Deployment-related Cigarette Smoking Behaviors and Pulmonary Function Among U.S. Veterans.

INTRODUCTION: The effects of smoking on lung function among post-9/11 Veterans deployed to environments with high levels of ambient particulate matter are incompletely understood. MATERIALS AND METHODS: We analyzed interim data (04/2018-03/2020) from the Veterans Affairs (VA) Cooperative Studies Program #595, "Service and Health Among Deployed Veterans". Veterans with ≥1 land-based deployments enrolled at 1 of 6 regional Veterans Affairs sites completed questionnaires and spirometry. Multivariable linear regression models assessed associations between cigarette smoking (cumulative, deployment-related and non-deployment-related) with pulmonary function. RESULTS: Among 1,836 participants (mean age 40.7 ± 9.6, 88.6% male), 44.8% (n = 822) were ever-smokers (mean age 39.5 ± 9.5; 91.2% male). Among ever-smokers, 86% (n = 710) initiated smoking before deployment, while 11% (n = 90) initiated smoking during deployment(s). Smoking intensity was 50% greater during deployment than other periods (0.75 versus 0.50 packs-per-day; P < .05), and those with multiple deployments (40.4%) were more likely to smoke during deployment relative to those with single deployments (82% versus 74%). Total cumulative pack-years (median [IQR] = 3.8 [1, 10]) was inversely associated with post-bronchodilator FEV1%-predicted (-0.82; [95% CI] = [-1.25, -0.50] %-predicted per 4 pack-years) and FEV1/FVC%-predicted (-0.54; [95% CI] = [-0.78, -0.43] %-predicted per 4 pack-years). Deployment-related pack-years demonstrated similar point estimates of associations with FEV1%-predicted (-0.61; [95% CI] = [-2.28, 1.09]) and FEV1/FVC%-predicted (-1.09; [95% CI] = [-2.52, 0.50]) as non-deployment-related pack-years (-0.83; [95% CI] = [-1.26, -0.50] for FEV1%-predicted; -0.52; [95% CI] = [-0.73, -0.36] for FEV1/FVC%-predicted). CONCLUSIONS: Although cumulative pack-years smoking was modest in this cohort, an inverse association with pulmonary function was detectable. Deployment-related pack-years had a similar association with pulmonary function compared to non-deployment-related pack-years.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

Area under the expiratory flow-volume curve: predicted values by regression and deep learning methods and recommendations for clinical practice.

BACKGROUND: In spirometry, the area under expiratory flow-volume curve (AEX-FV) was found to perform well in diagnosing and stratifying physiologic impairments, potentially lessening the need for complex lung volume testing. Expanding on prior work, this study assesses the accuracy and the utility of several models of estimating AEX-FV based on forced vital capacity (FVC) and several instantaneous flows. These models could be incorporated in regular spirometry reports, especially when actual AEX-FV measurements are not available. METHODS: We analysed 4845 normal spirometry tests, performed on 3634 non-smoking subjects without known respiratory disease or complaints. Estimated AEX-FV was computed based on FVC and several flows: peak expiratory flow, isovolumic forced expiratory flow at 25%, 50% and 75% of FVC (FEF25, FEF50 and FEF75, respectively). The estimations were based on simple regression with and without interactions, by optimised regression models and by a deep learning algorithm that predicted the response surface of AEX-FV without interference from any predictor collinearities or normality assumption violations. RESULTS: Median/IQR of actual square root of AEX-FV was 3.8/3.1-4.5 L2/s. The per cent of variance (R2) explained by the models selected was very high (>0.990), the effect of collinearities was negligible and the use of deep learning algorithms likely unnecessary for regular or routine pulmonary function testing laboratory usage. CONCLUSIONS: In the absence of actual AEX-FV, a simple regression model without interactions between predictors or use of optimisation techniques can provide a reasonable estimation for clinical practice, thus making AEX-FV an easily available additional tool for interpreting spirometry.

Obstructive Lung Disease and Obstructive Sleep Apnea (OLDOSA) cohort study: 10-year assessment.

STUDY OBJECTIVES: Asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea (OSA) are very prevalent disorders. Their coexistence in the same individual has an unclear effect on natural history and long-term outcomes. METHODS: The OLDOSA (Obstructive Lung Disease and Obstructive Sleep Apnea) cohort enrolled 4,980 veterans with an acute hospitalization and in whom asthma, COPD, OSA, overlapping conditions, or none of these disorders at baseline had been diagnosed. Pulmonary function, polysomnography, positive airway pressure (PAP) recommendations and adherence, and vital status were collected and analyzed. Various proportional hazards models were built for patients with OSA to test the effect of PAP therapy on survival. RESULTS: Ten-year all-cause cumulative mortality rate was 52.8%; median time to death was 2.7 years. In nonoverlapping asthma, OSA and COPD, mortality rates were 54.2%, 60.4%, and 63.0%, respectively. The overlap syndromes had the following mortality: COPD-OSA 53.2%, asthma-COPD 62.1%, asthma-OSA 63.5%, and triple overlap asthma-COPD-OSA 67.8%. In patients with OSA not on PAP therapy, after adjustment for age, comorbidities, and lung function, risk of death was 1.34 (1.05-1.71) times higher than those undergoing treatment. Similarly, in patients with OSA nonadherent to PAP therapy the adjusted risk of death was 1.78 (1.13-2.82) times higher versus those using it at least 70% of nights and more than 4 hours nightly. CONCLUSIONS: In this large longitudinal cohort of hospitalized veterans with high comorbid burden, asthma, COPD, OSA and their overlap syndromes had very high long-term mortality. In patients with OSA, PAP initiation and superior therapeutic adherence were associated with significantly better survival.

Calcium and Bone Turnover Markers in Acromegaly: A Prospective, Controlled Study.

Context: Acromegaly has been associated with calcium-phosphate and bone turnover alterations. Controlled studies of these interactions are sparse. Objective: To evaluate calcium and bone metabolism in active and treated acromegaly. Design/Setting/Patients: We conducted a controlled, prospective study at a tertiary referral center. We studied 22 patients with acromegaly referred for surgical or medical therapy (ACM) and 22 with nonfunctioning pituitary adenomas referred for surgery (control). Main Outcome Measures: Calcium (serum and urine), phosphorus, parathyroid hormone (PTH), 25-hydroxy- and 1,25-dihydroxy-vitamin D, bone turnover markers [serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)], and cytokines [receptor activator of nuclear factor κB ligand (RANK-L) and osteoprotegerin (OPG)] at baseline and 3 to 6 months after treatment. Results: At baseline, the ACM group had lower PTH levels than controls (36.3 ± 13.9 pg/mL vs 56.0 ± 19.9 pg/mL) and higher phosphorus (4.34 ± 0.71 mg/dL vs 3.55 ± 0.50 mg/dL) (P < 0.01). Groups had similar levels of serum and urine calcium and 25-hydroxy- and 1,25-dihydroxy-vitamin D. The ACM group had higher bone turnover markers than control; P1NP and CTX were strongly correlated (r2 = 0.82, P < 0.05). CTX was dependent on age and disease group but not on sex or gonadal status. After treatment of acromegaly, serum calcium (9.52 ± 0.43 mg/dL to 9.26 ± 0.28 mg/dL), phosphorus (4.34 ± 0.71 mg/dL to 3.90 ± 0.80 mg/dL), and CTX (0.91 ± 0.75 ng/mL to 0.63 ± 0.68 ng/mL) decreased, while PTH increased (36.3 ± 13.9 pg/mL to 48.9 ± 16.7 pg/mL) (P < 0.01). 25-hydroxy-vitamin D, P1NP, and RANK-L/OPG ratio did not change significantly. Conclusion: Acromegaly patients exhibited PTH-independent calcium-phosphate alterations and enhanced coupled bone formation and resorption. Within 6 months of treatment, bone resorption decreased, whereas RANK-L/OPG changes were inconsistent.

Asthma and obstructive sleep apnea: clinical and pathogenic interactions.

Asthma and obstructive sleep apnea (OSA) are among the most prevalent chronic human diseases of the 21st century. They share several risk and aggravating factors such as obesity, smoking, gastroesophageal reflux, sinonasal disease or upper airway involvement, systemic inflammation, etc. Although the association between OSA and chronic obstructive pulmonary disease or "overlap syndrome" is better known and characterized, the association of asthma and OSA or "alternative overlap syndrome" is less clearly defined and understood. Nevertheless, their coexistence has synergistic effects on patient symptoms, response to therapy, and general outcomes. Taxonomically, asthma and OSA are syndromically defined entities that are quite heterogeneous, being characterized by a plethora of clinical phenotypes. The complex interactions between these conditions should take into account more specific etiopathogenic mechanisms or distinct disease endotypes. The potential clinical, pathogenic, and therapeutic significance of the disease endotypes is still emerging and needs further evaluation. We present here a review on the bidirectional relationships between asthma and OSA, including their clinical, pathophysiologic, and therapeutic connections. Furthermore, we propose here to look at these interactions beyond the development of comprehensive inventories of genotypes, clinical and pathophysiologic phenotypes, but in the larger context of obstructive lung and airway disorders, with the goal to reassess meaningful syndromes based on natural history and predictable patient outcomes, which will help us better stratify therapy in an era of personalized medicine.

Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome.

Obstructive lung diseases (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) are very prevalent conditions. Disease phenotypes (e.g. chronic bronchitis, emphysema, etc.) often overlap, and significant confusion exists about their optimal nosologic characterization. Obstructive sleep apnoea (OSA) is also a common condition that features bidirectional interactions with OLD. OSA appears to be more commonly seen in patients with OLD, perhaps as a result of shared risk factors, for example obesity, smoking, increased airway resistance, local and systemic inflammation, anti-inflammatory therapy. Conversely, OSA is associated with worse clinical outcomes in patients with OLD, and continuous positive airway pressure therapy has potential beneficial effects on this vicious pathophysiological interaction. Possible shared mechanistic links include increased parasympathetic tone, hypoxaemia-related reflex bronchoconstriction/vasoconstriction, irritation of upper airway neural receptors, altered nocturnal neurohormonal secretion, pro-inflammatory mediators, within and inter-breath interactions between upper and lower airways, lung volume-airway dependence, etc. While the term overlap syndrome has been defined as the comorbid association of COPD and OSA, the interaction between asthma and OSA has not been integrated yet nosologically; in this review, the latter will be called alternative overlap syndrome. In an effort to bolster further investigations in this area, an integrated, lumping nomenclature for OSA in the setting of OLD is proposed here--OLDOSA (obstructive lung disease and obstructive sleep apnoea) syndrome.

Dyspnea in a patient with Mounier-Kuhn syndrome.

Poorly differentiated non-small cell lung carcinoma with a component of sarcoma-like (spindle and/or giant cells) or sarcoma (malignant bone, cartilage, or skeletal muscle) cells are called pleomorphic carcinoma. These carcinoma represent one of the 5 subtypes of rare pulmonary malignancies collectively classified as sarcomatoid carcinoma by the World Health Organization histologic classification of lung tumors. The pathogenesis of sarcomatoid carcinoma remains unclear, and treatment of this malignant tumor is less defined. Very few cases of sarcomatoid carcinoma involving the upper respiratory tract have been reported in the literature. We report here an atypical presentation and location of this tumor (in the trachea), causing obstruction with a positional ball-valve effect, in a patient with tracheobronchomegaly (Mounier-Kuhn syndrome). In addition, we discuss the recurrent nature of the disease and the potential therapeutic difficulties.

Diffuse alveolar hemorrhage: diagnosing it and finding the cause.

Diffuse alveolar hemorrhage is an acute, life-threatening event, and repeated episodes can lead to organizing pneumonia, collagen deposition in small airways, and, ultimately, fibrosis. Among the many conditions it can accompany are Wegener granulomatosis, microscopic polyangiitis, Goodpasture syndrome, connective tissue disorders, antiphospholipid antibody syndrome, infectious or toxic exposures, and neoplastic conditions. Its many causes and presentations pose an important challenge to the clinician.