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Juan Marco Figueira‐Gonçalves,1,2 Miguel Ángel García-Bello,3,4 Yolanda Ramallo‐Fariña,3– 5 Raúl Méndez,6– 9 Ana Latorre Campos,6,7 Paula González-Jiménez,6,7,9 Germán Peces-Barba,10 María Molina-Molina,11 Pedro Pablo España,12 Estela García,13 Santiago de Jorge Domínguez-Pazos,14 Marta García Clemente,15 Carolina Panadero,16 David de la Rosa-Carrillo,17 Oriol Sibila,18 María Dolores Martínez-Pitarch,19 Nuria Toledo-Pons,20 Cecilia López-Ramirez,21 Wanda Almonte-Batista,22 Abigail Macías-Paredes,23 Diana Badenes-Bonet,24 Eli Nancy Pérez-Rodas,25 Javier Lázaro,26 Sarai Quirós Fernández,27 Rosa Cordovilla,28 Irene Cano-Pumarega,8,29 Antoni Torres,8,18 Rosario Menendez6– 9 On behalf of RECOVID1Pneumology and Thoracic Surgery Service, Unit for Patients with Highly Complex COPD, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 2University Institute of Tropical Disease and Public Health of the Canary Islands, University of La Laguna, Santa Cruz de Tenerife, Spain; 3Evaluation Unit (SESCS), Canary Islands Health Research Institute Foundation (FIISC), Tenerife, Spain; 4Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Tenerife, Spain; 5Health Services Research on Chronic Patients Network (REDISSEC), Madrid, Spain; 6Pneumology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 7Respiratory InFections, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; 8CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; 9Medicine Department, University of Valencia, Valencia, Spain; 10Pulmonology Department, Hospital Fundación Jiménez Díaz, Madrid, Spain; 11ILD Unit, Respiratory Department, Hospital de Bellvitge, Hospitalet de Llobregat, Spain; 12Respiratory Service, Hospital de Galdakao-Usansolo, Galdakao, Spain; 13Respiratory Service, Hospital de Cabueñes, Gijón, Spain; 14Respiratory Service, Hospital Universitario de A Coruña, A Coruña, Spain; 15Respiratory Service, Hospital Universitario Central de Asturias, Oviedo, Spain; 16Respiratory Service, Hospital de Getafe, Getafe, Spain; 17Respiratory Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 18Respiratory Service, Hospital Clínic, Barcelona, Spain; 19Respiratory Service, Hospital Lluís Alcanyís, Játiva, Spain; 20Respiratory Service, Hospital Son Espases, Palma, Spain; 21Medical Surgical Unit of Respiratory Diseases, Hospital Virgen del Rocío, Sevilla, Spain; 22Respiratory Service, Hospital de Albacete, Albacete, Spain; 23Respiratory Service, Hospital de Sant Jaume, Calella, Spain; 24Respiratory Service, Hospital del Mar, Barcelona, Spain; 25Respiratory Service, Hospital Municipal de Badalona, Badalona, Spain; 26Respiratory Service, Hospital Royo Villanova, Zaragoza, Spain; 27Respiratory Service, Hospital Basurto, Bilbao, Spain; 28Respiratory Service, Hospital de Salamanca, Salamanca, Spain; 29Respiratory Service, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, SpainCorrespondence: Juan Marco Figueira‐Gonçalves, Pneumology and Thoracic Surgery Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain, Tel +34654959246, Email juanmarcofigueira@gmail.comBackground: Chronic obstructive pulmonary disease (COPD) has been associated with worse clinical evolution/survival during a hospitalization for SARS-CoV2 (COVID-19). The objective of this study was to learn the situation of these patients at discharge as well as the risk of re-admission/mortality in the following 12 months.Methods: We carried out a subanalysis of the RECOVID registry. A multicenter, observational study that retrospectively collected data on severe acute COVID-19 episodes and follow-up visits for up to a year in survivors. The data collection protocol includes general demographic data, smoking, comorbidities, pharmacological treatment, infection severity, complications during hospitalization and required treatment. At discharge, resting oxygen saturation (SpO2), dyspnea according to the mMRC (modified Medical Research Council) scale and long-term oxygen therapy prescription were recorded. The follow-up database included the clinical management visits at 6 and 12 months, where re-admission and mortality were recorded.Results: A total of 2047 patients were included (5.6% had a COPD diagnosis). At discharge, patients with COPD had greater dyspnea and a greater need for prescription home oxygen. After adjusting for age, sex and Charlson comorbidity index, patients with COPD had a greater risk of hospital re-admission due to respiratory causes (HR 2.57 [1.35– 4.89], p = 0.004), with no significant differences in survival.Conclusion: Patients with COPD who overcome a serious SARS-CoV2 infection show a worse clinical situation at discharge and a greater risk of re-admission for respiratory causes.Keywords: chronic obstructive pulmonary disease, COPD, COVID-19, coronavirus disease 2019, RECOVID, Spanish COVID-19 registry, SARS-CoV2, severe acute respiratory syndrome coronavirus 2, SEPAR, respiratory failure

Rationale: Obstructive sleep apnea and systemic hypertension (SH) are highly prevalent. Although their association has been suggested in cross-sectional studies, conflicting evidence has emerged from longitudinal studies. Objectives: To assess the association between obstructive sleep apnea and SH in the middle-aged general population. Methods: A total of 2,148 subjects were included in a longitudinal study of the Vitoria Sleep Cohort, a general population sample aged 30-70 years. We analyzed data on office blood pressure, anthropometric measures, health history, and home polygraphy. Out of 1,557 subjects who completed the 7.5-year follow-up, 377 were excluded for having SH at baseline. The odds ratios for the incidence of SH, according to the respiratory disturbance index (RDI) at baseline, were estimated in 1,180 subjects (526 men and 654 women) after adjustment for age; sex; body mass index; neck circumference; fitness level; and alcohol, tobacco, and coffee consumption. The RDI was divided into quartiles (0-2.9, 3-6.9, 7-13.9, and >= 14), using the first quartile as reference. Measurements and Main Results: The crude odds ratio for incident hypertension increased with higher RDI category with a dose-response effect (P < 0.001), but was not statistically significant after adjustment for age (P = 0.051). Adjustments for sex (P = 0.342), body mass index (P = 0.803), neck circumference (P = 0.885), and fitness level and alcohol, tobacco, and coffee consumption (P = 0.708) further reduced the strength of the association between RDI and SH. No differences were observed between men and women. Conclusions: Our findings do not suggest an association between obstructive sleep apnea and the incidence of SH in the middle-aged general population. Long-term follow-up longitudinal studies are needed to better ascertain this association. [ABSTRACT FROM AUTHOR]

Study Objectives: The STOP-Bang questionnaire is a validated screening tool for obstructive sleep apnea (OSA). We conducted this study to validate it among patients hospitalized with acute symptomatic pulmonary embolism (PE)., Methods: This prospective cohort study enrolled consecutive stable patients with acute PE who underwent an overnight sleep study within 7 days after diagnosis. Our outcomes were: i) the STOP-Bang questionnaire's utility for risk stratification, ii) the discrimination of the STOP-Bang questionnaire categories, iii) the false negative rate of STOP-Bang questionnaire prediction, and iv) the clinical utility of the STOP-Bang questionnaire to exclude OSA. We also calculated the test performance characteristics to predict OSA., Results: During the study period, 268 patients completed a sleep study. OSA was found in 47% of patients. OSA incidence in low-, moderate-, and high-risk STOP-Bang groups was 22.4%, 48.2%, and 61.5%, respectively (P <0.001). The area under the receiver operating characteristics curve of the STOP-Bang questionnaire for risk of OSA was 0.65. The false negative rate of a low-risk STOP-Bang questionnaire result to rule out OSA was 22.4% and the clinical utility was 21.6%. The sensitivity was 89.8% (97.2% for men and 80.4% for women)., Conclusions: The STOP-Bang questionnaire showed poor discrimination for the risk of OSA in hospitalized patients with acute symptomatic PE. It had a high false negative rate and a low clinical utility. The STOP-Bang questionnaire had a good sensitivity in men, and might be used to rule out OSA in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Obstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing. It is associated with adverse co-morbidities, being the most scientific evidence of cardiovascular (CV) disease. Currently, OSA is measured through the apnea-hypopnea index (AHI), the total number of respiratory events per hour of sleep. However, different studies have questioned its utility in OSA management, highlighting the need to search for new parameters that better reflect the heterogeneity of the disease. Hypoxic burden (HB) has emerged as a novel biomarker that informs about the frequency, duration and depth of the desaturation related to the respiratory events. We conducted a systematic review in order to find publications about the heterogeneity of OSA measured by HB and its associations with future disease., Methods: Systematic review was conducted using PubMed and Web of Science. The terms "sleep apne" and "hypoxic burden" were used to look for publications from the date of inception to August 15, 2023. Inclusion criteria: articles in English published in peer-reviewed journals. Exclusion criteria: (1) not available publications; (2) duplicated articles; (3) letters, editorials, and congress communications; (4) articles not including information about HB as a specific biomarker of OSA., Results: 33 studies were included. The results were classified in 2 main sections: (1) HB implication in the CV sphere: HB showed to be a better predictor of CV risk in OSA patients than traditional measures such as AHI with possible clinical management implication in OSA. (2) HB response to OSA treatment: pharmacological and nonpharmacological treatments have demonstrated to be effective in improving hypoxia measured through the HB., Conclusions: HB could be a better and more effective parameter than traditional measurements in terms of diagnosis, risk prediction and therapeutic decisions in patients with OSA. This measure could be incorporated in sleep units and could play a role in OSA management, driving the clinic to a more personalized medicine., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Home Respiratory Therapies (HRT) encompass a variety of treatments for patients with chronic respiratory diseases, administered at home over extended periods. The Service Providers of HRT (SPHRT) collaborate with hospital resources to address chronic respiratory diseases, acting as strategic partners. The contracting of HRT in the public health system involves contests where the SPHRT present technical and economic offers. The purpose of this document is to provide a technical basis that can assist professionals, SPHRT, and the administration in making decisions when calling for, evaluating, and deciding on such contests., (© 2024 Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Published by Elsevier España, S.L.U.)

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Interestingly, adenosinergic signaling has emerged as a powerful immune checkpoint driving tumor development and progression., Methods: Here, we explored the expression of the adenosinergic ecto-enzymes CD39 and CD73 in T-lymphocytes of OSA patients without any evidence of cancer, as well as their soluble forms in plasma (sCD39 and sCD73), along with adenosine. In addition, we explored the role of intermittent hypoxia (IH) in this context by in vitro models., Results: Our results showed that CD39 is upregulated while CD73 is downregulated in OSA T-cells' membrane. Moreover, our findings suggest that IH, through HIF-1, mediates the upregulation of both CD39 and CD73; and that CD73 downregulation could be mediated by a higher release of sCD73 by OSA T-lymphocytes. Importantly, we found that both sCD39 and sCD73 are upregulated in OSA plasma, suggesting T-lymphocytes as a potential source for plasmatic sCD73. Finally, our data propose the alterations in CD39/CD73 axis could underlie the upsurge of adenosine levels in the plasma of OSA patients., Conclusion: Our study reveals a hypoxia-mediated alteration of the CD39/CD73 axis in OSA patients, which could trigger ADO upregulation, thus potentially contributing to the immune suppressive environment and ultimately facilitating tumor development and progression. Therefore, our data highlights the need for new longitudinal studies evaluating CD39 and/or CD73 as potential cancer-risk prognostic biomarkers in OSA patients., (Copyright © 2024 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: /Objective: Sleep-disordered breathing (SDB) may change from the acute to stable phase of some cardiovascular disorders, but little is known whether these dynamic changes also exist in pulmonary embolism (PE). This study aimed to analyze the changes in the apnea-hypopnea index (AHI) from the acute to stable phase of PE as well as the factors associated., Patients/methods: We conducted a prospective, longitudinal and multicenter study of consecutive adults requiring hospitalization for non-hypotensive acute PE, with a protocol including clinical, imaging (transthoracic echocardiography [TTE] and computed tomography), blood tests and a sleep study within 48 h of diagnosis of PE. After 3 months of follow-up, the sleep study was repeated. Right ventricular (RV) dysfunction was defined according to TTE criteria., Results: One hundred and eleven patients (mean age [SD]: 63 [15] years; body mass index: 28.4 [4.7] kg/m 2 ) were included. The initial AHI was 24.4 (21.8) events/h (AHI≥5: 82.8 %; AHI≥30: 33.3 %). Seventy-seven patients (69.4 %) had RV dysfunction. In the overall cohort, the AHI decreased by 8.7 events/h from the acute to stable phase (24.4/h vs. 15.7/h; p=0.013). Patients with RV dysfunction showed a greater decrease in AHI (mean decrease 12.3/h vs. 0.43/h). In the multivariable analysis a drop of an AHI≥5 events/hour was independently associated with the presence of initial RV dysfunction (hazard ratio 3.9; 95%CI 1.3 to 12.1)., Conclusions: In hemodynamically stable patients with acute PE, there is a transient but clinically significant decrease in the AHI from the acute to stable phase, particularly when initially presenting with RV dysfunction., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alberto G reports financial support was provided by Spanish Society of Pneumology and Thorax Surgery., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Nocturnal hypoxemia has been associated with cardiovascular and non-cardiovascular morbidity and mortality. This study aimed to investigate the prognostic value of nocturnal hypoxemia among patients with hemodynamically stable acute symptomatic pulmonary embolism (PE)., Methods: We performed an ad hoc secondary analysis of clinical data from a prospective cohort study. Nocturnal hypoxemia was measured by the percent sleep registry with oxygen saturation <90% [TSat90]). Outcomes assessed over the 30-days after the diagnosis of PE included PE-related death, other cardiovascular deaths, clinical deterioration requiring an escalation of treatment, recurrent venous thromboembolism (VTE), acute myocardial infarction [AMI], or stroke., Results: Of the 221 hemodynamically stable patients with acute PE from which the TSat90 could be calculated and did not receive supplemental oxygen, the primary outcome occurred in 11 (5.0%; 95% confidence interval [CI], 2.5% to 8.7%) within 30-days after the diagnosis of PE. When categorized by quartiles, TSat90 was not significantly associated with the occurrence of the primary outcome in unadjusted Cox regression analysis (hazard ratio, 0.96; 95% CI, 0.57 to 1.63; P = 0.88), or after adjustment for body mass index (adjusted hazard ratio, 0.97; 95% CI, 0.57 to 1.65; P = 0.92). When examined as a completely continuous variable (between 0 and 100), TSat90 was not associated with a significant increase in the adjusted hazard of 30-day primary outcome rates (hazard ratio, 0.97; 95% CI, 0.86 to 1.10; P = 0.66)., Conclusions: In this study, nocturnal hypoxemia did not identify stable patients with acute symptomatic PE at increased risk for adverse cardiovascular events., Competing Interests: Declaration of Competing Interest E.B. has nothing to disclose. C.R. has nothing to disclose. E.M. has nothing to disclose. A.R. has nothing to disclose. A.GO. has nothing to disclose. A.GS. has nothing to disclose. I.CP. has nothing to disclose. MA.MG. has nothing to disclose. D.J. has nothing to disclose. Dr. Jiménez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy., Methods: The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models., Results: Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia., Discussion: In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Díaz-García, García-Sánchez, Alfaro, López-Fernández, Mañas, Cano-Pumarega, López-Collazo, García-Río and Cubillos-Zapata.)

Introduction: After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, patients may show lung sequelae on radiology and functional impairment at the 1-year follow-up. We aimed to describe the persistence of symptoms, radiological alterations, or reduced diffusing capacity of the lung for carbon monoxide (D LCO ) at 1-year follow-up in patients from the Spanish Registry RECOVID., Methods: RECOVID collected symptom and radiological and functional lung tests data on hospitalized patients with coronavirus disease 2019 during the acute phase and at the 6- and 12-month follow-up visits., Results: Of the 2500 enrolled survivors (90% admitted to the ward), 1874 had follow-up visits for up to a year. Of these, 42% continued to present with symptoms, 27% had radiological sequelae and 31% had reduced D LCO . Independently associated factors included female sex, asthma and the requirement for invasive or non-invasive mechanical ventilation. Complete radiological resolution was 72.2% at 12 months; associated factors with incomplete recovery were age, male sex, oxygen or respiratory support, corticosteroids and an initial SpO 2 /FiO 2 <450 or CURB-65 ≥2. Reduced D LCO was observed in 31% of patients at 12 months; associated factors were older age, female sex, smoking habit, SpO 2 /FiO 2 <450 and CURB-65 ≥2 and the requirement of respiratory support.At 12 months, a proportion of the asymptomatic patients showed reduced D LCO (9.5%), radiological findings (25%) or both (11%)., Conclusions: The factors associated with symptom persistence, incomplete radiological resolution and D LCO <80% differed according to age, sex, comorbidities and respiratory support. The burden of symptoms, reduced D LCO and incomplete radiological resolution were considerable in patients with SARS-CoV-2 pneumonia at the 1-year follow-up after hospitalisation., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Obstructive sleep apnea (OSA) in children is a prevalent, but still, today, underdiagnosed illness, which consists of repetitive episodes of upper airway obstruction during sleep with important repercussions for sleep quality. OSA has relevant consequences in the pediatric population, mainly in the metabolic, cardiovascular (CV), and neurological spheres. However, contrary to adults, advances in diagnostic and therapeutic management have been scarce in the last few years despite the increasing scientific evidence of the deleterious consequences of pediatric OSA. The problem of underdiagnosis and the lack of response to treatment in some groups make an update to the management of OSA in children necessary. Probably, the heterogeneity of OSA is not well represented by the classical clinical presentation and severity parameters (apnea/hypopnea index (AHI)), and new strategies are required. A specific and consensus definition should be established. Additionally, the role of simplified methods in the diagnosis algorithm should be considered. Finally, the search for new biomarkers for risk stratification is needed in this population. In conclusion, new paradigms based on personalized medicine should be implemented in this population.

Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-β) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-β pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.

Background: In patients with obstructive sleep apnoea (OSA), intermittent hypoxia induces overexpression of paraspeckle component (PSPC)1, a master modulator of transforming growth factor (TGF)-β signalling, which promotes cell cancer progression through epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. However, the persistence of intermittent hypoxia-induced effects on PSPC1, and their consequences in cancer patients are not known. To this effect, circulating PSPC1 levels were compared in patients with cutaneous melanoma with or without OSA, and their relationship with tumour aggressiveness along with the in vitro effects of soluble PSPC1 and intermittent hypoxia on melanoma cell aggressiveness mechanisms were assessed., Methods: In 292 cutaneous melanoma patients, sleep studies and serum levels of PSPC1 and TGF-β were evaluated. The effect of PSPC1 on expression of EMT and CSC transcription factors was assessed using melanoma cell lines with patient sera under both normoxia and intermittent hypoxia conditions., Results: PSPC1 levels were higher in patients with moderate-severe OSA compared with mild OSA or non-OSA patients. Serum levels of PSPC1 were associated with several cutaneous melanoma clinical aggressiveness indicators. Both intermittent hypoxia exposures and serum from OSA patients upregulated TGF-β expression and amplified the expression of transcription factors associated with EMT activation and acquisition of CSC characteristics., Conclusion: In cutaneous melanoma patients, OSA severity is associated with higher PSPC1 serum levels, which jointly with intermittent hypoxia would enhance the self-reprogramming capabilities of EMT and CSC feature acquisition of melanoma cells, promoting their intrinsic aggressiveness., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Current data support an increase in the prevalence of high blood pressure (HBP) in pediatric patients with sleep-disordered breathing (SDB). Adeno-tonsillectomy has been shown to be an effective treatment for most patients. Our objective was to determine the prevalence of HBP in pediatric patients with SDB and the impact of adeno-tonsillectomy with a multicenter, longitudinal, and prospective study that included 286 children referred for suspected SDB. The diagnosis of SDB was established by polysomnography (PSG) and the diagnosis of HBP by 24-h ambulatory blood pressure monitoring (ABPM). In patients without SDB and SDB without treatment indication, these tests were repeated six months after the baseline visit. For patients with medical treatment for SDB, the tests were repeated six months after the treatment initiation. Finally, in patients with surgery indication, ABPM was performed just before surgical treatment and ABPM and PSG six months after the intervention. The study contributes to elucidating the association between SDB and HBP in pediatric patients. Moreover, it contributes to determining if intervention with adeno-tonsillectomy is associated with BP reduction. The results have direct implications for the management of SDB, providing essential information on treatment indications for existing clinical guidelines. NCT03696654.

The intermediate respiratory care units (UCRI) are areas of monitoring and specialized care of patients with acute or chronic-exacerbated respiratory failure, whose severity does not require admission to an intensive care unit, but which due to their complexity cannot be treated in conventional hospitalization. Although the COVID-19 pandemic has proven its usefulness in the management of critical respiratory patients, the historical trajectory of the UCRI comes from many years ago, in which its cost-effectiveness has been demonstrated by far. This document presents a series of questions and answers on the history of the UCRI, in addition to the criteria for admission, infrastructure, human and technical resources, and the types of existing Units. Within the UCRI year 2021-2022 designated by the Spanish Society of Pneumology and Thoracic Surgery, any scientific dissemination linked to the in-depth knowledge of these units is timely, where multidisciplinarity and the work of professionals related to the care of critical respiratory patients converge., (© 2022 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Neumología y Cirugía Torácica (SEPAR).)

There is a paucity of data examining the prognostic significance of untreated obstructive sleep apnea (OSA) in hemodynamically stable patients with acute pulmonary embolism (PE). This prospective cohort study enrolled consecutive non-hypotensive patients with acute PE who underwent an overnight sleep study within 48 h after diagnosis. The patients were divided into 2 groups based on apnea-hypopnea index (AHI): OSA (AHI ≥15) and non-OSA (AHI <15) groups. The study used a composite of fatal or nonfatal cardiovascular events, including PE-related death, other cardiovascular deaths, clinical deterioration requiring an escalation of treatment, recurrent venous thromboembolism, acute myocardial infarction, or stroke within 30-days after the diagnosis of PE as the primary outcome. Between January 1, 2018, and December 31, 2020, 283 eligible patients were prospectively enrolled in 2 academic hospitals, of whom 268 patients completed a sleep study within 7 days of PE diagnosis. OSA was found in 47% (95% confidence interval [CI], 41 to 54%) of patients. The primary outcome occurred in 13 (4.9%) patients within 30-days after the diagnosis of PE. The crude incidence of the composite was not significantly different in the OSA than the non-OSA group (30-day estimate, 6.3% versus 3.5%; P = 0.30). OSA did not significantly predict the incidence of the primary outcome after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, and oxygen saturation (adjusted hazard ratio, 2.15; 95% confidence interval, 0.67-6.87). In this study, untreated OSA was not a significant multivariable predictor of adverse cardiovascular events in patients with acute PE., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Study Objectives: Obstructive sleep apnea (OSA) has been associated with cardiovascular events (CVEs), although recent randomized controlled trials have not demonstrated that long-term continuous positive airway pressure (CPAP) prevents CVEs. Our objective was to determine the effect of CPAP on older adults with moderate OSA regarding CVE reduction., Methods: An observational and multicenter study of a cohort of older adults (> 70 years of age) diagnosed with moderate OSA (apnea-hypopnea index 15.0-29.9 events/h) was conducted. Two groups were formed: (1) CPAP treatment and (2) standard of care. The primary endpoint was CVE occurrence after OSA diagnosis. Association with CPAP treatment was assessed by propensity score matching and inverse weighting probability. Secondary endpoints were incidence of CVE separately and time to first CVE., Results: A total of 614 patients were included. After matching, 236 older adults (111 men, mean age 75.9 ± 4.7 years) with a follow-up of 47 months (interquartile range: 29.6-64.0 months) were considered for primary and secondary endpoint evaluations. Forty-one patients presented at least 1 CVE (17.4%): 20 were in the standard-of-care group (16.9%) and 21 were in the CPAP group (17.8%), with a relative risk of 1.05 (95% confidence interval [CI], 0.60-1.83; P = .43) for CPAP treatment. Inverse probability weighting of the initial 614 patients determined an adjusted relative risk of 1.24 (95% CI, 0.79-1.96; P = .35) for CPAP treatment. No statistical differences were found in secondary endpoint analyses., Conclusions: CPAP should not be prescribed to reduce CVE probability in older adults with moderate OSA., Citation: López-Padilla D, Terán-Tinedo J, Cerezo-Lajas A, et al. Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score-matched multicenter study (CPAGE-MODE study). J Clin Sleep Med . 2022;18(2):553-561., (© 2022 American Academy of Sleep Medicine.)

Objective: To evaluate the relation between systemic iron parameters (SIP) and substantia nigra (SN) iron deposits, as assessed by transcranial sonography (TCS) in restless legs syndrome (RLS)., Methods: We conducted a cross-sectional study in RLS patients, from whom blood samples with SIP were obtained, consisting of total iron-binding capacity (TIBC), serum ferritin, hemoglobin, transferrin saturation (TSAT), serum iron, and serum transferrin. TCS was performed over the SN, and the substantia nigra echogenicity index (SNEI) was determined according to established methods. Symptom severity was evaluated using the international restless legs scale (IRLS). A Spearman correlation was performed., Results: A total of 167 patients were studied. Correlations between SNEI and SIP were as follows: serum ferritin (R = 0.0422; n.s.), TSAT (R = 0.0883; n.s.), TIBC (R = -0.1091; n.s.), serum transferrin (R = -0.0420; n.s.), hemoglobin (R = 0.0185; n.s.), serum iron (R = 0.0389; n.s.). No correlation was found with age and IRLS (R = 0.1375; n.s. and R = 0.0880, n.s., respectively)., Conclusions: SIP are not correlated with SN iron content in RLS, quantified by means of TCS. TCS of the SN might be a more valid estimate and could be useful in the evaluation of RLS patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sleep-related rhythmic movements disorder (SRRMD), typically considered a benign pediatric sleep disorder, comprise a group of movement disorders that occur predominantly early in childhood with an average age of onset of 9 months of age. Although it usually resolves spontaneously as the child ages, it can persist into adulthood. In this article, the authors review the identification, diagnosis, and management of SRRMD in children and adults., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Restless legs syndrome (RLS) is one of the most common neurologic conditions, with an estimated prevalence in European and North American heritage populations of about 2% to 5%. Because RLS diagnosis is essentially clinical, a careful evaluation of the symptoms is mandatory. It is important to exclude RLS mimics and evaluate factors that could exacerbate RLS symptoms. It is mandatory to evaluate systemic iron parameters, because the initial treatment depends on this result. Other complementary tests could help support the diagnosis or exclude mimics. The decision about when and how to treat should be carefully tailored to each patient., Competing Interests: Disclosure C. Garcia-Malo reports grants from IRLSSG, outside the submitted work. The other authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Midkine (MDK) might mediate the proangiogenic effect of intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) and cutaneous melanoma (CM). We compare circulating MDK in CM patients with and without OSA, and their relationship with tumor aggressiveness, while exploring in vitro effects of soluble MDK on human lymphatic endothelial (HLEC) and melanoma cell proliferation. In 360 CM patients, sleep studies and MDK serum level measurements were performed. The effect of MDK on cell proliferation was assessed using HLEC and melanoma cell lines with patient sera under both normoxia and IH. MDK levels were higher in severe OSA compared to mild OSA or non-OSA patients, whereas no differences in VEGF levels emerged. In OSA patients, MDK levels correlated with nocturnal hypoxemia and CM mitotic rate. In vitro, MDK promotes HLEC proliferation under IH conditions. Moreover, cultures of the human melanoma cell line C81-61 with sera from patients with the highest MDK levels promoted tumor cell proliferation, which was attenuated after the addition of MDK antibody. These responses were enhanced by IH exposures. In conclusion, in CM patients, OSA severity is associated with higher MDK levels, which, appear to enhance both the lymphangiogenesis as the intrinsic aggressiveness of CM tumor cells., (© 2020 Federation of American Societies for Experimental Biology.)

Objective: To evaluate the incidence of iron overload and anaphylaxis following intravenous (IV) iron treatment of restless legs syndrome (RLS)., Methods: A total of 58 consecutive RLS patients, meeting clinical requirements for IV iron treatment according to current IRLSSG guidelines were recruited. IV iron treatment consisted of two 500 mg infusions of ferric carboxymaltose (FCM) administered five days apart. During each of the three follow-up visits we obtained blood samples, substantia nigra echogenity index (SNEI) by means of transcranial sonography (TCS), and assessed the severity of RLS symptoms (IRLS scale). "Iron overload risk" was defined as transferrin saturation (TSAT) > 45% on two consecutive follow-up visits. In patients who had a reduction in systemic iron levels following treatment, an additional 500 mg of FCM was administered when feasible. In such cases an additional two follow-up visits were performed., Results: Among the total sample, only 2/58 participants met criteria for iron overload risk. They had no evidence of liver damage and did not require additional treatment. Among the 21 patients receiving an additional 500 mg infusion after, only one patient was diagnosed with iron overload risk. Among these three patients, only one was a hemochromatosis gene carrier. No anaphylaxis or other side-effects were reported., Conclusions: In real-life clinical conditions, the risk of iron overload is low when IV FCM is administered according to the safety limits defined in the current RLS treatment guidelines. However, a close clinical follow-up with periodic blood sampling for iron status, is needed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Active transforming growth factor-β1 (TGF-β1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors. We determine whether obstructive sleep apnea (OSA) increases serum levels of active TGF-β1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-β1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-β1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-β1 levels correlated with mitotic index, Breslow index and melanoma growth rate, and were increased in presence of ulceration or higher Clark levels. In CM patients, OSA was associated with higher TGF-β1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-β1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-β1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-β1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common neurological disorder affecting up to 5% to 10% of the population, but it remains an underdiagnosed condition. RLS/WED is characterized by uncomfortable sensations, mainly in the legs, which appear during inactivity and worsen in the evening or at night. The prevalence of RLS/WED and periodic leg movements (PLMs) is increased in patients with sleep-disordered breathing, particularly in those with OSA, the most common sleep disorder encountered in sleep centers. New advances in the pathophysiology of RLS/WED have shown important implications for various genetic markers, neurotransmitter dysfunction, and iron deficiency. A practical approach to RLS/WED management includes an accurate diagnosis, the identification of reversible contributing factors, and the use of nonpharmacological therapies, including iron substitution (oral or IV) therapy. Many pharmacological agents are effective for the treatment of RLS/WED. Until recently, the first-line treatment of RLS/WED consisted of low-dose dopamine agonists (DA). However, given the fact that DAs cause high rates of augmentation of symptoms, international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand, and avoidance of dopaminergic agents unless absolutely necessary. If necessary, the lowest effective dose should be used for only the shortest possible time. The symptoms of RLS/WED can disrupt the quality of sleep as well as the quality of life. IV iron therapy may be considered in patients with refractory RLS. A better understanding of RLS/WED pathophysiology will allow patients to receive tailored therapy, resulting in an improved quality of life., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To analyze changes in substantia nigra (SN) iron deposits, assessed by quantitative transcranial sonography (TCS), to obtain and compare substantia nigra echogenicity indices (SNEI) at baseline and after intravenous (IV) iron therapy in patients with restless legs syndrome (RLS)/Willis-Ekbom disease (WED)., Methods: A total of 30 consecutive subjects diagnosed with RLS/WED were recruited and underwent IV iron treatment. The SNEI, total daily dose of dopamine equivalents, and International Restless Legs Syndrome Rating Scale (IRLS) scores were obtained at baseline and following IV iron administration. Comparative statistics were performed by means of nonparametric testing., Results: The sample was stratified into two groups according to the median baseline SNEI and the grade of SN hypoechogenicity: severely hypoechogenic (HE) (n = 13) and moderately HE (n = 17). Following IV iron, the increase in SNEI among severely HE subjects was 19% (0.038 ± 0.046 cm 2 ; P < 0.01), whereas in moderately HE subjects it was 10% (0.021 ± 0.069 cm 2 ; P = 0.28). Among severely HE subjects, the average reduction in IRLS following IV iron was 10 ± 7.12 points (P < 0.01), in contrast to 1.85 ± 9.85 (not significant) among moderately HE subjects. Finally, we quantified the percentage of patients in each group who were able to reduce by ≥30% their total daily dopaminergic requirements (TDR) after IV iron, with a 57.14% reduction in the severely HE group vs 25% in the moderately HE group (P = 0.1). Three of 30 subjects (17%) were able to completely cease all dopaminergic treatment., Conclusion: Intravenous iron caused changes in SNEI in both groups of patients, reflecting an increase in brain iron stores. However, the increase in SNEI was greater in patients previously defined as severely HE. Furthermore, RLS/WED symptoms also improved more in severely HE subjects, and there was a greater reduction in TDR. This study highlights the role of TCS in quantifying brain iron deposits and in predicting which patients will likely benefit from IV iron., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Sleep is considered an essential part of life and plays a vital role in good health and well-being. Equally important as a balanced diet and adequate exercise, quality and quantity of sleep are essential for maintaining good health and quality of life. Sleep-disordered breathing is one of the most prevalent conditions that compromises the quality and duration of sleep, with obstructive sleep apnea (OSA) being the most prevalent disorder among these conditions. OSA is a chronic and highly prevalent disease that is considered to be a true public health problem. OSA has been associated with increased cardiovascular, neurocognitive, metabolic and overall mortality risks, and its management is a challenge facing the health care system. To establish the main future lines of research in sleep respiratory medicine, the Spanish Sleep Network (SSN) promoted the 1st World Café experts' meeting. The overall vision was established by consensus as "Sleep as promoter of health and the social impact of sleep disturbances". Under this leitmotiv and given that OSA is the most prevalent sleep disorder, five research lines were established to develop a new comprehensive approach for OSA management: (1) an integrated network for the comprehensive management of OSA; (2) the biological impact of OSA on comorbidities with high mortality, namely, cardiovascular and metabolic diseases, neurocognitive diseases and cancer; (3) Big Data Analysis for the identification of OSA phenotypes; (4) personalized medicine in OSA; and (5) OSA in children: current needs and future perspectives., (Copyright © 2019 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway obstruction caused by a loss of upper airway dilator muscle tone during sleep and an inadequate compensatory response by these muscles in the context of an anatomically compromised airway. The genioglossus (GG) is the main upper airway dilator muscle. Currently, continuous positive airway pressure is the first-line treatment for OSA. Nevertheless, problems related to poor adherence have been described in some groups of patients. In recent years, new OSA treatment strategies have been developed to improve GG function. (A) Hypoglossal nerve electrical stimulation leads to significant improvements in objective (apnea-hypopnea index, or AHI) and subjective measurements of OSA severity, but its invasive nature limits its application. (B) A recently introduced combination of drugs administered orally before bedtime reduces AHI and improves the responsiveness of the GG. (C) Finally, myofunctional therapy also decreases AHI, and it might be considered in combination with other treatments. Our objective is to review these therapies in order to advance current understanding of the prospects for alternative OSA treatments.

Obstructive sleep apnoea (OSA) and restless legs syndrome (RLS) are two of the most prevalent sleep disorders and can coexist within the same patient. Nonetheless, the recognition of RLS among OSA patients has important clinical implications, since RLS can disrupt sleep despite adequate treatment of sleep disordered breathing and should be treated accordingly. Furthermore, the presence of OSA can also increase the severity of RLS. Therefore, it is important to be able to correctly identify both disorders and treat them effectively. The present article reviews our current knowledge on this comorbidity and discusses potential treatment options for RLS in the context of OSA., Competing Interests: Conflict of interest: S. Romero-Peralta has nothing to disclose. Conflict of interest: I. Cano-Pumarega has nothing to disclose. Conflict of interest: C. Garcia-Malo has nothing to disclose. Conflict of interest: L. Agudelo Ramos has nothing to disclose. Conflict of interest: D. Garcia-Borreguero reports personal fees from American Regent and grants from Merck, during the conduct of the study., (Copyright ©ERS 2019.)

Objectives: To determine whether long-term treatment with dopaminergic agents (DAs) might dampen the response to a non-dopaminergic agent, such as gabapentin enacarbil., Methods: We performed a two-week randomized, double-blind, crossover, and placebo-controlled study in a single, referral center in dopamine treatment-naive patients and non-augmented patients continuously treated with dopaminergics for the last five consecutive years. Following washout from any previous CNS-active drugs, patients were randomized into one of two groups for two consecutive two-week treatment periods with gabapentin enacarbil (GBPen) and placebo. Treatment was administered at 7 PM at a fixed dose of 600 mg/day. RLS severity was measured weekly using the International RLS Scale (IRLS) and Clinical Global Improvement (CGI). An M-SIT was also performed between 6 pm and midnight at the end of each treatment condition., Results: There were no significant differences between groups in age, sex, duration of disease, ferritin levels, RLS severity at baseline, or existing concomitant conditions. Both groups improved more during treatment with GBPen than during placebo on the IRLS scale, CGI and mSIT. However, improvements were greater in the DA-naïve group than in long-term treatment with DAs group on the IRLS (p < 0.05), CGI (p < 0.01), and mSIT (p < 0.01)., Conclusions: Previous long-term treatment with DAs reduces future response to GBPen in RLS patients. Potential pathiophysiological explanations are discussed. Our finding has strong implications for the initial choice of treatment in RLS and supports the notion that initial treatment should not be started with DAs., Classification of Evidence: The study provides class II evidence supporting reduced effects of gabapentin enacarbil in RLS patients previously exposed to long-term treatment with dopamine agonists., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity of OSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects., Competing Interests: Conflict of interest: C. Cubillos-Zapata has nothing to disclose. Conflict of interest: M.Á. Martínez-García has nothing to disclose. Conflict of interest: F. Campos-Rodríguez has nothing to disclose. Conflict of interest: M. Sánchez de la Torre has nothing to disclose. Conflict of interest: E. Nagore has nothing to disclose. Conflict of interest: A. Martorell-Calatayud has nothing to disclose. Conflict of interest: L. Hernández Blasco has nothing to disclose. Conflict of interest: E. Chiner Vives has nothing to disclose. Conflict of interest: J. Abad-Capa has nothing to disclose. Conflict of interest: J.M. Montserrat has nothing to disclose. Conflict of interest: V. Cabriada-Nuño has nothing to disclose. Conflict of interest: I. Cano-Pumarega has nothing to disclose. Conflict of interest: J. Corral-Peñafiel has nothing to disclose. Conflict of interest: T. Diaz-Cambriles has nothing to disclose. Conflict of interest: O. Mediano has nothing to disclose. Conflict of interest: M. Somoza-González has nothing to disclose. Conflict of interest: J. Dalmau-Arias has nothing to disclose. Conflict of interest: I. Almendros has nothing to disclose. Conflict of interest: R. Farré has nothing to disclose. Conflict of interest: E. López-Collazo has nothing to disclose. Conflict of interest: D. Gozal has nothing to disclose. Conflict of interest: F. García-Río has nothing to disclose., (Copyright ©ERS 2019.)

Two types of drugs have been extensively investigated for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED): dopamine agonists and α2δ ligands to the α2δ subunit of calcium channels. Comparative studies show that both classes of drugs are similarly effective in treating RLS symptoms over the short- and long-term. While dopamine agonists are more effective in treating periodic limb movements (PLMs), α2δ ligands are more effective in consolidating sleep. However, given the fact that dopamine agonists cause high rates of augmentation of symptoms, recent international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand. In fact, the most effective preventive strategy involves not using dopaminergic agents unless absolutely necessary. Indeed, should dopaminergic treatment be needed to handle the symptoms effectively, then it is recommended that the dopaminergic load be reduced by using the lowest effective dose for the shortest possible period of time. However, it must be taken into account that the only α2δ ligand approved for RLS/WED is gabapentin enacarbil, which is not yet available in Europe. Furthermore, recent studies have also reported on the efficacy of opioids as a second-line treatment of RLS/WED, following treatment failure with dopamine agonists. Recent guidelines have taken these new data into account and highlight that a low dose of an opioid (prolonged-release oxycodone or methadone) may be considered in patients with very severe augmentation of symptoms. Alternative non-dopaminergic treatment concepts based on glutamatergic and adenosinergic mechanisms are currently in development, and are likely to provide encouraging therapeutic alternatives., (© 2019 Elsevier Inc. All rights reserved.)

Dopaminergic drugs have been widely used over the last decades for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED). While the majority of studies show an initial improvement in symptoms, longer studies and clinical experience show that either treatment efficacy decreases with time, and/or augmentation develops: dopaminergic augmentation has been reported to be the main reason for treatment discontinuation and treatment failure in RLS/WED. The current review discusses the main reasons for treatment failure in RLS/WED and outlines the most recent expert-based strategies to prevent and manage it. The main strategy for preventing augmentation is to consider non-dopaminergic medications such as α2δ ligands for initial RLS/WED treatment; these effective drugs have been shown to have little risk of augmentation. Alternatively, should dopaminergic drugs be elected as initial treatment, then the daily dose should be kept low and not exceed maximum recommended doses, however, it should be kept in mind that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment should start only when symptoms significantly impact quality of life in terms of frequency and severity; while intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can continue by dividing or advancing the dose, or increasing the dose if there are breakthrough nighttime symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation, the patient can be switched to an α2δ ligand or rotigotine, noting that rotigotine may produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: Recent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A 1 receptors (A1R) in the striatum and cortex. We hypothesized that an increase in extracellular adenosine induced by inhibitors of adenosine transporters, such as the non-selective ENT1/ENT2 inhibitor dipyridamole, would result in an improvement in RLS symptoms., Methods: In a prospective two-month open-label, non-placebo controlled clinical trial, 15 untreated idiopathic RLS patients began treatment with 100 mg dipyridamole (with uptitration to 400 mg if necessary). Multiple Suggested Immobilization Tests and polysomnography were performed at baseline and at eight weeks. Severity was assessed at four and eight weeks using the IRLS, and the CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score)., Results: Thirteen patients completed the study. IRLS score improved from a mean (±S.D.) of 23.4 ± 4.6 at baseline to 10.7 ± 4.5 at eight weeks. Six out of 13 patients were full responders and four were partial responders. The mean (±S.D.) effective dose of dipyridamole at eight weeks was 281.8 ± 57.5 mg/day. Sleep variables also improved, and the mean (±S.D.) periodic leg movement index decreased from 26.7 ± 7.2 to 4.3 ± 1.9. Dipyridamole was generally well tolerated. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing., Conclusions: These preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS., Classification of Evidence: The study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS., (Copyright © 2018. Published by Elsevier B.V.)

Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1α and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea-hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1α were performed, and the percentage of positive cells (0, <25, 25-50, 51-75, >75%) was blindly tabulated for VEGF expression, and as 0, 0-5.9, 6.0-10.0, >10.0% for HIF-1α expression, respectively. Cases with HIF-1α expression >6% (high expression) were compared with those <6%, and VEGF expression >75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1α were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1α was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01-1.06)] and Breslow index [OR 1.28 (95% CI: 1.18-1.46)], but not AHI, remained independently associated with the presence of high HIF-1α expression. Thus, IH emerges as an independent risk factor for higher HIF-1α expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators.

The goal of this study was to assess the relationship between the severity of obstructive sleep apnoea (OSA) and the levels of carcinogenesis- and tumour growth-related biomarkers in patients with cutaneous melanoma.This multicentre observational study included patients who were newly diagnosed with melanoma. The patients were classified as non-OSA (apnoea-hypopnoea index (AHI) 0-5 events·h -1 ), mild OSA (AHI 5-15 events·h -1 ) and moderate-severe OSA (AHI >15 events·h -1 ). ELISAs were performed to analyse the serum levels of hypoxia- and tumour adhesion-related biomarkers (vascular endothelial growth factor (VEGF), interleukin (IL)-8, intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM)-1) and markers of tumour aggressiveness (S100 calcium-binding protein B (S100B) and melanoma inhibitory activity (MIA)). A logistic model adjusted for age, sex and body mass index was fitted to each biomarker, and the AHI served as the dependent variable.360 patients were included (52.2% male, median (interquartile range) age 55.5 (43.8-68.0) years and AHI 8.55 (2.8-19.5) events·h -1 ). The levels of VEGF, IL-8, ICAM-1, S100B and MIA were not related to the severity of OSA. The levels of VCAM-1 were higher in patients with OSA than those without OSA (mild OSA: odds ratio (OR) 2.07, p=0.021; moderate-severe OSA: OR 2.35, p=0.013).In patients with cutaneous melanoma, OSA was associated with elevated circulating levels of VCAM-1 that could indicate the contribution of OSA in tumorigenesis via integrin-based adhesion., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Melanoma is a highly prevalent cancer that is associated with substantial mortality. Although clinical staging procedures can serve as relatively robust prognostic indicators, we aimed to determine whether assessments of the abundance of hypoxia inducible factor-1α (HIF-1α) or vascular endothelial growth factor (VEGF) in postexcisional melanoma tumor tissues may enable more accurate determination of tumor aggressiveness. We carried out a multicenter prospective study, in which we systematically evaluated 376 consecutive patients diagnosed with melanoma, and performed histochemical assessments for both HIF-1α and VEGF immunoreactivity in the tumor biopsies. Multivariate analyses showed that higher HIF-1α expression, but not high VEGF, were associated significantly and independently with increased tumor aggressiveness as derived from several well-established aggressiveness criteria. A limitation of this study was that this was a descriptive prospective study lacking a post-hoc verification arm. Thus, the presence of increased numbers of positively labeled HIF-1α cells in melanoma tumors may potentially serve as an indicator of tumor phenotype and prognosis, and accordingly guide therapy.

Background: Evidence from longitudinal studies has reported contradictory results regarding the association between OSA and hypertension. In a previous analysis of the Vitoria Sleep Cohort, the relationship between OSA and the risk of developing hypertension was evaluated and no independent association after adjustment for confounding factors was found. In the present study, a post hoc analysis to assess the association between OSA and incident stage 2 hypertension (systolic BP ≥ 160 mm Hg and/or diastolic BP ≥ 100 mm Hg) was made on the basis of sex differences., Methods: A prospective study was performed over 7.5 ± 0.8 years on a middle-aged general population, which included 1,155 normotensive subjects (43.7% men) who completed the follow-up. BP measurements (at baseline and follow-up) and polygraphy at baseline were performed. Logistic regression models were used to determine the association between the respiratory disturbance index (RDI) and stage 2 hypertension and a recursive partitioning method was used to determine the variables related to the incidence of stage 2 hypertension. The RDI was divided into subgroups (0-2.9, 3-6.9, 7-13.9, and ≥ 14), using the first subgroup as reference., Results: For men, an RDI ≥ 14 was associated with a significantly increased OR for stage 2 hypertension (OR, 2.54 [95% CI, 1.09-5.95], P = .032). This association was not statistically significant among women (P = .371)., Conclusions: The results suggest an association between moderate and severe OSA, and the incidence of more severe forms of hypertension occurring in men but not in women. However, because this is a community-based study, the women's population characteristics may differ from women usually seen in sleep-disorders clinics., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED) is a neurological condition with an overall prevalence in adults of 5-10% in Europe and North America. It is characterised by strong feelings of restlessness and distressing paraesthesia-like sensations in the lower legs, particularly when at rest. The symptoms vary considerably in severity and frequency. RLS/WED has a variable clinical expression influenced by genetic, environmental, and medical factors. Research into the pathophysiology of RLS/WED has found that various genetic markers and existing dysfunctions in dopaminergic mechanisms and iron mechanisms play a central role. Until recently, the first line treatment of RLS/WED was with low dose dopamine agonists, with three drugs having been approved by the US Food and Drug Administration and the European Medicines Agency. However, the occurrence of dopaminergic augmentation and an overall increase in severity of symptoms during long term treatment with dopamine agonists is leading to a shift towards non-dopaminergic alternatives as initial treatments, and particularly to α 2 δ ligands. Recent international guidelines recommend, whenever possible, to start treatment with these drugs (α 2 δ ligands) to avoid augmentation from the start. Other (eg, glutamatergic or adenosine) neurotransmitters might also play an important role in causing RLS/WED and might thus lead to new treatments., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)