Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975.

The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo pathway, forms the complex with a transcriptional coactivator yes-associated protein (YAP) or a transcriptional coactivator PDZ-binding motif (TAZ). Their excessive activations are involved in carcinogenesis such as malignant pleural mesothelioma (MPM), and thus inhibition of the TEAD complex is expected to have potent anticancer activity against MPM. On the other hand, YAP or TAZ conditional knockout mice have been reported to show abnormal findings in various tissues, including the kidney, liver, and lung. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. When K-975 was administered orally to rats for 1 week, proteinuria suggestive of nephrotoxicity was observed. Electron microscopy revealed that K-975 at 300 mg/kg induced glomerular podocyte foot process effacement. After a 2-week recovery period, proteinuria with foot process effacement was recovered completely. Urinalysis and urinary biomarker evaluation suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by 2-week recovery periods, nephrotoxicity was reversible; however, incomplete reversibility was observed in rats with severe proteinuria. In conclusion, this study revealed that in rats, oral K-975 treatment induced severe proteinuria by podocyte foot process effacement, which was reversible and monitorable by the urinary albumin index, suggesting important information for developing K-975 as an anticancer drug.

Photon-counting detector CT allows significant reduction in radiation dose while maintaining image quality and noise on non-contrast chest CT.

Purpose: To investigate if clinical non-contrast chest CT studies obtained with PCD CT using much lower radiation exposure can achieve the same image quality as with the currently established EID protocol. Materials/methods: A total of seventy-one patients were identified who had a non-contrast chest computed tomography (CT) done on PCD CT and EID CT scanners within a 4-month interval. Five fellowship trained chest radiologists, blinded to the scanner details were asked to review the cases side-by-side and record their preference for images from either the photon-counting-detector (PCD) CT or the energy-integrating detector (EID) CT scanner. Results: The median CTDIvol for PCD-CT system was 4.710 mGy and EID system was 7.80 mGy (p < 0.001). The median DLP with the PCD-CT was 182.0 mGy.cm and EID system was 262.60 mGy.cm (p < 0.001). The contrast to noise ratio (CNR) was superior on the PCD-CT system 59.2 compared to the EID-CT 53.3; (p < 0.001). Kappa-statistic showed that there was poor agreement between the readers over the image quality from the PCD and EID scanners (κ = 0.19; 95 % CI: 0.12 - 0.27; p < 0.001). Chi-square analysis revealed that 3 out of 5 readers showed a significant preference for images from the PCDCT (p ≤ 0.012). There was no significant difference in the preferences of two readers between EID-CT and PCD-CT images. Conclusion: The first clinical PCD-CT system allows a significant reduction in radiation exposure while maintaining image quality and image noise using a standardized non-contrast chest CT protocol.

The relationship between interstitial lung abnormalities, mortality, and multimorbidity: a cohort study.

BACKGROUND: Interstitial lung abnormalities (ILAs) are associated with increased mortality. It is unclear whether multimorbidity accounts for the mortality association or how strongly ILA is associated with mortality relative to other common age-associated diseases. We determined the association of ILA with all-cause mortality adjusted for multimorbidity, compared mortality associated with ILA and prevalent cardiovascular disease (CVD), diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease and cancer and also determined the association between ILA and these diseases. METHODS: We measured ILA (none, indeterminant, definite) using blinded reads of CT images, prevalent chronic diseases and potential confounders in two observational cohorts, the Framingham Heart Study (FHS) (n=2449) and Age, Gene/Environment Susceptibility - Reykjavik Study (AGES-Reykjavik) (n=5180). We determined associations with mortality using Cox proportional hazards models and between ILA and diseases with multinomial logistic regression. RESULTS: Over a median (IQR) follow-up of 8.8 (1.4) years in FHS and 12.0 (7.7) years in AGES-Reykjavik, in adjusted models, ILAs were significantly associated with increased mortality (HR, 95% CI 1.95, 1.23 to 3.08, p=0.0042, in FHS; HR 1.60, 1.41 to 1.82, p<0.0001, in AGES-Reykjavik) adjusted for multimorbidity. In both cohorts, the association of ILA with mortality was of similar magnitude to the association of most other diseases. In adjusted models, ILAs were associated only with prevalent kidney disease (OR, 95% CI 1.90, 1.01 to 3.57, p=0.0452) in FHS and with prevalent CVD (OR 1.42, 1.12 to 1.81, p=0.0040) in AGES-Reykjavik. CONCLUSIONS: ILAs were associated with mortality adjusted for multimorbidity and were similarly associated with increased mortality compared with several common chronic diseases. ILAs were not consistently associated with the prevalence of these diseases themselves.

Traction Bronchiectasis/Bronchiolectasis on CT Scans in Relationship to Clinical Outcomes and Mortality: The COPDGene Study.

Background The clinical impact of interstitial lung abnormalities (ILAs) on poor prognosis has been reported in many studies, but risk stratification in ILA will contribute to clinical practice. Purpose To investigate the association of traction bronchiectasis/bronchiolectasis index (TBI) with mortality and clinical outcomes in individuals with ILA by using the COPDGene cohort. Materials and Methods This study was a secondary analysis of prospectively collected data. Chest CT scans of participants with ILA for traction bronchiectasis/bronchiolectasis were evaluated and outcomes were compared with participants without ILA from the COPDGene study (January 2008 to June 2011). TBI was classified as follows: TBI-0, ILA without traction bronchiectasis/bronchiolectasis; TBI-1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion; TBI-2, ILA with mild to moderate traction bronchiectasis; and TBI-3, ILA with severe traction bronchiectasis and/or honeycombing. Clinical outcomes and overall survival were compared among the TBI groups and the non-ILA group by using multivariable linear regression model and Cox proportional hazards model, respectively. Results Overall, 5295 participants (median age, 59 years; IQR, 52-66 years; 2779 men) were included, and 582 participants with ILA and 4713 participants without ILA were identified. TBI groups were associated with poorer clinical outcomes such as quality of life scores in the multivariable linear regression model (TBI-0: coefficient, 3.2 [95% CI: 0.6, 5.7; P = .01]; TBI-1: coefficient, 3.3 [95% CI: 1.1, 5.6; P = .003]; TBI-2: coefficient, 7.6 [95% CI: 4.0, 11; P < .001]; TBI-3: coefficient, 32 [95% CI: 17, 48; P < .001]). The multivariable Cox model demonstrated that ILA without traction bronchiectasis (TBI-0-1) and with traction bronchiectasis (TBI-2-3) were associated with shorter overall survival (TBI-0-1: hazard ratio [HR], 1.4 [95% CI: 1.0, 1.9; P = .049]; TBI-2-3: HR, 3.8 [95% CI: 2.6, 5.6; P < .001]). Conclusion Traction bronchiectasis/bronchiolectasis was associated with poorer clinical outcomes compared with the group without interstitial lung abnormalities; TBI-2 and 3 were associated with shorter survival. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Im in this issue.

Interstitial lung abnormalities are associated with decreased mean telomere length.

BACKGROUND: Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL). METHODS: Telomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality. RESULTS: In all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5-3.4, p=0.0001, and OR 2.6, 95% CI 1.4-4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (-767 bp, 95% CI 76-1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1-1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4-1.7, p=0.6, and HR 1.2, 95% CI 0.6-2.2, p=0.5, respectively). CONCLUSION: ILA are associated with decreased MTL.

Fat Content Quantification Using Dual-Energy CT for Differentiation of Anterior Mediastinal Lesions from Normal or Hyperplastic Thymus.

BACKGROUND: Detection of fat content in thymic lesions is crucial to differentiate thymic hyperplasia from thymic tumors or other anterior mediastinal pathologies. PURPOSE: To assess the feasibility of dual-energy CT (DECT) fat content quantification for the differentiation of anterior mediastinal lesions from benign thymic lesions and the normal spectrum of the thymus. MATERIALS AND METHODS: Chest DECT images of 465 patients (median 61 years, 63% female) were visually evaluated by two radiologists and semiquantitatively scored based on the degree of fatty degeneration ranging from completely fatty (score 0) to predominantly soft-tissue (score 3), and anterior mediastinal mass (score 4). A subset of scans (n =134 including all cases with scores 2-4 and 20 randomly-selected cases from scores 0 and 1) underwent quantitative DECT analysis (fat fraction, iodine density, and conventional CT value). DECT values were compared across the semiquantitative scores. RESULTS: Results of visual evaluation included 35 with predominantly solid thymus (score 3) and 15 with anterior mediastinal mass (score 4). The most common clinical diagnoses of the 15 masses (including 8 with pathologic confirmation) were metastases (n = 10) and lymphoma (n = 4). CT values in the abnormal thymus were significantly higher than those in score 3 (median: 69.7 HU versus 19.9 HU, P <0.001). There was no significant difference in iodine density values (median: 1.7 mg/ml versus 1 mg/ml, P = 0.09). However, the fat fraction value was significantly lower in the abnormal thymus (score 4) than in the predominantly soft-tissue attenuation thymuses (score 3) (median: 12.8% versus 38.7%, P <0.001). ROC curve analysis showed that fat fraction had an AUC of 0.96 (P <0.001), with a cutoff of <39.2% fat fraction yielding 100% sensitivity and 85% specificity. CONCLUSION: DECT fat fraction measurements of the thymus may provide additional value in distinguishing anterior mediastinal lesions from benign thymus. Use of DECT may reduce the need for subsequent imaging evaluation.

Progression of traction bronchiectasis/bronchiolectasis in interstitial lung abnormalities is associated with increased all-cause mortality: Age Gene/Environment Susceptibility-Reykjavik Study.

PURPOSE: The aim of this study is to assess the role of traction bronchiectasis/bronchiolectasis and its progression as a predictor for early fibrosis in interstitial lung abnormalities (ILA). METHODS: Three hundred twenty-seven ILA participants out of 5764 in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who had undergone chest CT twice with an interval of approximately five-years were enrolled in this study. Traction bronchiectasis/bronchiolectasis index (TBI) was classified on a four-point scale: 0, ILA without traction bronchiectasis/bronchiolectasis; 1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion; 2, ILA with mild to moderate traction bronchiectasis; 3, ILA and severe traction bronchiectasis and/or honeycombing. Traction bronchiectasis (TB) progression was classified on a five-point scale: 1, Improved; 2, Probably improved; 3, No change; 4, Probably progressed; 5, Progressed. Overall survival (OS) among participants with different TB Progression Score and between the TB progression group and No TB progression group was also investigated. Hazard radio (HR) was estimated with Cox proportional hazards model. RESULTS: The higher the TBI at baseline, the higher TB Progression Score (P < 0.001). All five participants with TBI = 3 at baseline progressed; 46 (90 %) of 51 participants with TBI = 2 progressed. TB progression was also associated with shorter OS with statistically significant difference (adjusted HR = 1.68, P < 0.001). CONCLUSION: TB progression was visualized on chest CT frequently and clearly. It has the potential to be the predictor for poorer prognosis of ILA.

The Association of Aging Biomarkers, Interstitial Lung Abnormalities, and Mortality.

Rationale: The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated.Objectives: To evaluate the associations among aging biomarkers, ILA, and all-cause mortality.Methods: In the FHS (Framingham Heart Study), we evaluated associations among plasma biomarkers (IL-6, CRP [C-reactive protein], TNFR [tumor necrosis factor α receptor II], GDF15 [growth differentiation factor 15], cystatin-C, HGBA1C [Hb A1C], insulin, IGF1 [insulin-like growth factor 1], and IGFBP1 [IGF binding protein 1] and IGFBP3]), ILA, and mortality. Causal inference analysis was used to determine whether biomarkers mediated age. GDF15 results were replicated in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) Study.Measurements and Main Results: In the FHS, there were higher odds of ILA per increase in natural log-transformed GDF15 (odds ratio [95% confidence interval], 3.4 [1.8-6.4]; P = 0.0002), TNFR (3.1 [1.6-5.8]; P = 0.004), IL-6 (1.8 [1.4-2.4]; P < 0.0001), and CRP (1.7 [1.3-2.0]; P < 0.0001). In the FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but the associations of GDF15 (hazard ratio, 2.0 [1.1-3.5]; P = 0.02), TNFR (1.8 [1.0-3.3]; P = 0.05), and IGFBP1 (1.3 [1.1-1.7]; P = 0.01) approached significance. In the COPDGene Study, higher natural log-transformed GDF15 was associated with ILA (odds ratio, 8.1 [3.1-21.4]; P < 0.0001) and mortality (hazard ratio, 1.6 [1.1-2.2]; P = 0.01). Causal inference analysis showed that the association of age with ILA was mediated by IL-6 (P < 0.0001) and TNFR (P = 0.002) and was likely mediated by GDF15 (P = 0.008) in the FHS and was mediated by GDF15 (P = 0.001) in the COPDGene Study.Conclusions: Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the associations among age, ILA, and mortality.

The Framingham Heart Study: Populational CT-based phenotyping in the lungs and mediastinum.

The Framingham Heart Study (FHS) is one of the largest and established longitudinal populational cohorts. CT cohorts of the FHS since 2002 provided a unique opportunity to assess non-cardiac thoracic imaging findings. This review deals with image-based phenotyping studies from recent major publications regarding interstitial lung abnormalities (ILAs), pulmonary cysts, emphysema, pulmonary nodules, pleural plaques, normal spectrum of the thymus, and anterior mediastinal masses, concluding with the discussion of future directions of FHS CT cohorts studies in the era of radiomics and artificial intelligence.

Projected lung areas using dynamic X-ray (DXR).

BACKGROUND: Dynamic X-ray (DXR) provides images of multiple phases of breath with less radiation exposure than CT. The exact images at end-inspiratory or end-expiratory phases can be chosen accurately. PURPOSE: To investigate the correlation of the projected lung area (PLA) by dynamic chest X-ray with pulmonary functions. MATERIAL AND METHODS: One hundred sixty-two healthy volunteers who received medical check-ups for health screening were included in this study. All subjects underwent DXR in both posteroanterior (PA) and lateral views and pulmonary function tests on the same day. All the volunteers took several tidal breaths before one forced breath as instructed. The outlines of lungs were contoured manually on the workstation with reference to the motion of diaphragm and the graph of pixel values. The PLAs were calculated automatically, and correlations with pulmonary functions and demographic data were analyzed statistically. RESULTS: The PLAs have correlation with physical characteristics, including height, weight and BMI, and pulmonary functions such as vital capacity (VC) and forced expiratory volume in one second (FEV1). VC and FEV1 revealed moderate correlation with the PLAs of PA view in forced inspiratory phase (VC: right, r = 0.65; left, r = 0.69. FEV1: right, r = 0.54; left, r = 0.59). Multivariate analysis showed that body mass index (BMI), sex and VC were considered independent correlation factors, respectively. CONCLUSION: PLA showed statistically significant correlation with pulmonary functions. Our results indicate DXR has a possibility to serve as an alternate method for pulmonary function tests in subjects requiring contact inhibition including patients with suspected or confirmed covid-19.

The associations of interstitial lung abnormalities with cancer diagnoses and mortality.

An increased incidence of lung cancer is well known among patients with idiopathic pulmonary fibrosis. It is not known whether interstitial lung abnormalities, i.e. early fibrotic changes of the lung, are a risk factor for lung cancer in the general population.The study's objective was to assess whether interstitial lung abnormalities were associated with diagnoses of, and mortality from, lung cancer and other cancers. Data from the AGES-Reykjavik study, a cohort of 5764 older Icelandic adults, were used. Outcome data were ascertained from electronic medical records. Gray's tests, Cox proportional hazards models and proportional subdistribution hazards models were used to analyse associations of interstitial lung abnormalities with lung cancer diagnoses and lung cancer mortality as well as diagnoses and mortality from all cancers.There was a greater cumulative incidence of lung cancer diagnoses (p<0.001) and lung cancer mortality (p<0.001) in participants with interstitial lung abnormalities than in others. Interstitial lung abnormalities were associated with an increased hazard of lung cancer diagnosis (hazard ratio 2.77) and lung cancer mortality (hazard ratio 2.89) in adjusted Cox models. Associations of interstitial lung abnormalities with all cancers were found in models including lung cancers but not in models excluding lung cancers.People with interstitial lung abnormalities are at increased risk of lung cancer and lung cancer mortality, but not of other cancers. This implies that an association between fibrotic and neoplastic diseases of the lung exists from the early stages of lung fibrosis and suggests that interstitial lung abnormalities could be considered as a risk factor in lung cancer screening efforts.

Traction Bronchiectasis/Bronchiolectasis is Associated with Interstitial Lung Abnormality Mortality.

PURPOSE: To investigate if the presence and severity of traction bronchiectasis/bronchiolectasis are associated with poorer survival in subjects with ILA. METHOD: The study included 3,594 subjects (378 subjects with ILA and 3,216 subjects without ILA) in AGES-Reykjavik Study. Chest CT scans of 378 subjects with ILA were evaluated for traction bronchiectasis/bronchiolectasis, defined as dilatation of bronchi/bronchioles within areas demonstrating ILA. Traction bronchiectasis/bronchiolectasis Index (TBI) was assigned as: TBI = 0, ILA without traction bronchiectasis/bronchiolectasis: TBI = 1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion: TBI = 2, ILA with mild to moderate traction bronchiectasis: TBI = 3, ILA and severe traction bronchiectasis and/or honeycombing. Overall survival (OS) was compared among the subjects in different TBI groups and those without ILA. RESULTS: The median OS was 12.93 years (95%CI; 12.67 - 13.43) in the subjects without ILA; 11.95 years (10.03 - not reached) in TBI-0 group; 8.52 years (7.57 - 9.30) in TBI-1 group; 7.63 years (6.09 - 9.10) in TBI-2 group; 5.40 years (1.85 - 5.98) in TBI-3 group. The multivariable Cox models demonstrated significantly shorter OS of TBI-1, TBI-2, and TBI-3 groups compared to subjects without ILA (P < 0.0001), whereas TBI-0 group had no significant OS difference compared to subjects without ILA, after adjusting for age, sex, and smoking status. CONCLUSIONS: The presence and severity of traction bronchiectasis/bronchiolectasis are associated with shorter survival. The traction bronchiectasis/bronchiolectasis is an important contributor to increased mortality among subjects with ILA.

Editorial for "MRI-Based Machine Learning for Differentiating Borderline From Malignant Epithelial Ovarian Tumors".

LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:905-905.

Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals.

Human hepatocytes are essential cell types for pharmacokinetics and the safety evaluation of pharmaceuticals. However, widely used primary hepatocytes with individual variations in liver function lose those functions rapidly in culture. Hepatic cell lines are convenient to use but have low liver functions. Human-Induced Pluripotent Stem (hiPS) cells can be expanded and potentially differentiated into any cell or tissue, including the liver. HiPS cell-derived Hepatocyte-Like Cells (hiPSHeps) are expected to be extensively used as consistent functional human hepatocytes. Many laboratories are investigating methods of using hiPS cells to differentiate hepatocytes, but the derived cells still have immature liver functions. In this paper, we describe the current uses and limitations of conventional hepatic cells, evaluating the suitability of hiPS-Heps to pharmacokinetics and the safety evaluation of pharmaceuticals, and discuss the potential future use of non-conventional non-monolayer culture methods to derive fully functional hiPS-Heps.

Determinants of Chest X-Ray Sensitivity for COVID- 19: A Multi-Institutional Study in the United States.

PURPOSE: To evaluate the sensitivity, specificity, and severity of chest x-rays (CXR) and chest CTs over time in confirmed COVID-19+ and COVID-19- patients and to evaluate determinants of false negatives. METHODS: In a retrospective multi-institutional study, 254 RT-PCR verified COVID-19+ patients with at least one CXR or chest CT were compared with 254 age- and gender-matched COVID-19- controls. CXR severity, sensitivity, and specificity were determined with respect to time after onset of symptoms; sensitivity and specificity for chest CTs without time stratification. Performance of serial CXRs against CTs was determined by comparing area under the receiver operating characteristic curves (AUC). A multivariable logistic regression analysis was performed to assess factors related to false negative CXR. RESULTS: COVID-19+ CXR severity and sensitivity increased with time (from sensitivity of 55% at ≤2 days to 79% at >11 days; p<0.001 for trends of both severity and sensitivity) whereas CXR specificity decreased over time (from 83% to 70%, p=0.02). Serial CXR demonstrated increase in AUC (first CXR AUC=0.79, second CXR=0.87, p=0.02), and second CXR approached the accuracy of CT (AUC=0.92, p=0.11). COVID-19 sensitivity of first CXR, second CXR, and CT was 73%, 83%, and 88%, whereas specificity was 80%, 73%, and 77%, respectively. Normal and mild severity CXR findings were the largest factor behind false-negative CXRs (40% normal and 87% combined normal/mild). Young age and African-American ethnicity increased false negative rates. CONCLUSION: CXR sensitivity in COVID-19 detection increases with time, and serial CXRs of COVID-19+ patients has accuracy approaching that of chest CT.

Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.

Radiographic pulmonary vessel volume, lung function and airways disease in the Framingham Heart Study.

Radiographic abnormalities of the pulmonary vessels, such as vascular pruning, are common in advanced airways disease, but it is unknown if pulmonary vascular volumes are related to measures of lung health and airways disease in healthier populations.In 2388 participants of the Framingham Heart Study computed tomography (CT) sub-study, we calculated total vessel volumes and the small vessel fraction using automated CT image analysis. We evaluated associations with measures of lung function, airflow obstruction on spirometry and emphysema on CT. We further tested if associations of vascular volumes with lung function were present among those with normal forced expiratory volume in 1 s and forced vital capacity.In fully adjusted linear and logistic models, we found that lower total and small vessel volumes were consistently associated with worse measures of lung health, including lower spirometric volumes, lower diffusing capacity and/or higher odds of airflow obstruction. For example, each standard deviation lower small vessel fraction (indicating more severe pruning) was associated with a 37% greater odds of obstruction (OR 1.37, 95% CI 1.11-1.71, p=0.004). A similar pattern was observed in the subset of participants with normal spirometry.Lower total and small vessel pulmonary vascular volumes were associated with poorer measures of lung health and/or greater odds of airflow obstruction in this cohort of generally healthy adults without high burdens of smoking or airways disease. Our findings suggest that quantitative CT assessment may detect subtle pulmonary vasculopathy that occurs in the setting of subclinical and early pulmonary and airways pathology.

Time-resolved quantitative evaluation of diaphragmatic motion during forced breathing in a health screening cohort in a standing position: Dynamic chest phrenicography.

OBJECTIVE: To assess diaphragmatic motion during forced breathing in a health screening center cohort by time-resolved quantitative analysis using dynamic chest radiography and demonstrate the characteristics and associations with demographics and pulmonary function of participants. MATERIALS AND METHODS: This prospective study includes 174 volunteers (99 males; median 57, range 36-93 years old) that underwent dynamic chest radiography with a flat panel detector system during forced breathing in a standing position. We automatically tracked and recorded the positions of the top of the diaphragms and the excursions on images of each participant and calculated peak motion speeds based on the data. We investigated the associations with demographics and pulmonary function statistically. RESULTS: The average excursions of the diaphragms during forced breathing were 49.1 ± 17.0 mm (right; mean ± standard deviation) and 52.1 ± 15.9 mm (left). The peak motion speeds were 26.7 ± 10.0 mm/s (right) and 32.2 ± 12.4 mm/s (left) in the inspiratory phase and 22.1 ± 12.7 mm/s (right) and 24.3 ± 10.3 mm/s (left) in the expiratory phase. Excursions and peak motion speeds of the left diaphragm were significantly greater than the right. Higher body mass index (BMI) and vital capacity (VC) were associated with greater excursions and faster peak motion speeds of the diaphragms. CONCLUSIONS: Time-resolved quantitative analysis of the diaphragms with dynamic chest radiography demonstrated the characteristics of diaphragmatic motion during forced breathing in a health screening cohort. Higher BMI and VC were associated with excursions and peak motion speeds of the diaphragms.

Interstitial lung abnormality in stage IV non-small cell lung cancer: A validation study for the association with poor clinical outcome.

PURPOSE: The presence of interstitial lung abnormality (ILA) at diagnosis of stage IV non-small cell lung cancer (NSCLC) patients has previously shown to be associated with shorter overall survival (OS). The present study aimed to validate the association between ILA and shorter OS in a larger cohort of treatment-naïve stage IV NSCLC patients. MATERIALS AND METHODS: This study includes 484 patients (205 men and 279 women) with a pathological diagnosis of stage IV NSCLC with pretreatment baseline CT available for review. ILA was visually scored on the baseline chest CT with a 3-point scale (0=no ILA, 1=indeterminate for ILA, 2 = ILA) as published previously. Clinical characteristics and overall survival (OS) were compared in patients with ILA score 2 vs. those with ILA score 0 or 1. RESULTS: ILA was present (score 2) on baseline CT in 19 of 484 patients (3.9%, 95%CI2.4-6.1%). Patients with ILA were significantly older (p = 0.0008) and more commonly male (p = 0.03) compared to those with ILA score 0 or 1. Patients with ILA score 2 showed significantly shorter OS compared to those with ILA score 0 or 1 (median OS 9.95 months vs. 16.95 months; p = 0.0002). In multivariate analyses, baseline ILA score 2 remained significant as a marker for shorter OS (HR = 2.09, p = 0.004) after adjustments for age (HR = 1.48; p = 0.001), gender (HR = 1.22, p = 0.06), and smoking (HR = 0.79; p = 0.051). CONCLUSIONS: ILA on baseline CT at diagnosis of stage IV NSCLC patients was associated with shorter OS (HR = 2.09, p = 0.004), validating ILA as an independent marker for poor clinical outcome.