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Background: Trastuzumab emtansine has been recently suspected to be associated with the development of pulmonary arterial hypertension (PAH)., Research Question: Is there an association between trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan and the development of PAH?., Study Design and Methods: Characteristics of incident PAH cases treated with trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan were analyzed from the French PH Registry, the VIGIAPATH program, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization pharmacovigilance database using a broad definition of pulmonary hypertension (PH) and a narrow definition of PAH. A signal of disproportionate reporting was deemed significant if the lower boundary of the 95% credibility interval of the information component (IC) was superior to 0. The variables were expressed as median (interquartile range)., Results: In the French PH Registry, we identified 8 incident cases of PAH after trastuzumab emtansine exposure and none with trastuzumab alone or trastuzumab deruxtecan. All cases occurred in females (age, 56; 49-61 years) with breast cancer. The delay between first exposure and PAH diagnosis was 43 months (4.5-55). At diagnosis, 5 were in New York Heart Association functional class III/IV with severe hemodynamic impairment (mean pulmonary artery pressure, 42 mm Hg; cardiac index, 2.51 L/min/m 2 ; pulmonary vascular resistance, 9.7 Wood units). Disproportionality analysis showed that only trastuzumab emtansine demonstrated a significant signal of disproportionate reporting using both a broad definition of PH (IC, 1.46; 0.86-1.95) and a narrow definition of PAH (IC, 1.76; 0.83-2.46). Trastuzumab displayed a significant signal using only the broad definition of PH, whereas trastuzumab deruxtecan was not associated with any significant signals of disproportionate reporting., Interpretation: Our results suggest that more patients exposed to trastuzumab emtansine developed PH compared with trastuzumab alone. Further assessment of this safety signal and exploration of pathophysiological mechanisms is needed., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) continues to present significant challenges to the medical community, both in terms of diagnosis and treatment. The advent of the updated 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines has introduced pivotal changes that reflect the rapidly advancing understanding of this complex disease. These changes include a revised definition of PH, updates to the classification system, and treatment algorithm. While these guidelines offer a critical framework for the management of PH, they have also sparked new discussions and questions. The 5th French Pulmonary Hypertension Network Meeting (Le Kremlin-Bicêtre, France, 2023), addressed these emergent questions and fostering a deeper understanding of the disease's multifaceted nature. These discussions were not limited to theoretical advancements but extended into the practical realms of patient management, highlighting the challenges and opportunities in applying the latest guidelines to clinical practice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BOUCLY Athénaïs reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory, and speaking and lecture fees. BOUCLY Athénaïs reports a relationship with Merck Sharp & Dohme UK Ltd that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. BOUCLY Athénaïs reports a relationship with Astra Zeneca that includes: speaking and lecture fees. BOUCLY Athénaïs reports a relationship with AOP Orphan that includes: board membership, consulting or advisory, and speaking and lecture fees. BOUCLY Athénaïs reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. BERTOLETTI Laurent reports a relationship with MSD that includes: board membership, consulting or advisory, and speaking and lectures fees. BERTOLETTI Laurent reports a relationship with PFIZER/BMS that includes: board membership, and speaking and lectures fees. BERTOLETTI Laurent reports a relationship with LEO-Pharma that includes: board membership, consulting or advisory, and speaking and lectures fees. BERTOLETTI Laurent reports a relationship with VIATRIS that includes: consulting or advisory, and speaking and lectures fees. BERTOLETTI Laurent reports a relationship with BAYER that includes: board membership. FAUVEL Charles reports a relationship with Pfizer that includes funding grants. Fauvel Charles reports a relationship with Novartis that includes funding grants. Fauvel Charles reports a relationship with Boehringer Ingelheim Ltd that includes speaking and lecture fees. Fauvel Charles reports a relationship with Astra Zeneca that includes speaking and lecture fees. Fauvel Charles reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. GALLANT DEWAVRIN Mélanie reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. GERGES Christian reports a relationship with Grupo Ferrer Internacional SA that includes: speaking and lecture fees. Gerges Christian reports a relationship with AOPHealth that includes: speaking and lecture fees. Gerges Christian reports a relationship with OrphaCare that includes: funding grants. GRYNBLAT Julien reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. GUIGNABERT Christophe reports a relationship with Acceleron Pharma (Cambridge, MA, USA), a wholly-owned subsidiary of Merck & Co., Inc. (Rahway, NJ, USA) that includes: one funding grant outside the submitted work. Guignabert Christophe a relationship with Merck Sharp & Dohme UK Ltd that includes: one funding grants outside the submitted work and speaking and lecture fees. Guignabert Christophe a relationship with Corteria pharmaceutical that includes: one funding grant outside the submitted work. Guignabert Christophe a relationship with Structure therapeutics (ex ShouTi) that includes: one funding grant outside the submitted work. HASCOET Sébastien reports a relationship with Société Française de Cardiologie that includes: board membership, research grants. HASCOET Sébastien reports a relationship with Fédération Francaise de Cardiologie that includes: research grants. HASCOET Sébastien reports a relationship with Edwards Lifesciences that includes: consulting or advisory, and research grant. HASCOET Sébastien reports a relationship with Abbott vascular that includes: consulting or advisory, and research grant. None of these relationships influence the work reported in this paper. JAIS Xavier reports a relationship with MSD that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Jais Xavier reports a relationship with Janssen Pharmaceuticals Inc that includes: board membership, funding grants, and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JUTANT Etienne-Marie reports a relationship with Merck Sharp & Dohme UK Ltd that includes: consulting or advisory, speaking and lecture fees. Jutant Etienne-Marie reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. Jutant Etienne-Marie reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. Jutant Etienne-Marie reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. Jutant Etienne-Marie reports a relationship with AstraZeneca that includes: speaking and lecture fees. LAMBLIN Nicolas reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. MEYRIGNAC Olivier reports a relationship with Boehringer Ingelheim Ltd that includes: board membership, consulting or advisory, and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. RIOU Marianne reports a relationship with Grupo Ferrer Internacional SA that includes: board membership. RIOU Marianne reports a relationship with MSD France that includes board membership and speaking and lecture fees. RIOU Marianne reports a relationship with Boehringer Ingelheim Ltd that includes: board membership and speaking and lecture fees. RIOU Marianne reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. RIOU Marianne reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. RIOU Marianne reports a relationship with Menarini that includes: speaking and lecture fees. SAVALE Laurent reports a relationship with Merck Sharp & Dohme UK Ltd that includes: board membership, funding grants, and speaking and lecture fees. SAVALE Laurent reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. SAVALE Laurent reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. TROMEUR Cécile reports a relationship with Merck Sharp & Dohme: board membership, consulting or advisory, and speaking and lecture fees. Tromeur Cécile reports a relationship with UK Ltd that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Tromeur Cécile reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. Tromeur Cécile reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. Tromeur Cécile reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. TURQUIER Ségolène reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory. TURQUIER Ségolène reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. VALENTIN Simon reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. SIMONNEAU Gerald reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory, and speaking and lecture fees. Montani David reports a relationship with Merck Sharp & Dohme UK Ltd that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Montani David reports a relationship with Boehringer Ingelheim Ltd that includes: board membership, consulting or advisory, and speaking and lecture fees. Montani David reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. Montani David reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. Montani David reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. HUMBERT Marc reports a relationship with 35 Pharma that includes: consulting or advisory fees. Humbert Marc reports a relationship with Aerovate that includes: board membership, consulting or advisory fees. Humbert Marc reports a relationship with AOP Pharma that includes: board membership, consulting or advisory fees, speaking and lecture fees, funding grants. Humbert Marc reports a relationship with Bayer that includes: speaking and lecture fees. Humbert Marc reports a relationship with Chiesi Pharmaceuticals Inc that includes: board membership, consulting or advisory fees. Humbert Marc reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory, and speaking and lecture fees. Humbert Marc reports a relationship with Janssen that includes: board membership, consulting or advisory, and speaking and lecture fees. Humbert Marc reports a relationship with Keros that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Humbert Marc reports a relationship with United Therapeutics that includes: board membership, consulting or advisory. Olivier SITBON reports relationships with pharmaceutical companies including Aerovate, Altavant, AOP Orphan, Gossamer Bio, Ferrer, Janssen, Liquidia, Merck, Respira Therapeutics, Roivant and United Therapeutics. In addition to being investigator in clinical trials involving these companies, relationships include board membership, consulting or advisory, and speaking and lecture fees. In addition, Dr Sitbon's institution received funding grants from AOP Orphan, Gossamer Bio, Ferrer, Janssen and Merck. MONTANI David reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory, and speaking and lecture fees. Montani David reports a relationship with Merck Sharp & Dohme UK Ltd that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Montani David reports a relationship with Boehringer Ingelheim Ltd that includes: board membership, consulting or advisory, and speaking and lecture fees. Montani David reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. Montani David reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. Montani David reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 SPLF and Elsevier Masson SAS. All rights reserved.)

Pulmonary hypertension (PH) associated with chronic lung disease (CLD) is both common and underrecognised. The presence of PH in the setting of lung disease has been consistently shown to be associated with worse outcomes. Recent epidemiological studies have advanced understanding of the heterogeneity of this patient population and shown that defining both the specific type of CLD as well as the severity of PH ( i.e. deeper phenotyping) is necessary to inform natural history and prognosis. A systematic diagnostic approach to screening and confirmation of suspected PH in CLD is recommended. Numerous uncontrolled studies and one phase 3 randomised, controlled trial have suggested a benefit in treating PH in some patients with CLD, specifically those with fibrotic interstitial lung disease (ILD). However, other studies in diseases such as COPD-PH showed adverse outcomes with some therapies. Given the expanding list of approved pharmacological treatments for pulmonary arterial hypertension, developing a treatment algorithm for specific phenotypes of CLD-PH is required. This article will summarise existing data in COPD, ILD and other chronic lung diseases, and provide recommendations for classification of CLD-PH and approach to the diagnosis and management of these challenging patients., Competing Interests: Conflict of interest: O.A. Shlobin reports consultancy fees from United Therapeutics, Merck, Janssen and Aerami, payment or honoraria for lectures, presentations, manuscript writing or educational events from Ferrera and United Therapeutics, participation on a data safety monitoring board or advisory board with Janssen, and leadership roles with ACCP/Chest and World Symposium on Pulmonary Hypertension task force. Y. Adir reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD Israel and Bayer Israel, support for attending meetings from BI Israel and RAFA Israel, and participation on a data safety monitoring board or advisory board with MSD, GB and Acceleron. J.A. Barbera reports grants from Merck Sharp & Dome and Ferrer International, consultancy fees from Merck Sharp & Dome, Janssen-Cilag and Ferrer International, payment or honoraria for lectures, presentations, manuscript writing or educational events from Merck Sharp & Dome, Janssen-Cilag, Ferrer International and AOP Orphan, support for attending meetings from Merck Sharp & Dome and Janssen-Cilag, and a leadership role with the World Symposium on Pulmonary Hypertension task force. V. Cottin reports consultancy fees and payment or honoraria for lectures, presentations, or educational events from Ferrer/United Therapeutics. S. Harari reports consultancy fees from Roche-Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, participation on a data safety monitoring board or advisory board “Prise en charge pragmatique de la fibrose pulmonaire idiopathique en progression: essai randomisé PROGRESSION-IPF”, and leadership roles with the World Symposium on Pulmonary Hypertension task force, FERS of the ERS and officer of the society, and FATS of the ATS. E-M. Jutant reports consultancy fees from Chiesi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, GSK, MSD and AstraZeneca, support for attending meetings from Janssen and MSD, and a leadership role with the World Symposium on Pulmonary Hypertension task force. J. Pepke-Zaba reports grants from MSD, consultancy fees from MSD, Janssen, Gossamer and Ferrer, support for attending meetings from Janssen, and a leadership role with the World Symposium on Pulmonary Hypertension task force. H-A. Ghofrani reports consultancy fees from Gossamer Bio, Inc., Aerovate, Altavant, Bayer AG, Attgeno, Janssen/Actelion, MSD/Acceleron, Pfizer, Liquidia, Morphic and Keros, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer AG, Janssen/Actelion, Gossamer Bio, Keros and MSD/Acceleron, participation on a data safety monitoring board or advisory board with Aerovate, Altavant, Attgeno, Janssen/Actelion, Insmed, MSD/Acceleron, Pfizer and Bayer AG, and the following financial (or non-financial) interests: the author's spouse is and employee of Liquidia. R. Channick reports consultancy fees from Bayer, Merck, Gossamer, Respira and Janssen, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer and Janssen, and participation on a data safety monitoring board or advisory board with Altavant., (Copyright ©The authors 2024.)

Background: Sleep deprivation is common in intensive care units (ICUs) and may alter respiratory performance. Few studies have assessed the role of sleep disturbances on outcomes in critically ill patients., Objectives: We hypothesized that sleep disturbances may be associated with poor outcomes in ICUs., Methods: Post-hoc analysis pooling three observational studies assessing sleep by complete polysomnography in 131 conscious and non-sedated patients included at different times of their ICU stay. Sleep was assessed early in a group of patients admitted for acute respiratory failure while breathing spontaneously (n = 34), or under mechanical ventilation in patients with weaning difficulties (n = 45), or immediately after extubation (n = 52). Patients admitted for acute respiratory failure who required intubation, those under mechanical ventilation who had prolonged weaning, and those who required reintubation after extubation were considered as having poor clinical outcomes. Durations of deep sleep, rapid eye movement (REM) sleep, and atypical sleep were compared according to the timing of polysomnography and the clinical outcomes., Results: Whereas deep sleep remained preserved in patients admitted for acute respiratory failure, it was markedly reduced under mechanical ventilation and after extubation (p < 0.01). Atypical sleep was significantly more frequent in patients under mechanical ventilation than in those breathing spontaneously (p < 0.01). REM sleep was uncommon at any time of their ICU stay. Patients with complete disappearance of REM sleep (50% of patients) were more likely to have poor clinical outcomes than those with persistent REM sleep (24% vs. 9%, p = 0.03)., Conclusion: Complete disappearance of REM sleep was significantly associated with poor clinical outcomes in critically ill patients., (© 2024. The Author(s).)

Background: Objective structured clinical examinations (OSCEs) are extensively used in many medical schools worldwide with the stated objective to assess students' clinical skills acquired during internships. The objective of the present study was to assess the factors associated with success in university summative OSCEs, especially the impact of previous hospital internships in corresponding disciplines and supervision during internships., Methods: This was a cross-sectional study assessing the results in the summative OSCEs of 4th year medical students during the 2021-2022 academic year in a French medical school. The summative OSCEs included five stations for each student. Each student answered a survey at the end of summative OSCEs about previous internships, the supervision they had and perceived difficulty levels for each station. The scores in each station were assessed according to previous hospital internships in the corresponding discipline. Analysis of predictive factors of success in OSCEs, defined by a score ≥ 10/20 at each station, were performed using univariate and multivariate logistic regression., Results: Out of the 220 students participating in the summative OSCEs, 182 (83%) answered the survey. One hundred and forty-four (79%) of these students had carried out hospital internships in at least one of the disciplines evaluated during the OSCEs. Students having completed an internship in the corresponding discipline had significantly higher OSCEs scores for interrogation, communication, therapeutic education and procedure stations compared to those who had not. Previous internship in corresponding disciplines was independently associated with success in OSCEs in interrogation (OR 9.45 [1.34-66.8] p = 0.02), clinical examination (OR 6.93 [1.88-25.57] p = 0.004, and therapeutic education (OR 3.09 [1.22-7.82] p = 0.02) stations., Conclusion: Previous hospital internships in the discipline evaluated by the OSCEs are associated with success in summative OSCEs. This reinforces the importance of student involvement during their hospital internships., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Carsuzaa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pulmonary vascular diseases such as pulmonary embolism and pulmonary hypertension are important and frequently under-recognised conditions. This article provides an overview of key highlights in pulmonary vascular diseases from the European Respiratory Society International Congress 2023. This includes insights into disease modification in pulmonary arterial hypertension and novel therapies such as sotatercept and seralutinib. Exciting developments in our understanding of the mechanisms underpinning pulmonary hypertension associated with interstitial lung disease are also explored. A comprehensive overview of the complex relationship between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension (CTEPH) is provided along with our current understanding of the molecular determinants of CTEPH. The importance of multidisciplinary and holistic care cannot be understated, and this article also addresses advances beyond medication, with a special focus on exercise training and rehabilitation., Competing Interests: Conflict of interest: S. Cullivan reports travel grant from Janssen outside the submitted work. Conflict of interest: A. Boucly reports honoraria for lectures or travel support from AOP Orphan, Janssen, Ferrer and MSD outside the submitted work. Conflict of interest: M. Jevnikar reports travel grants from MSD, Janssen and AstraZeneca, and consulting fees from Janssen, outside the submitted work. Conflict of interest: B. Lechatier reports participation on advisory boards and travel grants from MSD and Janssen outside the submitted work. Conflict of interest: S. Ulrich receives grant money from the Swiss National Science Foundation and Swiss Lung League; and received grant money, travel fees, consultancy and for patient enrolment into trials from Janssen SA, MSD SA, Novartis SA and OrPha Swiss. Conflict of interest: L. Bertoletti reports personal fees and nonfinancial support from BMS/Pfizer, LEO-Pharma and Viatris; grants from Bayer; and grants, personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: O. Sitbon reports relationships with pharmaceutical companies including Merck, Janssen, Enzyvant, Gossamer Bio, Respira Therapeutics, Ferrer and AOP Orphan, outside the submitted work; relationships include grants for research and educational programmes, fees for lectures and membership of scientific advisory boards. Conflict of interest: A. Vonk-Noordegraaf reports participation on advisory boards for Ferrer, MSD and Johnson & Johnson, outside the submitted work. A. Bokan has nothing to declare. D-H. Park reports support for attending meetings and/or travel from Janssen, outside the submitted work. Conflict of interest: L. Genecand has nothing to declare. Conflict of interest: J. Guiot reports grants paid to his institution from Roche, Janssen and Merk; consulting fees from Oncoradiomics, Janssen, Boehringer Ingelheim, Pfizer and AstraZeneca; honoraria from Janssen, SMB, GSK and Chiesi; and travel support from Merck and Chiesi, all outside the submitted work. Conflict of interest: E-M. Jutant reports consulting fees from Chiesi; honoraria from Chiesi, GSK, MSD and AstraZeneca; and travel support from Janssen and MSD. Conflict of interest: L. Piccari reports grants from Janssen and Ferrer; lecture honoraria from Janssen, Ferrer, MSD and United Therapeutics; participation on advisory boards with Janssen, Ferrer and United Therapeutics; and travel support from Janssen, Ferrer and MSD, outside the submitted work. Conflict of interest: M. Lichtblau reports travel support, lecture honoraria and participation on advisory boards from Janssen, MSD and Orpha Swiss, outside the submitted work., (Copyright ©The authors 2024.)

Objectives: Whether COVID-19 leads to long-term pulmonary sequelae or not remains unknown. The aim of this study was to assess the prevalence of persisting radiological pulmonary fibrotic lesions in patients hospitalized for COVID-19., Materials and Methods: We conducted a prospective single-center study among patients hospitalized for COVID-19 between March and May 2020. Patients with residual symptoms or admitted into intensive care units were investigated 4 months after discharge by a chest CT (CCT) and pulmonary function tests (PFTs). The primary endpoint was the rate of persistent radiological fibrotic lesions after 4 months. Secondary endpoints included further CCT evaluation at 9 and 16 months, correlation of fibrotic lesions with clinical and PFT evaluation, and assessment of predictive factors., Results: Among the 1151 patients hospitalized for COVID-19, 169 patients performed a CCT at 4 months. CCTs showed pulmonary fibrotic lesions in 19% of the patients (32/169). These lesions were persistent at 9 months and 16 months in 97% (29/30) and 95% of patients (18/19) respectively. There was no significant clinical difference based on dyspnea scale in patients with pulmonary fibrosis. However, PFT evaluation showed significantly decreased diffusing lung capacity for carbon monoxide (p < 0.001) and total lung capacity (p < 0.001) in patients with radiological lesions. In multivariate analysis, the predictive factors of radiological pulmonary fibrotic lesions were pulmonary embolism (OR = 9.0), high-flow oxygen (OR = 6.37), and mechanical ventilation (OR = 3.49)., Conclusion: At 4 months, 19% of patients investigated after hospitalization for COVID-19 had radiological pulmonary fibrotic lesions; they persisted up to 16 months., Clinical Relevance Statement: Whether COVID-19 leads to long-term pulmonary sequelae or not remains unknown. The aim of this study was to assess the prevalence of persisting radiological pulmonary fibrotic lesions in patients hospitalized for COVID-19. The prevalence of persisting lesions after COVID-19 remains unclear. We assessed this prevalence and predictive factors leading to fibrotic lesions in a large cohort. The respiratory clinical impact of these lesions was also assessed., Key Points: • Nineteen percent of patients hospitalized for COVID-19 had radiological fibrotic lesions at 4 months, remaining stable at 16 months. • COVID-19 fibrotic lesions did not match any infiltrative lung disease pattern. • COVID-19 fibrotic lesions were associated with pulmonary function test abnormalities but did not lead to clinical respiratory manifestation., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Leptin receptor (ObR-b) is overexpressed in pulmonary artery smooth muscle cells (PA-SMCs) from patients with pulmonary arterial hypertension (PAH) and is implicated in both mechanisms that contribute to pulmonary vascular remodeling: hyperproliferation and inflammation. Our aim was to investigate the role of ubiquitin-specific peptidase 8 (USP8) in ObR-b overexpression in PAH., Methods: We performed in situ and in vitro experiments in human lung specimens and isolated PA-SMCs combined with 2 different in vivo models in rodents and we generated a mouse with an inducible USP8 deletion specifically in smooth muscles., Results: Our results showed an upregulation of USP8 in the smooth muscle layer of distal pulmonary arteries from patients with PAH, and upregulation of USP8 expression in PAH PA-SMCs, compared to controls. USP8 inhibition in PAH PA-SMCs significantly blocked both ObR-b protein expression level at the cell surface as well as ObR-b-dependant intracellular signaling pathway as shown by a significant decrease in pSTAT3 expression. USP8 was required for ObR-b activation in PA-SMCs and its inhibition prevented Ob-mediated cell proliferation through STAT3 pathway. USP8 inhibition by the chemical inhibitor DUBs-IN-2 protected against the development of experimental PH in the 2 established experimental models of PH. Targeting USP8 specifically in smooth muscle cells in a transgenic mouse model also protected against the development of experimental PH., Conclusions: Our findings highlight the role of USP8 in ObR-b overexpression and pulmonary vascular remodeling in PAH., Competing Interests: Disclosure statement EMJ, MKC, MO, RT, BLV, LT and AH declare none. Outside the submitted work, MH reports grants to his institution and/or personal fees from Acceleron, Janssen, Merck, AOP and CG grants to his institution and/or personal fees from Acceleron, Janssen, ShouTi, MSD. The authors thank Professor Klaus-Peter KNOBELOCH for providing the Usp8fl/fl mouse, Dr Marie-Odile FAUVARQUE, Dr Julie DAM, the Department of Pathology at Marie Lannelongue Hospital and UMS IPSIT animal facility for their help in this study. This work was supported by a grant from French National Agency for Research ANR (ANR-17-CE14-0011, CoVeR) and by European Respiratory Society Main Award in Novel Research in PAH 2020 awarded to AH. EMJ is supported by INSERM (Poste d′Accueil 2019)., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models., Competing Interests: Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work, consulting fees from Acceleron, Janssen, Merck MSD and Ferrer, outside the submitted work, and payment or honoraria for speakers’ bureaus from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. E-M. Jutant reports consulting fees from Chiesi, outside the submitted work, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK and Chiesi, outside the submitted work, and support for attending meetings and/or travel from Janssen, outside the submitted work. M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti, Tiakis and United Therapeutics, outside the submitted work, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and Merck, outside the submitted work, and participation on a data safety monitoring board or advisory board for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

Background: Sleep deprivation alters respiratory muscle performance and may precipitate respiratory failure. This study aimed to assess sleep in subjects admitted to ICU for acute hypoxemic respiratory failure and its role in the risk of intubation., Methods: This was a prospective observational single-center cohort study including subjects admitted to ICU for de novo acute hypoxemic respiratory failure defined as breathing frequency ≥ 25 breaths/min or clinical signs of respiratory distress and P aO 2 /F IO 2 < 300 mm Hg while receiving high-flow nasal oxygen. Subjects with altered consciousness, central nervous or psychiatric disorders, continuous sedation or neuroleptic medication, or were uncooperative were excluded. Sleep was assessed by complete polysomnography (PSG) the night following ICU admission. The main outcome was to assess sleep among subjects with acute hypoxemic respiratory failure and to compare sleep between subjects who eventually required intubation to those who did not., Results: Over a 24-month inclusion period, 34 subjects had complete PSG, among whom 5 (15%) required intubation in the ICU. Total sleep time was 4.2 h in median (interquartile range 2.9-6.8); deep-sleep duration was 70 min (34-127), and rapid eye movement (REM) sleep duration was 9 min (0-28). Among them, 13 subjects (38%) had no REM sleep. Total sleep time and duration of deep and REM sleep stages did not differ between subjects who required intubation and those successfully treated with high-flow nasal oxygen., Conclusions: Whereas total sleep time remained relatively preserved in critically ill subjects with acute hypoxemic respiratory failure, REM sleep time was uncommon or completely absent in a large number of subjects. Sleep did not differ between subjects who required intubation and those who did not. However, given a trend toward an increased risk of intubation in subjects with a complete absence of REM sleep, further studies are needed to better explore the impact of REM sleep on the risk of intubation., Competing Interests: Dr Thille discloses relationships with the French Ministry of Health, Fisher & Paykel Healthcare, GE Healthcare, and Philips. Dr Coudroy discloses relationships with the French Ministry of Health and Fisher & Paykel Healthcare. Dr Frat discloses relationships with the French Ministry of Health, Fisher & Paykel Healthcare, and SOS Oxygène. The remaining authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Rationale: Precapillary pulmonary hypertension (PH) is a rare and largely unrecognized complication of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Objectives: To describe characteristics and outcomes of MPN-associated PH. Methods: We report clinical, functional, and hemodynamic characteristics, classification, and outcomes of patients with PV, ET, or primary MF in the French PH registry. Measurements and Main Results: Ninety patients with MPN (42 PV, 35 ET, 13 primary MF) presented with precapillary PH with severe hemodynamic impairment, with a median mean pulmonary arterial pressure and pulmonary vascular resistance of 42 mm Hg and 6.7 Wood units, respectively, and impaired clinical conditions, with 71% in New York Heart Association functional classes III/IV and having a median 6-minute-walk distance of 310 m. Half of the patients were diagnosed with chronic thromboembolic PH (CTEPH); the other half were considered to have group 5 PH. MF was preferentially associated with group 5 PH, whereas PV and ET were generally related to CTEPH. Proximal lesions were diagnosed in half of the patients with CTEPH. Thromboendarterectomy was performed in 18 selected patients with high risk of complications (5 early deaths). Overall survival at 1, 3, and 5 years was 67%, 50%, and 34% in group 5 PH and 81%, 66%, and 42% in CTEPH, respectively. Conclusions: PH is a life-threatening condition potentially occurring in MPN. There are multiple mechanisms, with equal diagnoses of CTEPH and group 5 PH. Physicians should be aware that PH strongly affects the burden of patients with MPN, especially in group 5 PH, with unknown pathophysiological mechanisms.

In the aftermath of acute infection with the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), a large number of symptoms persist or appear, constituting a real syndrome called "long COVID-19" or "post-COVID- 19" or "post-acute COVID-19 syndrome". Its incidence is very high, half of patients showing at least one symptom at 4-6 months after Coronarovirus infectious disease 2019 (COVID-19). They can affect many organs. The most common symptom is persistent fatigue, similar to that seen after other viral infections. Radiological pulmonary sequelae are relatively rare and not extensive. On the other hand, functional respiratory symptoms, primarily dyspnoea, are much more frequent. Dysfunctional breathing is a significant cause of dyspnoea. Cognitive disorders and psychological symptoms are also very common, with anxiety, depression and post-traumatic stress symptoms being widely described. On the other hand, cardiac, endocrine, cutaneous, digestive or renal sequelae are rarer. The symptoms generally improve after several months, even if their prevalence at two years remains significant. Most of the symptoms are favored by the severity of the initial illness, and the psychic symptoms by the female sex. The pathophysiology of most symptoms is poorly understood. The influence of the treatments used in the acute phase is also important. Vaccination, on the other hand, seems to reduce their incidence. The sheer number of affected patients makes long-term COVID-19 syndrome a public health challenge., (© 2023 Published by Elsevier Masson SAS on behalf of l'Académie nationale de médecine.)

This international overview of the use of objective structured clinical examinations (OSCEs) in respiratory training highlights the heterogeneity in use between countries as well as the positive experience of OSCEs amongst users https://bit.ly/3Zee6zP., Competing Interests: Conflict of interest: L. Sesé reports personal fees and nonfinancial support from Roche/Genentech, and nonfinancial support from Boehringer Ingelheim, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Dyspnoea is a common persistent symptom after COVID-19. Whether it is associated with functional respiratory disorders remains unclear., Methods: We assessed the proportion and characteristics of patients with "functional respiratory complaints" (FRCs) (as defined by Nijmegen Questionnaire >22) among 177 post-COVID-19 individuals who benefited from outclinic evaluation in the COMEBAC study ( i.e. , symptomatic and/or intensive care unit (ICU) survivors at 4 months). In a distinct explanatory cohort of 21 consecutive individuals with unexplained post-COVID-19 dyspnoea after routine tests, we also analysed the physiological responses to incremental cardiopulmonary exercise testing (CPET)., Findings: In the COMEBAC cohort, 37 patients had significant FRCs (20.9%, IC95: 14.9-26.9). The prevalence of FRCs ranged from 7.2% (ICU patients) to 37.5% (non-ICU patients). The presence of FRCs was significantly associated with more severe dyspnoea, lower 6-min walk distance, more frequent psychological and neurological symptoms (cognitive complaint, anxiety, depression, insomnia and post-traumatic stress disorders) and poorer quality of life (all p<0.01). In the explanatory cohort, seven out of 21 patients had significant FRCs. Based on CPET, dysfunctional breathing was identified in 12 out of 21 patients, five out of 21 had normal CPET, three out of 21 had deconditioning and one out of 21 had evidence of uncontrolled cardiovascular disease., Interpretation: FRCs are common during post-COVID-19 follow-up, especially among patients with unexplained dyspnoea. Diagnosis of dysfunctional breathing should be considered in those cases., Competing Interests: Conflict of interest: A. Beurnier reports personal fees from Sanofi and AstraZeneca, outside the submitted work. Conflict of interest: L. Savale reports personal fees and nonfinancial support from Janssen and MSD, and grants, personal fees and nonfinancial support from GSK, outside the submitted work. Conflict of interest: X. Jaïs reports grants and personal fees from Janssen, grants and personal fees from MSD, and grants from Bayer and GSK, outside the submitted work. Conflict of interest: T. Gille reports personal fees from Roche SAS, and other support from Oxyvie (oxygen provider), Vivisol France (oxygen provider) and Menarini France, outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, AOP Orphan, Janssen, GSK and MSD; consulting fees from Altavant, Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; and participation on advisory boards for Acceleron, Altavant, Gossamer Bio, Janssen, MSD and Ferrer, all outside the submitted work. Conflict of interest: Marc Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics; lecture honoraria from Janssen and Merck; and advisory board participation for Acceleron, Altavant, Janssen, Merck and United Therapeutics, all outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; and lecture honoraria from Bayer, Janssen and Merck, all outside the submitted work. Conflict of interest: All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Right atrial pressure (RAP) is an important prognostic criterion in pulmonary hypertension (PH). The main goals were to evaluate the following: (i) the accuracy of Doppler assessment of common femoral vein flow waveform to detect elevated RAP and (ii) the diagnostic accuracy of RAP assessed by echocardiography (eRAP). Fifty-seven patients, addressed for right heart catheterization, were included in a retrospective cross-sectional study during a 6-month period. Forty-five patients (78.9%) had PH confirmed by RHC. Elevated RAP was defined by RAP ≥ 10 mmHg. Femoral venous stasis index (FVSI) was highly correlated to RAP on both univariate (p < 0.001) and multivariate analysis (p = 0.003), and showed good diagnostic performances to detect elevated RAP (specificity: 92.3% [80.0-99.3], diagnosis accuracy: 90.4 [77.4-97.3], positive likelihood ratio: 12.5 [3.01-51.97]). Diagnosis accuracy of eRAP was only 51.2% (36.2-66.1). FVSI is independently correlated to RAP and a useful tool to predict elevated RAP in PH patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with pulmonary endothelial dysfunction. There are limited data available on the outcomes of coronavirus disease (COVID-19) in patients with pulmonary hypertension (PH), a disease characterized by pulmonary endothelial dysfunction. Objectives: To describe characteristics and outcomes of patients with precapillary PH and COVID-19. Methods: We prospectively collected characteristics, management, and outcomes of adult patients with precapillary PH in the French PH network who had COVID-19 between February 1, 2020, and April 30, 2021. Clinical, functional, and hemodynamic characteristics of PH before COVID-19 were collected from the French PH registry. Measurements and Main Results: A total of 211 patients with PH (including 123 with pulmonary arterial hypertension, 47 with chronic thromboembolic PH, and 41 with other types of PH) experienced COVID-19, and 40.3% of them were outpatients, 32.2% were hospitalized in a conventional ward, and 27.5% were in an ICU. Among hospitalized patients ( n  = 126), 54.0% received corticosteroids, 37.3% high-flow oxygen, and 11.1% invasive ventilation. Right ventricular and acute renal failure occurred in 30.2% and 19.8% of patients, respectively. Fifty-two patients (all hospitalized) died from COVID-19. Overall mortality was 24.6% (95% CI [confidence interval], 18.8-30.5) and in-hospital mortality 41.3% (95% CI, 32.7-49.9). Nonsurvivors were significantly older, more frequently male and suffering comorbidities (diabetes, chronic respiratory diseases, systemic hypertension, chronic cardiac diseases, and/or chronic renal failure), and had more severe PH at their most recent evaluation preceding COVID-19 diagnosis (in terms of functional class and 6-minute-walk distance; all P  < 0.05). Use of pulmonary arterial hypertension therapy was similar between survivors and nonsurvivors. Conclusions: COVID-19 in patients with precapillary PH was associated with a high in-hospital mortality. The typical risk factors for severe COVID-19 and severity of PH were associated with mortality in this population.

Introduction: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators., Methods: We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches., Results: At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk., Conclusions: The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach., Competing Interests: Conflict of interest: A. Boucly reports personal fees from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc., grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, outside the submitted work. Conflict of interest: L. Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work. Conflict of interest: P. de Groote reports consulting fees from Actelion, Janssen, MSD, Novartis, Servier, Boehringer Ingelheim, Abbott, Boston, AstraZeneca, Bayer; lecture honoraria from Abbott, Vifor, MSD, Servier, Novartis, AstraZeneca, Actelion, Janssen, Medtronic; outside the submitted work. Conflict of interest: V. Cottin reports advisory board fees and non-financial support from Actelion, advisory board fees from Bayer/MSD, outside the submitted work. Conflict of interest: G. Prévot reports personal fees from Actelion and GSK, outside the submitted work. Conflict of interest: A. Chaouat reports consulting fees from GSK, Actelion and Bayer, outside the submitted work. Conflict of interest: F. Picard has nothing to disclose. Conflict of interest: D. Horeau-Langlard reports grants from Acceleron, outside the submitted work. Conflict of interest: A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim; consulting fees from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Amgen; lecture honoraria from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Roche; travel support from Boehringer Ingelheim, Chiesi, Sanofi Regeneron, AstraZeneca, GSK, Roche; participation on advisory boards at AB science, AstraZeneca, GSK, Sanofi Regeneron, Novartis, Acceleron; and acted as investigator in clinical trials for Vertex, Abbvie, Galapagos, Fibrogen, Nuvaira, PulmonX, Gossamer, Acceleron; outside the submitted work. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: X. Jais reports grants from Bayer, Janssen and Merck; lecture honoraria from Janssen and Merck; outside the submitted work. Conflict of interest: G. Simonneau reports grants and personal fees from Janssen (formerly Actelion), Bayer and MSD; personal fees from Acceleron, outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; steering committee fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD; steering committee fees from Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; advisory board participation at Acceleron, Janssen and MSD; outside the submitted work. Conflict of interest: M. Humbert reports grants, steering committee consulting fees, and advisory board participation from Acceleron, Janssen and Merck; lecture honoraria from AOP, Janssen and Merck; steering committee participation at United Therapeutics; outside the submitted work., (Copyright ©The authors 2022.)

This article aims to summarise the latest research presented at the virtual 2021 European Respiratory Society (ERS) International Congress in the field of pulmonary vascular disease. In light of the current guidelines and proceedings, knowledge gaps are addressed and the newest findings of the various forms of pulmonary hypertension as well as key points on pulmonary embolism are discussed. Despite the comprehensive coverage of the guidelines for pulmonary embolism at previous conferences, discussions about controversies in the diagnosis and treatment of this condition in specific cases were debated and are addressed in the first section of this article. We then report on an interesting pro-con debate about the current classification of pulmonary hypertension. We further report on presentations on Group 3 pulmonary hypertension, with research exploring pathogenesis, phenotyping, diagnosis and treatment; important contributions on the diagnosis of post-capillary pulmonary hypertension are also included. Finally, we summarise the latest evidence presented on pulmonary vascular disease and COVID-19 and a statement on the new imaging guidelines for pulmonary vascular disease from the Fleischner Society., Competing Interests: Conflict of interest: M. Lichtblau has nothing to disclose. Conflict of interest: L. Piccari reports grants, personal fees and nonfinancial support from Janssen, and nonfinancial support from Menarini, outside the submitted work. Conflict of interest: S. Ramjug has nothing to disclose. Conflict of interest: A. Bokan has nothing to disclose. Conflict of interest: B. Lechartier has nothing to disclose. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: M. Barata has nothing to disclose. Conflict of interest: A.R. Garcia has nothing to disclose. Conflict of interest: L.S. Howard reports grants and personal fees from Janssen, personal fees from MSD, GSK, Bayer, Third Pole, Gossamer Bio, Endotronix and United Therapeutics, outside the submitted work. Conflict of interest: Y. Adir reports personal fees from Teva, grants and personal fees from GSK and AstraZeneca, personal fees from Sanofi, grants and personal fees from Yansen, and personal fees from BI and Acceleron, outside the submitted work. Conflict of interest: M. Delcroix has nothing to disclose. Conflict of interest: L. Jara-Palomares has nothing to disclose. Conflict of interest: L. Bertoletti reports personal fees from Sanofi, personal fees and nonfinancial support from Leo-Pharma and Aspen, personal fees from Bayer, personal fees and nonfinancial support from BMS/Pfizer, and grants, personal fees and nonfinancial support from MSD, during the conduct of the study. Conflict of interest: O. Sitbon reports grants and personal fees from Acceleron Pharmaceuticals, personal fees from AOP Orphan, grants, personal fees and nonfinancial support from Bayer, personal fees from Ferrer and Gossamer Bio, grants from GlaxoSmithKline, and grants, personal fees and nonfinancial support from Janssen and MSD, outside the submitted work. Conflict of interest: S. Ulrich reports grants from Johnson and Johnson SA, the Swiss National Science Foundation, Zurich Lung and Orpha Swiss, and personal fees from MSD Switzerland and SA, outside the submitted work. Conflict of interest: A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012-08 PHAEDRA and CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610). In addition, his institute has received speaker's money from Johnson & Johnson, MSD, Actelion, Bayer and Ferrer in the past 3 years. Finally, he served as a member of the scientific advisory boards of Morphogen-X, Ferrer and Johnson & Johnson., (Copyright ©The authors 2022.)

Background: Medical professional performances can be assessed by objective structured clinical examinations (OSCEs) where medical trainees go through a series of simulated clinical situations. OSCEs are now the gold standard for the assessment of medical students' competence during their training. In France, the first national OSCEs will take place in May 2024 and respiratory teachers will be involved in this reform and will use OSCEs for students' training and assessment in respiratory medicine. Students training regarding this final OSCE may vary across medical faculties and may impact students' results. Therefore, we aimed to provide a national overview of OSCE's training performed by respiratory teachers and their interest in developing a common French databank of OSCEs., Methods: We conducted a national anonymous online survey among the members of the French college of respiratory teachers (CEP), from 2021 February the 15th to 2021 June the 15th. The survey consisted of 32 questions., Results: Among 118 French pulmonologists teachers, 52 (45%) responded to the survey. We received a response from at least one of each of the French Medical Universities. Twenty-two (42%) had received specific training on how to conduct an OSCE. Twenty-eight (54%) of respondents used OSCEs for training purposes and 24 (46%) for assessment purposes, for less than 1 year in more than half of the participants. The average satisfaction scores out of 10 about OSCEs was 7.3 ± 1.7 for training and 7.4 ± 1.5 for students' assessment. Respondents were willing (8.9 ± 1.8 out of ten) to develop a common databank to share OSCEs subjects in respiratory medicine in France., Conclusions: This survey confirms heterogeneity in the training and the use of OSCEs among French respiratory teachers. However, a common national databank could be a useful tool to reduce these disparities., Competing Interests: Conflict of Interest None., (Copyright © 2022 SPLF and Elsevier Masson SAS. All rights reserved.)

Rationale: The characteristics of patients with respiratory complaints and/or lung radiologic abnormalities after hospitalisation for coronavirus disease 2019 (COVID-19) are unknown. The objectives were to determine their characteristics and the relationships between dyspnoea, radiologic abnormalities and functional impairment., Methods: In the COMEBAC (Consultation Multi-Expertise de Bicêtre Après COVID-19) cohort study, 478 hospital survivors were evaluated by telephone 4 months after hospital discharge, and 177 who had been hospitalised in an intensive care unit (ICU) or presented relevant symptoms underwent an ambulatory evaluation. New-onset dyspnoea and cough were evaluated, and the results of pulmonary function tests and high-resolution computed tomography of the chest were collected., Results: Among the 478 patients, 78 (16.3%) reported new-onset dyspnoea, and 23 (4.8%) new-onset cough. The patients with new-onset dyspnoea were younger (56.1±12.3 versus 61.9±16.6 years), had more severe COVID-19 (ICU admission 56.4% versus 24.5%) and more frequent pulmonary embolism (18.0% versus 6.8%) (all p≤0.001) than patients without dyspnoea. Among the patients reassessed at the ambulatory care visit, the prevalence of fibrotic lung lesions was 19.3%, with extent <25% in 97% of the patients. The patients with fibrotic lesions were older (61±11 versus 56±14 years, p=0.03), more frequently managed in an ICU (87.9 versus 47.4%, p<0.001), had lower total lung capacity (74.1±13.7 versus 84.9±14.8% pred, p<0.001) and diffusing capacity of the lung for carbon monoxide ( D LCO ) (73.3±17.9 versus 89.7±22.8% pred, p<0.001). The combination of new-onset dyspnoea, fibrotic lesions and D LCO <70% pred was observed in eight out of 478 patients., Conclusions: New-onset dyspnoea and mild fibrotic lesions were frequent at 4 months, but the association of new-onset dyspnoea, fibrotic lesions and low D LCO was rare., Competing Interests: Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: O. Meyrignac has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: X. Jaïs has nothing to disclose. Conflict of interest: T. Pham has nothing to disclose. Conflict of interest: L. Morin has nothing to disclose. Conflict of interest: A. Boucly has nothing to disclose. Conflict of interest: S. Bulifon has nothing to disclose. Conflict of interest: S. Figueiredo has nothing to disclose. Conflict of interest: A. Harrois has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: N. Noël has nothing to disclose. Conflict of interest: J. Pichon has nothing to disclose. Conflict of interest: A. Roche has nothing to disclose. Conflict of interest: A. Seferian has nothing to disclose. Conflict of interest: S. Soliman has nothing to disclose. Conflict of interest: J. Duranteau has nothing to disclose. Conflict of interest: L. Becquemont has nothing to disclose. Conflict of interest: X. Monnet has nothing to disclose. Conflict of interest: O. Sitbon has nothing to disclose. Conflict of interest: M-F. Bellin has nothing to disclose. Conflict of interest: M. Humbert has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: D. Montani has nothing to disclose., (Copyright ©The authors 2022.)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic that has resulted in millions of deaths and a major strain on health systems worldwide. Medical treatments for COVID-19 (anticoagulants, corticosteroids, anti-inflammatory drugs, oxygenation therapy and ventilation) and vaccination have improved patient outcomes. The majority of patients will recover spontaneously or after acute-phase management, but clinicians are now faced with long-term complications of COVID-19 including a large variety of symptoms, defined as "post-acute COVID-19 syndrome". Most studies have focused on patients hospitalised for severe COVID-19, but acute COVID-19 syndrome is not restricted to these patients and exists in outpatients. Given the diversity of symptoms and the high prevalence of persistent symptoms, the management of these patients requires a multidisciplinary team approach, which will result in the consumption of large amounts of health resources in the coming months. In this review, we discuss the presentation, prevalence, pathophysiology and evolution of respiratory complications and other organ-related injuries associated with post-acute COVID-19 syndrome., Competing Interests: Conflict of interest: D. Montani has no conflicts to disclose. Conflict of interest: L. Savale has no conflicts to disclose. Conflict of interest: N. Noel has no conflicts to disclose. Conflict of interest: O. Meyrignac has no conflicts to disclose. Conflict of interest: R. Colle has no conflicts to disclose. Conflict of interest: M. Gasnier has no conflicts to disclose. Conflict of interest: E. Corruble has no conflicts to disclose. Conflict of interest: A. Beurnier has no conflicts to disclose. Conflict of interest: E-M. Jutant has no conflicts to disclose. Conflict of interest: T. Pham has no conflicts to disclose. Conflict of interest: A-L. Lecoq has no conflicts to disclose. Conflict of interest: J-F. Papon has no conflicts to disclose. Conflict of interest: S. Figuereido has no conflicts to disclose. Conflict of interest: A. Harrois has no conflicts to disclose. Conflict of interest: M. Humbert has no conflicts to disclose. Conflict of interest: X. Monnet has no conflicts to disclose., (Copyright ©The authors 2022.)

Rationale: Acute pulmonary hypertension (PH) may develop during sickle-cell acute chest syndrome (ACS), and is associated with an increased mortality. Its mechanisms remain poorly known. We questioned whether there is endothelial dysfunction and hypercoagulability in severe ACS, with and without acute PH., Methods: In a prospective monocentre cohort follow-up study, all sickle-cell adult patients with ACS admitted to the intensive care unit underwent transthoracic echocardiography and measurement of biomarkers of coagulation, endothelial activation and platelet and erythrocyte activation. Acute PH was defined as a high echocardiographic probability of PH. The biological profiles of sickle-cell patients were analysed at the time of ACS, contrasting with the existence of acute PH, and compared with steady-state and with non-sickle-cell controls (healthy subjects and community-acquired pneumonia)., Results: Most patients (36 patients with 39 ACS episodes; 23 males; median age 27 years) had thoracic pain, dyspnoea and computed tomography scan lung consolidation. Acute PH was diagnosed in seven (19%) patients. Erythrocyte- and platelet-derived microparticles and the pro-coagulant activity of microparticles were higher in ACS patients with acute PH, compared with their counterparts. Compared with healthy controls, ACS patients had higher levels of tissue factor, fibrin monomers, D-dimer, release of pro-coagulant microparticles and erythrocyte- and platelet-derived microparticles. Compared with community-acquired pneumonia patients, ACS patients had increased levels of fibrin monomers and erythrocyte- and platelet-derived microparticles., Conclusions: Severe ACS is characterised by endothelial dysfunction and hypercoagulability, with a marked pro-coagulant profile in cases of associated PH., Competing Interests: Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: G. Voiriot reports grants and personal fees from Biomérieux, and grants from Janssen and SOS Oxygene, outside the submitted work. Conflict of interest: V. Labbé reports personal fees from AMOMED outside the submitted work. Conflict of interest: L. Savale reports personal fees and nonfinancial support from Actelion and MSD, and grants, personal fees and nonfinancial support from GSK, outside the submitted work. Conflict of interest: H. Mokrani has nothing to disclose. Conflict of interest: P. Van Dreden has nothing to disclose. Conflict of interest: G. Gerotziafas has nothing to disclose. Conflict of interest: M. Fartoukh reports grants from BioMerieux and personal fees from Pfizer, outside the submitted work., (Copyright ©The authors 2021.)

The level of knowledge about a direct link between sleep-related breathing disorders and pre-capillary pulmonary hypertension (PH) is low and there is a chicken and egg question to know which disease causes the other. On one hand, sleep-related breathing disorders are considered as a cause of group 3 PH, in the subgroup of patients with hypoxemia without lung disease. Indeed, isolated sleep-related breathing disorders can lead to mild pre-capillary PH on their own, although this is rare for obstructive sleep apnea and difficult to establish for obesity-hypoventilation syndrome, the evolution towards PH being observed especially in the presence of respiratory comorbidities. The hemodynamic improvement under treatment with continuous positive airway pressure or non-invasive ventilation also argues for a causal link between pre-capillary PH and sleep-related breathing disorders. On the other hand, patients followed for pre-capillary PH, particularly pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, develop more sleep-related breathing disorders than the general population, especially sleep hypoxemia, central sleep apnea in patients with severe PH and obstructive sleep apnea in older patients with higher body mass index. The main objective of this article is therefore to answer two main questions, which will then lead us to discuss the bilateral link between these diseases: are sleep-related breathing disorders independent risk factors for pre-capillary PH and does pre-capillary PH induce sleep-related breathing disorders? In other words, who is the chicken and who is the egg?, (Copyright © 2021 SPLF and Elsevier Masson SAS. All rights reserved.)

Rationale: The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. Methods: A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin). Measurements and Main Results: Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) ( P  < 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients ( n  = 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients ( n  = 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80; P  = 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy. Conclusions: Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.

Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH., Competing Interests: Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion and GSK, and personal fees and non-financial support from MSD and Bayer, outside the submitted work. Conflict of interest: S. Akagi has nothing to disclose. Conflict of interest: L. Tu has nothing to disclose. Conflict of interest: A. Cumont has nothing to disclose. Conflict of interest: R. Thuillet has nothing to disclose. Conflict of interest: C. Phan has nothing to disclose. Conflict of interest: B. Le Vely has nothing to disclose. Conflict of interest: N. Berrebeh has nothing to disclose. Conflict of interest: A. Huertas has nothing to disclose. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: V. Cottin has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: C. Tromeur has nothing to disclose. Conflict of interest: A. Boucly reports personal fees and non-financial support from Actelion and personal fees from MSD, outside the submitted work. Conflict of interest: E.M. Jutant has nothing to disclose. Conflict of interest: O. Mercier has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: M. Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, United Therapeutics and Acceleron, outside the submitted work. Conflict of interest: Y. Tamura has nothing to disclose. Conflict of interest: C. Guignabert has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Sleep-related breathing disorders, including sleep apnea and hypoxemia during sleep, are common in pulmonary arterial hypertension, but the underlying mechanisms remain unknown. Overnight fluid shift from the legs to the upper airway and to the lungs promotes obstructive and central sleep apnea, respectively, in fluid-retaining states. The main objective was to evaluate if overnight rostral fluid shift from the legs to the upper part of the body is associated with sleep-related breathing disorders in pulmonary arterial hypertension. In a prospective study, a group of stable patients with idiopathic, heritable, related to drugs, toxins, or treated congenital heart disease pulmonary arterial hypertension underwent a polysomnography and overnight fluid shift measurement by bioelectrical impedance in the month preceding or following a one-day hospitalization according to regular pulmonary arterial hypertension follow-up schedule with a right heart catheterization. Results show that among 15 patients with pulmonary arterial hypertension (women: 87%; median (25-75th percentiles); age: 40 (32-61) years; mean pulmonary arterial pressure 56 (46-68) mmHg; pulmonary vascular resistance 8.8 (6.4-10.1) Wood units), two patients had sleep apnea and eight (53%) had hypoxemia during sleep without apnea. The overnight rostral fluid shift was 168 (118-263) mL per leg. Patients with hypoxemia during sleep had a greater fluid shift (221 (141- 361) mL) than those without hypoxemia (118 (44-178) mL, p  = 0.045). In conclusion, this pilot study suggests that hypoxemia during sleep is associated with overnight rostral fluid shift in pulmonary arterial hypertension., (© The Author(s) 2021.)

Leptin is a pleotropic hormone known to regulate a wide range of systemic functions, from satiety to inflammation. Increasing evidence has shown that leptin and its receptor (ObR) are not only expressed in adipose tissue but also in several organs, including the lungs. Leptin levels were first believed to be elevated only in the lungs of obese patients, and leptin was suspected to be responsible for obesity-related lung complications. Aside from obesity, leptin displays many faces in the respiratory system, independently of body weight, as this cytokine-like hormone plays important physiological roles, from the embryogenic state to maturation of the lungs and the control of ventilation. The leptin-signaling pathway is also involved in immune modulation and cell proliferation, and its dysregulation can lead to the onset of lung diseases. This review article addresses the thousand faces of leptin and its signaling in the lungs under physiological conditions and in disease., (Copyright © 2020. Published by Elsevier Inc.)

Background: Viral respiratory infections are the main causes of asthma exacerbation. The susceptibility of patients with asthma to develop an exacerbation when they present with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. The objective of this study was to investigate the characteristics and outcomes of asthmatic patients with coronavirus disease 2019 (COVID-19) pneumonia who required hospitalisation during the spring 2020 outbreak in Paris, France., Methods: A prospective cohort follow-up was carried out from 15 March to 15 April 2020 in Bicêtre Hospital, University Paris-Saclay, France. All hospitalised patients with a SARS-CoV-2 infection who reported a history of asthma were included., Results: Among 768 hospitalised patients, 37 (4.8%) reported a history of asthma, which had been previously confirmed by a pulmonologist in 85% of cases. These asthmatic patients were mainly female (70%) and nonsmokers (85%), with a median age of 54 years (interquartile range (IQR) 42-67 years). None of them presented with an asthma exacerbation. 22 (59%) had major comorbidities and 31 (84%) had a body mass index ≥25 kg·m -2 . The most common comorbidities were obesity (36%), hypertension (27%) and diabetes (19%). All patients had a confirmed diagnosis of COVID-19 pneumonia on computed tomography of the chest. Eosinopenia was a typical biological feature with a median count of 0 cells·mm -3 (IQR 0-0 cells·mm -3 ). 11 patients (30%) were admitted into the intensive care unit, with three deaths (8.1%) occurring in the context of comorbidities., Conclusion: Asthma patients were not overrepresented among those with severe pneumonia due to SARS-CoV-2 infection who required hospitalisation. The worst outcomes were observed mainly in patients with major comorbidities., Competing Interests: Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: A. Boucly has nothing to disclose. Conflict of interest: J. Pichon has nothing to disclose. Conflict of interest: M. Preda has nothing to disclose. Conflict of interest: M. Frank has nothing to disclose. Conflict of interest: J. Laurent has nothing to disclose. Conflict of interest: C. Richard has nothing to disclose. Conflict of interest: X. Monnet has nothing to disclose. Conflict of interest: J. Duranteau has nothing to disclose. Conflict of interest: A. Harrois has nothing to disclose. Conflict of interest: M-C. Chaumais has nothing to disclose. Conflict of interest: M-F. Bellin has nothing to disclose. Conflict of interest: N. Noël has nothing to disclose. Conflict of interest: S. Bulifon has nothing to disclose. Conflict of interest: X. Jaïs has nothing to disclose. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: A. Seferian has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, grants and personal fees from Bayer, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: D. Montani has nothing to disclose. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from AstraZeneca, Novartis, Roche, Sanofi and Teva, outside the submitted work., (Copyright ©ERS 2020.)

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1. Objectives: To describe characteristics and outcomes of PH-NF1. Methods: We reported the clinical, functional, radiologic, histologic, and hemodynamic characteristics, response to pulmonary arterial hypertension (PAH)-approved drugs, and transplant-free survival of patients with PH-NF1 from the French PH registry. Measurements and Main Results: We identified 49 PH-NF1 cases, characterized by a female/male ratio of 3.9 and a median (minimum-maximum) age at diagnosis of 62 (18-82) years. At diagnosis, 92% were in New York Heart Association functional class III or IV. The 6-minute-walk distance was 211 (0-460) m. Pulmonary function tests showed low Dl CO (30% [12-79%]) and severe hypoxemia (Pa O 2 56 [38-99] mm Hg). Right heart catheterization showed severe precapillary PH with a mean pulmonary artery pressure of 45 (10) mm Hg and a pulmonary vascular resistance of 10.7 (4.2) Wood units. High-resolution computed tomography images revealed cysts (76%), ground-glass opacities (73%), emphysema (49%), and reticulations (39%). Forty patients received PAH-approved drugs with a significant improvement in functional class and hemodynamic parameters. Transplant-free survival at 1, 3, and 5 years was 87%, 54%, and 42%, respectively, and four patients were transplanted. Pathologic assessment showed nonspecific interstitial pneumonia and major pulmonary vascular remodeling. Conclusions: PH-NF1 is characterized by a female predominance, a low Dl CO , and severe functional and hemodynamic impairment. Despite a potential benefit of PAH treatment, prognosis remains poor, and double-lung transplantation is an option for eligible patients.

About 70% patients waiting for liver transplantation have a dyspnea. Two pulmonary vascular disorders can be associated with portal hypertension or chronic liver diseases: portopulmonary hypertension (PoPH) related to pulmonary small arteries remodeling and obstruction and hepatopulmonary syndrome (HPS) characterized by pulmonary capillaries dilatations and proliferations. PoPH is defined by the combination of pulmonary arterial hypertension (PAH) (mean pulmonary artery pressure [PAP]≥25mmHg, with normal pulmonary artery wedge pressure≤15mmHg and pulmonary vascular resistance [PVR]>3 Wood units [WU]) and portal hypertension. HPS is a triad of intrapulmonary vascular dilatations, hypoxemia (increased alveolar-arterial oxygen gradient) and liver disease or isolated portal hypertension. The pathophysiology of both syndromes is complex and poorly understood. PoPH and HPS have a negative impact on functional and vital prognosis in patients with portal hypertension. Liver transplantation is the established treatment standard in HPS. PoPH treatment is improved over the years with the use of specific PAH treatment despite the lack of randomized assay in this indication. Liver transplantation could be considered in PoPH leading to stabilization, improvement or recovery in selected patients (mean PAP<35mmHg without severe right ventricular dysfunction and PVR<4 WU)., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Sleep apnea is a common condition associated with increased morbidity and mortality. Continuous positive airway pressure and oral appliances are efficient for treating sleep apnea; however, they are often poorly tolerated. Therefore, alternative therapies are needed. Overnight rostral fluid shift has been implicated in the pathogenesis of sleep apnea, particularly in conditions associated with fluid overload. Fluid shift predisposes to both obstructive and central sleep apnea, with the type of sleep apnea being related to whether the fluid shifts from the legs into the neck or chest, respectively. The amount of fluid that shifts from the legs to the upper part of the body at night is correlated with the severity of sleep apnea. As a result of this observation, it has been suggested that the prevention of overnight fluid shift may reduce sleep apnea severity. It has recently been shown that interventions targeting fluid overload and daytime fluid accumulation in the legs consistently attenuate nocturnal fluid shift and sleep apnea, as greater reductions in fluid shift are correlated with greater reductions in sleep apnea severity. This review will focus on interventions that counteract fluid shift, such as diuretics, ultrafiltration/dialysis, physical activity, compression stockings and salt/fluid restriction, which have been shown to have efficacy in reducing sleep apnea severity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a frequent autosomal dominant genetic disorder with a prevalence of 1 in 3000. Pulmonary hypertension (PH) associated with NF1 (PH-NF1) is a rare but severe complication of NF1 and is classified as Group 5 PH, defined as "PH with unclear and/or multifactorial mechanisms". A literature review in PubMed on the association between NF1 and PH identified 18 articles describing 31 cases. PH-NF1 was characterised by a female predominance, an advanced age at diagnosis, an association with parenchymal lung disease in two out of three cases and poor long-term prognosis. NF1 is generally associated with interstitial lung disease but some cases of severe PH without parenchymal lung disease suggest that there could be a specific pulmonary vascular disease. There is no data available on the efficacy of specific pulmonary arterial hypertension treatment in PH-NF1. Therefore, these patients should be evaluated in expert PH centres and referred for lung transplantation at an early stage. As these patients have an increased risk of malignancy, careful assessment of the post-transplant malignancy risk prior to listing for transplantation is necessary. Clinical trials are needed to evaluate promising treatments targeting the RAS-downstream signalling pathways., Competing Interests: Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jäis reports grants, personal fees and non-financial support from Actelion, GSK, Bayer and MSD, outside the submitted work. Conflict of interest: L. Savale reports grants and personal fees from Actelion, grants, personal fees and non-financial support from MSD and Bayer, and personal fees and non-financial support from GSK, outside the submitted work. Conflict of interest: C. O'Connell has nothing to disclose. Conflict of interest: F. Perros has nothing to disclose. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Merck and GSK, grants and personal fees from Bayer, and personal fees from Arena Pharmaceuticals and Acceleron Pharmaceuticals, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Merck and United Therapeutics, and grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and personal fees from BMS, GSK, MSD and Pfizer, outside the submitted work., (Copyright ©ERS 2018.)

Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo. Using Sm22a-Cre Il6rfl/fl, which lack Il6r in SM22A-expressing cells, we found that these animals are protected against chronic hypoxia-induced PH with reduced PA-SMC accumulation, revealing the potent pro-survival potential of membrane-bound IL6R. Moreover, we determine that treatment with IL6R-specific antagonist reverses experimental PH in two rat models. This therapeutic strategy holds promise for future clinical studies in PAH.

Pleural effusion is a frequent side-effect of dasatinib, a second-generation tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. However, the underlying mechanisms remain unknown. We hypothesised that dasatinib alters endothelial integrity, resulting in increased pulmonary vascular endothelial permeability and pleural effusion.To test this, we established the first animal model of dasatinib-related pleural effusion, by treating rats with a daily regimen of high doses of dasatinib (10 mg·kg -1 ·day -1 for 8 weeks).Pleural ultrasonography revealed that rats chronically treated with dasatinib developed pleural effusion after 5 weeks. Consistent with these in vivo observations, dasatinib led to a rapid and reversible increase in paracellular permeability of human pulmonary endothelial cell monolayers as reflected by increased macromolecule passage, loss of vascular endothelial cadherin and zonula occludens-1 from cell-cell junctions, and the development of actin stress fibres. These results were replicated using human umbilical vein endothelial cells and confirmed by decreased endothelial resistance. Interestingly, we demonstrated that this increased endothelial permeability is a reactive oxygen species (ROS)-dependent mechanism in vitro and in vivo using a cotreatment with an antioxidant agent, N -acetylcysteine.This study shows that dasatinib alters pulmonary endothelial permeability in a ROS-dependent manner in vitro and in vivo leading to pleural effusion., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Pulmonary hypertension (PH) is a cardio-pulmonary disorder that may involve multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. Its definition is an increase in mean pulmonary artery pressure (mPAP) \hbox{$\geqslant $} ⩾ 25 mmHg at rest, leading to right heart failure and ultimately death. The clinical classification of pulmonary hypertension (PH) categorizes PH into groups which share similar pathophysiological and hemodynamic characteristics and treatments. Five groups of disorders that cause PH are identified: pulmonary arterial hypertension (Group 1) which is a pre-capillary PH, defined by a normal pulmonary artery wedge pressure (PAWP) \hbox{$\leqslant $} ⩽ 15 mmH, due to remodelling of the small pulmonary arteries (<500 μm); pulmonary hypertension due to left heart disease (Group 2) which is a post-capillary PH, defined by an increased pulmonary artery wedge pressure (PAWP) >15 mmHg; pulmonary hypertension due to chronic lung disease and/or hypoxia (Group 3); chronic thrombo-embolic pulmonary hypertension (Group 4); and pulmonary hypertension due to unclear and/or multifactorial mechanisms (Group 5). PAH (PH group 1) can be treated with agents targeting three dysfunctional endothelial pathways of PAH: nitric oxide (NO) pathway, endothelin-1 pathway and prostacyclin pathway. Patients at low or intermediate risk can be treated with either initial monotherapy or initial oral combination therapy. In patients at high risk initial combination therapy including intravenous prostacyclin analogues should be considered. Patients with inadequate clinical response to maximum treatment (triple therapy with an intravenous prostacyclin) should be assessed for lung transplantation. Despite progresses, PAH remains a fatal disease with a 3-year survival rate of 58%. Treatment of group 2, group 3 and group 5 PH is the treatment of the causal disease and PAH therapeutics are not recommended. Treatment of group 4 PH is pulmonary endarteriectomy if patients are eligible, otherwise balloon pulmonary angioplasty and/or medical therapy can be considered., (© Société de Biologie, 2016.)

Antisynthetase syndrome is an inflammatory myopathy frequently associated with pulmonary manifestations, especially interstitial lung diseases, and uncommonly pulmonary hypertension. In the context of a suggestive clinical and radiological picture, positive anti-RNA synthetase antibodies confirm the diagnosis. Anti-Jo1, anti-PL7, and anti-PL12 antibodies are the more commonly encountered. The presence of a number of extra-thoracic manifestations in association with pulmonary disease may suggest the diagnosis. These include: myalgia or muscular deficit, Raynaud's phenomenon, polyarthritis, fever, mechanics hands. Serum creatine kinase levels are usually increased. Electromyogram, muscular magnetic resonance imaging or muscle pathology are not mandatory to make the diagnosis. There is a high variability in symptoms and severity, between patients but also during the course of the disease in the same patient. The presence of an interstitial lung disease is a major prognostic factor and an indication for more intensive treatment, principally with systemic corticosteroids with or without immunosuppressive drugs. Improving respiratory physicians' knowledge of this disease, which is often revealed by its pulmonary manifestations, should help diagnosis, therapeutic management, and possibly prognosis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Patients with pulmonary arteriovenous malformations usually complain of dyspnoea upon exertion, fatigue or migraine, or may be asymptomatic. We describe a patient with an unreported manifestation of a pulmonary arteriovenous malformation: a severe chronic cough., Case Presentation: A 51-year old Caucasian non-smoking female police officer presented with a chronic cough. She had been diagnosed with hereditary haemorrhagic telangiectasia in 1992. She complained of a severe, dry cough at the time of the diagnosis and a pulmonary arteriovenous malformation in the upper left lobe as demonstrated by CT of the chest. The fistula was occluded and the cough disappeared rapidly but resumed in 1994. Recanalisation of the fistula led to a new embolisation procedure, and the cough disappeared. Similar episodes occurred in 1998 and 2004, leading to embolisation of a fistula in the right lower lobe and reperfused fistula in the upper left lobe, respectively. The patient was referred to our research team in 2010 because of reappearance of her dry cough that was more pronounced during exercise and exposure to volatile irritants, and absent during the night. Despite extensive investigations, no cause was found other than reperfusion of the fistula in the left upper lobe. The malformation was not accessible to embolisation, leading us to recommend surgical excision of the malformation. A surgeon undertook atypical resection of the left upper lobe in 2012. The cough disappeared immediately after surgery and has not recurred., Conclusion: Physicians caring for patients with pulmonary arteriovenous malformations should know that a severe, chronic cough can be caused by the malformation. A cough associated with a pulmonary arteriovenous malformation can be treated effectively by embolisation but may resume in cases of reperfusion of the malformation. In our case, the severity of the cough led to surgical excision because embolisation was not possible. The mechanism of action of this cough remains to be determined.

In recent years in the management of pulmonary arterial hypertension (PAH), endothelin receptor antagonists (ERAs) represent a well-established class of therapeutic agents with clear beneficial effects. Macitentan (Opsumit ® ), a dual ERA optimized for efficacy and safety, is the newest drug in the class. Macitentan presents a number of key beneficial characteristics, including increased in vivo preclinical efficacy versus existing ERAs, resulting from sustained receptor binding and physicochemical properties that allow enhanced tissue penetration. The clinical pharmacokinetics studies also indicated a low predilection of macitentan for drug-drug interactions. In the SERAPHIN trial, a phase III long-term study of PAH, macitentan significantly reduced morbidity and mortality by 45% versus placebo, providing sustained long-term improvements in exercise capacity. No association was found between changes in exercise capacity and long-term clinical outcomes, but improved cardiopulmonary hemodynamics were recorded in macitentan-treated patients irrespective of baseline background PAH therapy or World Health Organization functional class. Based on these favorable data, the US Food and Drug Administration approved the 10 mg/day dose in late 2013 and the same process has recently been concluded by the European Medicines Agency., (© The Author(s), 2014.)