Management of obstructive sleep apnea in Europe – A 10-year follow-up

Funding Information: Sleep medicine has been further established and recognized in the past 10 years. This is also shown by the fact that sleep-related diseases may receive a separate chapter in the new ICD-11 (International Classification of Diseases 11th Revision) [11]. However, the initial expansion in sleep laboratories and sleep centers seems to be over, at least in Europe, which stands in contradiction to the growing need. While sleep medical care still seems to be secured by the established structures, the gap between the increasing need and existing structures is still widening [ 12–14]. There is a lack of sleep medicine specialists, new outpatient structures, and new billing models with the sponsoring institutions. Approaches to solve these problems include the establishment and expansion of home sleep apnea testing (HSAT) [15] and telemedicine-based technologies in the diagnosis and treatment of OSA [16,17]. Telemedicine found its way into sleep medicine around 10 years ago [ 18–20]. One of the very first approaches as early as 1994 used a telephone circuit and a computer-controlled support system to improve OSA treatment by improving lifestyle through tele-guidance on nutrition and exercise [21]. Publisher Copyright: © 2022 The Authors Copyright © 2022 Elsevier B.V. All rights reserved.Objective: In 2010, a questionnaire-based study on obstructive sleep apnea (OSA) management in Europe identified differences regarding reimbursement, sleep specialist qualification, and titration procedures. Now, 10 years later, a follow-up study was conducted as part of the ESADA (European Sleep Apnea Database) network to explore the development of OSA management over time. Methods: The 2010 questionnaire including questions on sleep diagnostic, reimbursement, treatment, and certification was updated with questions on telemedicine and distributed to European Sleep Centers to reflect European OSA management practice. Results: 26 countries (36 sleep centers) participated, representing 20 ESADA and 6 non-ESADA countries. All 21 countries from the 2010 survey participated. In 2010, OSA diagnostic procedures were performed mainly by specialized physicians (86%), whereas now mainly by certified sleep specialists and specialized physicians (69%). Treatment and titration procedures are currently quite homogenous, with a strong trend towards more Autotitrating Positive Airway Pressure treatment (in hospital 73%, at home 62%). From 2010 to 2020, home sleep apnea testing use increased (76%–89%) and polysomnography as sole diagnostic procedure decreased (24%–12%). Availability of a sleep specialist qualification increased (52%–65%) as well as the number of certified polysomnography scorers (certified physicians: 36%–79%; certified technicians: 20%–62%). Telemedicine, not surveyed in 2010, is now in 2020 used in diagnostics (8%), treatment (50%), and follow-up (73%). Conclusion: In the past decade, formal qualification of sleep center personnel increased, OSA diagnostic and treatment procedures shifted towards a more automatic approach, and telemedicine became more prominent.Peer reviewe

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Protection and reliability : an examination of the quality and quantity of ant protection in the food-for- protection mutualism between Ferocactus viridescens, Crematogaster californica and the invasive Linepithema humile

In this study we investigate the effects of the invasive Argentine ant (Linepithema humile) on the food-for- protection mutualism between native ant species and the San Diego Barrel Cactus (Ferocactus viridescens). Mutualistic interactions may be disrupted by non-native species with possible detrimental effects for one or both partners. In the presence of L. humile, plant protection may be enhanced in the short term as a consequence of the Argentine ant's aggressive nature, yet may be compromised by pollinator harassment and abandonment of the cactus. Consequently, in the long term, this invasion may decrease the fitness of cacti by shifting the net effects of the interaction from a mutualism to one that is detrimental. To quantify ant protection, we used an established surrogate herbivore assay to compare protective services offered by Argentine ants with those offered by a common native ant C. californica. Our results support the existence of a mutualism between ants and F. viridescens. Ant presence discouraged leaf-footed bugs, the most commonly observed herbivores, from feeding on plant reproductive structures. Herbivory reduced mass per individual seed and seed mass per plant. This study adds to a growing body of work concerning the variation found in mutualistic interactions, allows for predictive measures of plant benefits with respect to partner identity, and examines how these interactions are affected by a behaviorally dominant and aggressive invasive ant. Furthermore, it explores the consequences of reduced ant richness, and the impacts that result from the loss of functional redundancy in the F. viridescens food-for- protection mutualis

MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients

MAP3K19 siRNA inhibits cigarette smoke-induced pulmonary inflammation.

<p>The acute model of cigarette smoke exposure subjected mice to cigarette smoke (7 cigarettes over a 1.75 hour period) on days 1 & 2, and dosed with either PBS, non-sense siRNA (100 μg in 50 μl volume), MAP3K19 siRNA or the CXCR-2 antagonist SB 265610 (10 mg/kg, p.o.) on days 1, 2 & 3 (n = 5 mice per treatment group). The inflammatory response was quantitated by performing bronchoalveolar lavage on day 4, counting the total number cells in the BAL, and enumerating the different cell types by morphological features. (A) MAP3K19 siRNA reduced the neutrophil influx compared to vehicle or non-sense siRNA treated mice. (B) ELISA analysis of the BAL fluid showed a significant decrease in KC, the murine homologue of CXCL-8, in MAP3K19 siRNA treated animals. This experiment was repeated three times and the average of 2 representative experiments is shown. (C & D) Mice treated with MAP3K19 siRNA had decreased pulmonary inflammation in a subchronic cigarette smoke exposure model. Mice (5 per cohort) were exposed to cigarette smoke on days 1, 2, 5–9, and 12–14, and dosed with PBS, non-sense siRNA or MAP3K19 siRNA on days 6–14. The mice were examined for pulmonary inflammation of day 15, and the percent of neutrophils in the BAL fluid was calculated (C), and the BAL fluid KC levels were determined by ELISA. This experiment was repeated two independent times with similar results, and a representative experiment is shown. In both experiments, the numbers shown are the mean ± SEM. Statistical differences between groups was determined by ANOVA analysis followed by the Tukey-Kramer pair-wise tests, and P<0.05 was considered significant. In both the acute and subchronic experiments, a cohort of mice were exposed to air instead of cigarette smoke, and treated with PBS delivered i.t., as a control.</p

Transfection of HEK293 cells with MAP3K19 or treatment with H₂O₂ induces production of CXCL-8, CCL-20 and CCL-7 via a MAP3K19-dependent mechanism.

<p>(A) HEK293 cells were transiently transfected with 5 μg of either MAP3K19, a kinase inactive version of MAP3K19 containing a K1089R mutation, an empty vector or mock transfected. After 24 hours, the supernatants were assayed by ELISA for CXCXL-8, CCL-7 and CCL-20. The results shown are the mean of triplicates ± SEM. A representative experiment is shown, and the CXCL-8 was repeated over 20 independent times, CCL-7 and CCL-20 experiments were repeated a minimum of three times. Similar results were observed with HeLa, A549, THP-1, U937 and NIH3T3 cells. (B) HEK293 cells were transfected with empty vector or 5 μg of MAP3K19 in the absence or presence of 5 nM non-sense siRNA or MAP3K19 siRNA. The supernatants were assayed for CXCL-8 production by ELISA after 24 hours. A representative of three independent experiments is shown, and the results depict the mean of triplicate samples ± SEM. (C) HEK293 or NIH3T3 cells were transfected with 5 nM of human or mouse anti-MAP3K19 siRNA or non-sense siRNA, or mock transfected. After 18 hours, the cells were treated with 500 μM H₂O₂ for an additional 24 hours. At that point, the supernatants were assayed for CXCL-8 production (HEK293 cells) or KC production (NIH3T3 cells) by ELISA. The results of triplicate samples are shown as the mean ± SEM. The statistical significance was determined by ANOVA analysis followed by Tukey-Kramer pair-wise tests. Each arm of this experiment was repeated a minimum of two independent times, and a representative experiment is shown.</p

MAP3K19 inhibition blocks pulmonary neutrophilia and reduces viral load in an acute viral exacerbation model of COPD.

<p>Mice were orally dosed with either vehicle, dexamethasone (1 mg/kg), Compound C (10 mg/kg) on days 1–8 of the study. The mice were exposed to cigarette smoke (3 x 45 minute exposures per day) on days 2–5, and inoculated with 10^4.5 pfu of influenza A virus via transnasal administration on day 6. On day 9, bronchoalveolar lavage was performed and the total number of neutrophils in the BAL fluid was enumerated (A). The lung tissue was isolated and the amount of infective virus in the lungs was quantitated (B). The viral titer was expressed as PFU/g of lung tissue. The number of mice in each cohort was as follows: (1) control mice, treated with sham + diluent + vehicle (n = 5); (2) smoke control mice received smoke + diluent + vehicle (n = 5); (3) flu control mice were treated with sham + flu + vehicle (n = 5); (4) smoke + flu + vehicle (n = 8); (5) smoke + flu + Compound C (n = 8); and (6) smoke + flu + dexamethasone (n = 8). ND–not detected. Statistically significant differences between groups was determined by ANOVA analysis followed by Boniferroni’s post-test as detailed in the Materials and Methods.</p

Histological analysis shows that cigarette smoke-induced airspace enlargement is abrogated by MAP3K19 inhibitors.

<p>Lung sections from mice that underwent the chronic cigarette smoke exposure model were stained with a rabbit polyclonal anti-MAP3K19 antibody, RabK19, which is shown in brown. No statistical difference was observed in the MAP3K19 staining between the different cohorts. In the animals exposed to cigarette smoke, lymphoid follicles are clearly visible, and most of the cells composing the follicles express MAP3K19. The sections were counterstained with hematoxylin.</p

MAP3K19 is induced by the environmental stressors cigarette smoke extract, osmotic stress and oxidative stress.

<p>Freshly isolated CD14⁺ peripheral blood monocytes, A549 and Beas-2B pulmonary epithelial cell lines were incubated with 10% cigarette smoke extract, 95 mM KCl, 1 mM H₂O₂, 1 μM thapsigargin, 1 ng/ml TGF-β1, 1 ug/ml Poly I:C and 1 ug/ml LPS for 12 twelve hours. RNA was harvested, and the level of MAP3K19 mRNA expression was measured by RT-qPCR. All samples were normalized to GAPDH, and the results are expressed as fold change relative to the untreated (No Tx, denoted by the dotted line) sample. The RT-qPCR was run in duplicate, and the mean ± SEM are shown. This experiment was repeated two independent times and a representative experiment is shown. Similar results were obtained when either β-actin or 18s ribosomal RNA genes were used as reference genes. Cell viability, as determined by an XTT assay, was not affected by the different noxious stimuli over the course of the 12 hour experiment. THP-1 and U937 cells also yielded similar results to those shown for A549, Beas-2B and CD14⁺ peripheral blood monocytes. Statistical significance was determined by ANOVA analysis followed by Tukey-Kramer pair-wise tests and P<0.05 was considered significant.</p