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Hyperuricemia is a known predictor of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) (pulmonary arterial hypertension), but its role in excluding PH secondary to chronic lung diseases (WHO Group 3) remains unclear. We retrospectively analyzed data from 323 patients with severe chronic pulmonary diseases who underwent evaluation for lung transplantation at a tertiary medical center between June 2017 and February 2023. We examined the association between hyperuricemia (serum uric acid > 6 mg/dL or > 0.357 mmol/L) and PH [mean pulmonary arterial pressure (MPAP) > 20 mmHg]. Compared to the normouricemia group (n = 211), hyperuricemic patients (n = 112) were more likely to be younger (P = 0.02), male (P < 0.001), and present with PH (P = 0.001) and severe PH (MPAP > 35 mmHg; P < 0.001). These patients also had a higher body mass index (P = 0.004), plasma N-terminal pro-B-type natriuretic peptide (P < 0.001), serum creatinine (P < 0.001), and C-reactive protein levels (P = 0.03). Significant associations with PH included higher body mass index (P = 0.005), uric acid levels (P < 0.001), total lung capacity (P = 0.02), and residual volume (P = 0.01); shorter 6-min walk test distance (P = 0.005); and lower forced expiratory volume in one second (P = 0.006) and diffusing capacity for carbon monoxide (P < 0.001). Multivariate analysis showed elevated uric acid levels remained significantly associated with PH (OR 1.29, 95% CI 1.05-1.58, P = 0.01). In conclusion, normal serum uric acid levels serve as a significant predictor for excluding pulmonary hypertension in patients with severe chronic lung diseases., (© 2024. The Author(s).)

Objective: To study the relationship between umbilical cord blood vitamin A (VA) and neonatal lung diseases and explore the impact of umbilical cord blood VA on neonatal lung diseases., Method: Umbilical vein blood was collected at birth, and its VA content was measured. According to the VA levels in umbilical cord blood, a VA deficiency (VAD) group, a marginal deficiency group and a normal group were created and followed up until 28 days after birth., Results: The umbilical cord blood VA level in the neonatal group with lung disease was 0.13 ± 0.05 mg/L, while the result for the VA level in the non-lung disease group was 0.15 ± 0.05 mg/L. The umbilical cord blood VA levels in the neonatal lung disease group were significantly lower than those in the non-lung disease group. The incidence of neonatal pulmonary diseases was highest in the VAD group, and the incidence decreased as the level of VA in umbilical cord blood increased. Umbilical cord blood VAD and premature birth were found to be independent risk factors for neonatal respiratory disease., Conclusion: Umbilical cord blood VAD and premature birth are independent risk factors for neonatal pulmonary diseases. The lower the level of VA in umbilical cord blood, the more susceptible infants will be to neonatal respiratory infections in the neonatal period., Competing Interests: Declaration of competing interest All of the authors had no any personal, financial, commercial, or academic conflicts of interest separately., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Clara cell 16-kDa protein (CC16) is an anti-inflammatory, immunomodulatory secreted pulmonary protein with reduced serum concentrations in obesity according to recent data., Objective: Studies focused solely on bodyweight, which does not properly reflect obesity-associated implications of the metabolic and reno-cardio-vascular system. The purpose of this study was therefore to examine CC16 in a broad physiological context considering cardio-metabolic comorbidities of primary pulmonary diseases., Methods: CC16 was quantified in serum samples in a subset of the FoCus (N = 497) and two weight loss intervention cohorts (N = 99) using ELISA. Correlation and general linear regression analyses were applied to assess CC16 effects of lifestyle, gut microbiota, disease occurrence and treatment strategies. Importance and intercorrelation of determinants were validated using random forest algorithms., Results: CC16 A38G gene mutation, smoking and low microbial diversity significantly decreased CC16. Pre-menopausal female displayed lower CC16 compared to post-menopausal female and male participants. Biological age and uricosuric medications increased CC16 (all p < 0.01). Adjusted linear regression revealed CC16 lowering effects of high waist-to-hip ratio (est. -11.19 [-19.4; -2.97], p = 7.99 × 10 -3 ), severe obesity (est. -2.58 [-4.33; -0.82], p = 4.14 × 10 -3 ) and hypertension (est. -4.31 [-7.5; -1.12], p = 8.48 × 10 -3 ). ACEi/ARB medication (p = 2.5 × 10 -2 ) and chronic heart failure (est. 4.69 [1.37; 8.02], p = 5.91 × 10 -3 ) presented increasing effects on CC16. Mild associations of CC16 were observed with blood pressure, HOMA-IR and NT-proBNP, but not manifest hyperlipidemia, type 2 diabetes, diet quality and dietary weight loss intervention., Conclusion: A role of metabolic and cardiovascular abnormalities in the regulation of CC16 and its modifiability by behavioral and pharmacological interventions is indicated. Alterations by ACEi/ARB and uricosurics could point towards regulatory axes comprising the renin-angiotensin-aldosterone system and purine metabolism. Findings altogether strengthen the importance of interactions among metabolism, heart and lungs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: Lung dysfunction and high apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio are both recognized risk factors for cardiovascular disease. However, few studies have examined the association between the apoB/ApoA-I ratio and lung function. Therefore, we investigated whether this ratio is associated with decreased lung function in a large healthy cohort., Methods: We performed a cohort study on 68,418 healthy Koreans (34,797 males, mean age: 38.1 years) who underwent a health examination in 2019. ApoB/apoA-I ratio was categorized into quartiles. Spirometric values at the fifth percentile in our population were considered the lower limit of normal (LLN), which was used to define lung function impairment. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs), using the lowest quartile as the reference, were estimated to determine lung function impairment., Results: Mean apoB/apoA-I ratio was 0.67 ± 0.21. Subjects with the highest quartile of this ratio had the lowest predicted forced expiratory volume in one second (FEV 1 %) and forced vital capacity (FVC%) after controlling for covariates ( P < 0.001). However, FEV 1 /FVC ratio was not significantly different among the four quartiles ( P = 0.059). Compared with the lowest quartile (Q1, reference), the aORs (95% CI) for FEV 1 % < LLN across increasing quartiles (from Q2 to Q4) were 1.216 (1.094-1.351), 1.293 (1.156-1.448), and 1.481 (1.311-1.672) ( P for trend < 0.001), respectively. Similarly, the aORs for FVC% < LLN compared with the reference were 1.212 (1.090-1.348), 1.283 (1.147-1.436), and 1.502 (1.331-1.695) with increasing quartiles ( P for trend < 0.001). However, the aORs for FEV 1 /FVC < LLN were not significantly different among groups ( P for trend = 0.273)., Conclusion: High apoB/apoA-I ratio was associated with decreased lung function. However, longitudinal follow-up studies are required to validate our findings., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening., (© 2023. The Author(s).)

Background: Chronic lung allograft dysfunction in lung transplant recipients (LTxRs) has 2 phenotypes: obstructive bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Our goal was to define distinct immunologic markers of exosomes from LTxRs with BOS or RAS., Methods: Plasma was collected from LTxRs with BOS (n = 18), RAS (n = 13), and from stable LTxRs (n = 5). Antibodies to lung self-antigens (SAgs) were determined by ELISA. Exosomes were isolated by ultracentrifugation. Donor specific antibodies to HLA were quantified using Luminex. Exosomes were characterized for lung SAgs, transcription factors, 20S proteasome, HLA class I and II, and polymeric immunoglobulin receptor protein using western blot. Exosome miRNA was analyzed using NanoString. The exosome-induced immune response was determined in mice., Results: LTxRs with RAS, but not BOS, had donor specific antibodies at diagnosis. CIITA, NFkB, polymeric immunoglobulin receptor protein, 20S proteasome, HLA-DQ, and HLA-DR were significantly higher in RAS exosomes than in BOS exosomes. RAS plasma had high levels of proinflammatory cytokines and distinct exosomal miRNA. Immunization of C57BL/6 mice with RAS exosomes showed severe inflammation and peribronchial fibrosis, whereas BOS exosomes induced patchy inflammation and fibrosis., Conclusion: LTxRs with BOS or RAS had exosomes with distinct molecular and immunologic profiles. RAS samples had a higher concentration of proinflammatory factors, HLA class II, lung SAgs, and antibodies to HLA class II molecules, indicating severe allograft injury. Mice immunized with RAS exosomes developed lesions in airways, pleura, interlobular septum, and alveoli, whereas BOS exosomes induced mild to patchy inflammation with lung fibrosis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. All authors have reviewed and approved the manuscript and have contributed in a substantial and intellectual manner to the work., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia., Patients and Methods: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days., Results: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78)., Conclusions: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers., Competing Interests: The authors have declared that no competing interests exist.

Exposure to benzo[a]pyrene (B[a]P) may be a risk factor for pulmonary diseases. To investigate the correlations among B[a]P exposure level, DNA strand breaks and pulmonary inflammation, we recruited 83 children diagnosed with pulmonary diseases and 63 healthy children from Guangzhou, China. Results showed that the levels of Benzo[a]pyrene diol epoxide (BPDE) DNA adduct in blood and IL-8 in serum in case group were significantly higher than those in control group ( p < 0.01). Moreover, levels of atmospheric B[a]P in case group was about twice of those in control group, which was consistent with the levels of BPDE-DNA adduct in blood. Significant positive correlations were observed among the levels of BPDE-DNA adduct, IL-8 and DNA strand breaks ( p < 0.05). Our findings indicate that environmental air is an important exposure source of B[a]P and higher B[a]P exposure may contribute to the occurrence of pulmonary inflammation and lead to high health risks.

Carcinoembryonic antigen (CEA) is not only used to aid the diagnosis of lung cancer, but also help monitor recurrence and determine the prognosis of lung cancer as well as evaluate the therapeutic efficacy for lung cancer. However, studies have also shown that CEA is present at low levels in the serum of patients with benign lung diseases (BLD), which will interfere with the accurate judgment of the disease. Due to difference in sample size, detection methods, cutoff values and sources of BLD, the positive rate of CEA in BLD is different with different literature. Therefore, it is necessary to define CEA levels in patients of different BLD in a large sample study. 4796 patients with BLD were included in this study. The results showed that the CEA levels of 3.1% (149/4796) patients with BLD were elevated, with three cases exceeds 20 ng/mL (0.06%, 3/4796). The results from the literature showed that BLD had a mean positive rate of 5.99% (53/885) and only two cases had CEA above 20 ng/mL. The CEA elevations mainly distributed in chronic obstructive pulmonary disease (COPD), pneumonitis and interstitial lung disease and significantly correlated with age of patients (OR 2.69, 95% CI 1.94-3.73, p < 0.001). Pulmonary tuberculosis (7/1311, 0.53%) had the lowest positive rate of CEA elevations while pulmonary alveolar proteinosis (6/27, 22.22%) had the highest positive rate. The majority of patients with abnormally elevated CEA levels had multiple underlying diseases, mainly diseases of the circulatory system (42.28% [63/149]), endocrine diseases (26.85% [40/149]), and respiratory or heart failure (24.16% [36/149]. In endocrine diseases, 87.5% (35/40) of patients had diabetes. In conclusion, CEA is present at a low positive rate in the serum of patients with BLD, but few exceed 20 ng/mL. For lung disease patients, if CEA levels rise, we should carry out comprehensive analysis of types of lung diseases, age of patients, and comorbid diseases., (© 2021. The Author(s).)

Background: Alpha-1 antitrypsin deficiency (AATD) is considered one of the most common genetic diseases and is characterised by the misfolding and polymerisation of the alpha-1 antitrypsin (AAT) protein within hepatocytes. The relevance of circulating polymers (CP) of AAT in the pathogenesis of lung and liver disease is not completely understood. Therefore, the main objective of our study was to determine whether there is an association between the levels of CP of AAT and the severity of lung and liver disease., Method: This was a cross-sectional study in patients with different phenotypes of AATD and controls. To quantify CP, a sandwich ELISA was performed using the 2C1 monoclonal antibody against AAT polymers. Sociodemographic data, clinical characteristics, and liver and lung parameters were collected., Results: A cohort of 70 patients was recruited: 32 Pi*ZZ (11 on augmentation therapy); 29 Z-heterozygous; 9 with other genotypes. CP were compared with a control group of 47 individuals (35 Pi*MM and 12 Pi*MS). ZZ patients had the highest concentrations of CP (p < 0.001) followed by Z heterozygous. The control group and patients with Pi*SS and Pi*SI had the lowest CP concentrations. Pi*ZZ also had higher levels of liver stiffness measurements (LSM) than the remaining AATD patients. Among patients with one or two Z alleles, two patients with lung and liver impairment showed the highest concentrations of CP (47.5 µg/mL), followed by those with only liver abnormality (n = 6, CP = 34 µg/mL), only lung (n = 18, CP = 26.5 µg/mL) and no abnormalities (n = 23, CP = 14.3 µg/mL). Differences were highly significant (p = 0.004)., Conclusions: Non-augmented Pi*ZZ and Z-patients with impaired lung function and increased liver stiffness presented higher levels of CP than other clinical phenotypes. Therefore, CP may help to identify patients more at risk of developing lung and liver disease and may provide some insight into the mechanisms of disease., (© 2021. The Author(s).)

Objective: The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19., Methods: We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated., Results: Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001)., Conclusion: We found that MR-proADM could represent a prognostic biomarker of COVID-19., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

C57BL/6 mice with pristane-induced lupus develop macrophage-dependent diffuse alveolar hemorrhage (DAH), which is blocked by treatment with liver X receptor (LXR) agonists and is exacerbated by low IL-10 levels. Serp-1, a myxomavirus-encoded serpin that impairs macrophage activation and plasminogen activation, blocks DAH caused by MHV68 infection. We investigated whether Serp-1 also could block DAH in pristane-induced lupus. Pristane-induced DAH was prevented by treatment with recombinant Serp-1 and macrophages from Serp1-treated mice exhibited an anti-inflammatory M2-like phenotype. Therapy activated LXR, promoting M2 polarization and expression of Kruppel-like factor-4 (KLH4), which upregulates IL-10. In contrast, deficiency of tissue plasminogen activator or plasminogen activator inhibitor had little effect on DAH. We conclude that Serp-1 blocks pristane-induced lung hemorrhage by enhancing LXR-regulated M2 macrophage polarization and KLH4-regulated IL-10 production. In view of the similarities between DAH in pristane-treated mice and SLE patients, Serp-1 may represent a potential new therapy for this severe complication of SLE., (Copyright © 2021. Published by Elsevier Inc.)

Research on vitamin D in patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) is limited. We aimed to compare the vitamin D parameters of patients with NTM-PD to those of a healthy control group, and to assess the possible predictive markers for a clinical response. We prospectively enrolled 53 patients with NTM-PD between January 2014 and December 2016. The clinical data and vitamin D indices, including total, free, bioavailable 25-(OH)D, and vitamin D binding protein (VDBP) genotyping, were measured at baseline and six months after enrollment. An external dataset of 226 healthy controls was compared with the NTM-PD group. The mean age of subjects was 53 years; 54.5% were male. The NTM-PD group was older, predominantly female, and had a lower body mass index (BMI) than the controls. The proportion of patients with vitamin D concentration <50 nmol/L was 52.8% in the NTM-PD group and 54.9% in the control group ( p = 0.789). The bioavailable 25-(OH)D concentrations of the NTM-PD group and the controls were similar (6.9 nmol/L vs. 7.6 nmol/L, p = 0.280). In the multivariable analysis, bioavailable 25-(OH)D concentrations were associated with NTM-PD, adjusting for age, sex, BMI, and VDBP levels. Bioavailable 25-(OH)D concentrations were significantly associated with susceptibility to NTM-PD, but not with treatment outcomes. Lower bioavailable 25-(OH)D might be a risk factor for NTM-PD.

Background: A decrease in the level of pulse oxygen saturation as measured by pulse oximetry (SpO 2 ) is an indicator of hypoxemia that may occur in various respiratory diseases, such as chronic obstructive pulmonary disease (COPD), sleep apnea syndrome, and COVID-19. Currently, no mass-market wrist-worn SpO 2 monitor meets the medical standards for pulse oximeters., Objective: The main objective of this monocentric and prospective clinical study with single-blind analysis was to test and validate the accuracy of the reflective pulse oximeter function of the Withings ScanWatch to measure SpO 2 levels at different stages of hypoxia. The secondary objective was to confirm the safety of this device when used as intended., Methods: To achieve these objectives, we included 14 healthy participants aged 23-39 years in the study, and we induced several stable plateaus of arterial oxygen saturation (SaO 2 ) ranging from 100%-70% to mimic nonhypoxic conditions and then mild, moderate, and severe hypoxic conditions. We measured the SpO 2 level with a Withings ScanWatch on each participant's wrist and the SaO 2 from blood samples with a co-oximeter, the ABL90 hemoximeter (Radiometer Medical ApS)., Results: After removal of the inconclusive measurements, we obtained 275 and 244 conclusive measurements with the two ScanWatches on the participants' right and left wrists, respectively, evenly distributed among the 3 predetermined SpO 2 groups: SpO 2 ≤80%, 80%2 ≤90%, and 90%2 . We found a strong association and a high level of agreement between the measurements collected from the devices, with high Pearson correlation coefficients of r=0.944 and r=0.954 on the correlation plots, low Pearson correlation coefficients of r=0.083 (P=.17) and r=0.23 (P=.001) on Bland-Altman plots, biases of 0.98% (95% CI 0.65-1.32) and 1.56% (95% CI 1.24-1.87), and root mean square errors of 2.97% and 3.00% from the participants' right and left hands, respectively., Conclusions: In conclusion, the Withings ScanWatch is able to measure SpO 2 levels with adequate accuracy at a clinical grade. No undesirable effects or adverse events were reported during the study., Trial Registration: ClinicalTrials.gov NCT04380389; http://clinicaltrials.gov/ct2/show/NCT04380389., (©Romain Kirszenblat, Paul Edouard. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.04.2021.)

Based on a previous study and by incorporating new knowledge, the goal of our study was to understand more fully the pathogenesis of hemorrhagic pneumonia of severe human leptospirosis, highlighting the onset of capillary lesions by Leptospira itself and/or its antigenic/toxic products acting on the endothelium and binding to cadherins. Both events lead to loss of endothelial integrity, alter permeability, cause rupture, and open intercellular junctions, contributing to the hemorrhagic phenomena associated with severe leptospirosis.

Background: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases., Results: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data., Conclusions: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

Background: Even when resting pulse oximetry is normal in the patient with acute Covid-19, hypoxia can manifest on exertion. We summarise the literature on the performance of different rapid tests for exertional desaturation and draw on this evidence base to provide guidance in the context of acute Covid-19., Main Research Questions: 1. What exercise tests have been used to assess exertional hypoxia at home or in an ambulatory setting in the context of Covid-19 and to what extent have they been validated? 2. What exercise tests have been used to assess exertional hypoxia in other lung conditions, to what extent have they been validated and what is the applicability of these studies to acute Covid-19?, Method: AMED, CINAHL, EMBASE MEDLINE, Cochrane and PubMed using LitCovid, Scholar and Google databases were searched to September 2020. Studies where participants had Covid-19 or another lung disease and underwent any form of exercise test which was compared to a reference standard were eligible. Risk of bias was assessed using QUADAS 2. A protocol for the review was published on the Medrxiv database., Results: Of 47 relevant papers, 15 were empirical studies, of which 11 described an attempt to validate one or more exercise desaturation tests in lung diseases other than Covid-19. In all but one of these, methodological quality was poor or impossible to fully assess. None had been designed as a formal validation study (most used simple tests of correlation). Only one validation study (comparing a 1-min sit-to-stand test [1MSTST] with reference to the 6-min walk test [6MWT] in 107 patients with interstitial lung disease) contained sufficient raw data for us to calculate the sensitivity (88%), specificity (81%) and positive and negative predictive value (79% and 89% respectively) of the 1MSTST. The other 4 empirical studies included two predictive studies on patients with Covid-19, and two on HIV-positive patients with suspected pneumocystis pneumonia. We found no studies on the 40-step walk test (a less demanding test that is widely used in clinical practice to assess Covid-19 patients). Heterogeneity of study design precluded meta-analysis., Discussion: Exertional desaturation tests have not yet been validated in patients with (or suspected of having) Covid-19. A stronger evidence base exists for the diagnostic accuracy of the 1MSTST in chronic long-term pulmonary disease; the relative intensity of this test may raise safety concerns in remote consultations or unstable patients. The less strenuous 40-step walk test should be urgently evaluated.

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL + T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

Background: Cardiac surgery can cause similar inflammatory reactions with infection; antibacterial treatment may be inappropriately used. Early and accurate diagnosis of infection still is a difficult problem worldwide. Procalcitonin (PCT) helps to identify sepsis caused by bacterial infections. However, its application in the diagnosis of pulmonary infections after off-pump coronary artery bypass grafting (OPCABG) has not been well studied. We investigated the early predictive value of PCT for the diagnosis of pulmonary infections after OPCABG., Methods: We retrospectively analyzed the clinical data, including conditions in the intensive care unit, postoperative complications, mortality rate, plasma PCT in the morning on the first postoperative day, routine white blood cell (WBC) count, and high-sensitivity C-reactive protein (hs-CRP) levels of patients who underwent elective OPCABG. Patients were divided into an infection group and a noninfection group, according to the occurrence of pulmonary infections. A receiver operating characteristic (ROC) curve was used to analyze the predictive value of PCT for the diagnosis of postsurgical infections., Results: In total, 131 patients who underwent OPCABG were included, of whom 23 (17.6%) developed pulmonary infections. The plasma PCT level significantly was higher in the infection group than in the noninfection group (6.0 ± 6.3 ng/ml vs. 2.0 ± 2.2 ng/ml, P = 0.007). WBC and hs-CRP values were not significantly different between the infection group and the noninfection group (12.3 ± 3.9×109/L vs. 11.1 ± 2.8×109/L, P = 0.171 and 12.4 ± 0.7 mg/L vs. 12.4 ± 0.8 mg/L, P = 0.903, respectively). The area under the ROC for predicting pulmonary infections after OPCABG by plasma PCT was 0.783 (P < 0.001, with a 95% confidence interval of 0.674-0.893), with a cut-off value of 3.55 ng/ml, a sensitivity of 0.609, and a specificity of 0.861., Conclusion: From our study results, we postulate that PCT has a high early predictive value for the diagnosis of pulmonary infections after OPCABG., (2021 Forum Multimedia Publishing, LLC)

Double-positive disease, defined by double-seropositivity for serum anti-glomerular basement membrane (GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA) is a rare cause of pulmonary-renal syndrome. Here, we present an exceptional course of a 20-year-old male with seropositivity for anti-myeloperoxidase anti-neutrophil cytoplasmic antibodies and anti-GBM antibody, who presented first with renal impairment due to focal necrotizing crescentic glomerulonephritis. After receiving treatment, he presented two years later with a relapse manifesting with diffuse alveolar hemorrhage and multiple splenic infarcts. We discuss the clinical presentation patterns and treatment strategies of this entity.

The objective of this study was to evaluate a novel microstream method by comparison with PaCO 2 and the more standard mainstream capnometer in intubated pediatric patients. We hypothesized that the novel microstream method would superior compared to the traditional mainstream method in predicting PaCO 2 . This was a prospective single-center comparative study. The study was carried out on 174 subjects with a total of 1338 values for each method. Data were collected prospectively from mainstream and microstream capnometer simultaneously and compared with PaCO 2 results. Although both mainstream PetCO 2 (mainPetCO 2 ) and microstream PetCO 2 (microPetCO 2 ) were moderately correlated (r = 0.63 and r = 0.68, respectively) with PaCO 2 values, mainPetCO 2 was in better agreement with PaCO 2 in all subjects (bias ± precision values of 3.8 ± 8.9 and 7.3 ± 8.2 mmHg, respectively). In those with severe pulmonary disease, the mainPetCO 2 and microPetCO 2 methods were highly correlated with PaCO 2 (r = 0.80 and r = 0.81, respectively); however, the biases of both methods increased (14.8 ± 9.1 mmHg and 16.2 ± 9.0 mmHg, respectively). In cases with increased physiologic dead space ventilation, the agreement levels of mainPetCO 2 and microPetCO 2 methods became distorted (bias ± precision values of 20.9 ± 11.2 and 25.0 ± 11.8 mm Hg, respectively) even though mainPetCO 2 and microPetCO 2 were highly correlated (r = 0.78 and r = 0.78, respectively). It was found that the novel microstream capnometer method for PetCO 2 measurements provided no superiority to the traditional mainstream method. Both capnometer methods may be useful in predicting the trend of PaCO 2 due to significant correlations with the gold standard measurement in cases with severe pulmonary disease or increased physiological dead space -despite reduced accuracy.

In this hypothesis paper, we suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce intravascular pulmonary thrombosis, which may result in the rapid worsening of clinical conditions and, eventually, exitus. Previously published papers have demonstrated that increased levels of D-dimer at hospital admission correlate with a more severe disease (0.5 mg/L) or occurrence of death (1 mg/L). The potential prothrombotic action of the SARS-CoV-2 is supported by the topographical involvement of the lung regions with a predilection for the lower lobe with peripheral involvement. If this hypothesis is demonstrated, this could suggest the benefit of using antithrombotic/coagulation regimens for SARS-CoV-2 and, at the same time, the urgency to identify drugs that could alter the inflammatory storm, thus protecting the vessel wall., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite more than 30 years after utilization of sulfur mustard or bis (2-chloroethyl) sulfide (SM) by Iraqi troops against Iranian military members and civilians, there are a lot of reported delayed complications for the exposed people. Nonetheless, the molecular mechanism of action from this chemical warfare agent is not recognized yet., Material and Method: In this study, we employed two dimensional gel electrophoresis (2DE) technique to investigate the serum proteins from chemical exposed people compared to non-exposed individuals to provide an inside into molecular mechanism of this chemical agent. Each group was divided into two subgroups including individuals with, and without respiratory complications. For each group, 10 individuals were included after informed consent., Result: The results showed protein spots, which were exclusively/mainly expressed in chemical exposed patients with complications, including T cell receptor alpha, and hematopoietic cell signal transducer. Also there were protein spots that were expressed only in all exposed groups (with and without complications). On the other hand, we could identify protein spots that were exclusively expressed/altered only in non-exposed group with complications including Pre T-cell antigen receptor, CD40 ligand, and multidrug and toxin extrusion proteins., Conclusion: Our investigation could result in identification of proteins that are associated to chemical exposure, as well as those specific for respiratory complications irrespective of chemical exposure. These candidate proteins can be used as biomarker, as well as a base for understanding the molecular mechanism of this chemical agent., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest in this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Immunoglobulin G4-related lung disease (IgG4-RLD) is the pulmonary manifestation of a systemic fibroinflammatory disease characterized by lymphoplasmacytic infiltration with an abundance of IgG4-positive plasma cells. Long-term clinical course and outcomes of IgG4-RLD remain unclear. We aimed to identify clinical characteristics, treatment outcomes, and longitudinal pulmonary function changes in patients with IgG4-RLD according to the radiologic classification., Methods: Chest computed tomography findings of 37 subjects were classified into five subtypes: solid nodular, bronchovascular, alveolar interstitial, round ground glass opacity, and alveolar consolidative. Radiologic treatment outcomes and longitudinal pulmonary function changes were compared among the different radiologic subtypes., Results: The mean age of the subjects was 55.6 years, and 78.4% were male. Among the five radiologic subtypes, alveolar consolidative and solid nodular type were most common, accounting for approximately 29.7% each of the total cases. Prednisone with or without azathioprine was administered to 31 patients (median treatment duration 14 months). In the treated patients, serial images showed complete response or partial response in 77.4%. However, relapse was documented in 25.0% of those who showed complete or partial response. In patients whose longitudinal lung function data were available (n = 20), the lung function was found to be stable during follow-up. Alveolar consolidative type showed the highest complete response rate, whereas alveolar interstitial type showed the lowest response rate, either complete or partial., Conclusions: Most patients showed a favorable outcome with regards to radiologic improvement and maintenance of pulmonary function; however, the response differed according to the radiologic subtype.

Objective: This paper was aimed at investigating the effects of bronchoalveolar lavage (BAL) with ambroxol hydrochloride (AH) on treating pulmonary infection and on serum proinflammatory cytokines and oxidative stress responses in patients with cerebral infarction (CI)., Methods: One hundred and two patients with cerebral infarction complicated with pulmonary infection (CIPI) who were treated in our hospital were enrolled as research objects, divided into an observation group (52 cases; AH combined with BAL) and a control group (50 cases; single AH) based on therapeutic schemes. They were compared in terms of the therapeutic effect and pre- and posttreatment serum inflammatory cytokines, pulmonary function, and serum indices of oxidative stress. Their adverse reactions during treatment were also recorded and compared., Results: The therapeutic effect in the observation group was remarkably better than that in the control group ( P < 0.05). After treatment, the serum inflammatory cytokines, pulmonary function, and serum indices of oxidative stress were remarkably improved in the two groups ( P < 0.05), but the improvement was remarkably better in the observation group ( P < 0.05). The differences were not significant in intratreatment adverse reactions between the two groups ( P > 0.05)., Conclusion: For CIPI patients, BAL with AH has a better therapeutic effect and higher safety and can control the patients' systemic inflammatory responses and oxidative stress responses, so it is worthy of further promotion in clinical practice., Competing Interests: We have no conflict of interest to declare., (Copyright © 2020 Fanhua Meng et al.)

Background: The goal of this study was to investigate the association between bactericidal permeability increasing (BPI)-antineutrophil cytoplasmic antibody (ANCA) protein levels and primary Sjogren's syndrome (pSS) with lung involvement, as well as the potential diagnostic performance of BPI-ANCA., Methods: The levels of BPI-ANCA in pSS patients with (n = 36) and without (n = 85) lung involvement were measured using a commercial ELISA kit. Serological biomarkers and cytokines were measured in these patients as well. Lung involvement was determined by high-resolution computed tomography (HRCT) and/or clinical symptoms. The diagnostic performance of lung involvement was determined by receiver operating characteristic (ROC) curves., Results: The percentage of neutrophils (NEUT%), neutrophil-lymphocyte ratio (NLR), erythrocyte sedimentation rate (ESR), and the levels of BPI-ANCA, C-reactive protein (CRP), interleukin-2 (IL-2) and IL-6 exhibited an upward trend, while the percentage of lymphocytes (LYMP%) and albumin (ALB) level exhibited a downward trend in the lung involvement group. The combination of BPI-ANCA, NEUT% and ALB significantly increased the area under the ROC curve (AUC) to 0.837 (95% confidence interval: 0.742-0.907, sensitivity: 82.14%, specificity: 81.36%, P < 0.001)., Conclusions: Increased BPI-ANCA was found in pSS patients with lung involvement and was associated with inflammation. A combination of BPI-ANCA, NEUT% and ALB had the best AUC, and may serve as anadjunct to distinguish between pSS patients with and without lung involvement., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Acute aortic dissection (AAD) is an acute life-threatening cardiovascular disease, which is frequently complicated with oxygenation impairment (OI). We aim to investigate predictors of the development of OI in the patients with AAD., Methods: We retrospectively collected clinical data of AAD in hypertensive patients from July 2012 to March 2020. The patients included in this study were divided into OI (+) group (oxygenation index≤200) and OI (-) group (oxygenation index> 200). Both groups were compared according to demographic and clinical characteristics, and laboratory findings. Characteristics of hypertension in the patients with AAD were described. Predictors for the development of OI were assessed. And cutoff values were determined by receiver operating characteristics (ROC) curve., Results: A total of 208 patients were included in this study and the incidence of OI was 32.2%. In OI (+) group, patients had significantly higher peak body temperature (37.85 ± 0.60 vs 37.64 ± 0.44 °C, P = .005), higher levels of CRP (42.70 ± 28.27 vs 13.90 ± 18.70 mg/L, P = .000) and procalcitonin (1.07 ± 3.92 vs 0.31 ± 0.77μg/L, P = .027), and lower levels of albumin (34.21 ± 5.65 vs 37.73 ± 4.70 g/L, P = .000). Spearman's rank correlation test showed that the minimum oxygenation index was positively correlated with albumin, and was negatively correlated with the peak body temperature, serum CRP, procalcitonin, BNP and troponin. The stepwise multiple linear regression analysis showed that the peak body temperature, serum CRP and albumin were independently associated with development of OI. An optimal cutoff value for CRP for predicting OI was ≥9.20 mg/L, with a sensitivity of 91.0% and a specificity of 61.0%., Conclusions: The peak body temperature, serum CRP and albumin were independent predictors of OI development in the patients with AAD. The serum CRP on admission≥9.20 mg/L might be a valuable and reliable indicator in predicting the development of OI.

Background: Inflammatory myopathies (IM) are characterized by muscular inflammation that can be associated with systemic disorders including lung. Anti-NXP2 antibody (Ab) is a rare myositis-specific antibody and its association with pulmonary involvement is still unknown. In this study, we investigated the characteristics of lung disease in patients with IM associated with anti-NXP2 Ab., Methods: Adult patients with confirmed IM and positive anti-NXP2 antibodies were recruited in our University departments (Assistance Publique- Hôpitaux de Marseille, France), between 2015 and 2019 to perform a retrospective study., Results: Seven patients were identified. Mean age was 55 ± 13 years, with a predominance of females (71%). Two patients (29%) had respiratory symptoms. CT-scan shows abnormalities in three patients (organizing pneumonia, nonspecific interstitial pneumonia, and bilateral pleural effusion). An altered diffusing capacity for carbon monoxide was found in four patients., Conclusion: We observed that subclinical lung involvement is not rare in patients with IM associated with positive anti-NXP2 Ab, with various radiological patterns and a significant lung function defect. Such data deserve to be known by the pulmonologist in order to perform a complete lung screening in all patients with positive anti-NXP2 antibody and to detect earlier a concomitant lung impairment.

Liquid biopsy has become widely applied in clinical medicine along with the progress in innovative technologies, such as next generation sequencing, but the origin of circulating tumor DNA (ctDNA) has not yet been precisely established. We reported bimodal peaks of long fragment circulating free DNA (cfDNA) of 5 kb and short fragment cfDNA of 170 bp in patients with advanced lung cancer, and both contained ctDNA. In this paper, we demonstrate that the total amount of cfDNA is higher when patients with lung cancer have extrathoracic metastases, and the amount of long fragment cfDNA is significantly higher in those patients. To investigate the origin of long fragment cfDNA, conditioned media isolated from lung cancer cell lines was fractionated. Long fragment cfDNA was found concomitant with extracellular vesicles (EVs), but short fragment cfDNA was not observed in any fractions. However, in peripheral blood from a metastatic animal model both fragments were detected even with those same lung cancer cell lines. In human plasma samples, long fragment cfDNA was observed in the same fraction as that from conditioned media, and short fragment cfDNA existed in the supernatant after centrifugation at 100,000g. Concentration of ctDNA in the supernatant was two times higher than that in plasma isolated by the conventional procedure. Long fragment cfDNA associated with tumor progression might therefore be released into peripheral blood, and it is possible that the long fragment cfDNA escapes degradation by co-existing with EVs. Examination of the biological characteristics of long fragment cfDNA is a logical subject of further investigation., Competing Interests: The authors have declared that no competing interests exist.

Within the last several years, frequency of vitamin D testing has multiplied substantially all over the world, since it has been shown to have an important role in many diseases and conditions. Even though liquid chromatography - tandem mass spectrometry (LC-MS/MS) has been identified as "gold standard" method for vitamin D measurement, most laboratories still use immunochemistry methods. Besides analytical problems (hydrophobicity, low circulating concentrations, ability to bind to lipids, albumins and vitamin D binding protein, presence of multiple vitamin D metabolites and variable ratios of 25(OH)D 2 and 25(OH)D 3 in the blood), vitamin D shows great preanalytical variability, since its concentration is drastically influenced by seasonal changes, exposure to sun, type of clothes or sun block creams. Vitamin D is mostly measured in serum or plasma, but new studies are showing importance of measuring vitamin D in pleural effusions, breast milk, urine, synovial fluid and saliva. Besides the main role in calcium homeostasis and bone metabolism, many studies linked vitamin D deficiency with cancer, cardiovascular diseases, diabetes, fertility and many other conditions. However, even though initial observational studies indicated that supplementation with vitamin D might be beneficial in disease development and progression; first results of well-designed randomized controlled prospective studies did not find differences in frequency of cardiovascular events or invasive cancer between patients taking vitamin D supplementation compared to placebo. In the light of these recent findings, validity of excessive vitamin D testing remains an open question., Competing Interests: Potential conflict of interest:None declared., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Objectives: Continuous monitoring of carbon dioxide (CO 2 ) levels can be achieved by capnography. Our aims were to compare the performance of a sidestream capnograph with a low dead space and sampling rate to a mainstream device and evaluate whether its results correlated with arterial/capillary CO 2 levels in infants with different respiratory disease severities., Working Hypotheses: End-tidal carbon dioxide (EtCO 2 ) results by sidestream and mainstream capnography would correlate, but the divergence of EtCO 2 and CO 2 results would occur in more severe lung disease., Study Design: Prospective cohort study., Patient-Subject Selection: Fifty infants with a median (interquartile range) gestational age of 31.1 (27.1-37.4) weeks and birth weight of 1.37 (0.76-2.95) kg., Methodology: Concurrent measurements of EtCO 2 in ventilated infants were made using a new Microstream sidestream device and a mainstream capnograph (gold standard). Results from both devices were compared with arterial or capillary CO 2 levels. The ratio of dead space to tidal volume (Vd/Vt) was calculated to assess respiratory disease severity., Results: The mean difference between the concurrent measurements of EtCO 2 was -0.54 ± 0.67 kPa (95% agreement levels - 1.86 to 0.77 kPa), the correlation between the two was r = .85 (P < .001). Sidestream capnography results correlated better with partial pressure of CO 2 (PCO 2 ) levels in infants with less (Vd/Vt < 0.35; r 2  = .66, P < .001) rather than more severe (Vd/Vt > 0.35; r 2  = .33, P = .01) lung disease., Conclusions: The sidestream capnography performed similarly to the mainstream capnography. The poorer correlation of EtCO 2 to PCO 2 levels in infants with severe respiratory disease should highlight to clinicians increased ventilation-perfusion mismatch., (© 2020 Wiley Periodicals, Inc.)

Although carbohydrate antigen 19-9 (CA 19-9) may be elevated in benign diseases, elevated CA 19-9 may cause a fear of cancer and unnecessary follow-up studies. Research on how to approach systematically in this case is very limited. The purpose of this study was to analyze the clinical features and the causes of CA 19-9 elevation without evidence of malignant or pancreatobiliary diseases. We retrospectively reviewed the medical records of patients who had CA 19-9 elevation (≥80 U/mL) and were found to be unrelated to cancer after follow-up. After exclusion, 192 patients were included in this study. The median level of CA 19-9 was 136.5 U/mL. The causes of CA 19-9 elevation were determined in 147 (76.6%) patients, and that was unknown in 45 (23.4%). The estimated causative diseases were hepatic diseases in 63 patients, pulmonary diseases in 32, gynecologic diseases in 38, endocrine diseases in 13, and spleen disease in 1. Of 45 patients with unknown cause, 35 had normalization of CA 19-9 and 10 had persistently elevated CA 19-9. In conclusion, CA 19-9 elevation without malignancies or pancreatobiliary diseases should be systematically evaluated and followed up. We suggest an algorithm to investigate the causes and follow up these patients.

Background: COVID-19 is a new infectious disease, for which there is currently no treatment. It is therefore necessary to explore biomarkers to determine the extent of lung lesions and disease severity., Objective: We aimed to assess the usefulness of CRP levels in the early stage of COVID-19 and to correlate them with lung lesions and severe presentation., Methods: Confirmed cases of COVID-19 were selected at the Fever Unit in two regions of Guizhou, China. On admission CRP levels were collected, and the diameter of the largest lung lesion was measured in the most severe lung lesion by lung CT scan. Differences in the diameter and CRP levels were compared in the following groups of patients: mild group, moderate group, severe group, and critical group., Result: CRP levels and the diameter of the largest lung lesion in the moderate group were higher than those in the mild group (Mann-Whitney test=-2.647, -2.171, P˂0.05), those in the severe group were higher than those in the moderate group (Mann-Whitney test=0.693, -2.177, P˂0.05), and those in the critical group were higher than those in the severe group (Mann-Whitney test=-0.068, -1.549, P˂0.05). The difference was statistically significant. CRP levels were positively correlated with the diameter of lung lesion and severe presentation (correlation coefficient=0.873, 0.734, P˂0.001)., Conclusion: In the early stage of COVID-19 CRP levels were positively correlated with lung lesions and could reflect disease severity., (Copyright © 2020 The Author. Published by Elsevier Masson SAS.. All rights reserved.)

Ambient particulate matter pollution is one of the leading causes of global disease burden. Epidemiological studies have revealed the connections between particulate exposure and cardiovascular and respiratory diseases. However, until now, the real species of ambient ultrafine particles (UFPs) in humans are still scarcely known. Here we report the discovery and characterization of exogenous nanoparticles (NPs) in human serum and pleural effusion (PE) samples collected from non-occupational subjects in a typical polluted region. We show the wide presence of NPs in human serum and PE samples with extreme diversity in chemical species, concentration, and morphology. Through chemical multi-fingerprinting (including elemental fingerprints, high-resolution structural fingerprints, and stable iron isotopic fingerprints) of NPs, we identify the sources of the NPs to be abiogenic, particularly, combustion-derived particulate emission. Our results provide evidence for the translocation of ambient UFPs into the human circulatory system, and also provide information for understanding their systemic health effects.

Glucocorticoids (GCs) play a central role in modulation of inflammation in various diseases, including respiratory diseases such as sarcoidosis. Surprisingly, the specific anti-inflammatory effects of GCs on different myeloid cells especially in macrophages remain poorly understood. Sarcoidosis is a systemic granulomatous disease of unknown etiology that occurs worldwide and is characterized by granuloma formation in different organs. Alveolar macrophages play a role in sarcoidosis granuloma formation and progressive lung disease. The goal of the present study is to identify the effect of GCs on transcriptomic profiles and the cellular pathways in sarcoidosis alveolar macrophages and their corresponding blood myeloid cells. We determined and compared the whole transcriptional signatures of alveolar macrophages from sarcoidosis patients and blood CD14 + monocytes of the same subjects in response to in vitro treatment with dexamethasone (DEX) via RNA-sequencing. In response to DEX, we identified 2,834 genes that were differentially expressed in AM. Predominant pathways affected were as following: metabolic pathway (FDR = 4.1 × 10 -10 ), lysosome (FDR = 6.3 × 10 -9 ), phagosome (FDR = 3.9 × 10 -5 ). The DEX effect on AMs is associated with metabolic derangements involving glycolysis, oxidative phosphorylation and lipid metabolisms. In contrast, the top impacted pathways in response to DEX treatment in blood CD14 + monocytes were as following; cytokine-cytokine receptor interaction (FDR = 6 × 10 -6 ) and transcriptional misregulation in cancer (FDR = 1 × 10 -4 ). Pathways similarly affected in both cell types were genes involved in lysosomes, cytoskeleton and transcriptional misregulation in cancer. These data suggest that the different effects of DEX on AMs and peripheral blood monocytes are partly dictated by lineage specific transcriptional programs and their physiological functions., (Copyright © 2020 Talreja, Bauerfeld, Sendler, Pique-Regi, Luca and Samavati.)

Premature infants are often exposed to positive pressure ventilation and supplemental oxygen, which leads to the development of chronic lung disease (CLD). There are currently no standard serum biomarkers used for prediction or early detection of patients who go on to develop CLD. MicroRNAs (miRNAs) are a novel class of naturally occurring, short, noncoding substances that regulate gene expression at the posttranscriptional level and cause translational inhibition and/or mRNA degradation and present in body fluids packaged in extracellular vesicles (EVs), rendering them remarkably stable. Our aim was to evaluate miRNAs identified in serum EVs of premature infants as potential biomarkers for CLD. Serum EVs were extracted from premature infants at birth and on the 28th day of life (DOL). Using a human miRNA array, we identified 62 miRNAs that were universally expressed in CLD patients and non-CLD patients. Of the 62 miRNAs, 59 miRNAs and 44 miRNAs were differentially expressed on DOL0 and DOL28 in CLD and non-CLD patients, respectively. Of these miRNAs, serum EV miR-21 was upregulated in CLD patients on DOL28 compared with levels at birth and downregulated in non-CLD patients on DOL28 compared with levels at birth. In neonatal mice exposed to hyperoxia for 7days, as a model of CLD, five miRNAs (miR-34a, miR-21, miR-712, miR-682, and miR-221) were upregulated, and 7 miRNAs (miR-542-5p, miR-449a, miR-322, miR-190b, miR-153, miR-335-3p, miR-377) were downregulated. MiR-21 was detected as a common miRNA that changed in CLD patients and in the hyperoxia exposed mice. We conclude that EV miR-21 may be a biomarker of CLD.

The TEMPI syndrome is a rare and acquired disorder characterized by 5 salient features, which compose its name: (1) telangiectasias; (2) elevated erythropoietin and erythrocytosis; (3) monoclonal gammopathy; (4) perinephric fluid collections; and (5) intrapulmonary shunting. Complete resolution of symptoms following treatment with plasma cell-directed therapy supports the hypothesis that the monoclonal antibody is causal and pathogenic. Understanding the basis of the TEMPI syndrome will depend on the identification of additional patients and a coordinated international effort., (© 2020 by The American Society of Hematology.)

Background: Insulin-like growth factor binding-protein 2 (IGFBP-2) was originally identified as an IGF-carrier, governing IGF half-life, tissue accessibility and biological effects. Later, IGFBP-2 was discovered to possess IGF-independent effects. IGFBP-2 circulates in several forms, as free protein, complexed with IGF-I or IGF-II, or as IGFBP-2 fragments. The various IGFBP-2 forms are all included when measuring serum IGFBP-2 concentrations by immunoassay (i.e., immunoreactive (ir-)IGFBP-2). In this study, we describe a novel method to measure the amount of IGF that circulates bound to IGFBP-2., Method: IGFBP-2 was immunoprecipitated from human serum using magnetic beads, which were subsequently eluted by acidification. After neutralization, eluates were assayed for ir-IGFBP-2, IGF-I and IGF-II and compared to serum concentrations. This allowed measurement of IGFBP-2-compexed IGF-I and IGF-II, respectively. To test the method clinically, serum from 146 patients with lung cancer, 151 patients with non-cancer pulmonary diseases and 28 healthy controls were analyzed., Results: We immuno-precipitated 97 ± 3.3% of serum IGFBP-2 and recovered > 75% of IGFBP-2-complexed IGFs, with intra- and inter-assay coefficient of variations (CVs) averaging < 5% and < 13%, respectively. No co-precipitation with IGFBP-1, -3 or - 4 was detected. Serum levels of ir-IGFBP-2 (median [25;75%]) differed between groups (cancer patients vs. non-cancer patients vs. healthy controls): 342 [260;480] vs. 262 [189;388] vs. 190 [141;269] μg/l (p < .0001). In parallel with this, concentrations of IGF-II carried by IGFBP-2 averaged: 45.0 [33.3;52.5] vs. 34.2 [25.4;46.1] vs. 19.8 [14.1;26.0] μg/l (p < .0001), and concentrations of IGF-I 8.0 [5.2;11.8] vs. 5.4 [3.6;7.3] vs. 7.0 [3.8;13.0] μg/l (p < .0001). Thus, IGFBP-2 carried more IGF-II than IGF-I in all groups (p < .0001). When expressed relative to IGF-concentrations, IGFBP-2 carried 9.0 [5.3;15.5] % of the IGF-I and 4.8 [2.9;5.8] % of the IGF-II in serum from healthy subjects. Notably, in patients, IGFBP-2 carried relatively less IGF-I, but more IGF-II (p < .0001)., Conclusion: Using our novel assay, we demonstrate: that IGFBP-2 carries ≈10% of circulating IGF-I and ≈5% of circulating IGF-II in healthy subjects; that IGF-II is the primary ligand for IGFBP-2; and that IGFBP-2 carries even more IGF-II in patients than in healthy subjects. Thus, our assay may provide information on IGFBP-2 beyond what is achievable by simply measuring ir-IGFBP-2., Competing Interests: Declaration of Competing Interest Jan Frystyk, who is co-authoring this paper, also serves as Editor-in-Chief of Growth Hormone and IGF Research. However, this has not influenced on the handling of the paper, which has been subjected to the Journal's usual procedures. Thus, the peer review process has been handled independently of Jan Frystyk, who has been blinded to the review process. The remaining authors have nothing to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) are found to increase in patients who develop postoperative complications (PCs). The aim of the present study was to explore the association of the perioperative changes of NLR (ΔNLR) and PLR (ΔPLR) with PCs in non-small cell lung cancer (NSCLC). Clinical data of 509 patients, who were diagnosed with NSCLC and underwent thoracoscopic radical resection between January 1, 2014 and July 31, 2016 at the Department of Thoracic Surgery, West China Hospital, were reviewed. Patients were divided into PC and non-PC groups, and clinical characteristics including ΔNLR and ΔPLR were compared between them. The optimal cut-off values of ΔNLR and ΔPLR were determined by receiver operating characteristics (ROC) curves and patients were assigned to high ΔNLR/ΔPLR and low ΔNLR/ΔPLR groups in terms of the cut-off values. Clinicopathologic characteristics and the incidence of different PCs were compared between the dichotomized groups. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for PCs. The results showed that the ΔNLR and ΔPLR in the PC group were signifcantly higher than those in the non-PC group (P<0.001 for both). The optimal cutoff values of ΔNLR and ΔPLR were 6.6 and 49, respectively. Patients with ΔNLR>6.6 or ΔPLR>49 were more likely to experience postoperative pulmonary complications (PPCs) (P<0.001 for both). Multivariate logistic regression analysis demonstrated that smoking [odds ratio (OR): 2.450, 95% confdence interval (95% CI): 1.084-5.535, P=0.031)], tumor size (OR: 1.225, 95% CI: 1.047-1.433, P=0.011), ΔNLR>6.6 (OR: 2.453, 95% CI: 1.224-4.914, P=0.011) and ΔPLR>49 (OR: 2.231, 95% CI: 1.182-4.212, P=0.013) were predictive of PPCs. In conclusion, the ΔNLR and ΔPLR may act as novel predictors for PPCs in NSCLC patients undergoing thoracoscopic radical lung resection, and patients with ΔNLR>6.6 or ΔPLR>49 should be treated more actively to prevent or reduce PPCs.

Accumulating evidence has shown that toxic metals exposure can have adverse effects on children, but the effects of blood Pb, Hg, and Cd co-exposure on pulmonary function in children remains to be clarified. This cross-sectional multicenter study was conducted in Wuxi City, China. A total of 221 healthy children free from chronic obstructive pulmonary disease were recruited. The blood samples were collected while blood Pb, Hg, and Cd levels were determined. The forced vital capacity volume (FVC) and forced expiratory volume in the 1 s (FEV1) were measured. The associations between metals concentration and pulmonary function were analyzed by multiple linear regression models. The geometric means of the blood Pb, Hg, and Cd levels in our study were 37.27 μg/L, 1.41 μg/L, and 0.28 μg/L, respectively. After adjusting for age, sex, maternal education, annual family income, fish consumption, and second-hand smoking exposure, only the blood Pb levels were significantly negatively associated with the pulmonary function. In addition, a significantly positive interaction between blood Pb and blood Cd on pulmonary function were also detected. Although causal relationship cannot be confirmed in this study, at least higher levels of Pb in blood are associated with decreased pulmonary parameters in children.

Pulmonary disease (PD) due to nontuberculous mycobacteria (NTM) is increasing globally, but specific biomarkers for NTM-PD have not been established. As circulating miRNAs are promising biomarkers for various diseases, we investigated whether miRNAs have potential as NTM-PD biomarkers. Sera from 12 NTM-PD patients due to Mycobacterium avium, M. intracellulare, M. abscessus, or M. massiliense and three healthy controls were initially evaluated via small RNA sequencing. Multiple miRNAs showed significant differences in expression in patients compared to in healthy controls, with some expression differences unique to PD caused by a specific mycobacterial species. Notably, 14 miRNAs exhibited significant expression differences in PD associated with all four mycobacteria. Validation by quantitative reverse-transcription-PCR in an additional 40 patients with NTM-PD and 40 healthy controls confirmed that four differentially expressed miRNAs (hsa-miR-484, hsa-miR-584-5p, hsa-miR-625-3p, and hsa-miR-4732-5p) showed significantly higher serum expressions in NTM-PD patients than in controls. Receiver operating characteristic curve analysis of these four miRNAs supported the discriminative potential for NTM-PD and their combination provided an improved diagnostic value for NTM-PD. Furthermore, bioinformatics analysis revealed their 125 target genes, which were mostly associated with immune responses. Collectively, this study identified four miRNAs as potential biomarkers for NTM-PD and provided insight into NTM-PD pathophysiology.

Background: Cathepsin B (CTSB) and cystatin C (CYSC) are new biomarkers for several physiological and pathological processes as their activities increase with age. The aim of this study was to explore population-level associations between serum CTSB and CYSC with an age-related pulmonary subclinical state., Methods: We examined 401 healthy participants (aged 36-87 years, of which 44.3% were male) in northern Chinese cities. We used a standard spirometer to determine lung function. Serum CTSB and CYSC levels were measured by enzyme-linked immunosorbent assay (ELISA)., Results: For all participants, serum CTSB was related to maximum vital capacity (VC MAX), forced vital capacity (FVC), forced expiratory volume in 1 s, peak expiratory flow, forced expiratory flow at 25% of FVC, forced expiratory volume in 3 s (FEV3), and inspiratory vital capacity (VC IN). These associations were lost after full adjustment. CYSC remained significantly associated with inspiratory capacity (IC), breath frequency (BF; p  < 0.001), minute ventilation (MV), the ratio of FEV3 and FVC (FEV3%FVC), and expiratory reserve volume ( p  < 0.05) after adjusting for all other possible confounders. In males, serum CYSC levels exhibited significant and independent associations with FVC, FEV3 ( p  < 0.05), and IC ( p  < 0.001) and serum CTSB levels exhibited significant and independent associations with BF ( p  < 0.05)., Conclusions: Our results confirmed serum CYSC concentration associations with an age-related lung function in healthy people. However, the association between serum CTSB and lung function was not well confirmed. Serum measurements of CYSC may provide valuable predictors of pulmonary function in healthy people, especially healthy elderly adults. The reviews of this paper are available via the supplemental material section .

Background: The risk factors for Mycobacterium avium complex lung disease (MAC-LD) are not well known. We hypothesized that low serum estradiol (E2) levels are related to MAC-LD as most patients with MAC-LD are postmenopausal women., Methods: This cross-sectional study compared patients with MAC-LD and healthy controls. Study subjects were postmenopausal women aged 65 years or younger. Serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and E2 levels were measured and categorized as high or low based on median levels. We performed multivariate analysis, receiver operating characteristic (ROC) curve analysis, and age- and body mass index (BMI)-matched subgroup analysis to evaluate the association between low serum E2 levels and MAC-LD. Additionally, using blood samples obtained for other clinical studies, the levels of sex steroid hormones were compared between age- and BMI-matched MAC-LD and bronchiectasis female patients without non-tuberculosis mycobacterial infections (non-NTM BE)., Results: Forty-two patients with MAC-LD and 91 healthy controls were included. The median E2 (2.20 pg/mL vs. 15.0 pg/mL, p < 0.001), testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005), and DHEA-S (82.5 μg/dL vs. 114.0 μg/dL, p < 0.001) levels were lower in the MAC-LD group than in the control group. Multivariate analysis revealed that low serum E2 (adjusted odds ratio = 34.62, 95% confidence interval = 6.02-199.14) was independently related to MAC-LD, whereas low DHEA-S and testosterone were not. ROC analysis illustrated a strong relationship between low serum E2 levels and MAC-LD (area under the curve = 0.947, 95% confidence interval = 0.899-0.995). Even the age- and BMI-matched subgroup analysis of 17 MAC-LD patients and 17 healthy controls showed lower serum E2 in MAC-LD patients than in healthy controls. Additionally, serum E2 levels of 20 MAC-LD patients were lower than plasma E2 levels of 11 matched non-NTM BE patients (1.79 pg/mL vs. 11.0 pg/mL, p < 0.001)., Conclusions: Low serum E2 levels were strongly related to MAC-LD in postmenopausal women.

Measurement of cytokines in peripheral blood and bronchoalveolar lavage fluid (BALF) is a useful method to assess human immune responses in a large range of pulmonary diseases. One of the major pre-analytical challenges of cytokine analysis is the quality and stability of cytokines in the timeframe between sample collection and the separation of supernatant from cells. To evaluate if the method of storage may affect cytokine quantification, whole blood and BALF were collected, aliquoted, and left at room temperature (RT) to be processed at different time points. In addition, sera and BALF were left either at RT or at 4 °C for 24 h after cell separation to test cytokine variations in the absence of cells. Samples were analysed by a multiple array containing ten cytokines. Most of the cytokines analysed (interleukin (IL)-4, IL-5, IL-6, IL-12p70, IL-13, IL-17A, IL-23, interferon (IFN)-γ, and tumour necrosis factor (TNF)-α) did not show significant variations in whole blood and BALF. Levels of IL-8 however, increased after storage of whole blood and BALF for 24 h at RT. Ex vivo IL-8 production seems to correlate with higher numbers of macrophages in collected BALF. These data demonstrate that many cytokines are stable for a brief time after sample collection. For IL-8, freshly collected whole blood and BALF should be quickly processed and frozen to avoid false positive results., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Welders' lung disease refers to mixed exposure to different kinds of metals and chemicals from welding fumes, which affect all parts of the respiratory tract including airways and parenchyma together. This study aimed to investigate the oxidative status in patients with welders' lung (PWL) by means of thiol-disulfide homeostasis and ischemia-modified albumin (IMA) levels. The male welder workers diagnosed with welders' lung disease and healthy individuals were recruited in the study. Plasma levels of disulfide, disulfide/native thiol ratio, disulfide/total thiol ratio, IMA, and catalase (CAT) were determined. Pulmonary function test parameters of both groups were compared. The thiol-disulfide homeostasis parameters of PWL and control group were as follows: disulfide (20.5 ± 6.3 vs. 16.2 ± 3.9 μmol L -1 , p < 0.001), disulfide/native thiol (4.36 (1.59) vs. 4.0 (1.64), p = 0.024), and disulfide/total thiol (4.01 (1.34) vs. 3.71 (1.41), p = 0.024). IMA levels in PWL were significantly higher than the control group (1.37 (0.27) mg dL -1 vs. 0.49 (0.61) mg dL -1 , p < 0.001), whereas CAT activities were significantly higher in the control group (106.6 (54.5) kU L -1 vs. 78.3 (67.8) kU L -1 , p = 0.003). The findings of the present study revealed that oxidative stress plays a key role in the pathogenesis of welders' lung disease. Plasma thiol-disulfide homeostasis and IMA levels might be indicators of oxidative stress in PWL.

Introduction: Sulfur mustard (SM) as a chemical warfare agent has short- and long-term complications on its victims. Complications of exposure to SM depend on the level of contamination. Long-term pulmonary complications are the most serious problems. Recent evidence has shown that absorbed SM can be conducted to other tissues by the bloodstream. In this study, we evaluated the long-term effects of SM on the vital activity of peripheral blood mononuclear cells (PBMCs) in SM-exposed patients with long-term pulmonary complications., Materials and Methods: Our study samples were 110 patients with long-term pulmonary complications in the SM-exposed group and 109 unexposed individuals in the control group. After clinical examination and pulmonary function tests, the severity of pulmonary complications was classified. Also, the participants' peripheral blood was taken into EDTA-treated Vacutainer tubes. Then, the complete blood count (CBC) was calculated, and PBMCs was purified from whole blood using Ficol-Paque gradient method, finally, the vital activity was assessed by MTT assay., Result: The vital activity of PBMCs in the SM-exposed group with the mitogen was significantly lower than that in the control group (P = 0.016). Whereas, there was no significant difference in the viability of PBMCs without the mitogen between two groups. Furthermore, hematologic findings indicated that the SM-exposed group had a significant increase in the total count of WBC, neutrophil, MCV, and HCT values but the lymphocyte count and MCHC value were significantly lower than those in the control group., Conclusion: Exposure to SM even after a long time, can affect hematologic parameters and vital activity of PBMCs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The present study aimed to evaluate serum prooxidant -antioxidant balance (PAB) in an Iranian population exposed to sulfur mustard (SM) more than 20 years ago. In this study, 42 SM-exposed subjects and 30 unexposed subjects (as controls) were recruited. Serum PAB, biochemical, and hematological parameters were measured in all subjects. Correlation of PAB with biochemical and hematological parameters was determined. The mean PAB values in the SM-exposed group (82.5 ± 34.8 HK) were significantly higher than that in the control group [47.5 ± 17.8 HK] ( p  < 0.001). The results demonstrated that serum PAB values were positively correlated with alkaline phosphatase activities in the SM-exposed group. Furthermore, PAB values showed a significant negative correlation with hepatic enzymes (AST, ALT), triglycerides, total bilirubin, and mean corpuscular hemoglobin concentrations. PAB values showed a borderline significant negative correlation with uric acid. The present results suggest that late oxidative stress and alterations in biochemical and hematological parameters may be a consequence of the frequent respiratory infections rather than direct toxic effects of SM.

Rheumatoid arthritis (RA) is characterized by extra-articular involvement including lung disease, yet the mechanisms linking the two conditions are poorly understood. The collagen-induced arthritis (CIA) model was combined with the organic dust extract (ODE) airway inflammatory model to assess bone/joint-lung inflammatory outcomes. DBA/1J mice were intranasally treated with saline or ODE daily for 5 weeks. CIA was induced on days 1 and 21. Treatment groups included sham (saline injection/saline inhalation), CIA (CIA/saline), ODE (saline/ODE), and CIA +  ODE (CIA/ODE). Arthritis inflammatory scores, bones, bronchoalveolar lavage fluid, lung tissues, and serum were assessed. In DBA/1J male mice, arthritis was increased in CIA +  ODE >  CIA >  ODE versus sham. Micro-computed tomography (µCT) demonstrated that loss of BMD and volume and deterioration of bone microarchitecture was greatest in CIA +  ODE. However, ODE-induced airway neutrophil influx and inflammatory cytokine/chemokine levels in lavage fluids were increased in ODE >  CIA +  ODE versus sham. Activated lung CD11c + CD11b + macrophages were increased in ODE >  CIA +  ODE >  CIA pattern, whereas lung hyaluronan, fibronectin, and amphiregulin levels were greatest in CIA +  ODE. Serum autoantibody and inflammatory marker concentrations varied among experimental groups. Compared with male mice, female mice showed less articular and pulmonary disease. The interaction of inhalation-induced airway inflammation and arthritis induction resulted in compartmentalized responses with the greatest degree of arthritis and bone loss in male mice with combined exposures. Data also support suppression of the lung inflammatory response, but increases in extracellular matrix protein deposition/interstitial disease in the setting of arthritis. This coexposure model could be exploited to better understand and treat RA-lung disease. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

In the clinical diagnosis of tumor, the immunological detection of single tumor markers may lead to errors and missed inspection. Therefore, it is necessary to establish an accurate and effective method for the simultaneous detection of multiple tumor markers. Thus, we developed a time-resolved chemiluminescence immunoassay (TRCLIA) to simultaneously detect carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) in human serum. Horseradish peroxidase (HRP) and alkaline phosphatase (ALP) were used as the detection probes to label the monoclonal antibodies of CEA and NSE by strain-promoted azide-alkyne cycloaddition (SPAAC), respectively. Based on a sandwich immunoassay, the targets in the samples were captured by antibodies immobilized on the surface of carboxylate-modified polystyrene microspheres (CPSMS) and sandwiched by other antibodies labeled with HRP and ALP. Since HRP and ALP had different dynamic characteristics, the CEA and NSE signals were recorded at 0.5 s and 20 min, respectively, and cross-interference could be avoided effectively. The whole signal detection processes could be completed in 20 min. The linear ranges of CEA and NSE were 0.1-64 ng mL-1 and 0.05-64 ng mL-1 and the limits of detection were 0.085 ng mL-1 and 0.044 ng mL-1 (S/N = 2), respectively. Also, 45 human serum samples obtained from patients having lung disease were tested by TRCLIA and commercial chemiluminescence enzyme-linked immunoassay (CLEIA) kits with good correlation. The correlation coefficients of CEA and NSE were 0.985 and 0.970, respectively. The results demonstrated a novel, effective, reliable and convenient TRCLIA method for the clinical diagnosis of CEA and NSE. The TRCLIA method has the potential to be an effective clinical tool for the early screening of lung cancer and can be applied in clinical diagnosis.