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Rahul G Sangani,1 Vishal Deepak,1 Javeria Anwar,1 Zalak Patel,2 Andrew J Ghio3 1Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, West Virginia University, Morgantown, WV, USA; 2Department of Radiology, West Virginia University, Morgantown, WV, USA; 3US EPA, Chapel Hill, NC, USACorrespondence: Rahul G Sangani, Section of Pulmonary, Critical Care, and Sleep Medicine, West Virginia University School of Medicine, 1 Medical Center Dr, PO BOX 9166, Morgantown, WV, 26506, USA, Tel +1 304 293-4661 option &num;2, Fax +1 304-293-3724, Email rgsangani@hsc.wvu.eduBackground: Cigarette smoking (CS)-related monocytosis contributes to the development of chronic lung injuries via complex mechanisms. We aim to determine correlations between measures of CS and monocytes, their capacities to predict chronic lung diseases, and their associations with mortality.Methods: A single-center retrospective study of patients undergoing surgical resection for suspected lung nodules/masses was performed. CS was quantified as cigarettes smoked per day (CPD), duration of smoking, composite pack years (CPY), current smoking status, and smoking cessation years. A multivariate logistic regression analysis was performed.Results: Of 382 eligible patients, 88% were ever smokers. In this group, 45% were current smokers with mean CPD of 27.2± 40.0. CPY and duration of smoking showed positive linear correlations with percentage monocyte count. Physiologically, CPY was associated with progressive obstruction, hyperinflation, and reduced diffusion capacity (DLCO). Across the quartiles of smoking, there was an accumulation of radiologic and histologic abnormalities. Anthracosis and emphysema were associated with CPD, while lung cancer, respiratory bronchiolitis (RB), emphysema, and honeycombing were statistically related to duration of smoking. Analysis using consecutive CPY showed associations with lung cancer (≥ 10 and < 30), fibrosis (≥ 20 and < 40), RB (≥ 50), anthracosis and emphysema (≥ 10 and onwards). Percentage monocytes correlated with organizing pneumonia (OP), fibrosis, and emphysema. The greater CPY increased mortality across the groups. Significant predictors of mortality included percentage monocyte, anemia, GERD, and reduced DLCO.Conclusion: Indices of CS and greater monocyte numbers were associated with endpoints of chronic lung disease suggesting a participation in pathogenesis. Application of these easily available metrics may support a chronology of CS-induced chronic lung injuries. While a relative lesser amount of smoking can be associated with lung cancer and fibrosis, greater CPY increases the risk for emphysema. Monocytosis predicted lung fibrosis and mortality. Duration of smoking may serve as a better marker of monocytosis and associated chronic lung diseases.Keywords: smoking, monocyte, pulmonary fibrosis, lung cancer, mortality, emphysema

Andrew J Ghio,1 Elizabeth N Pavlisko,2 Victor L Roggli,2 Nevins W Todd,3 Rahul G Sangani4 1Human Studies Facility, US Environmental Protection Agency, Chapel Hill, NC, 27514, USA; 2Department of Pathology, Duke University, Durham, NC, USA; 3Department of Medicine, University of Maryland, Baltimore, MD, 21201, USA; 4Department of Medicine, West Virginia University, Morgantown, WV, USACorrespondence: Andrew J GhioHuman Studies Facility, US Environmental Protection Agency, 104 Mason Farm Road, Chapel Hill, NC, USAEmail ghio.andy@epa.govAbstract: It is proposed that the mechanistic basis for non-neoplastic lung injury with cigarette smoking is a disruption of iron homeostasis in cells after exposure to cigarette smoke particle (CSP). Following the complexation and sequestration of intracellular iron by CSP, the host response (eg, inflammation, mucus production, and fibrosis) attempts to reverse a functional metal deficiency. Clinical manifestations of this response can present as respiratory bronchiolitis, desquamative interstitial pneumonitis, pulmonary Langerhans’ cell histiocytosis, asthma, pulmonary hypertension, chronic bronchitis, and pulmonary fibrosis. If the response is unsuccessful, the functional deficiency of iron progresses to irreversible cell death evident in emphysema and bronchiectasis. The subsequent clinical and pathological presentation is a continuum of lung injuries, which overlap and coexist with one another. Designating these non-neoplastic lung injuries after smoking as distinct disease processes fails to recognize shared relationships to each other and ultimately to CSP, as well as the common mechanistic pathway (ie, disruption of iron homeostasis).Keywords: iron, ferritins, pulmonary disease, chronic obstructive, pulmonary emphysema, chronic bronchitis, hypertension, pulmonary, pulmonary fibrosis

Rahul Sangani,1 Andrew Ghio,2 Stacey Culp,3 Zalak Patel,4 Sunil Sharma1 1Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, West Virginia University, Morgantown, WV, USA; 2Human Studies Facility, US Environmental Protection Agency, Chapel Hill, NC, USA; 3Department of Biostatistics, West Virginia University, Morgantown, WV, USA; 4Department of Radiology, West Virginia University, Morgantown, WV, USACorrespondence: Andrew GhioHuman Studies Facility, US Environmental Protection Agency, Chapel Hill, NC, USATel +1 919 966-0670Fax +1 919 966-6271Email ghio.andy@epa.govBackground: Disease heterogeneity in idiopathic pulmonary fibrosis (IPF) often complicates the systematic study of disease, management of patients and clinical investigations.Objective: To describe combined pulmonary fibrosis emphysema (CPFE) phenotype in a rural Appalachian IPF cohort with the highest smoking rates in the United States.Methods: CPFE patients (n = 60) in a developed IPF cohort (n = 153) were characterized. Groups (CPFE vs IPF without emphysema) were categorized based on the predominant HRCT patterns of UIP (n = 109). Demographics, clinical variables, and treatment details were recorded. Kaplan–Meier survival and multivariate logistic regression analysis were performed.Results: The prevalence of CPFE in our IPF cohort was 45% (n = 49). The CPFE group was younger (73.9 vs 78.2), had a more extensive smoking history (93.9% vs 53.3%) with greater mean smoking pack years (49.09 vs 15.39) and had lower percentage predicted DLCO on presentation (38.35 vs 51.09) compared to IPF without emphysema group. Both groups shared equivalent higher burden of comorbidities, including pulmonary hypertension (PH) (46.9% vs 33.3%). One-fifth of patients were prescribed antifibrotics and only a subset (5%) of patients underwent lung transplantation. There was a non-significant trend towards reduced survival in CPFE (p = 0.076). Smoking status and DLCO predicted CPFE in our cohort. Body mass index (BMI), PH, and pirfenidone use were significant predictors of mortality.Conclusion: CPFE was highly prevalent in our rural IPF cohort. In contrast to previous studies, CPFE group was older and had higher female (approx. 30%) occurrence. A greater exposure to cigarette smoke and reduced DLCO at diagnosis predicted CPFE. Lower BMI and PH predicted higher mortality whereas use of pirfenidone improved survival in our cohort. This study highlights a complex interaction of cigarette smoking, advanced fibrosis of UIP, PH and potential utility of antifibrotic agents in CPFE phenotype. Substantial burden of comorbidities, older age, and the limited utilization of advanced therapeutics in the cohort emphasize the challenges faced by rural Appalachian patients.Keywords: combined pulmonary fibrosis emphysema; CPFE, cigarette smoking, pulmonary hypertension; PH, pirfenidone, body mass index; BMI, rural population

Andrew J Ghio, Elizabeth D Hilborn Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Chapel Hill, NC, USA Abstract: Cigarette smoking results in the accumulation of iron both systemically and locally, in the lung thereby causing imbalance in iron homeostasis. This disruption in iron homeostasis can be associated with oxidative stress and consequent tissue injury. Therefore, in this study, we tested the association between iron homeostasis and airway obstruction by examining a large cohort of smokers and non-smokers for relationships between 1) serum ferritin and iron concentrations and transferrin saturation and 2) forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and their ratio (FEV1/FVC). Data from the National Health and Examination Survey III were analyzed. The study population included persons aged 20 years and above with their following data recorded: race, gender, serum ferritin and iron concentrations, and transferrin saturation; the final sample number was 7,251. In the total population, Pearson correlation coefficients between 1) serum ferritin and iron concentrations and transferrin saturation and 2) FVC and FEV1 were significantly positive; whereas those between 1) serum ferritin concentrations and transferrin saturation and 2) FEV1/FVC were significantly negative. With separate analyses, serum ferritin concentrations demonstrated positive associations with FVC and FEV1 but an inverse relationship with FEV1/FVC in smokers and non-smokers. Serum ferritin levels increased with worsening airway obstruction among smokers, and its highest concentrations were found among those with the lowest values of FEV1/FVC ratio (

We used a novel linguistic training paradigm to investigate the experience-dependent acquisition, representation, and processing of novel emotional and neutral abstract concepts. Participants engaged in mental imagery (n = 32) or lexico-semantic rephrasing (n = 34) of linguistic material during five training sessions and successfully learned the novel abstract concepts. Feature production after training showed that specifically emotion features enriched the emotional concepts' representations. Unexpectedly, for participants engaging in vivid mental imagery during training a higher semantic richness of the acquired emotional concepts slowed down lexical decisions. Rephrasing, in turn, promoted a better learning and processing performance than imagery, probably due to stronger established lexical associations. Our results confirm the importance of emotional and linguistic experience and additional deep lexico-semantic processing for the acquisition, representation, and processing of abstract concepts.

The current study sought to test hypotheses derived from the social cognitive model of career self-management (CSM; Lent & Brown, 2013) applied to the process of career exploration and decision-making. We examined how well personality traits, contextual factors, and social cognitive predictors, collectively, account for exploration behavior and career decision-making outcomes. Specifically, we determine the relationships between personality traits with career decision self-efficacy, career goals, and decisional criteria in a sample of 302 high school students. The participants completed domain-specific measures of four personality traits (conscientiousness, intellect/openness, extraversion, and neuroticism), social support, self-efficacy, outcome expectations, goals, level of career indecision, and decisional anxiety. The model fit the data well overall, though certain predictors were linked to the criterion variables only indirectly via mediated pathways. The structural equation model analysis suggested, consistent with previous studies, that the contribution of personality on career exploration and decision-making was mediated by sociocognitive mechanisms. Multiple group analysis suggests that neither sex nor the type of institution (state/private) that students attend determines the relationships among the variables of the proposed theoretical model. Limitations, further research, practical implications, and methodological implications for the CSM model are discussed.

Bernard M Fischer,1,* Judith A Voynow,2,* Andrew J Ghio3,* 1Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; 2Department of Pediatrics, Children's Hospital of Richmond at Virginia Commonwealth University, Richmond, VA, USA; 3National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, USA *These authors contributed equally to this work Abstract: Chronic obstructive pulmonary disease (COPD) is one of the most common chronic illnesses in the world. The disease encompasses emphysema, chronic bronchitis, and small airway obstruction and can be caused by environmental exposures, primarily cigarette smoking. Since only a small subset of smokers develop COPD, it is believed that host factors interact with the environment to increase the propensity to develop disease. The major pathogenic factors causing disease include infection and inflammation, protease and antiprotease imbalance, and oxidative stress overwhelming antioxidant defenses. In this review, we will discuss the major environmental and host sources for oxidative stress; discuss how oxidative stress regulates chronic bronchitis; review the latest information on genetic predisposition to COPD, specifically focusing on oxidant/antioxidant imbalance; and review future antioxidant therapeutic options for COPD. The complexity of COPD will necessitate a multi-target therapeutic approach. It is likely that antioxidant supplementation and dietary antioxidants will have a place in these future combination therapies. Keywords: cigarette smoking, mucins, gene regulation, Chinese herbs, acupuncture, dietary antioxidants

Rahul G Sangani,1 Andrew J Ghio,2 John E Parker11Department of Pulmonary and Critical Care Medicine, West Virginia University, Morgantown, WV, USA; 2Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, USABledsoe et al presents an interesting study examining the disparities between radiologic and pathologic diagnoses of asbestosis in cases referred for consultation in pulmonary malignancy.1 The authors conclude that the clinical diagnosis of asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers. These findings highlight the confounding role of cigarette smoking in the diagnosis of asbestosis when it is based on non-pathologic criteria.View original paper by Bledsoe et al.

In the last decades, the development of computerized adaptive testing (CAT) has allowed more precise measurements with a smaller number of items. In this study, we develop an item bank (IB) to generate the adaptive algorithm and simulate the functioning of CAT to assess the domains of mathematical knowledge in Argentinian university students (N=773). Data were analyzed from the Rasch model. A simulation design created with the R software was used to determine the necessary items of the IB to estimate examinee ability. Our results indicate that the IB in the domains of mathematical knowledge is adequate to be applied in CAT, especially to estimate average ability levels. The use of CAT is recommended for rapidly generating indicators of the knowledge acquired by students and to design educational strategies that enhance student performance. Results, constrains, and implications of this study are discussed.

Andrew J Ghio,1 Joleen M Soukup,1 Judy H Richards,1 Bernard M Fischer,2 Judith A Voynow,2 Donald E Schmechel31US Environmental Protection Agency, Chapel Hill, NC, USA; 2Division of Pediatric Pulmonary Medicine, Department of Pediatrics,3Joseph and Kathleen Bryan Alzheimer Disease Research Center, Department of Medicine (Neurology), Duke University Medical Center, Durham, NC, USAAbstract: There is evidence that proteases and antiproteases participate in the iron homeostasis of cells and living systems. We tested the postulate that α-1 antitrypsin (A1AT) polymorphism and the consequent deficiency of this antiprotease in humans are associated with a systemic disruption in iron homeostasis. Archived plasma samples from Alpha-1 Foundation (30 MM, 30 MZ, and 30 ZZ individuals) were analyzed for A1AT, ferritin, transferrin, and C-reactive protein (CRP). Plasma samples were also assayed for metals using inductively coupled plasma atomic emission spectroscopy (ICPAES). Plasma levels of A1AT in MZ and ZZ individuals were approximately 60% and 20% of those for MM individuals respectively. Plasma ferritin concentrations in those with the ZZ genotype were greater relative to those individuals with either MM or MZ genotype. Plasma transferrin for MM, MZ, and ZZ genotypes showed no significant differences. Linear regression analysis revealed a significant (negative) relationship between plasma concentrations of A1AT and ferritin while that between A1AT and transferrin levels was not significant. Plasma CRP concentrations were not significantly different between MM, MZ, and ZZ individuals. ICPAES measurement of metals confirmed elevated plasma concentrations of nonheme iron among ZZ individuals. Nonheme iron concentrations correlated (negatively) with levels of A1AT. A1AT deficiency is associated with evidence of a disruption in iron homeostasis with plasma ferritin and nonheme iron concentrations being elevated among those with the ZZ genotype.Keywords: α-1-antitrypsin deficiency, serpins, proteinase inhibitor proteins, ferritin, transferrin

Background: Sacubitril/valsartan (S/V) is a cornerstone treatment for heart failure (HF). Beneficial effects on hospitalization rates, mortality, and left ventricular remodeling have been observed in patients with heart failure and reduced ejection fraction (HFrEF). Despite the positive results, the influence of S/V on renal function during long-term follow-up has received little attention. Aims: We investigated the long-term effects of S/V therapy on renal function in a large cohort of patients with HFrEF. Additionally, we examined the effects of the drug in patients with chronic kidney disease (CKD) compared to those with preserved renal function and identified primary risk characteristics Methods: We studied 776 outpatients with HFrEF and left ventricular ejection fraction (LVEF) 1000 pg/ml (HR 1.95[1.38, 2.77], p < 0.001), furosemide dose >50 mg (HR 2.04 [1.48, 2.82], p < 0.001), and creatinine values >1.5 mg/dl occurred during follow-up (HR 1.74 [1.24, 2.43], p < 0.001) were linked to increased risk. At multivariable analysis, increased doses of loop diuretics, advanced NYHA class, creatinine >1.5 mg/dl, and atrial fibrillation were independent predictors of adverse events. Conclusion: Long-term S/V therapy is associated with improved outcomes and renal protection in patients with HFrEF. This effect is more pronounced in patients who tolerate escalating doses. The positive effects of the drug are maintained in both CKD and preserved renal function. Future research may study the safety and underlying causes of current protection.

Atopic dermatitis (AD) is a chronic inflammatory skin condition increasing in industrial nations at a pace that suggests environmental drivers. We hypothesize that the dysbiosis associated with AD may signal microbial adaptations to modern pollutants. Having previously modeled the benefits of health-associated Roseomonas mucosa, we now show that R. mucosa fixes nitrogen in the production of protective glycerolipids and their ceramide by-products. Screening EPA databases against the clinical visit rates identified diisocyanates as the strongest predictor of AD. Diisocyanates disrupted the production of beneficial lipids and therapeutic modeling for isolates of R. mucosa as well as commensal Staphylococcus. Last, while topical R. mucosa failed to meet commercial end points in a placebo-controlled trial, the subgroup who completed the full protocol demonstrated sustained, clinically modest, but statistically significant clinical improvements that differed by study site diisocyanate levels. Therefore, diisocyanates show temporospatial and epidemiological association with AD while also inducing eczematous dysbiosis.