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Rationale: Outdoor air pollution contributes to asthma development and exacerbations, yet its effects on airway pathology have not been defined in children. Objectives: To explore the possible link between air pollution and airway pathology, we retrospectively examined the relationship between environmental pollutants and pathological changes in bronchial biopsy specimens from children undergoing a clinically indicated bronchoscopy. Methods: Structural and inflammatory changes (basement membrane [BM] thickness, epithelial loss, eosinophils, neutrophils, macrophages, mast cells, and lymphocytes) were quantified in biopsy specimens by using immunohistochemistry. The association between exposure to particulate matter less than 10 μm in aerodynamic diameter (PM10), SO2 and NO2 and biopsy findings was evaluated by using a generalized additive model with Gamma family to allow for overdispersion, adjusted for atmospheric pressure, temperature, humidity, and wheezing. Results: Overall, 98 children were included (age 5.3 ± 2.9 yr; 53 with wheezing/45 without wheezing). BM thickness increased with prolonged exposure to PM10 (rate ratio [RR], 1.29; 95% confidence interval [CI], 1.09–1.52), particularly in children with wheezing. Prolonged exposure to PM10 was also associated with eosinophilic inflammation in children with wheezing (RR, 3.16; 95% CI, 1.35–7.39). Conversely, in children without wheezing, increased PM10 exposure was associated with a reduction of eosinophilic inflammation (RR, 0.12; 95% CI, 0.02–0.6) and neutrophilic inflammation (RR, 0.36; 95% CI, 0.14–0.89). Moreover, NO2 exposure was also linked to reductions in neutrophil infiltration (RR, 0.57; 95% CI, 0.34–0.93) and eosinophil infiltration (RR, 0.33; 95% CI, 0.14–0.77). Conclusions: Different patterns of association were observed in children with wheezing and in children without wheezing. In children without wheezing, exposure to PM10 and NO2 was linked to reduced eosinophilic and neutrophilic inflammation. Conversely, in children with wheezing, prolonged exposure to PM10 was associated with increased BM thickness and eosinophilic inflammation, suggesting that it might contribute to asthma development by promoting airway remodeling and inflammation.

Background FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF). Methods Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted). Results 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study. Conclusions FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF. Trial registration: NCT02803580

Introduction: Originally described as an anti-inflammatory in vitro, the Suppressor of Cytokine Signalling (SOCS) proteins seem to have an opposite effect in vivo. Along with this possibility we have previously observed a higher expression of SOCS3 in alveolar macrophages (AM) in COPD lungs than in healthy smoker and nonsmoker lungs. Aim: To investigate: 1) if AM-derived MV in BAL could reflect SOCS3 expression in lung AM; and 2) if SOCS3 expression in AM is regulated by the SOCS3 post-transcriptional regulators, miR-19a-3p and miR-221-3p in MV. Methods: BAL from 5 nonsmokers (NS), 11 smokers w/o COPD (S) and 9 smokers with COPD was collected. Differential centrifugation of BAL was performed and the final sample divided in 2 aliquots to: 1) isolate and detect by flow cytometry MV of AM origin expressing SOCS3 (CD14+SOCS3+); 2) analyse and quantify by quantitative PCR the differential expression of miR-19a-3p and miR-221-3p in AM-derived MV. Results: CD14+SOCS3+ expression in MV from BAL was increased in COPD compared to NS [33(26-97) vs 9(8-17) events/?l p=0.003] and to S [16(12-22) p=0.03]. Conversely the expression in BAL MV of the SOCS3 regulators miR-19a-3p and miR-221-3p was increased in S when compared to COPD [19(2-53) vs 3(0.6-8) p=0.03 and 3(0.005-9.6) vs 0.2(0.08-0.7) p=0.06, respectively]. Conclusions: BAL-derived MV are able to reflect the differential expression of SOCS3 in lung AM of smokers with and w/o COPD. Furthermore, with the use of MV we showed that SOCS3 expression in COPD is enhanced by the decreased expression of regulatory miRNAs. These results underline the role of MV as a tool for the study of lung events.

Pneumothorax (PNX) and pneumomediastinum (PNM) are potential complications of COVID-19, but their influence on patients’ outcomes remains unclear. The aim of the study was to assess incidence, risk factors, and outcomes of severe COVID-19 complicated with PNX/PNM. Methods: A retrospective multicenter case-control analysis was conducted in COVID-19 patients admitted for respiratory failure in intermediate care units of the Treviso area, Italy, from March 2020 to April 2021. Clinical characteristics and outcomes of patients with and without PNX/PNM were compared. Results: Among 1213 patients, PNX and/or PNM incidence was 4.5%. Among these, 42% had PNX and PNM, 33.5% only PNX, and 24.5% only PNM. COVID-19 patients with PNX/PNM showed higher in-hospital (p = 0.02) and 90-days mortality (p = 0.048), and longer hospitalization length (p = 0.002) than COVID-19 patients without PNX/PNM. At PNX/PNM occurrence, one-third of subjects was not mechanically ventilated, and the respiratory support was similar to the control group. PNX/PNM occurrence was associated with longer symptom length before hospital admission (p = 0.005) and lower levels of blood lymphocytes (p = 0.017). Conclusion: PNX/PNM are complications of COVID-19 associated with a worse prognosis in terms of mortality and length of hospitalization. Although they are more frequent in ventilated patients, they can occur in non-ventilated, suggesting that mechanisms other than barotrauma might contribute to their presentation.

IntroductionAir pollution is a risk factor for respiratory infections and asthma exacerbations. We previously reported impaired Type-I and Type-III interferons (IFN-β/λ) from airway epithelial cells of preschool children with asthma and/or atopy. In this study we analyzed the association between rhinovirus-induced IFN-β/λ epithelial expression and acute exposure to the principal outdoor air pollutants in the same cohort.MethodsWe studied 34 children (17asthmatics/17non-asthmatics) undergoing fiberoptic bronchoscopy for clinical indications. Bronchial epithelial cells were harvested by brushing, cultured and experimentally infected with Rhinovirus Type 16 (RV16). RV16-induced IFN-β and λ expression was measured by quantitative real time PCR, as was RV16vRNA. The association between IFNs and the mean exposure to PM10, SO2 and NO2 in the day preceding bronchoscopy was evaluated using a Generalized Linear Model (GLM) with Gamma distribution.ResultsAcute exposure to PM10 and NO2 was negatively associated to RV16-induced IFNβ mRNA. For each increase of 1ug/m3 of NO2 we found a significative decrease of 2.3x103 IFN-β mRNA copies and for each increase of 1ug/m3 of PM10 a significative decrease of 1x103 IFN-β mRNA copies. No significant associations were detected between IFN-λ mRNA and NO2 nor PM10. Increasing levels of NO2 (but not PM10) were found to be associated to increased RV16 replication.ConclusionsShort-term exposure to high levels of NO2 and PM10 is associated to a reduced IFN-β expression by the airway epithelium, which may lead to increased viral replication. These findings suggest a potential mechanism underlying the link between air pollution, viral infections and asthma exacerbations.

Introduction: Malignant pleural effusion (PE) is a common complication of advanced malignancy, especially lung and breast cancer (BC). The incidence of pleural metastasis in BC is known to be higher within the first years from diagnosis and rarer after 10-12 years. Aim: To evaluate the incidence of ultra-late pleural metastasis in patients with breast cancer-related PE, and whether clinical aspects may be associated with this late recurrence. Methods: A single-centre retrospective study of all patients that underwent medical thoracoscopy for suspected malignant PE from 2013 to 2019 was performed. Ultra-late metastasis were defined as recurrence appearing later than 10 years from BC diagnosis. Data regarding BC histotype (Luminal A, Luminal B, HER2+ and triple negative), macroscopic pleural appearance (nodules or diffuse thickening), amount of PE (litres) and side of PE compared to primary BC were recorded. Results: Of the 491 patients evaluated, 40 (8%) had BC pleural involvement. Four (10%) had a first diagnosis of BC after thoracoscopy. Of the other 36 patients, 19 (52%) had BC diagnosed more than 10 years before, and 7 of them even more than 20. The amount of PE, macroscopic appearance, side of PE involvement and histotype were similar between those 10 years from BC. There was a significantly higher time to recurrence (months) in Luminal B compared to triple negative (166±101 vs 76±74; p=0.02) and a trend in diffuse pleural involvement compared to nodules (175.6±105.6 vs 114.3±84.5; p=0.08). Conclusions: Ultra-late pleural BC metastasis are not uncommon in our cohort of patients with breast cancer-related PE. Longer time to recurrence was found in Luminal B histotype and in diffuse pleural involvement.

Background/aim In the present retrospective study, we assessed the molecular profile and clinicopathological correlations of Greek colorectal carcinoma (CRC) patients. Patients and methods Data from 157 CRC patients were collected. High Resolution Melting Analysis and Pyrosequencing/Sanger sequencing were applied to identify KRAS, BRAF, NRAS mutations and microsatellite instability (MSI) status. Immunohistochemistry was performed to characterize the associated Mismatch Repair Protein loss. Statistical calculations were performed using the statistical package SPSS v21.0. Results KRAS mutations were detected in 39.3% of cases, BRAF in 10.9% and NRAS in 4.9%. MSI status was recognized in 11.5% of CRC patients and was associated with right colon tumors. MSI phenotype was inversely correlated with stage, N status and KRAS mutations and positively correlated with BRAF mutations. Conclusion MSI positive CRCs in the Greek population are more often right-sided, free of metastasis, KRAS wild type and BRAF mutated. Providing more detailed clinicopathological and molecular data for specific populations will enable better clinical management and individualized therapy in the future.

Objective:Our primary objective is to give weight to the unanswered and recently heavily debated question, as to whether endometriosis is a statistically significant risk factor for ectopic pregnancy. Our study also provides information on the ethnicity, age and parity of each woman. We report the clinical presentation, the presence of other risk factors as well as intraoperative findings.Design:A retrospective cohort study.Settings:Whipps Cross University Hospital, Bart’s Health NHS Trust which is a district general University hospital in East London.Population:All women, over 10-year period (2005–2014), who were surgically treated for an ectopic pregnancy.Methods:In total, 800 patients were surgically managed. A total of 100 had incomplete data and were, therefore, excluded from analysis. The clinical details, demographics and operation notes were retrospectively analysed for 700 patients. Data were analysed using the student’s t test or chi-square analysis as appropriate.Results:In total, 37 women (5.3%) had endometriosis and 663 women (94.7%) had no evidence of endometriosis. Of the 37 patients, 24 had stage 1, 11 had stage 2 and 2 patients had stage 3 endometriosis.Conclusion:Our data support the theory that endometriosis is not a statistically significant occurrence in women with surgically managed ectopic pregnancy and is not risk factor for ectopic pregnancy.

Supplemental Digital Content is available in the text., Objectives: Autophagy plays a dual role in tumorigenesis. In the initial stages, it promotes cell survival and suppresses carcinogenesis, whereas in cancer development, it induces cancer cell survival. In this study, we investigate the role of autophagy as a protective or tumor suppressor mechanism in colorectal cancer (CRC) cell lines and evaluate its role as a potential biomarker in human tumor samples. Materials and Methods: The data of 68 patients with CRC treated at our Department from January 1 to December 31, 2016 were analyzed. Immunohistochemistry evaluation of p62, LC3B, Beclin-1, and Rab-7 in formalin-fixed paraffin-embedded tissue samples was performed and their expression was correlated with clinicopathologic characteristics, mutation status, and therapeutic approach. The χ2 was used to test an association among categorical variables. Survival curves were estimated using the Kaplan-Meier method and differences were assessed using the log-rank test. Colo-205, HT29, SW-480, and Caco-2 cell lines were also used so as to test the autophagy markers with oxaliplatin, irinotecan, hydroxychloroquine, and 3-methyladenine. Results: Overexpression of Beclin-1 is associated with poor survival (P=0.001) in patients with CRC treated with chemotherapy, irrespective of the stage and mutational status. Rab-7 is also correlated with progression-free survival (PFS) (P=0.088). Oxaliplatin (10 and 20 μΜ) and irinotecan (10 and 20 μΜ) inhibit autophagy in microsatellite stable (MSS) CRC cell lines. The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through monodancylcadaverine staining. Moreover, inhibition of autophagy with molecules such as hydroxychloroquine (20 μΜ) and 3-methyladenine (5 mM) was identified by the accumulation of p62 and LC3B. Conclusions: Beclin-1 is an independent prognostic factor of overall survival and PFS. Also, Rab-7 is identified as an independent prognostic factor of PFS. Besides, several chemotherapeutic drugs such as oxaliplatin and irinotecan inhibit autophagy in MSS CRC cell lines in a similar way like hydroxychloroquine and 3-methyladenine. Thus, in MSS patients who develop chemoresistance, a combination of other therapies that include an autophagy inhibitor could be more beneficial. Further clinical trials are needed to investigate these therapeutic strategies.

Patients suffering from body integrity dysphoria (BID) desire to become disabled, arising from a mismatch between the desired body and the physical body. We focus here on the most common variant, characterized by the desire for amputation of a healthy limb. In most reported cases, amputation of the rejected limb entirely alleviates the distress of the condition and engenders substantial improvement in quality of life. Since BID can lead to life-long suffering, it is essential to identify an effective form of treatment that causes the least amount of alteration to the person’s anatomical structure and functionality. Treatment methods involving medications, psychotherapy, and vestibular stimulation have proven largely ineffective. In this hypothesis article, we briefly discuss the characteristics, etiology, and current treatment options available for BID before highlighting the need for new, theory driven approaches. Drawing on recent findings relating to functional and structural brain correlates of BID, we introduce the idea of brain–computer interface (BCI)/neurofeedback approaches to target altered patterns of brain activity, promote re-ownership of the limb, and/or attenuate stress and negativity associated with the altered body representation.

The impact that COVID-19 could have on patients with COPD is a real concern. In this study we evaluated, in a cohort of longitudinally followed COPD subjects, the incidence of COVID-19, seeking for possible risk factors and prognostic factors predicting the clinical outcome. In our cohort of 370 patients (followed for 5.3 ± 2.7 years), 22 developed COVID-19 (COPD/COVID-19+) between February/November 2020 (5.9%). Cardio-metabolic conditions (hypertension, dyslipidemia, obesity, diabetes) but not respiratory abnormalities (FEV1, DLCO, emphysema and exacerbation history), were risk factors for development of COVID-19 in COPD patients. Out of the 22 COPD/COVID-19+ patients, 10 needed intensive care. Low DLCO and emphysema, but also metabolic comorbidities, were related to the need for intensive care.

Aberrant Wnt signaling is implicated in carcinogenesis triggering efforts for the development of new therapeutic agents, many of which have entered clinical trials. We extend our previous analysis of WNT3, FZD7, LEF1 expression levels in breast and colorectal cancer including WNT2, FZD4 and β-catenin expression, in an effort to delineate their relative expression levels along with concurrent expression patterns and possible prognostic value. We analyzed 82 breast and 102 colorectal carcinomas for relative mRNA expression levels of the investigated genes by RT-PCR relative quantification with the ΔΔCt method. Statistical analysis was performed in order to determine associations of relative mRNA expression and linear correlations. β-catenin expression was determined by immunochemistry. Regarding breast carcinomas, decreased relative mRNA expression levels of WNT2, FZD4 were found frequently and WNT2 expression was correlated with ER/ PR status (p = 0.045/p = 0.028), whereas β-catenin with grade (p = 0.026). In colorectal carcinomas, increased relative mRNA expression levels of WNT2 and FZD4 were found in 59% and 32% of cases respectively, whereas β-catenin showed decreased mRNA expression levels in 57% of cases and a correlation with pN-category (p = 0.037). Linear correlations were observed between WNT2/FZD4 (R=0.542, p 0.001), WNT2/β-catenin (R=0.254, p = 0.010), FZD4/β-catenin (R=0.406, p 0.001) expression and a correlation between mRNA expression and membranous/cytoplasmic β-catenin emerged (p = 0.039/0.046). Our results suggest a possible clinical significance for Wnt pathway gene expression levels in both tumour types. The concurrent expression of the investigated genes as well as the different expression profiles, underlines the complexity of this pathway and the necessity of patient selection in order to maximize the efficacy of drugs targeting Wnt pathway.

Frauke Pedersen,1,2 Frederik Trinkmann,3 Mustafa Abdo,2 Anne-Marie Kirsten,1 Klaus F Rabe,2 Henrik Watz,1 Simonetta Baraldo,4 Marina Saetta,4 Jens M Hohlfeld,5,6 Olaf Holz5 1Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Respiratory Diseases Clinic, University of Padova, Padova, Italy; 5Fraunhofer ITEM, Clinical Airway Research - Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 6Department of Respiratory Medicine, Hannover Medical School (MHH), Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, GermanyCorrespondence: Frauke PedersenPulmonary Research Institute at LungenClinic Grosshansdorf, Wöhrendamm 80, Grosshansdorf, D-22927, GermanyTel +49-4102-6016845Fax +49-4102-8881114Email f.pedersen@pulmoresearch.dePurpose: We recently introduced a sputum cell quality score to rate how cell morphology, cellular debris and squamous cell contamination influence inflammatory cell identification during microscopic evaluation. However, sputum cell quality is generally not considered for the interpretation of sputum fluid phase biomarkers. Therefore, we compared the soluble protein concentrations between sputum samples with different cell quality. The impact of cell quality was compared to other factors potentially affecting soluble biomarker concentrations.Methods: A comprehensive sputum dataset from 154 clinically stable COPD patients was used to analyse the differences and the variability of sputum supernatant concentrations for 23 proteins between low, medium, and high sputum cell quality samples. A model was developed and tested to compare the impact of different factors on sputum supernatant protein levels.Results: Mean percentages of sputum macrophages, neutrophils, eosinophils, monocytes and lymphocytes showed no significant differences between low, medium and high cell quality levels. The mean percentage of squamous cells were lower, while total cell count/mL sputum and cell viability were significantly higher in sputum samples with higher cell quality. The concentrations of Interleukin-6, Interleukin-8 and Tumor Necrosis Factor Receptor 2 were significantly increased in sputum samples of higher cell quality. The variability of most protein concentrations declined with increasing cell quality levels. Sixteen proteins showed significantly negative correlations with the percentage of squamous cells. For 14 proteins we observed a positive correlation with cell number/mL sputum. Multiple regression analysis shows that generally less than 30% of the protein variability can be explained by the included factors.Conclusion: Sputum cell quality has a significant impact on some soluble biomarker concentrations in sputum supernatant. Sputum samples with low sputum cell quality show a higher variability of fluid phase proteins in comparison to medium and high sputum cell quality levels.Keywords: sputum cell quality score, soluble biomarkers, sputum supernatant

Objectives Innate lymphoid cells (ILCs) secrete cytokines, such as IFN‐γ, IL‐13 and IL‐17, which are linked to chronic obstructive pulmonary disease (COPD). Here, we investigated the role of pulmonary ILCs in COPD pathogenesis. Methods Lung ILC subsets in COPD and control subjects were quantified using flow cytometry and associated with clinical parameters. Tissue localisation of ILC and T‐cell subsets was determined by immunohistochemistry. Mice were exposed to air or cigarette smoke (CS) for 1, 4 or 24 weeks to investigate whether pulmonary ILC numbers and activation are altered and whether they contribute to CS‐induced innate inflammatory responses. Results Quantification of lung ILC subsets demonstrated that ILC1 frequency in the total ILC population was elevated in COPD and was associated with smoking and severity of respiratory symptoms (COPD Assessment Test [CAT] score). All three ILC subsets localised near lymphoid aggregates in COPD. In the COPD mouse model, CS exposure in C57BL/6J mice increased ILC numbers at all time points, with relative increases in ILC1 in bronchoalveolar lavage (BAL) fluid. Importantly, CS exposure induced increases in neutrophils, monocytes and dendritic cells that remained elevated in Rag2/Il2rg‐deficient mice that lack adaptive immune cells and ILCs. However, CS‐induced CXCL1, IL‐6, TNF‐α and IFN‐γ levels were reduced by ILC deficiency. Conclusion The ILC1 subset is increased in COPD patients and correlates with smoking and severity of respiratory symptoms. ILCs also increase upon CS exposure in C57BL/6J mice. In the absence of adaptive immunity, ILCs contribute to CS‐induced pro‐inflammatory mediator release, but are redundant in CS‐induced innate inflammation., In this article, we investigated the role of pulmonary innate lymphoid cells (ILCs) in the pathogenesis of chronic obstructive pulmonary disease (COPD). We found that the ILC1 subset is increased in COPD patients and correlates with smoking and severity of respiratory symptoms. In C57BL/6 mice, ILCs increase upon cigarette smoke (CS) exposure. In the absence of adaptive immunity, ILCs contribute to CS‐induced pro‐inflammatory mediator release, but they are redundant in CS‐induced innate inflammation.

Background: Smokers with and without chronic obstructive pulmonary disease (COPD) are at risk of severe outcomes like exacerbations, cancer, respiratory failure, and decreased survival. The mechanisms for these outcomes are unclear; however, there is evidence that blood lymphocytes (BL) number might play a role. Objective: The objective of this study is to investigate the relationship between BL and their possible decline over time with long-term outcomes in smokers with and without COPD. Methods: In 511 smokers, 302 with COPD (COPD) and 209 without COPD (noCOPD), followed long term, we investigated whether BL number and BL decline over time might be associated with long-term outcomes. Smokers were divided according to BL number in high-BL (≥1,800 cells/µL) and low-BL (Results: BL count was lower in COPD (1,880 cells/µL) than noCOPD (2,300 cells/µL; p < 0.001). 43% of COPD and 23% of noCOPD had low-BL count (p < 0.001). BL decline over time was higher in COPD than noCOPD (p = 0.040). 22.5% of the whole cohort developed cancer which incidence was higher in low-BL subjects and in BL decliners than high-BL (31 vs. 18%; p = 0.001) and no decliners (32 vs. 19%; p = 0.002). 26% in the cohort died during follow-up. Furthermore, low-BL count, BL decline, and age were independent risk factors for mortality by Cox regression analysis. Conclusion: BL count and BL decline are related to worse outcomes in smokers with and without COPD, which suggests that BL count and decline might play a mechanistic role in outcomes deterioration. Insights into mechanisms inducing the fall in BL count could improve the understanding of COPD pathogenesis and point toward new therapeutic measures.

Background A common variant located in the promoter region of MUC5B (rs35705950) is the strongest risk factor for sporadic and familiar IPF, as well as a predictor of outcome. However, there are no data on the effect of MUC5B rs35705950 genotype on the prognosis of IPF patients on antifibrotic treatment. The aim of this study is to determine, in a phenotypically well-characterized population of patients with IPF treated with antifibrotics, the impact of MUC5B rs35705950 genotype on disease progression and survival. Methods 88 IPF patients on antifibrotic treatment were followed-up from 2014 until transplantation, death or end of follow-up (December 2019). Disease progression was defined as a forced vital capacity (FVC) loss ≥ 5% per year. All patients were genotyped for MUC5B rs35705950 by PCR amplification and Sanger sequencing. Results Out of 88 patients, 61 (69%) carried the mutant T allele (TT or TG) and 27 (31%) did not (GG). Carriage of the MUC5B rs35705950 T allele was not associated with a faster decline in FVC. Conversely, at the end of the follow-up, overall survival in carriers of the TT/TG genotype was longer compared to that of the GG genotype carriers. FVC (L) at baseline and time to respiratory failure at rest were independent predictors of worse prognosis. Conclusions In IPF patients on antifibrotic treatment, carriage of the MUC5B rs35705950 T allele is associated with longer survival, highlighting the usefulness of MUC5B genetic data in clinical decision making.

Obesity as well as metabolic and cardiovascular comorbidities are established, significant predictors of worse prognosis in the overall COVID-19 population, but limited information is available on their roles in young and middle-aged adults (aged ≤ 50 years). The main objectives of the present Italian multi-center study were to describe clinical characteristics and role of selected prognostic predictors in a large cohort of young and middle-aged hospitalized patients. Nine pulmonology units, across north and center of Italy, were involved in this retrospective study. Comorbidities were classified according to their known or potential association with COVID-19. A total of 263 subjects were included. The prevalence of obesity was 25.9%, mechanical ventilation (MV) was needed in 27.7%, and 28 in-hospital deaths occurred (10.6%). Obesity and older age were the only independent, significant predictors for MV. Comorbidities, such as hypertension, diabetes, asthma, and increased D-dimer levels were significantly associated with higher mortality risk, regardless of age, body mass index, and MV. Obesity in young and middle-aged adults is a strong predictor of a more complicated COVID-19, without, however, evidence of a significant effect on in-hospital mortality. Selected comorbidities, including hypertension, diabetes and asthma, significantly impact survival even in a younger population, suggesting the need for prompt recognition of these conditions.

Chronic obstructive pulmonary disease (COPD) is a complex condition in which systemic inflammation plays a role in extrapulmonary manifestations, including cardiovascular diseases: interleukin (IL)-6 has a role in both COPD and atherogenesis. The 2011 GOLD document classified patients according to FEV1, symptoms, and exacerbations history, creating four groups, from A (less symptoms/low risk) to D (more symptoms/high risk). Extracellular vesicles (EV) represent potential markers in COPD: nevertheless, no studies have explored their value in association to both disease severity and inflammation. We conducted a pilot study to analyze circulating endothelial-(E) and monocyte-derived (M) EV levels in 35 COPD patients, who were grouped according to the 2011 GOLD document, the relationship between EV and plasmatic markers of inflammation was analyzed. We found a statistically significant trend for increasing EEV, MEV, IL-6, from group A to D, and a significant correlation between EEV and IL-6. The associations between both EEV and MEV and disease severity, and between EEV and IL-6, suggest a significant interplay between pulmonary disease and inflammation, with non-respiratory cells (endothelial cells and monocytes) involvement, along with the progression of the disease. Thus, EV might help identify a high-risk population for extrapulmonary events, especially in the most severe patients.

Eating Disorders (ED) are associated with multiple physical complications that strongly affect the physical health of these young and fragile patients and can also cause significant mortality, the highest among psychiatric pathologies. Among the various organic complications, albeit still little known, the gynecological implications, up to infertility, are very widespread. Both among adolescent and adult patients, gynecological symptoms can be very widespread and range from menstrual irregularities to amenorrhea, from vaginitis to ovarian polycystosis, up to complications during the gestational phase and in postpartum, in addition to the possible consequences on the unborn child. Among the most frequent and significant gynecological disorders in women with ED, there are menstrual irregularities that may occur with oligomenorrhea or even amenorrhea. This symptom, although no longer part of the DSM-5 diagnostic criteria for defining Anorexia Nervosa (AN), must be considered a very relevant event in the overall evaluation of young women and adolescents with eating disorders. Functional Hypothalamic Amenorrhea in ED patients is related to psychological distress, excessive exercise, disordered eating, or a combination of these factors which results in suppression of the hypothalamic- pituitary-ovarian axis, resulting in hypoestrogenism. The objective of this paper is to summarize the causes and the mechanism underlying the menstrual disorders and to provide a better understanding of the correlation between the reproductive system and the mechanisms that regulate food intake and eating habits. In addition, early recognition of risk factors for eating disorders for gynecological implications can help put more accurate assessments of patients to prevent potentially fatal complications. The importance of the involvement of specialist gynecologists in the multidisciplinary team that has to follow patients with eating disorders is also discussed.

Microvesicles (MVs) released from almost all cells are recognized as cell communication tools. MVs have been investigated in several inflammatory diseases but poorly in biological fluids like bronchoalveolar lavage (BAL) of smokers. The purpose of this study was to investigate the presence and source of MVs in BAL of smokers with and without chronic obstructive pulmonary disease (COPD) compared with nonsmoking controls. Using flow cytometry in BAL, we detected endothelial and alveolar macrophage (AM)-derived MVs and found a higher number of AM-MVs in the BAL of smokers with COPD than in smokers without COPD and nonsmokers, which correlated with the pack-years ( r = 0.46; P = 0.05) and with the degree of airway obstruction measured by the forced expiratory volume in 1 s percent predicted ( r = −0.56; P = 0.01). Endothelial and alveolar macrophage-derived MVs are present and measurable in human BAL fluid. In response to smoking and to the development of COPD, inflammatory signals in AM-derived MVs can be quantified, and their numbers are related to the pack-years and the decrease in lung function. These results open the opportunity for future investigation of these microvesicles as biomarkers and possible mechanistic guides in COPD.

During autoscopic phenomena, people perceive a double of themselves in extrapersonal space. Such clinical allocentric self-experiences sometimes co-occur with auditory hallucinations, yet experimental setups to induce similar illusions in healthy participants have generally neglected acoustic cues. We investigated whether feeling the presence of an auditory double could be provoked experimentally by recording healthy participants’ own versus another person’s voice and movements using binaural headphones from an egocentric (the participants' own) and an allocentric (a dummy head located elsewhere) perspective. When hearing themselves allocentrically, participants reported feeling a self-identified presence extracorporeally, an arguably distinct quality of autoscopy. Our results suggest that participants without hallucinatory experiences localized their own voice closer to themselves compared to that of another person. Explorative findings suggest that distinct patterns for hallucinators should be further investigated. This study suggests a successful induction of the feeling of an acoustic doppelganger, bridging clinical phenomena and experimental work.

Background: MUC5B polymorphism rs35705950 (T) is the strongest genetic risk factor for familiar and sporadic IPF as well as a predictor of outcome. No study has yet investigated the impact of MUC5B genotype on response to treatment and disease behavior in IPF patients on antifibrotic treatment. Aim: To determine whether MUC5B genotype (GGvs.TT/TG) affects functional decline and survival of IPF patients on antifibrotic therapy (pirfenidone or nintedanib). Methods: 88 IPF patients on antifibrotic treatment were followed from treatment initiation until transplantation or death. Time to progression was defined as the time (months) from treatment initiation to an absolute decline in forced vital capacity (FVC)%pred≥5%. All patients were genotyped for MUC5B rs35705950 by PCR amplification and Sanger sequencing. Results: 61/88 patients (69%) carried the minor T allele (TT/TG) while 27/88 (31%) did not (GG). Carriers of the T allele displayed similar FVC loss in the 1-year of treatment and time to progression (19vs.20 months, HR 0.86, 95%CI0.49–1.50;p= 0.59) compared to GG carriers. However, at the end of the follow-up, overall survival was significantly longer in carriers of the mutant T allele (TT/GT) compared to that of GG (56vs.41 months, HR 0.40, 95%CI 0.18–0.91;p= 0.006). FVC(ml) at baseline and time to occurrence of respiratory failure at rest were additional independent predictors of mortality. Conclusions: Carriage of MUC5B rs35705950 T allele is associated with longer survival in IPF patients on antifibrotic therapy and may potentially be useful as predictor of outcome. More data are needed to unravel the mechanisms underlying this association.

Background: Outdoor air pollution contributes to asthma exacerbations and development; yet its effects on airway pathology have not been defined, especially in children. To investigate the effects of pollution on airway pathology we examined retrospectively the effect of environmental exposure on pathological changes in bronchial biopsies (BB) in 99 children undergoing a clinically indicated bronchoscopy (age5.3±2.9yrs;53wheezing/46non-wheezing). Methods: Structural and inflammatory changes (Basement Membrane-BM thickness, epithelial loss, eosinophils, neutrophils, macrophages, mast-cells, lymphocytes) were quantified in BB by immunohistochemistry. PM10, NO2 and SO2 levels were obtained from monitoring stations closest to child home in the 90 days preceding BB. The association between average levels of pollutants and biopsy findings was evaluated using a Generalized Additive Model with negative binomial family to allow for overdispersion, adjusted for atmospheric pressure, temperature, humidity. Results: SO2 exposure was negligible while high levels of exposure were recorded for PM10 (46[33-60]μg/m3) and NO2 (40[31-48]μg/m3). BM thickness increased with increasing levels of PM10 (Relative Risk, RR90days1.34,CI1.0-1.7), particularly in wheezing children. Exposure to PM10 reduced neutrophilic inflammation (RR90d0.46,CI0.2-0.8), particularly in non-wheezing children. Short-term exposure to NO2 also reduced neutrophils (RR3d0.61,CI0.4-0.95). Conclusions: Chronic exposure to PM10 affects BM thickness in wheezing children, suggesting that it can contribute to asthma development by promoting airway remodeling. Exposure to NO2 and PM10 was associated to reduced neutrophilic inflammation, possibly unravelling impaired innate immunity.

Background: The Suppressor of Cytokine Signalling (SOCS) proteins, particularly SOCS3, and its regulation by TNF-α, have been originally described in animal and in vitro studies as inhibitors of cytokine-signalling in response to a chronic inflammation. However, more recently, the suppressive role of SOCS3 has been questioned by other animal studies, which suggested an important proinflammatory role for this protein. Aim: To investigate in a human inflammatory disease, COPD, the expression of SOCS3 and its inducer TNF-α in alveolar macrophages (AM). Methods: SOCS3 and TNF-α expression was quantified in alveolar macrophages (SOCS3+AM%, TNF-α+AM%) in lungs from 19 smokers with COPD (COPD) [FEV1: 60±31(%)], 16 smokers without COPD (noCOPD) and 9 nonsmokers (NS) using immunochemistry. Results: The percentage of SOCS3+AM was higher in COPD [68(31-95)%] than in noCOPD [48(22-78)% p=0.04] and NS [10(4-56)% p=0.005]. This pattern was paralleled by the expression of TNF-α in AM, that was higher in COPD [90(52-97)%] than in noCOPD [32(17-60)%] and in NS [1(0-15)% p Conclusions: The increased expression of SOCS3 and its modulator TNF-α in alveolar macrophages of COPD, a chronic inflammatory disease, casts some doubts about SOCS3 suppressor function and rather favours a role for SOCS3 as a proinflammatory mediator.

Idiopathic pulmonary fibrosis presents a progressive and heterogeneous functional decline. CA 19-9 has been proposed as biomarker to predict disease course, but its role remains unclear. We assessed CA 19-9 levels and clinical data in end-stage ILD patients (48 IPF and 20 non-IPF ILD) evaluated for lung transplant, to correlate these levels with functional decline. Patients were categorized based on their rate of functional decline as slow (n = 20; ΔFVC%pred ≤ 10%/year) or rapid progressors (n = 28; ΔFVC%pred ≥ 10%/year). Nearly half of the entire patients (n = 32; 47%) had CA 19-9 levels ≥37kU/L. CA 19-9 levels in IPF were not different from non-IPF ILD populations, however, the latter group had a median CA 19-9 level above the normal cut-off value of 37 KU/l (60 [17–247] kU/L). Among IPF patients, CA 19-9 was higher in slow than in rapid progressors with a trend toward significance (33vs17kU/L; p = 0.055). In the whole population, CA19-9 levels were inversely related with ΔFVC/year (r = −0.261; p = 0.03), this correlation remained in IPF patients, particularly in rapid progressors (r = −0.51; p = 0.005), but not in non. Moreover, IPF rapid progressors with normal CA 19-9 levels showed the greater ΔFVC/year compared to those with abnormal CA 19-9 (0.95 vs. 0.65 L/year; p = 0.03). In patients with end-stage ILD, CA 19-9 may represent a marker of disease severity, whereas its level is inversely correlated with functional decline, particularly among IPF rapid progressors.

Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic with lung disease representing the main cause of morbidity and mortality. Conventional chest-X ray (CXR) and ultrasound (US) are valuable instruments to assess the extent of lung involvement. We investigated the relationship between CXR scores on admission and the level of medical care required in patients with COVID-19. Further, we assessed the CXR-US correlation to explore the role of ultrasound in monitoring the course of COVID-19 pneumonia. Clinical features and CXR scores were obtained at admission and correlated with the level of intensity of care required [high- (HIMC) versus low-intensity medical care (LIMC)]. In a subgroup of patients, US findings were correlated with clinical and radiographic parameters. On hospital admission, CXR global score was higher in HIMCs compared to LIMC. Smoking history, pO2 on admission, cardiovascular and oncologic diseases were independent predictors of HIMC. The US score was positively correlated with FiO2 while the correlation with CXR global score only trended towards significance. Our study identifies clinical and radiographic features that strongly correlate with higher levels of medical care. The role of lung ultrasound in this setting remains undetermined and needs to be explored in larger prospective studies.

We describe the case of a 56 years-old man with a subacute onset of symptoms mimicking a granulomatosis with polyangiitis. He was admitted to our hospital with acute respiratory failure requiring oxygen therapy, fever and crusted rhinitis. Despite initial improvement in radiological and clinical features with a steroids therapy, his condition worsened rapidly and he was re admitted to our department with ARDS. Despite antibiotic, antiviral and antifungal therapy, an endotracheal intubation was necessary and ultimately the patient passed away. Only a histological examination on autopsy had shown the presence of a diffuse Anaplastic Large Cell Lymphoma (ALCL), a rare type of non-Hodgkin lymphoma (NHL) originated from mature post-thymic T cells. It represents 1–3% of NHL. Different subtypes have been described: Kinase (ALK)-negative ALCL, ALK-positive ALCL and breast implantassociated ALCL. ALK-negative ALCL affects mainly old males and has the worst prognosis.

Objective: To examine the effect of pirfenidone on the survival of patients hospitalized due to acute exacerbation of idiopathic pulmonary fibrosis (AE–IPF).Methods: The outcomes of 11 consecutive ...

Background Severe asthma is heterogeneous clinically and biologically and is often difficult to control. In particular, the type 2 (T2) immunity endotype of severe asthma is gaining increasing interest because it is susceptible to newly developed biologic treatments that can transform the quality of life of these patients. The aim of this study was to analyze periostin concentrations in the airways of patients with severe asthma, evaluating its role in clustering the T2 endotype. Methods We enrolled 40 consecutive patients with severe asthma (T2 endotype: n = 25; non-T2 endotype: n = 15), 21 patients with mild to moderate asthma, and 15 healthy control subjects. All subjects enrolled underwent exhaled breath condensate (EBC) and sputum collection, eosinophil count in blood, fractional exhaled nitric oxide, and IgE measurement. Periostin was assessed by an enzyme-linked immunosorbent assay kit on EBC and induced sputum (IS) supernatant. Results We were able to detect higher periostin levels in the EBC (0.75 ± 0.46 vs 0.70 ± 0.19 vs 0.11 ± 0.05 ng/mL, P Conclusions We found that periostin is measurable in the airways and increased in patients with severe asthma, especially in those from the T2 endotype. Unlike serum periostin, which may be derived from several sources outside the lung, airways periostin is a useful marker of severe eosinophilic asthma and may help to phenotype patients that will respond to the biologic agents.

Wheeze is a common symptom in infants, but not all wheezers develop asthma. Indeed, up to 50% of wheezing children outgrow their symptoms by school age. How to predict if early wheeze will become asthma is still a matter of vivid debate. In this work, we sought to assess the clinical and pathological factors that might predict the future development of asthma in children. Eighty children (mean age 3.8 ± 1 yr) who underwent a clinically indicated bronchoscopy were followed prospectively for a median of 5 years. At baseline, clinical characteristics with a particular focus on wheezing and its presentation (episodic or multitrigger) were collected, and structural and inflammatory changes were quantified in bronchial biopsies. Follow-up data were available for 74 of the 80 children. Children who presented with multitrigger wheeze were more likely to have asthma at follow-up than those with episodic wheeze (P = 0.04) or without wheeze (P0.0001). Children with asthma also had lower birth weights (P = 0.02), a lower prevalence of breastfeeding (P = 0.02), and a trend for increased IgE (P = 0.07) at baseline than those with no asthma. Basement membrane thickness and airway eosinophils at baseline were increased in children who developed asthma at follow-up (P = 0.001 and P = 0.026, respectively). Multivariate analysis showed that among all clinical and pathological factors, multitrigger wheezing, basement membrane thickening, and reduced birth weight were predictive of future asthma development. We conclude that multitrigger wheeze and reduced birth weight are clinical predictors of asthma development. Basement membrane thickening in early childhood is closely associated with asthma development, highlighting the importance of airway remodeling in early life as a risk factor for future asthma.

Phantom limbs are the phenomenal persistence of postural and sensorimotor features of an amputated limb. Although immaterial, their characteristics can be modulated by the presence of physical matter. For instance, the phantom may disappear when its phenomenal space is invaded by objects (“obstacle shunning”). Alternatively, “obstacle tolerance” occurs when the phantom is not limited by the law of impenetrability and co-exists with physical objects. Here we examined the link between this under-investigated aspect of phantom limbs and apparent motion perception. The illusion of apparent motion of human limbs involves the perception that a limb moves through or around an object, depending on the stimulus onset asynchrony (SOA) for the two images. Participants included 12 unilateral lower limb amputees matched for obstacle shunning (n = 6) and obstacle tolerance (n = 6) experiences, and 14 non-amputees. Using multilevel linear models, we replicated robust biases for short perceived trajectories for short SOA (moving through the object), and long trajectories (circumventing the object) for long SOAs in both groups. Importantly, however, amputees with obstacle shunning perceived leg stimuli to predominantly move through the object, whereas amputees with obstacle tolerance perceived leg stimuli to predominantly move around the object. That is, in people who experience obstacle shunning, apparent motion perception of lower limbs was not constrained to the laws of impenetrability (as the phantom disappears when invaded by objects), and legs can therefore move through physical objects. Amputees who experience obstacle tolerance, however, had stronger solidity constraints for lower limb apparent motion, perhaps because they must avoid co-location of the phantom with physical objects. Phantom limb experience does, therefore, appear to be modulated by intuitive physics, but not in the same way for everyone. This may have important implications for limb experience post-amputation (e.g., improving prosthesis embodiment when limb representation is constrained by the same limits as an intact limb).

TNF-related, apoptosis-inducing ligand (TRAIL) apoptotic pathway constitutes a promising therapeutic target due to high selectivity and low toxicity of TRAIL targeting agents when administered in combination therapies. 106 colorectal cancers were examined for: relative mRNA expression of TRAIL pathway genes, decoy receptors TRAIL-R3 and TRAIL-R4 promoter methylation and the presence of KRAS, NRAS, BRAF mutations. Elevated mRNA levels were observed in 26%, 15%, 13%, 12% and 10% of the cases for TRAIL-R4, TRAIL-R3, TRAIL-R2, TRAIL-R1 and TRAIL genes respectively. Reduced mRNA levels were detected in 77%, 65%, 64%, 60% and 37% of the cases for TRAIL, TRAIL-R2, TRAIL-R3, TRAIL-R1 and TRAIL-R4 genes respectively. TRAIL-R3 and TRAIL-R4 promoter methylation was detected in 55% and 16% of the analysed samples respectively. TRAIL-R1, TRAIL-R2 elevated relative mRNA levels inversely correlated with tumor stage (p = .036, p = .048). Strong linear correlations of TRAIL receptors' mRNA levels were found: TRAIL-R1/TRAIL-R2 (R = 0.653, p .001), TRAIL-R2/TRAIL-R3 (R = 0.573, p .001). Finally, relative expression of TRAIL was correlated with KRAS, BRAF and NRAS mutation status, defining an inverse correlation between increased TRAIL expression and the absence of mutations in Mitogen-activated protein kinase (MAPK) pathway. In conclusion, simultaneous analysis of TRAIL pathway membrane components, pointed towards a significant deregulation of mRNA expression in colorectal tumours. Death receptor overexpression was an indicator of a less aggressive phenotype. The multiple expression patterns of TRAIL pathway components in colorectal tumours underscore the importance of patient selection in order to achieve maximum efficiency with TRAIL targeted therapy.

Primary Sjogren’s syndrome (pSS) confers increased risk for non-Hodgkin lymphoma (NHL) development. Two common polymorphisms, the c. 677C > T and c. 1298A > C, of the methylene-tetrahydrofolate reductase (MTHFR) gene, an enzyme essential in DNA synthesis and methylation, have been associated with susceptibility to NHL. Herein, we tested the hypothesis that MTHFR variants contribute to pSS-related lymphomagenesis. 356 pSS patients, of whom 75 had MALT and 19 non-MALT NHL and 600 healthy controls were genotyped for the detection of MTHFR polymorphisms. DNA methylation levels were assessed by pyrosequencing of the LINE-1 retroelement promoter in DNA from 55 salivary gland tissues from pSS patients. DNA double-strand breaks were determined in peripheral blood mononuclear cells from 13 pSS patients, using comet assay. Αnalysis according to lymphoma subtype revealed increased frequency of c. 677C > T TT genotype and T allele, as well as reduced prevalence of the c. 1298A > C C allele in the pSS non-MALT group compared to controls and patients without NHL. MTHFR c. 677C > T TT genotype was associated with reduced DNA methylation levels, while MTHFR c. 1298A > C AC genotype with reduced DNA double-strand breaks levels. MTHFR variants may be involved in SS non-MALT NHL development, through contribution to defective DNA methylation and genomic instability.

BACKGROUND: Between January 2000 and September 2016, there have been 27 documented shark attacks on La Reunion Island. The insular nature of La Reunion has allowed us to carry out an extensive survey of these attacks. The objective was to describe the clinical features of these shark attacks, as only case reports have been published up to now. METHODS: This was a retrospective observational study of the 27 cases of non-provoked shark attacks that have occurred between January 2000 and September 2016. Post-humate predation, provoked attacks and isolated attack on devices were excluded. All bone and vascular injuries were documented in the 21 remaining cases. Prehospital tourniquet use was specifically recorded. RESULTS: Among the 21 victims, 8 died (38%) despite rapid use of resuscitation techniques in 5 cases when it was feasible; these techniques were not needed in the survivors. Thirteen patients were immediately treated in the operating room. Amputation or disarticulation occurred 13 times in 10 victims, 5 of whom died. Twelve injuries to major vascular structures were found in 11 victims, 6 of which died. A prehospital tourniquet was applied in 4 of the 5 surviving victims who had injuries to major vascular structures (including 1 victim with major humeral and femoral artery damage) and in 1 victim who died (the very proximal wound was not controlled). CONCLUSION: Our study found that quickly applying a tourniquet to the injured limb(s) contributes to the victim's survival. Disarticulation is a particular feature of shark attacks. The number and severity of shark attacks at La Reunion Island are worse than in the rest of the world. LEVEL OF EVIDENCE: Epidemiological study, IV. Language: en

Background: Obesity as well as metabolic and cardiovascular comorbidities are established, significant predictors of worse prognosis in overall COVID-19 population, but limited information are available on their specific roles in young adults (aged ≤ 50 years). The main objectives of the present Italian multi-center study were to describe clinical characteristics, and role of selected prognostic predictors, in particular obesity, in a large cohort of young hospitalized patients with COVID-19 pneumonia. Methods: Nine Pulmonology Units, across North and Centre of Italy, were involved in this retrospective study. Demographic and clinical characteristics as well as radiological features were registered for all cases. Comorbidity were classified according to their known or potential association with COVID-19. Findings: A total of 263 subjects were included. The prevalence of obesity was 25.9%, mechanical ventilation (MV) was needed in 73 patients (27.7%), and 28 in-hospital deaths occurred (10.6%). Obesity and older age were the only significant predictors for MV in a full model adjusted for comorbidities and markers of severity. Pre-existing comorbidities, such as hypertension, diabetes and asthma, and increased D-dimer level were significantly associated with higher mortality risk, regardless of age, body mass index, and MV. Interpretation: Obesity in young adults is, per se, a strong, independent, predictor of a more complicated COVID-19, without, however, influencing in-hospital mortality. On the other hand, selected comorbidities, mainly hypertension, diabetes and asthma, significantly impact survival even in a young population, and prompt recognition of these conditions as well as a closer surveillance of this subgroup are highly recommended. Funding: none. Declaration of Interests: Prof. Bonifazi reports speaker fees from Boehringer Ingelheim and Roche, outside the submitted work; Dr. Harari reports personal fees from Roche, grants and personal fees from Actelion and Boehringer Ingelheim, outside the submitted work. Ethics Approval Statement: Anonymized data of patients included in the study cohort were retrospectively collected from electronic medical records. The study protocol complies to the ethical guidelines of the 1975 Declaration of Helsinki and it was notified and approved by the coordinator ethics committee (n. 2020131) and by each local ethics committee and the need for patient’s informed consent was waived.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease that commonly affects older adults and is associated with the histopathological and/or radiological patterns of usual interstitial pneumonia (UIP). Despite significant advances in our understanding of disease pathobiology and natural history, what causes IPF remains unknown. A potential role for infection in the disease’s pathogenesis and progression or as a trigger of acute exacerbation has long been postulated, but initial studies based on traditional culture methods have yielded inconsistent results. The recent application to IPF of culture-independent techniques for microbiological analysis has revealed previously unappreciated alterations of the lung microbiome, as well as an increased bacterial burden in the bronchoalveolar lavage (BAL) of IPF patients, although correlation does not necessarily entail causation. In addition, the lung microbiome remains only partially characterized and further research should investigate organisms other than bacteria and viruses, including fungi. The clarification of the role of the microbiome in the pathogenesis and progression of IPF may potentially allow its manipulation, providing an opportunity for targeted therapeutic intervention.

Lung cancer is the leading cause of cancer death worldwide. Recently, promising therapies have emerged based on PD-1/PD-L1 immune checkpoint inhibitors, which have been approved even as frontline treatment for patients with non-small cell lung cancer (NSCLC). We examined the association between PD-L1 expression and clinicopathological parameters as well as overall survival in 220 NSCLC patients. PD-L1 expression was estimated by immunohistochemistry using 22C3 PharmDx Dako assay and was defined as high, if TPS was ≥ 50%, low, if TPS was 1%–49%, and absent, if TPS was