An atlas of epithelial cell states and plasticity in lung adenocarcinoma.

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

The association between body weight indices, behavioral factors, and type 2 diabetes mellitus in Africa: A systematic review and meta-analysis of population-based epidemiological studies.

BACKGROUND AND AIM: Type 2 diabetes mellitus (T2DM) is a significant public health concern in Africa. While the associations between modifiable risk factors and T2DM are likely to be Africa-specific, their overall estimations have not been published. This study aimed to use systematic and meta-analytic methods to examine the strength of associations between modifiable risk factors and T2DM in Africa. METHODS AND RESULTS: A systematic search of literature published between January 2000 to March 2022 was conducted. The review included only population-based studies and data extracted from 57 studies. Of these, unadjusted data from 50 studies were included in meta-analysis. With considerable heterogeneity between studies, random-effect models were calculated to ascertain the odds ratios (OR) and 95% confidence intervals (CI) for the associations between obesity (OB) and overweight (OV), defined by BMI; central obesity (waist circumference (OB-WC), waist-to-hip-ratio (OB-WHR)), alcohol, fruit and vegetable consumption, smoking, physical activity (PA) and T2DM. Moderator effects of age, African regions, and urban/rural location were assessed. Risk factors associated with T2DM include BMI-OB [OR = 3.05, 95% CI: (2.58, 3.61)], BMI-OV [OR = 2.38, 95% CI: (1.51, 3.75)], and BMI-OV/OB [OR = 2.07, 95% CI: (1.82, 2.34)]; OB-WC [OR = 2.58, 95% CI: (2.09, 3.18)] and OB-WHR [OR = 2.22, 95% CI: (1.69, 2.92)]; PA [OR = 1.85, 95% CI: (1.50, 2.30)]. Significant moderator effects were not observed. CONCLUSION: Obesity defined by BMI and central obesity, but not behavioral risk factors were most strongly associated with T2DM in African populations, emphasizing the need for obesity prevention to limit the rise of T2DM. REGISTRATION: The PROSPERO registration number is CRD42016043027.

Using an electronic diary and wristband accelerometer to detect exacerbations and activity levels in COPD: a feasibility study.

Background: Early and accurate identification of acute exacerbations of COPD may lead to earlier treatment and prevent hospital admission. Electronic diaries have been developed for symptom monitoring and accelerometers to monitor activity. However, it is unclear whether this technology is usable in the COPD population. This study aimed to assess the feasibility of an electronic diary (eDiary) for symptom reporting using the MoreCare app and activity monitoring with the Garmin Vivofit 2 in COPD. Methods: Participants were recruited from the London COPD Cohort. Participants were provided a Garmin Vivofit 2 activity monitor and an android tablet with the MoreCare app for a period of 3 months. Results: 25 COPD patients were recruited (mean±sd age 70.8±7.1 years, forced expiratory volume in 1 s (FEV1) 49.8±14.8% predicted). Age, gender, disease severity and exacerbation frequency had no impact on eDiary compliance. There was a moderate positive correlation between median daily very active minutes and FEV1 % pred (ρ=0.62, p=0.005). Daily step counts decreased during the initial 7 days of exacerbation and recovery compared to a pre-exacerbation baseline. A decision-tree model identified change in sputum colour, change in step count, severity of cold, exacerbation history and use of rescue medication as the most important predictors of acute exacerbations of COPD in this cohort. Conclusions: Symptom and activity monitoring using digital technology is feasible in COPD. Further large-scale digital health studies are needed to assess whether eDiaries can be used to identify patients at risk of exacerbation and guide early intervention.

Association between urban-rural location and prevalence of type 2 diabetes and impaired fasting glucose in West Africa: a cross-sectional population-based epidemiological study.

OBJECTIVES: We investigated the association between urban/rural location and both type 2 diabetes mellitus (T2DM) and pre-diabetes among populations of five West African countries. DESIGN: Cross-sectional studies, using the WHO Stepwise (STEPs) survey data. SETTING: National representative data of both urban and rural areas from Benin, Burkina Faso, Ghana, Liberia and Mali. PARTICIPANTS: Adults comprising 15 468 participants (6774 men and 8746 women; 7663 urban and 7805 rural residents) aged between 25 and 64 years. RESULTS: The age and sex-adjusted prevalence of T2DM was 6.2% for urban areas and 2.5% for rural areas. The prevalence of impaired fasting glucose (IFG) was 6.6% for urban areas, and 3.0% for rural areas. No differences by sex were observed. The crude relative risk (RR) and 95% CI of T2DM and IFG in urban compared with rural areas were 2.69 (1.85 to 3.91) and 2.37 (1.53 to 3.66), respectively. This reduced to RR: 2.03, 95% CI (1.34 to 3.08) and RR: 2.04, 95% CI (1.27 to 3.28), respectively, after adjusting for covariables. CONCLUSION: The prevalence of both T2DM and IFG was more than two times as high in urban areas compared with rural areas in West Africa. Behavioural risk factors are common among urban populations, with ongoing urbanisation expected to drive increases in the prevalence of T2DM. These results could guide planning for T2DM screening, preventive strategies and resource allocation in West Africa.

Computed tomography measure of lung injury and future interstitial features: the CARDIA Lung Study.

Introduction: Visually normal areas of the lung with high attenuation on computed tomography (CT) imaging, termed CT lung injury, may represent injured but not yet remodelled lung parenchyma. This prospective cohort study examined if CT lung injury is associated with future interstitial features on CT and restrictive spirometry abnormality among participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Methods: CARDIA is a population-based cohort study. CT scans obtained at two time points were assessed objectively for amount of lung tissue characterised as CT lung injury and interstitial features. Restrictive spirometry was defined as having a forced vital capacity (FVC) <80% predicted with forced expiratory volume in 1 s/FVC ratio >70%. Results: Among 2213 participants, the median percentage of lung tissue characterised as CT lung injury at a mean age of 40 years was 3.4% (interquartile range 0.8-18.0%). After adjustment for covariates, a 10% higher amount of CT lung injury at mean age 40 years was associated with a 4.37% (95% CI 3.99-4.74%) higher amount of lung tissue characterised as interstitial features at mean age 50 years. Compared to those with the lowest quartile of CT lung injury at mean age 40 years, there were higher odds of incident restrictive spirometry at mean age 55 years in quartile 2 (OR 2.05, 95% CI 1.20-3.48), quartile 3 (OR 2.80, 95% CI 1.66-4.72) and quartile 4 (OR 3.77, 95% CI 2.24-6.33). Conclusions: CT lung injury is an early objective measure that indicates risk of future lung impairment.

The Single-Cell Immunogenomic Landscape of B and Plasma Cells in Early-Stage Lung Adenocarcinoma.

Tumor-infiltrating B and plasma cells (TIB) are prevalent in lung adenocarcinoma (LUAD); however, they are poorly characterized. We performed paired single-cell RNA and B-cell receptor (BCR) sequencing of 16 early-stage LUADs and 47 matching multiregion normal tissues. By integrative analysis of ∼50,000 TIBs, we define 12 TIB subsets in the LUAD and adjacent normal ecosystems and demonstrate extensive remodeling of TIBs in LUADs. Memory B cells and plasma cells (PC) were highly enriched in tumor tissues with more differentiated states and increased frequencies of somatic hypermutation. Smokers exhibited markedly elevated PCs and PCs with distinct differentiation trajectories. BCR clonotype diversity increased but clonality decreased in LUADs, smokers, and with increasing pathologic stage. TIBs were mostly localized within CXCL13+ lymphoid aggregates, and immune cell sources of CXCL13 production evolved with LUAD progression and included elevated fractions of CD4 regulatory T cells. This study provides a spatial landscape of TIBs in early-stage LUAD. SIGNIFICANCE: While TIBs are highly enriched in LUADs, they are poorly characterized. This study provides a much-needed understanding of the transcriptional, clonotypic states and phenotypes of TIBs, unraveling their potential roles in the immunopathology of early-stage LUADs and constituting a road map for the development of TIB-targeted immunotherapies for the treatment of this morbid malignancy. This article is highlighted in the In This Issue feature, p. 2483.

Clinical validation and utility of Percepta GSC for the evaluation of lung cancer.

The Percepta Genomic Sequencing Classifier (GSC) was developed to up-classify as well as down-classify the risk of malignancy for lung lesions when bronchoscopy is non-diagnostic. We evaluated the performance of Percepta GSC in risk re-classification of indeterminate lung lesions. This multicenter study included individuals who currently or formerly smoked undergoing bronchoscopy for suspected lung cancer from the AEGIS I/ II cohorts and the Percepta Registry. The classifier was measured in normal-appearing bronchial epithelium from bronchial brushings. The sensitivity, specificity, and predictive values were calculated using predefined thresholds. The ability of the classifier to decrease unnecessary invasive procedures was estimated. A set of 412 patients were included in the validation (prevalence of malignancy was 39.6%). Overall, 29% of intermediate-risk lung lesions were down-classified to low-risk with a 91.0% negative predictive value (NPV) and 12.2% of intermediate-risk lesions were up-classified to high-risk with a 65.4% positive predictive value (PPV). In addition, 54.5% of low-risk lesions were down-classified to very low risk with >99% NPV and 27.3% of high-risk lesions were up-classified to very high risk with a 91.5% PPV. If the classifier results were used in nodule management, 50% of patients with benign lesions and 29% of patients with malignant lesions undergoing additional invasive procedures could have avoided these procedures. The Percepta GSC is highly accurate as both a rule-out and rule-in test. This high accuracy of risk re-classification may lead to improved management of lung lesions.

Effect of age and sex on the associations between potential modifiable risk factors and both type 2 diabetes and impaired fasting glycaemia among West African adults.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is becoming one of the leading causes of morbidity and mortality worldwide, including among Africans. Knowledge of the association between traditional risk factors and both diabetes and pre-diabetes, and whether these differ by age and sex, is important for designing targeted interventions. However, little is known about these associations for African populations. METHODS: The study used data from WHO STEPS surveys, comprising 15,520 participants (6,774 men and 8,746 women) aged 25-64 years, from 5 different West African countries, namely Burkina Faso (4,711), Benin (3,816), Mali (1,772), Liberia (2,594), and Ghana (2,662). T-test and chi-square tests were used to compare differences in the prevalence of traditional risk factors for both sexes. Multinomial logistic regression was conducted to ascertain the relative risks (RR) and 95% confidence intervals (CI) for both T2DM and impaired fasting glucose (IFG) relating to each risk factor, including obesity [defined by BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)], high blood pressure (HBP), fruit and vegetable consumption, physical inactivity, alcohol consumption, and smoking. Models for each of these traditional risk factors and interactions with age and sex were fitted. RESULTS: Factors associated with T2DM and IFG were age, obesity [defined by BMI, WC, WHtR, and WHR], HBP, smoking, physical inactivity, and fruit and vegetable consumption (p < 0.05). Analysis of interaction effects showed few significant differences in associations between risk factors and T2DM according to age or sex. Significant interaction with age was observed for HBP*age and T2DM [RR; 1.20, 95% CI: (1.01, 1.42)) (p = 0.04)], WHtR*age and T2DM [RR; 1.23, 95% CI: (1.06, 1.44) (p = 0.007)] and WHR*age and IFG [RR: 0.79, 95% CI: (0.67, 0.94) (p = 0.006)]. Some interactions with age and sex were observed for the association of alcohol consumption and both IFG and T2DM, but no clear patterns were observed. CONCLUSION: The study found that with very few exceptions, associations between traditional risk factors examined and both IFG and T2DM did not vary by age or sex among the West African population. Policies and public health intervention strategies for the prevention of T2DM and IFG should target adults of any age or sex in West Africa.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

RATIONALE: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. METHODS: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. RESULTS: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. INTERPRETATION: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Increased Monocyte-Derived CD11b+ Macrophage Subpopulations Following Cigarette Smoke Exposure Are Associated With Impaired Bleomycin-Induced Tissue Remodelling.

Rationale: The accumulation of macrophages in the airways and the pulmonary interstitium is a hallmark of cigarette smoke-associated inflammation. Notably, pulmonary macrophages are not a homogenous population but consist of several subpopulations. To date, the manner in which cigarette smoke exposure affects the relative composition and functional capacity of macrophage subpopulations has not been elucidated. Methods: Using a whole-body cigarette smoke exposure system, we investigated the impact of cigarette smoke on macrophage subpopulations in C57BL/6 mice using flow cytometry-based approaches. Moreover, we used bromodeoxyuridine labelling plus Il1a-/- and Il1r1-/- mice to assess the relative contribution of local proliferation and monocyte recruitment to macrophage accumulation. To assess the functional consequences of altered macrophage subpopulations, we used a model of concurrent bleomycin-induced lung injury and cigarette smoke exposure to examine tissue remodelling processes. Main Results: Cigarette smoke exposure altered the composition of pulmonary macrophages increasing CD11b+ subpopulations including monocyte-derived alveolar macrophages (Mo-AM) as well as interstitial macrophages (IM)1, -2 and -3. The increase in CD11b+ subpopulations was observed at multiple cigarette smoke exposure timepoints. Bromodeoxyuridine labelling and studies in Il1a-/- mice demonstrated that increased Mo-AM and IM3 turnover in the lungs of cigarette smoke-exposed mice was IL-1α dependent. Compositional changes in macrophage subpopulations were associated with impaired induction of fibrogenesis including decreased α-smooth muscle actin positive cells following intratracheal bleomycin treatment. Mechanistically, in vivo and ex vivo assays demonstrated predominant macrophage M1 polarisation and reduced matrix metallopeptidase 9 activity in cigarette smoke-exposed mice. Conclusion: Cigarette smoke exposure modified the composition of pulmonary macrophage by expanding CD11b+ subpopulations. These compositional changes were associated with attenuated fibrogenesis, as well as predominant M1 polarisation and decreased fibrotic activity. Overall, these data suggest that cigarette smoke exposure altered the composition of pulmonary macrophage subpopulations contributing to impaired tissue remodelling.

Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions.

OBJECTIVE: The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features. METHODS: Endobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and PML outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (ie, found in one patient only) and public (ie, found in two or more patients) TCRs was quantified, and the CDR3 sequences were compared with those found in curated databases with known antigen specificities. RESULTS: We detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T cell mediated immune activation (p=4e-4) associated with PML outcome. Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3396 (8.6%) found in more than one sample and 1057 (2.7%) found in two or more patients (ie, public); however, when compared with a public database of CDR3 sequences, 4543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among public TCRs (p<0.001). CONCLUSIONS: Decreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

Associations between obesity indices and both type 2 diabetes and impaired fasting glucose among West African adults: Results from WHO STEPS surveys.

BACKGROUND AND AIM: Various obesity indices such as BMI, waist circumference (WC), waist-hip ratio, (WHR) and waist-to-height ratio (WHtR) are associated with the risk of type 2 Diabetes Mellitus (T2DM). Given few studies examining the strength of the association in this population, we aimed to identify which obesity indices are most strongly associated with T2DM and impaired fasting glucose (IFG) among adults from five West African countries. METHODS AND RESULTS: Data from 15,520 participants from the World Health Organisation (WHO) STEPs surveys in Burkina Faso, Benin, Mali, Liberia, and Ghana were included in analyses. Multinomial logistic regression was used to calculate the relative risk (RR) per standard deviation (SD) of each anthropometric measure, modelled as both continuous variables and as categorical variables based on established cut-points. In the analyses with continuous variables, the unadjusted RRs for T2DM per SD were 1.30 (1.23, 1.37) for body mass index (BMI); 1.56 (1.46, 1.67) for WC; 2.57 (2.15, 3.09) for WHtR and 1.16 (1.03, 1.31) for WHR. WHtR showed the strongest association with T2DM in all adjusted analyses. For models using categorical variables based on established cut-points, obesity defined using waist circumference (OB-WC) and OB-BMI showed the strongest associations with T2DM, and OB-WHR, the weakest association in all adjusted analyses. CONCLUSION: WHtR and WC appear to be the indices most strongly associated with T2DM and IFG respectively. Given its simplicity, WC may be the metric that most usefully conveys risk for T2DM in West African adults.

Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing.

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355.

Single-Cell Expression Landscape of SARS-CoV-2 Receptor ACE2 and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients.

The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of ACE2 and SARS-CoV-2-priming proteases TMPRSS2 and TMPRSS4 in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of ACE2, TMPRSS2, and TMPRSS4. Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that ACE2 levels were highest in normal alveolar type 2 (AT2) cells and that TMPRSS2 was expressed in 65% of normal AT2 cells. Conversely, the expression of TMPRSS4 was highest and most frequently detected (75%) in lung cells with malignant features. ACE2-positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated HHIP, and the scavengers CD36 and DMBT1. Notably, the viral scavenger DMBT1 was significantly positively correlated with ACE2 expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.

Differential expression of sputum and serum autoantibodies in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease. Autoimmune processes have been hypothesized to contribute to disease progression; however, the presence of autoantibodies in the serum has been variable. Given that COPD is a lung disease, we sought to investigate whether autoantibodies in sputum supernatant would better define pulmonary autoimmune processes. Matched sputum and serum samples were obtained from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study and at the Guangzhou Institute of Respiratory Health (GIRH). Samples were collected from patients with varying severity of COPD, asymptomatic smokers, and healthy control subjects. IgG and IgM autoantibodies were detected in sputum and serum of all subjects in both cohorts using a broad-spectrum autoantigen array. No differences were observed in sputum autoantibodies between COPD and asymptomatic smokers in either cohort. In contrast, 16% of detectable sputum IgG autoantibodies were decreased in subjects with COPD compared to healthy controls in the ADEPT cohort. Compared to asymptomatic smokers, approximately 13% of detectable serum IgG and 40% of detectable serum IgM autoantibodies were differentially expressed in GIRH COPD subjects. Of the differentially expressed specificities, anti-nuclear autoantibodies were predominately decreased. A weak correlation between increased serum IgM anti-tissue autoantibodies and a measure of airspace enlargement was observed. The differential expression of specificities varied between the cohorts. In closing, using a comprehensive autoantibody array, we demonstrate that autoantibodies are present in subjects with COPD, asymptomatic smokers, and healthy controls. Cohorts displayed high levels of heterogeneity, precluding the utilization of autoantibodies for diagnostic purposes.

The cost of Medicare-funded medical and pharmaceutical services for mental disorders in children and adolescents in Australia.

OBJECTIVE: To examine the health care costs associated with mental disorders and subthreshold mental disorders within a nationally representative sample of children and adolescents in Australia. METHOD: Data were derived from the Young Minds Matter Survey (N = 6,310). Mental disorders were classified using the Diagnostic Interview Schedule for Children Version IV. Participant data were linked to administrative data on health care costs. Adjusted generalized linear regression models and two-part models were used to estimate mean differences in costs between those with a mental disorder or subthreshold disorder and those without. RESULTS: Costs associated with health care attendances and medications were higher for children and adolescents with mental disorders and subthreshold mental disorders compared to those without a mental disorder. The additional population health care costs due to mental disorders amounted to AUD$234 million annually in children and adolescents, of which approximately 16% was attributed to out-of-pocket costs. Findings showed that those with subthreshold mental disorders or comorbid mental disorders have substantial additional costs of Medicare-funded medical and pharmaceutical services. CONCLUSION AND IMPLICATION: Mental disorders in children and adolescents are associated with significant health care costs. Further research is needed to ensure that this population is receiving effective and efficient care.

Distinguishing Smoking-Related Lung Disease Phenotypes Via Imaging and Molecular Features.

BACKGROUND: Chronic tobacco smoke exposure results in a broad range of lung pathologies including emphysema, airway disease and parenchymal fibrosis as well as a multitude of extra-pulmonary comorbidities. Prior work using CT imaging has identified several clinically relevant subgroups of smoking related lung disease, but these investigations have generally lacked organ specific molecular correlates. RESEARCH QUESTION: Can CT imaging be used to identify clinical phenotypes of smoking related lung disease that have specific bronchial epithelial gene expression patterns to better understand disease pathogenesis? STUDY DESIGN AND METHODS: Using K-means clustering, we clustered participants from the COPDGene study (n = 5,273) based on CT imaging characteristics and then evaluated their clinical phenotypes. These clusters were replicated in the Detection of Early Lung Cancer Among Military Personnel (DECAMP) cohort (n = 360), and were further characterized using bronchial epithelial gene expression. RESULTS: Three clusters (preserved, interstitial predominant and emphysema predominant) were identified. Compared to the preserved cluster, the interstitial and emphysema clusters had worse lung function, exercise capacity and quality of life. In longitudinal follow-up, individuals from the emphysema group had greater declines in exercise capacity and lung function, more emphysema, more exacerbations, and higher mortality. Similarly, genes involved in inflammatory pathways (tumor necrosis factor-α, interferon-ß) are more highly expressed in bronchial epithelial cells from individuals in the emphysema cluster, while genes associated with T-cell related biology are decreased in these samples. Samples from individuals in the interstitial cluster generally had intermediate levels of expression of these genes. INTERPRETATION: Using quantitative CT imaging, we identified three groups of individuals in older ever-smokers that replicate in two cohorts. Airway gene expression differences between the three groups suggests increased levels of inflammation in the most severe clinical phenotype, possibly mediated by the tumor necrosis factor-α and interferon-ß pathways. CLINICAL TRIAL REGISTRATION: COPDGene (NCT00608764), DECAMP-1 (NCT01785342), DECAMP-2 (NCT02504697).