructive sleep apnea (OSA) is a sleep disorder caused by partial or complete collapse of the pharyngeal airway. Genioglossal advancement (GGA) is a well-tolerated surgical procedure intended to address hypopharyngeal collapse, yet there are few studies that monitor changes in airflow dynamics at this site. Computation fluid dynamics (CFD) utilizes airflow simulation to predict changes in airflow after anatomic manipulation. Study Design We investigated the change in volume and airflow dynamics of the pharyngeal airway after GGA in a cadaveric model. Methods We performed serial GGA from 1 mm (control) to 3, 7, and 9 mm on a lightly preserved cadaver. After each intervention, we performed high-resolution computed tomography scans, reconstructed the pharyngeal airway, and quantified airspace volume and CFD analysis with both laminar and large eddy simulation models. Results Airway volume increased with linear GGA. In both CFD simulation models, velocity increased and pressure decreased after 9-mm advancement secondary to increased airway diameter and less abrupt changes in airway geometry. Conclusions These results suggest that GGA may be effective in increasing airway volume and flow to address hypopharyngeal obstruction in OSA. Level of Evidence N/A. Laryngoscope, 123:3227–3232, 2013

Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease.To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below -950 Hounsfield units (-950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema-950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.

Entire Conducting Airway Of Breathing Human Lung Jiwoong Choi1,2, Youbing Yin1,2,5, Eric A. Hoffman3,4,5, Merryn H. Tawhai6, and Ching-Long Lin1,2 1Department of Mechanical & Industrial Engineering, 2IIHR-Hydroscience & Engineering, Departments of 3Biomedical Engineering, 4Medicine and 5Radiology, The University of Iowa, Iowa City, IA, USA 6Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand

High frequency oscillatory ventilation (HFOV) is considered an efficient and safe respiratory technique to ventilate neonates and patients with acute respiratory distress syndrome. HFOV has very different characteristics from normal breathing physiology, with a much smaller tidal volume and a higher breathing frequency. In this work, the high frequency oscillatory flow is studied using a computational fluid dynamics (CFD) analysis in three different geometrical models with increasing complexity: a straight tube, a single-bifurcation tube model, and a computed-tomography (CT)-based human airway model of up to seven generations. We aim to understand the counter-flow phenomenon at flow reversal and its role in convective mixing in these models using sinusoidal waveforms of different frequencies and Reynolds numbers. Mixing is quantified by the stretch rate analysis. In the straight-tube model, coaxial counter flow with opposing fluid streams is formed around flow reversal, agreeing with an analytical Womersley solution. However, counter flow yields no net convective mixing at end cycle. In the single-bifurcation model, counter flow at high Re is intervened with secondary vortices in the parent (child) branch at end expiration (inspiration), resulting in an irreversible mixing process. For the CT-based airway model three cases are considered, consisting of the normal breathing case, the high-frequency-normal-Re case, and the HFOV case. The counter-flow structure is more evident in the high-frequency-normal-Re case than the HFOV case. The instantaneous and time-averaged stretch rates at the end of two breathing cycles and in the vicinity of flow reversal are computed. It is found that counter flow contributes about 20% to mixing in HFOV.

The effects of intra- and intersubject variabilities in airway geometry on airflow in the human lungs are investigated by large eddy simulation. The airway models of two human subjects consisting of extra- and intrathoracic airways are reconstructed from CT images. For intrasubject study, airflows at two inspiratory flow rates are simulated on the airway geometries of the same subject with four different levels of truncation. These airway models are the original complete geometry and three geometries obtained by truncating the original one at the subglottis, the supraglottis, and the laryngopharynx, respectively. A comparison of the airflows in the complete geometry model shows that the characteristics of the turbulent laryngeal jet in the trachea are similar regardless of Reynolds number in terms of mean velocities, turbulence statistics, coherent structures, and pressure distribution. The truncated airway models, however, do not produce the similar flow structures observed in the complete geometry. An improved inlet boundary condition is then proposed for the airway model truncated at the laryngopharynx to improve the accuracy of solution. The new boundary condition significantly improves the mean flow. The spectral analysis shows that turbulent characteristics are captured downstream away from the glottis. For intersubject study, although the overall flow characteristics are similar, two morphological factors are found to significantly affect the flows between subjects. These are the constriction ratio of the glottis with respect to the trachea and the curvature and shape of the airways.

Nuclear factor-kappaB (NF-kappaB) has a dual role in the promotion or attenuation of cell death. Here, we demonstrated the role of NF-kappaB in the H(2)O(2)-induced death of astrocytes. H(2)O(2) evoked the release of lactate dehydrogenase (LDH), a marker of cell death, and concomitantly decreased the DNA binding and transcriptional activity of NF-kappaB in cultured astrocytes. H(2)O(2)-induced astrocyte death was markedly increased by the co-treatment with pyrrolidinedithiocarbamate, an NF-kappaB inhibitor. Moreover, the elevation of constitutive NF-kappaB activity by overexpressing p65 NF-kappaB subunit attenuated H(2)O(2) toxicity, whereas NF-kappaB inhibition by overexpressing IkappaB potentiated the toxicity. NF-kappaB activity and H(2)O(2) cytotoxicity was further found to be dependent on cell density. Compared with astrocytes in low cell density, those in high cell density exhibited a higher constitutive NF-kappaB activity and a stronger resistance to H(2)O(2) cytotoxicity. These results indicate that the constitutive activity of NF-kappaB in astrocytes is required for their survival under oxidative stress such as H(2)O(2).