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BACKGROUND: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores. METHODS: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy. RESULTS: At baseline, 9 patients (9%) showed a low (8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal. CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.

Aims This study aimed to evaluate a novel echocardiographic algorithm for quantitative estimation of pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance (PVR) in patients with heart failure and pulmonary hypertension (PH) scheduled to right heart catheterization (RHC). Methods and results In this monocentric study, 795 consecutive patients (427 men; age 68.4 ± 12.1 years) undergoing echocardiography and RHC were evaluated. Multiple regression analysis was performed to identify echocardiographic predictors of PAWP and PVR measured by RHC in the derivation group (the first 200 patients). The diagnostic accuracy of the model was then tested in the validation group (the remaining 595 patients). PH was confirmed by RHC in 507 (63.8%) patients, with 192 (24.2%) cases of precapillary PH, 248 (31.2%) of postcapillary PH, and 67 (8.4%) of combined PH. At regression analysis, tricuspid regurgitation maximal velocity, mitral E/e′ ratio, left ventricular ejection fraction, right ventricular fractional area change, inferior vena cava diameter, and left atrial volume index were included in the model (R = 0.8, P

Introduction Up to fifteen percent of patients with novel pandemic coronavirus disease (Covid-19) have acute respiratory failure (ARF). Ratio between arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2), P/F, is currently used as a marker of ARF severity in Covid-19. P/F does not reflect the respiratory efforts made by patients to maintain arterial blood oxygenation, such as tachypnea and hyperpnea, leading to hypocapnia. Standard PaO2, the value of PaO2 adjusted for arterial partial pressure of carbon dioxide (PaCO2) of the subject, better reflects the pathophysiology of hypoxemic ARF. We hypothesized that the ratio between standard PaO2 over FiO2 (STP/F) better predicts Covid-19 ARF severity compared to P/F. Methods Aim of this pilot prospectic observational study was to observe differences between STP/F and P/F in predicting outcome failure, defined as need of invasive mechanical ventilation and/or deaths in Covid-19 ARF. Accuracy was calculated using Receiver Operating Characteristics (ROC) analysis and areas under the ROC curve (AUROC) were compared. Results 349 consecutive subjects admitted to our respiratory wards due to Covid-19 ARF were enrolled. STP/F was accurate to predict mortality and superior to P/F with, respectively, AUROC 0.710 versus 0.688, p = 0.012.Both STP/F and PF were accurate to predict outcome failure (AUROC respectively of 0.747 and 0.742, p = 0.590). Discussion This is the first study assessing the role of STP/F in describing severity of ARF in Covid-19. According to results, STP/F is accurate and superior to P/F in predicting in-hospital mortality.

Background Health-related quality of life (HRQoL) impairment is often reported among COVID-19 ICU survivors, and little is known about their long-term outcomes. We evaluated the HRQoL trajectories between 3 months and 1 year after ICU discharge, the factors influencing these trajectories and the presence of clusters of HRQoL profiles in a population of COVID-19 patients who underwent invasive mechanical ventilation (IMV). Moreover, pathophysiological correlations of residual dyspnea were tested. Methods We followed up 178 survivors from 16 Italian ICUs up to one year after ICU discharge. HRQoL was investigated through the 15D instrument. Available pulmonary function tests (PFTs) and chest CT scans at 1 year were also collected. A linear mixed-effects model was adopted to identify factors associated with different HRQoL trajectories and a two-step cluster analysis was performed to identify HRQoL clusters. Results We found that HRQoL increased during the study period, especially for the significant increase of the physical dimensions, while the mental dimensions and dyspnea remained substantially unchanged. Four main 15D profiles were identified: full recovery (47.2%), bad recovery (5.1%) and two partial recovery clusters with mostly physical (9.6%) or mental (38.2%) dimensions affected. Gender, duration of IMV and number of comorbidities significantly influenced HRQoL trajectories. Persistent dyspnea was reported in 58.4% of patients, and weakly, but significantly, correlated with both DLCO and length of IMV. Conclusions HRQoL impairment is frequent 1 year after ICU discharge, and the lowest recovery is found in the mental dimensions. Persistent dyspnea is often reported and weakly correlated with PFTs alterations. Trial registration NCT04411459.

Background: Assessment of intrinsic dynamic positive end-expiratory pressure (PEEPi,dyn) may be clinically important in stable patients with chronic obstructive pulmonary disease (COPD), but epidemiological data are scant. Objectives: The aim of our study was (i) to assess the PEEPi,dyn in a large population of stable patients with COPD and (ii) to evaluate the correlations with some noninvasive measurements routinely assessed. Method: Retrospective analysis of lung mechanics, dynamic volumes, arterial blood gases, dyspnoea by means of the Medical Research Council (MRC) scale, the COPD Assessment Test score, and maximal inspiratory/expiratory pressures in 87 hypercapnic and 62 normocapnic patients. Results: The mean PEEPi,dyn was significantly higher in hypercapnic than normocapnic patients (2.8 ± 2.2 vs. 1.9 ± 1.6 cm H2O, respectively, p = 0.0094). PEEPi,dyn did not differ according to Global Initiative for Chronic Obstructive Lung Disease stage, MRC score, or use or not of long-term oxygen therapy. There were significant although weak correlations between PEEPi,dyn and airway obstruction, hyperinflation, respiratory muscle function, arterial CO2 tension, and number of exacerbations/year. The transdiaphragmatic pressure was the strongest variable associated to PEEPi,dyn (R = 0.5713, p = 0.001). Conclusion: In stable patients with COPD, PEEPi,dyn is higher in hypercapnic patients and weakly correlated to noninvasive measures of lung and respiratory muscle function.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterized by progressive airflow limitation. We conducted a pilot trial to investigate the incidence of sleep disorders, sleep quality and their relationship with disease severity. We performed pulmonary function tests, blood gas analysis, overnight 12-channels polysomnography and clinical assessments in 15 consecutive LAM patients. For statistics, p values < 0.05 were considered significant. Sleep efficiency (SE) was inversely correlated with RV/TLC (p = 0.035) and positively with daytime SpO2 (p = 0.010) and PaO2 (p = 0.011). Three cases had obstructive sleep apnea (OSA); seven patients (46.7%) showed a REMOSA. AHIREM was correlated with FEV1% (r = 0.75, p = 0.003), TLC% (r = 0.57, p = 0.026), RV% (r = 0.8, p= 0.05). four subjects had nocturnal hypoxia (T90 ≥ 1% of TST) showing lower values of DLCO%, daytime SpO2%, PaO2, FEV1% and a higher value of VR/TLC comparing with the subgroup with normal T90 (p < 0.05). This pilot study shows that sleep alterations could be frequent in LAM and associated to disease severity. Nocturnal hypoxemia and SE were related to lung function impairment. A dysregulation of sleep seems to involve exclusively REM phase, while NREM appears to be preserved. This phenomenon might be linked to the pathophysiology of disease: our study, even with the limits of the small sample size, showed that the presence of REMOSA is related to the disease severity, in particular to the degree of airflow limitation and hyperinflation. More studies are needed to assess this topic.

Objectives IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy. Methods Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes. Results PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts. Conclusion The impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.

Background Chronic Obstructive Pulmonary Disease (COPD) encompasses various phenotypes that severely limit the applicability of precision respiratory medicine. The present investigation is aimed to assess the circadian rhythm of symptoms in pre-defined clinical COPD phenotypes and its association with health-related quality of life (HR-QoL), the quality of sleep and the level of depression/anxiety in each clinical phenotype. Methods The STORICO (NCT03105999) Italian observational prospective cohort study enrolled COPD subjects. A clinical diagnosis of either chronic bronchitis (CB), emphysema (EM) or mixed COPD-asthma (MCA) phenotype was made by clinicians at enrollment. Baseline early-morning, day-time and nocturnal symptoms (gathered via the Night-time, Morning and Day-time Symptoms of COPD questionnaire), HR-QoL (via the St. George’s Respiratory Questionnaire), anxiety and depression levels (via the Hospital Anxiety and Depression Scale), quality of sleep (via COPD and Asthma Sleep Impact Scale), physical activity (via the International Physical Activity Questionnaire) as well as lung function were recorded. Results 606 COPD subjects (age 71.4 ± 8.2 years, male 75.1%) were studied. 57.9, 35.5 5.3 and 1.3% of the sample belonged to the CB, EM, MCA and EM + CB phenotypes respectively. The vast majority of subjects reported early-morning and day-time symptoms (79.5 and 79.2% in the CB and 75.8 and 77.7% in the EM groups); the proportion suffering from night-time symptoms was higher in the CB than in the EM group (53.6% vs. 39.5%, p = 0.0016). In both CB and EM, indiscriminately, the presence of symptoms during the 24-h day was associated with poorer HR-QoL, worse quality of sleep and higher levels of anxiety/depression. Conclusions The findings highlight the primary classificatory role of nocturnal symptoms in COPD. Trial registration Trial registration number: NCT03105999, date of registration: 10th April 2017.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

INTRODUCTION High-dose chemotherapy (HDCT)/autologous stem cell transplantation (ASCT) is the standard for patients with relapsed/refractory lymphomas and multiple myeloma (MM), thereby improving DFS and OS. Relapse after HDCT/ASCT remains the major cause of death in patients with lymphomas or MM after melphalan-based HDCT. Dose-intensified bendamustine by replacing carmustine in the BEAM regimen (BeEAM) or by combining it with melphalan (BenMel) is a promising strategy to lower the relapse rates.Renal toxicity after BeEAM emerges as a major concern. METHODS We investigated renal toxicity in consecutive lymphoma patients treated with BeEAM and in consecutive MM patients treated with the same dose of 400 mg/m2 bendamustine (split into 200 mg/m2 on two consecutive days) together with full-dosed (200 mg/m2) melphalan. Patients with a history of renal impairment before HDCT were included. We assessed renal damage summarized as acute kidney injury (AKI) by measuring renal parameters on a daily basis starting from the first day of HDCT until the last day of hospitalization for HDCT/ASCT. AKI: rise of s-creatinine ≥26.5 μmol/L in 48 hours or increase to more than or equal to twofold compared to baseline s-creatinine within 7 days (Kidney Disease International Global Organization, KDIGO, criteria). Grading of AKI: KDIGO. Treatment-related AKI (rAKI): occurred within 10 days from the last administration of bendamustine; no relation to sepsis. Consequently, we defined as treatment-unrelated AKI (uAKI) all renal damage occurring because of sepsis or later than 10 days since the last administration of bendamustine. Statistical Analysis Subgroup differences: Chi-squared test, Fisher Exact test. IBM SPSS software version 21. RESULTS Patient characteristics and therapy regimen: 122 consecutive patients with lymphomas or MM who underwent high- dose bendamustine regimen before ASCT in 01/2013-06/2016. Factors related to rAKIOccurrence of rAKI: correlated (p60 years, previous AKI, cardiovascular comorbidities and concomitant nephrotoxic drugs. In addition, rAKI correlated (p=0.004) with cardiovascular complications during hospitalization; details of subgroups analysis: Table 2.No differences in the incidence of rAKI MM (n=7/15; 46.7%) and lymphoma patients (n=44/107; 41.1%), p=0.683. Acute kidney Injury related to High Dose Bendamustine is reversible and manageable • Acute kidney injury related to bendamustine (rAKI): in 51 patients (41.8%); completely reversible in n=50/51 (98.0%). • rAKI: mild to moderate in 90% of affected patients; did not increase TRM after ASCT. • 3/51 patients (5.9%) with rAKI required transient renal dialysis to enable recovery from renal damage, whereas approaches such as additional hydration were sufficient in the vast majority (n=48 with rAKI; 94.1% of this subgroup). • The median duration of rAKI was 7 days (range, 1-22). ­ According to Cox ZL et al., Adverse Drug Events during AKI and its recovery, Clin J Am Soc Nephrol 2013; 8:1070-1078. CONCLUSION • Our data suggest that treatment-related acute renal toxicity is common in lymphoma and MM patients receiving dose-intensified bendamustine HDCT before ASCT. • However, renal impairment is reversible and manageable. • Our data identify a subgroup of patients at increased risk for the development of renal damage following bendamustine-based HDCT. • Such patients should be strictly monitored during hospitalization, and a generous hydration strategy before, during and after administration of bendamustine is recommended. • Assessing the pre-transplant renal risk profile may help to identify those patients, which may not be candidates for bendamustine-based HDCT thereby avoiding prolonged hospitalization due to rAKI and eventual transient dialysis treatment. • Our results may contribute to design appropriate selection criteria for dose-intensified bendamustine as part of the conditioning regimens preceding HDCT/ASCT in lymphoma and MM patients.

LAM is a rare and progressive pulmonary disease characterized by cystic radiological pattern and by the possible presence of angiomyolipomas in other organs. Functionally LAM consists in airway obstruction and progressive hypoxemia leading to respiratory failure. No studies, so far, investigated whether during sleep LAM patients show changes in the sleep profile. Aim of our study was to evaluate if, during sleep, the physiological modification of respiration is associated with polysomnographic (PSG) alterations. 8 patients affected by LAM underwent a whole-night polysomnography. Either respiratory failure or use of long-term oxygen therapy were exclusion criteria. All patients were female and had a normal BMI. 3 out of 8 patients (37.5%) had alterations to the PSG pattern: 1 patient showed obstructive sleep apnea (AHI 8.6), 1 patient had nocturnal desaturation (SatO2 time below 90% "T90" equal to 17.2%), while 1 patient had nocturnal desaturation (T90 = 27%) and obstructive sleep apnea (AHI 7.5). No arrhythmias were reported. Median sleep efficiency was 91% and median REM latency was 49 minutes. The two patients (25%) with nocturnal desaturation were treated with nocturnal oxygen therapy solving sleep desaturations, showing clinical improvement. This pilot study underlines the importance of assessing respiration during sleep in patients affected by LAM: these patients have a fragile respiratory balance and the normal physiological sleep modifications could translate in pathological desaturations, worsening the damage.

Pulmonary arterial hypertension (PAH) is characterized by the right ventricle (RV) remodeling and pulmonary endothelial dysfunction. We studied cardiac perfusion and innervation in PAH with a cadmium-zinc-telluride (CZT) scanner and lung uptake impairment of 123I-metaiodobenzylguanidine (123I-MIBG). In 13 patients with newly diagnosed PAH and 11 dilated cardiomyopathies (DCM, for comparative purposes), we assessed early and delayed 123I-MIBG uptake ratios of lung-to-mediastinum (L/M) and heart-to-mediastinum (H/M) on anterior planar images. A quantitative myocardial innervation with 123I-MIBG and perfusion with 99mTc-tetrofosmin using CZT-SPECT was performed. All patients underwent right heart catheterization. Early and delayed L/M ratios in PAH were lower than DCM (1.47 ± 0.14 vs 1.98 ± 0.11 and 1.40 ± 0.13 vs 1.83 ± 0.09; P

Initial combination therapy with ambrisentan and tadalafil (upfront therapy) offers clinical benefits in pulmonary arterial hypertension (PAH) and reduces the risk of clinical failure compared with monotherapy in naïve patients. The aim of study is to assess the efficacy of a 12-month upfront therapy with ambrisentan and tadalafil in improving haemodynamics in incident PAH patients.This is a multicentre retrospective analysis of real-world Italian clinical data in 56 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, WHO functional class, 6-min walk distance, and right heart catheterization, were collected from the patients' medical records at baseline and at 12-month follow-up.At baseline, there were 16, 34, and 6 patients in WHO functional class II, III, and IV, respectively. Over a median follow-up of 12 months, 54 (96%) patients were still alive, 6 (11%) of whom received parenteral prostanoids. Ambrisentan-tadalafil combination was associated with significant improvements in WHO functional class (2.2 ± 0.8 vs. 2.8 ± 0.6, P 0.001, improved in 29 patients), exercise capacity (395 ± 123 vs. 353 ± 101 m, P = 0.039), N-terminal probrain natriuretic peptide (528 ± 493 vs. 829 ± 620 pg/ml; P = 0.009), and haemodynamics (right atrial pressure 7 ± 4 vs. 9 ± 5 mmHg, P = 0.02; mean pulmonary artery pressure 45 ± 15 vs. 50 ± 13 mmHg, P = 0.03; cardiac index 3.0 ± 1.0 vs. 2.5 ± 0.9 l/min/m, P = 0.001; pulmonary vascular resistance 8 ± 4 vs. 11 ± 6 Wood units, P = 0.001) compared with baseline.Initial combination therapy with ambrisentan and tadalafil offers clinical benefits and significant haemodynamic improvement in newly diagnosed PAH patients.

Background: Initial combination treatment with ambrisentan and tadalafil (up-front therapy) offers clinical benefits in pulmonary arterial hypertension (PAH) and reduces the risk of clinical failure compared with monotherapy in naive patients. Aims: To assess the efficacy of 12 month up-front therapy with ambrisentan and tadalafil to improve hemodynamic changes in incident PAH patients. Methods: This is a multicentre retrospective analysis of real-world Italian clinical data in 56 patients with newly diagnosed PAH. Clinical evaluation, including demographics, medical history, World Health Organization (WHO) functional class, 6-minutes walk distance (6MWD), and right heart catheterization (RHC) were collected from medical records at baseline and 12 month of follow up. Results: WHO functional class at baseline was: II in 12 patients, III in 38 and IV in 6. Over a median follow-up period of 12 months, 53 (95%) patients are still alive, 6 (11%) of whom received parenteral prostanoids. Ambrisentan-tadalafil association was a associated with significant improvements in WHO-functional class (2.2±0.8 vs 2.8±0.6, p Conclusion: This study shows that initial combination with oral medications ambrisentan and tadalafil offers clinical benefits, and significant haemodynamic improvement in newly diagnosed PAH patients.

In PH the measure of pulmonary function tests (PFT) and arterial blood gases (ABG) are used to identify underlying lung disease. We wondered if there could be a relationship among indices of PFT, ABG (paO2, paCO2), gas exchange (A-a DO2, a-ADCO2, VDphy/VT) and haemodynamic variables in a population of PH patients. Methods: Sixteen patients with suspicion of PH underwent PFT, diffusing lung capacity (DLCO), ABG, gas exchange, right heart cath; physiological dead space to tidal volume was measured. Mean values and their SD were calculated. The relationships between the observed variables were evaluated by their mutual information. The global network was reconstructed using the ARACNE algorithm (Margolin A, et al.: ARACNE. BMC Bioinformatics, 2006; 20:1-7). Modules in the network were identified applying a multidimensional scaling procedure to the adjaceny matrix and, succesively, clustering the variables with a model-based bayesian approach (Fraley C, et al. JASA, 2002; 97:611-631). We conducted the analyses with R statistical software. Results: Pulmonary gas exchange was on average impaired with increased A-a DO2; a-A DCO2 as well as physiological dead space were abnormal thus indicating impairment of ventilation perfusion distribution ratio. The three most influential variables in the networks were: PCW (betweeness=20), RAP (betweeness=18) and VDphy/VT (betweeness=14). Three modules were identified: a (RAP, FEV1, VDphy/VT, CI, TLC); b (PCW, PVR, mPAP); g (aADO2, aADCO2, DsbHb, PaCO2). The three modules were well separated. VDphy and PVR were significantly correlated (p: 0,042; R: 0.53). Conclusions: It turns out from our results a narrow relationships between VDphy and RAP, CI and PVR.

A neoprene wetsuit is widely used to reduce thermal dispersion during diving. Recent observations have pointed out that elastic recoil of the wetsuit might have significant compressive effects, able to affect water and electrolyte homeostasis during both dry and immersed conditions. The aim of this study was to evaluate the possible cardiovascular and respiratory effects of the neoprene wetsuit in dry conditions in a sample of experienced divers. Twenty-four (24) healthy divers were evaluated by Doppler-echocardiography and by spirometry in basal conditions and while wearing a full neoprene wetsuit. During wetsuit conditions, we observed a significant decrease in heart rate (-5%; p

3067Background: Nivolumab is the first checkpoint inhibitor approved for the treatment of squamous non small cell lung cancer (Sq-NSCLC) to show a survival benefit in a randomised phase III trial. ...

Reportedly, patients with scleroderma-related pulmonary hypertension (SSc-PAH) respond poorly to new vasoactive drugs (NVD). Forty-nine SSc-PAH patients underwent right heart catheterization (RHC) and, according to NVD availability, divided as follows: Group 1 (n = 23, from 1999 to 2004, poor availability), and Group 2 (n = 26, from 2005 to 2010, good availability). Before diagnostic RHC, NVD had been given to 30 % of the patients in Group 1, and 58 % of those in Group 2 (p = 0.049). At diagnosis, patients in Group 1 had greater heart dilatation (p

Patients with inoperable chronic thromboembolic pulmonary hypertension (Inop-CTEPH) treated with conventional therapy have a poor survival. We compare the 3-year survival between those treated with conventional therapy and those treated with conventional therapy and a combination of novel drugs. We also evaluate the clinical course. A total of 34 Inop-CTEPH consecutive patients were evaluated from 1991 to 2009 including right heart catheterization (RHC) and perfusion lung scan (PLS): 7 underwent surgical treatment while 27 were confirmed inoperable. Of these 27 patients, 12 evaluated from 1991 to 2003 (Group 1) were treated with conventional therapy and 15 evaluated from 2004 to 2009 (Group 2) were treated with conventional and novel therapies. At baseline, no group difference emerged at RHC. Based on clinical course, novel drugs and oxygen supplementation were given to patients of Group 2. Seven of these who had worse clinical course repeated RHC and four of them also PLS during therapy. Those without repeat RHC had baseline pulmonary artery mean pressure and brain natriuretic peptide (NT-proBNP) lower and mixed venous saturation (SvO2) and exercise test higher (p = 0.022, 0.015, 0.044 and 0.003, respectively). During therapy, those with repeat RHC had total pulmonary vascular resistance reduced (p = 0.012), base excess increased (p = 0.002) and significant redistribution of pulmonary blood flow at PLS. At the 3-year follow-up, survival was 86% in Group 2 and 31% in Group 1 (p = 0.031). In Inop-CTEPH patients, the clinical course may help to select drugs and the level of oxygen supply that can improve hemodynamics, gas exchange and long-term survival.

Introduction - The added value of routine echocardiography, in respect to clinical examination and ECG, has received little attention. We sought to evaluate the contribution of two-dimensional echocardiography, in respect to clinical examination and ECG, in detecting left ventricular (LV) dilatation and systolic dysfunction. Method - A group of 100 patients, scheduled for cardiac magnetic resonance imaging (MRI), was prospectively studied. Results - Clinical examination identified moderate-to-severe LV dysfunction, defined as a LV ejection fraction (EF) < 45% at MRI, with a sensitivity of 62% and a specificity of 68%.After ECG, sensitivity and specificity slightly improved (71 and 70%, respectively).After the echocardiographic report, sensitivity reached 84% and specificity 90%. LV EF by echocardiography (routine studies) was closely related with that by MRI (r = 0.84). LV function was scored as undefined in 17% of patients after clinical examination, in 5% of patients after ECG and in no patient after echocardiography (P < 0.0001). Clinical examination identified patients with LV dilatation (LV end-diastolic volume ≥ 110 ml/m 2 ) with a poor sensitivity (33%) but a good specificity (88%). After ECG, sensitivity was 39% and specificity 87%; after echocardiography, sensitivity reached 53% and specificity 92%. Conclusion - Echocardiography provides information on LV function and dimensions that vastly exceeds that obtained by clinical examination and ECG.This study supports the use of echocardiography to improve patient diagnosis and management after history and physical examination.

Background Alveolar volume measured according to the American Thoracic Society-European Respiratory Society (ATS-ERS) guidelines during the single breath diffusion test can be underestimated when there is maldistribution of ventilation. Therefore, the alveolar volume calculated by taking into account the ATS-ERS guidelines was compared to the alveolar volume measured from sequentiallly collected samples of the expired volume in two groups of individuals: COPD patients and healthy individuals. The aim of this study was to investigate the effects of the maldistribution of ventilation on the real estimate of alveolar volume and to evaluate some indicators suggestive of the presence of maldistribution of ventilation. Methods Thirty healthy individuals and fifty patients with moderate-severe COPD were studied. The alveolar volume was measured either according to the ATS-ERS guidelines or considering the whole expired volume subdivided into five quintiles. An index reflecting the non-uniformity of the distribution of ventilation was then derived (DeltaVA/VE). Results Significant differences were found when comparing the two measurements and the alveolar volume by quintiles appeared to have increased progressively towards residual volume in healthy individuals and much more in COPD patients. Therefore, DeltaVA/VE resulted in an abnormal increase in COPD. Conclusion The results of our study suggest that the alveolar volume during the single breath diffusion test should be measured through the collection of a sample of expired volume which could be more representative of the overall gas composition, especially in the presence of uneven distribution of ventilation. Further studies aimed at clarifying the final effects of this way of calculating the alveolar volume on the measure of DLCO are needed. DeltaVA/VE is an index that can help assess the severity of inhomogeneity in COPD patients.

It is not known whether the asymptotic behavior of whole body O2 consumption (VO2) at maximal work rates (WR) is explained by similar behavior of VO2 in the exercising legs. To resolve this question, simultaneous measurements of body and leg VO2 were made at submaximal and maximal levels of effort breathing normoxic and hypoxic gases in seven trained male cyclists (maximal VO2, 64.7 +/- 2.7 ml O2.min-1.kg-1), each of whom demonstrated a reproducible VO2-WR asymptote during fatiguing incremental cycle ergometry. Left leg blood flow was measured by constant-infusion thermodilution, and total leg VO2 was calculated as the product of twice leg flow and radial arterial-femoral venous O2 concentration difference. The VO2-WR relationships determined at submaximal WR′s were extrapolated to maximal WR as a basis for assessing the body and leg VO2 responses. The differences between measured and extrapolated maximal VO2 were 235 +/- 45 (body) and 203 +/- 70 (leg) ml O2/min (not significantly different). Plateauing of leg VO2 was associated with, and explained by, plateauing of both leg blood flow and O2 extraction and hence of leg VO2. We conclude that the asymptotic behavior of whole body VO2 at maximal WRs is a direct reflection of the VO2 profile at the exercising legs.

To assess the relationships among single-breath diffusing capacity for CO (DLCOsb) (13), respiratory symptoms, and cigarette smoking in a general population sample, the data of 718 men and 894 women 20 yr of age or older were analyzed, and comparisons were performed with flow-volume curve (MEFV) variables and the slope of the alveolar plateau (DN2%/L) as well. Percent predicted DLCOsb and its correction for alveolar volume (DL/VA) were significantly lower in smokers than in nonsmokers. The relationship of presence/absence of respiratory symptoms and cigarette smoking with DLCOsb and DL/VA was significant. DLCO indices were almost always selected as discriminant variables in multivariate analysis between asymptomatic and symptomatic subjects. Poor concordance among lung function tests was evident: in men, 30% with abnormal (i.e., lower than 97.5% percentile) and 21% with normal DLCO indices also had abnormal MEFV parameters and/or DN2%/L. In women, the corresponding figures were 24 and 10%, respectively. In men, when considering only DLCO indices, the percentage of symptomatic subjects with abnormal lung function tests ranged from 33% in those with at least one symptom to 45% in those complaining of dyspnea. When the proportion of symptomatic subjects with DN2%/L and MEFV abnormalities were added, it increased to 56 and 66%, respectively. However, in women the proportion of symptomatic subjects with abnormal lung function indices was very small. These results indicate the usefulness of including CO diffusing capacity in epidemiologic surveys in the detection of abnormalities.

To assess the value of parameters derived from arterial blood gastests in the diagnosis of pulmonary embolism. We measured alveolar-arterial partial pressure of oxygen[P(A–a)O2] gradient, PaO2 and arterial partial pressureof carbon diaxide (PaCO2) in 773 consecutive patients with suspectedpulmonary embolism who were enrolled in the Prospective Investigative Study ofAcute Pulmonary Embolism. The study design required pulmonary angiography in all patientswith abnormal perfusion scans. Of 773 scans, 270 were classified as normal/near-normal and 503 asabnormal. Pulmonary embolism was diagnosed by pulmonary angiography in 312 of503 patients with abnormal scans. Of 312 patients with pulmonary embolism, 12,14 and 35% had normal P(A–a)O2, PaO2 andPaCO2, respectively. Of 191 patients with abnormal scans andnegative angiograms, 11, 13 and 55% had normal P(A–a)O2,PaO2 and PaCO2, respectively. The proportions of patientswith normal/near-normal scans who had normal P(A–a)O2,PaO2 and PaCO2 were 20, 25 and 37%, respectively. Nodifferences were observed in the mean values of arterial blood gas data betweenpatients with pulmonary embolism and those who had abnormal scans and negativeangiograms. Among the 773 patients with suspected pulmonary embolism, 364 (47%)had prior cardiopulmonary disease. Pulmonary embolism was diagnosed in 151(41%) of 364 patients with prior cardiopulmonary disease, and in 161 (39%) of409 patients without prior cardiopulmonary disease. Among patients withpulmonary embolism, there was no difference in arterial blood gas data betweenpatients with and those without prior CPD. These data indicate that arterial blood gas tests are of limitedvalue in the diagnostic work-up of pulmonary embolism if they are notinterpreted in conjunction with clinical and other laboratory tests.

The usefulness of single breath nitrogen test (SBN 2 ) was evaluated in a cross-sectional epidemiologic survey on a general population sample (n = 3,289) of North Italy. Each subject was submitted to CNR standardized questionnaire and to lung function testing using automated equipment (Hewlett-Packard 47804S). Acceptable closing volume (CV) and slope of alveolar plateau (DN 2 %/L) tracings were performed by only 1,370 and 1,982 subjects respectively, in comparison with the 2,638 diffusing capacity and the 3,079 forced vital capacity acceptable maneuvers. Prediction equations were computed on normal subjects for CV indices, with the exception of DN 2 %/L: they were similar to those found in other studies. Significant differences among smoking categories were found for all the SBN 2 parameters in males, but only for DN 2 %/L in females. The latter was also able to distinguish either subjects with airway obstruction from those without it or symptomatic from asymptomatic individuals, but DN 2 %/L did not give more information than V ˙ max 75 , a sensitive index of flow volume curve. Our results suggest that the place of SBN 2 in large scale epidemiologic testing has not been justified.

A computer program to measure breath by breath alveolar pressure (PA) and alveolar to arterial difference (AaD) for O2 and CO2, by a mass-spectrometer has been implemented. The program allows the determination of alveolar gas by different methods: 1. Bohr's equation (BE); 2. ideal alveolar air equation for O2 (IDO2); 3. end-tidal (ET); 4. by the Rahn's definition of 'mean alveolar gas', i.e., alveolar pressures are defined when instantaneous respiratory exchange ratio (IRQ) equals mean respiratory exchange ratio (MRQ). This automated technique has been used in 16 patients with chronic obstructive lung disease (COLD) and 15 patients with pulmonary embolism (APE). In both groups of patients it was always possible to find in each breath the point where IRQ = MRQ and therefore to measure AaD by RD. IDO2 was significantly lower than PAO2 by the other methods. Also ET values of O2 and CO2 were significantly different from RD and BE in both groups of patients, however the difference was consistently higher in COLD patients. The different shape of the expirograms (steeper expirograms in COLD) is responsible for this different result. RD and BE AaD characterize gas exchange more precisely than ET, because the contribution of high VA/Q units is also evaluated. This is particularly important in COLD patients. Consideration on dead space measurements are also reported both for COLD and APE patients. In conclusion this automated technique provides the assessment of gas exchange for the use in clinical respiratory physiology and for the monitoring of gas-exchange in critically ill patients.

The determination of alveolar to arterial differences (AaD) is a simple and available method to determine the overall efficiency of gas exchange. AaD are strongly related to the measurement of alveolar gas, and the different methods commonly used to measure alveolar gas concentrations are not able to give an estimate of the “mean alveolar gas”.