Cardiovascular consequences of obstructive sleep apnea in different study models and novel perspectives Purpose of review Obstructive sleep apnea (OSA) is heterogeneous in terms of contributing pathophysiological mechanisms, clinical presentation, and consequences. Different study models from animal models of intermittent hypoxia over case-control, cohort, and population-based observational studies to uncontrolled interventional and randomized controlled interventional trials have contributed to the knowledge base. Controversial findings on underlying mechanisms and consequences of untreated OSA have challenged the field and resulted in uncertainty in treatment recommendations. Recent findings The heterogeneity of OSA in pathogenesis and clinical outcomes and strengths and limitations of different study models and designs used for studying OSA pathophysiology and cardiovascular consequences are discussed on the background of controversial findings on cardiovascular outcomes in OSA. In addition, recent findings from randomized controlled continuous positive airway pressure therapy withdrawal trials, an efficient and controlled study model, are highlighted. Summary Novel designs for clinical trials on long-term outcomes in the highly prevalent patient group with OSA addressing the heterogeneity in underlying mechanisms, different phenotypes in terms of cardiovascular risk, and new treatment concepts are needed to improve clinical practice standards. Correspondence to Esther I. Schwarz, Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. Tel: +41 44 255 38 28; fax: +41/44 255 44 51; e-mail: estherirene.schwarz@usz.ch Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Diagnosis and management of nonrapid eye movement-parasomnias Purpose of review Nonrapid eye movement (NREM) parasomnias are common sleep disorders that potentially have significant personal, social and forensic implications. They represent a unique opportunity in nature to explore the coexistence of sleep and wake-state in the human brain. Recent findings Neuroimaging and electroencephalography have advanced our understanding of NREM-parasomnia pathophysiology, and the interplay between wakefulness and sleep. These disorders are increasingly viewed as resulting from an evolutionary process with a basis in uni-hemispheric brain activity in sleep seen in some animals, maintaining consciousness and ability to act against life-threatening situations. Although current classification of NREM parasomnia phenotypes distinguishes between disorders of arousal and other types of behaviours, evidence increasingly points to there being a significant overlap between the various phenotypes. Treatment practice appears more standardized nowadays based on larger case series, but randomized control trials are still needed. Summary NREM-parasomnia is a very common disorder of uncertain pathogenesis but of known pathophysiology, the diagnosis of which remains primarily clinical. Correspondence to Panagis Drakatos, Sleep Disorders Centre, Guy's Hospital, 1st Floor, Nuffield House, Great Maze Pond, London SE1 9RT, UK. Tel: +44 2071853390; fax: +44 2071886114; e-mail: panagis.drakatos@gstt.nhs.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Anti-alarmin approaches entering clinical trials Purpose of review The alarmins, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, are upstream regulators of T2 (type 2) inflammation and found to be expressed at high levels in airway epithelium of patients with T2 asthma. This review will summarize how alarmins regulate the inflamed asthmatic airways through previously described and newly identified mechanisms. Recent findings Alarmins drive allergic and nonallergic asthma through activation of innate lymphoid cell 2 (ILC2), which are a rich source of cytokines such as IL-5 and IL-13, with resulting effects on eosinophilopoeisis and remodelling, respectively. Findings from bronchial allergen challenges have illustrated widespread expression of alarmins and their receptors across many effector cells in airways, and recent studies have emphasized alarmin regulation of CD4+ T lymphocytes, eosinophils and basophils, and their progenitors. Furthermore, a link between alarmins and lipid mediators is being uncovered. Summary Alarmins can drive well defined inflammatory pathways through activation of dendritic cells and polarizing T cells to produce type 2 cytokines, as well as they can directly activate many other effector cells that play a central role in allergic and nonallergic asthma. Clinical trials support a central role for TSLP in driving airway inflammation and asthma exacerbations, while ongoing trials blocking IL-33 and IL-25 will help to define their respective role in asthma. Correspondence to Gail M. Gauvreau, McMaster University, 1200 Main St W., HSC 3U26, Hamilton, ON L8N 3Z5, Canada. Tel: +1 905 525 9140 x22791; e-mail: gauvreau@mcmaster.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prevention of chronic infection with Pseudomonas aeruginosa infection in cystic fibrosis Purpose of review This review provides an update on definitions of chronicity of infection, approaches to airway sampling to detect infection, strategies for Pseudomonas aeruginosa eradication, impact of cystic fibrosis transmembrane regualtor protein (CFTR) modulators and future challenges for clinical trials. Recent findings Rates of P. aeruginosa have decreased over the past two decades with establishment of effective eradication protocols. Definitions of chronic P. aeruginosa infection have required adaptation for healthier populations. Although molecular (PCR) approaches to early P. aeruginosa detection are sensitive, to date, earlier diagnosis has not impacted on clinical outcomes. Despite eradication regimens, some people with early P. aeruginosa fail to clear their infection. Most people also experience a recurrence and eventual transition to chronic infection. Several recent studies sought to address this gap. CFTR modulators (predominantly ivacaftor) demonstrated reduced P. aeruginosa density, although infection may persist or recur demonstrating the need for continued antiinfective therapies in the modulator era. Summary Future studies of approaches to P. aeruginosa eradication will be complex due to expanded availability and ongoing competitive clinical trials of CFTR modulators. Studies to address optimal eradication therapy, particularly in adults, will be required, though adequate recruitment to power these studies may prove challenging. Correspondence to Scott C. Bell, Adult Cystic Fibrosis Centre, The Prince Charles Hospital and QIMR Berghofer Medical Research Institute, Brisbane, Chermside, 4032, Queensland, Australia. E-mail: scott.bell@qimrberghofer.edu.au Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prevention of anxiety and depression in cystic fibrosis Purpose of review Anxiety and depression (A&D) are common in cystic fibrosis (CF). This review defines A&D in the context of CF and examines our current knowledge about A&D, the impact on CF, treatment and illness trajectory and explores potential areas for prevention. Recent findings CF and A&D are interrelated. The CF diagnosis, symptoms and treatment may trigger symptoms of A&D, leading in some patients, to a clinical diagnosis of anxiety or depression. In return A&D impacts CF, potentially worsening the prognosis, decreasing treatment adherence and overall well being. Research shows how prevention is often imbedded in treatment programmes, for example cognitive behavioural therapies or motivational interviewing. Strategies that may help to prevent the onset of clinical A&D or an increase in symptoms include the implementation of psychoeducation; techniques to enhance coping and resilience; building social support networks; increasing patients’ physical exercise; and potentially, the implementation of e-health in day-to-day care. Summary To date, most A&D interventions focus on psychotherapeutic treatments, with preventive measures imbedded in programmes. The challenge lies in the improvement of our knowledge and implementation of preventive strategies to advance our care for patients with CF and to avoid clinical A&D. Correspondence to Trudy Havermans, Cystic Fibrosis Centre, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel: +32 16 340268; e-mail: trudy.havermans@uzleuven.be Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Unilateral phrenic nerve stimulation in the therapeutical algorithm of central sleep apnoea in heart failure Purpose of review Central sleep apnoea (CSA) is highly prevalent in patients with heart failure and substantially impairs survival. If optimal cardiac treatment fails, alternative therapeutical options, including positive airway pressure (PAP) therapies, drugs or application of oxygen and carbon dioxide are considered to suppress CSA which interfere with the complex underlying pathophysiology. Most recently, unilateral phrenic nerve stimulation (PNS) has been studied in these patients. Therefore, there is an urgent need to critically evaluate efficacy, potential harm and positioning of PNS in current treatment algorithms. Recent findings Data from case series and limited randomized controlled trials demonstrate the feasibility of the invasive approach and acceptable peri-interventional adverse events. PNS reduces CSA by 50%, a figure comparable with continuous PAP or oxygen. However, PNS cannot improve any comorbid upper airways obstruction. A number of fatalities due to malignant cardiac arrhythmias or other cardiac events have been reported, although the association with the therapy is unclear. Summary PNS offers an additional option to the therapeutical portfolio. Intervention-related adverse events and noninvasive alternatives need clear discussion with the patient. The excess mortality in the SERVE-HF study has mainly been attributed to sudden cardiac death. Therefore, previous cardiac fatalities under PNS urge close observation in future studies as long-term data are missing. Correspondence to Winfried Randerath, MD, Professor of Medicine, Clinic for Pneumology and Allergology, Centre of Sleep Medicine and Respiratory Care, Institute of Pneumology at the University of Cologne, Bethanien Hospital, Aufderhöher Str. 169, 42699 Solingen, Germany. E-mail: randerath@klinik-bethanien.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Noninvasive volume-assured pressure support for chronic respiratory failure: a review Purpose of review Noninvasive ventilation (NIV) is an established treatment for chronic hypercapnic respiratory failure (CRF). Volume-assured pressure support (VAPS) is a mode of NIV that automatically adjusts inspiratory pressure in order to maintain a constant respiratory volume. We aim to discuss the role and application of VAPS in CRF. Recent findings Recently published meta-analyses and reviews fail to demonstrate a significant difference in gas exchange, sleep, or quality-of-life improvement in patients with CRF between VAPS and bilevel positive airway pressure (BPAP). A recent manuscript suggests that VAPS therapy in chronic obstructive pulmonary disease patients may reduce the number of exacerbations. It has been shown that with a protocol-driven approach BPAP and VAPS can both be successfully titrated during a single split-night polysomnography. Summary VAPS is as effective as other modes of NIV at improving ventilation and sleep in CRF. The potential advantage is a more consistent ventilatory support through daytime–nighttime variations and progression of disease over time. However, the impact on long-term outcomes, such as survival, has not been studied. Correspondence to Timothy I. Morgenthaler, MD, Department of Pulmonary and Critical Care Medicine and the Center for Sleep Medicine, Mayo Clinic, Rochester, MN 55905, USA. Tel: +507 266 6880; e-mail: TMorgenthaler@mayo.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.