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Objective Obstructive sleep apnea (OSA) syndrome is one of the most frequent chronic diseases in the general population. The nocturnal rostral fluid shift is accepted as a key mechanism in OSA pathogenesis in medical conditions associated with fluid overload. The main objective of this study was to assess the prevalence of OSA in patients with lymphedema. Methods A prospective study was conducted in patients with lymphedema hospitalized for complete decongestive therapy between December 2016 and November 2017. A nocturnal respiratory polygraphy, an Epworth sleepiness scale, and lymphedema volume measurements were performed on the first day of decongestive therapy. OSA was diagnosed in patients with an apnea-hypopnea index of five or more events per hour and patients who had been previously diagnosed with OSA and treated by continuous positive airway pressure were identified. Results Forty-three patients completed the study. The prevalence of OSA was 74% and was higher for patients with lymphedema of the lower limbs (85%) vs upper limbs (56%). OSA severity was correlated with a marker of lower limb lymphedema severity (P = .012). The body mass index was higher than in patients with OSA than patients without OSA (median, 31.0 kg/m2 [25th; 75th percentiles, 25.3; 37.0 kg/m2] vs median, 24.2 kg/m2 [25th; 75th percentiles, 22.7; 26.7 kg/m2]; P Conclusions Patients with lymphedema presenting for complete decongestive therapy present a high prevalence rate of OSA, particularly in those with lower limb lymphedema. OSA severity was correlated with a marker of lower limb lymphedema severity. These results suggest that overweight and obese patients with lymphedema should be screened systematically for OSA.

Background The management of patients with high cardiovascular risk and OSA must target not only improving adherence to CPAP, but should also include strategies aimed at reducing BP and increasing physical activity. The study aims to evaluate the effectiveness of an integrated intervention using remote patient telemonitoring in reducing BP in high cardiovascular risk patients with OSA. Methods In a multicenter, open, randomized trial, patients with OSA were randomly assigned at CPAP initiation to usual care or multimodal telemonitoring for 6 months. Telemonitoring used electronic equipment collecting information about BP, symptoms, CPAP side effects, and physical activity with home care providers prespecified protocoled actions. The primary effectiveness outcome was assessed using home self-measured BP on 3 consecutive days. Secondary outcomes included CPAP compliance, symptoms, and physical activity. Results Of 306 patients with a median age of 61.3 years [interquartile range, 54.1; 66.1], who were predominantly men, 226 (74%) with a BMI of 32.0 [28.7; 35.6] kg/m2 and an apnea-hypopnea index of 46 [35; 61] events/h, 149 received usual care and 157 received telemonitoring. After 6 months of CPAP, home self-measured BP did not differ significantly between groups. In secondary analyses, there was no significant difference in steps per day, but a significant increase in CPAP adherence and an improvement in daytime sleepiness and quality of life in favor of the multimodal telemonitoring. Conclusions In OSA patients with high cardiovascular risk, multimodal telemonitoring was not superior to usual CPAP care for improving home BP; however, telemonitoring improved adherence and patient-centered outcomes.

To determine the effect of continuous positive airway pressure (CPAP), the gold standard treatment for obstructive sleep apnea syndrome (OSAS), on gait control in severe OSAS patients. We conducted a randomized, double-blind, parallel-group, sham-controlled monocentric study in Grenoble Alpes University Hospital, France. Gait parameters were recorded under single and dual-task conditions using a visuo-verbal cognitive task (Stroop test), before and after the 8-week intervention period. Stride-time variability, a marker of gait control, was the primary study endpoint. Changes in the determinants of gait control were the main secondary outcomes. ClinicalTrials.gov Identifier: (NCT02345694). 24 patients [median (Q1; Q3)]: age: 59.5 (46.3; 66.8) years, 87.5% male, body mass index: 28.2 (24.7; 29.8) kg. m−2, apnea–hypopnea index: 51.6 (35.0; 61.4) events/h were randomized to be treated by effective CPAP (n = 12) or by sham-CPAP (n = 12). A complete case analysis was performed, using a mixed linear regression model. CPAP elicited no significant improvement in stride-time variability compared to sham-CPAP. No difference was found regarding the determinants of gait control. This study is the first RCT to investigate the effects of CPAP on gait control. Eight weeks of CPAP treatment did not improve gait control in severe non-obese OSAS patients. These results substantiate the complex OSAS-neurocognitive function relationship.

Background One of the major challenges in treating OSA is to achieve adequate CPAP adherence. Telemonitoring has the potential to provide individualized management and early recognition of problems during treatment. Research Question What is the effect of a multimodal telemonitoring intervention on treatment adherence, quality of life, and functional status in symptomatic patients with OSA and low cardiovascular risk? Study Design and Methods In a multicenter, randomized controlled trial, patients newly diagnosed with OSA were randomly assigned to multimodal telemonitoring for 6 months vs usual care (UC). Telemonitoring consisted of built-in electronic alert algorithms for early adjustment of CPAP treatment in case of side effects, leaks, or persistent residual events. The primary outcome was CPAP adherence (in hours per night). Secondary outcomes included daily symptoms such as fatigue and sleepiness, and quality of life measured by using self-reported questionnaires. Results A total of 206 patients with OSA and a median age of 50.6 years (interquartile range [IQR], 42.1; 58.1 years) were included in the study; they were predominantly male (63%) with a median BMI of 30.6 kg/m2 (IQR, 26.8; 35.1 kg/m2) and a median apnea-hypopnea index of 45.2 events/h (IQR, 34.0; 60.0 events/h). Of these, 102 received UC and 104 received telemonitoring. After 6 months of treatment, CPAP adherence was similar in the two groups when assessed either by mean duration of usage (4.73 ± 2.48 h per night in the telemonitoring group and 5.08 ± 2.44 h per night in the UC group; P = .30) or in percentage of patients adherent to treatment (> 4 h usage per night, > 70% nights; 64% in the telemonitoring group vs 72% in the UC group; P = .24). There was no significant difference between the groups in effect size of improvement in fatigue and sleepiness. Interpretation In patients with severe OSA and low cardiovascular risk, multimodal telemonitoring did not increase CPAP adherence. For both the telemonitoring and UC groups, similar improvements in daytime symptoms were achieved. Trial Registry ClinicalTrials.gov; No.: 01796769; URL: www.clinicaltrials.gov

Background: One of the major challenges in treating obstructive sleep apnea (OSA) is to achieve adequate continuous positive airway pressure (CPAP) adherence. We determined the effect of a multimodal telemonitoring intervention on CPAP adherence, quality of life and functional status in symptomatic OSA patients with low cardiovascular risk. Study Design and Methods: In a multicenter, randomized controlled trial, newly diagnosed OSA patients were randomly assigned to multimodal telemonitoring(TM) for 6 months vs usual care (UC). TMconsisted ofbuilt-in electronic alert algorithms for early adjustment of CPAP treatment in case of side effects, leaks or persistent residual events.The outcomesincluded CPAP adherence, daily symptoms such as fatigue and sleepiness, and quality of life. Results: Of 206 OSA patients aged 50.6 [42.1;58.1] (median [IQR]) years;predominantly male (63%) with body mass index of 30.6 [26.8;35.1] kg/m2and an AHI of 45.2 [34.0;60.0] events/hour) 102 received UC and 104 TM. After 6 months of treatment, CPAPadherence was similar in the two groups when assessed either by mean duration of usage (4.73±2.48 hours/night in the TM group and 5.08±2.44 hours/night in the UC group, p=0.30) or in % of patients adherent to treatment (over 4 hours usage/night, > 70% nights; 64% in TM vs 72% in UC, p=0.24). There was no significant difference between the groups in effect size of improvement in fatigue and sleepiness. Interpretation: In severe OSA patients with low cardiovascular risk, multimodal telemonitoring did not increase CPAP adherence. For both TM and UC groups similar improvements in daytime symptoms were achieved.

BackgroundMore advanced knowledge is needed on how COPD alters the clinical presentation of obstructive sleep apnea (OSA) and how the association of both diseases, known as 'overlap syndrome' (OVS), impacts on cardiovascular health.ObjectiveTo investigate differences between patients with OVS and those with moderate-to-severe OSA alone.MethodsA cross-sectional study conducted in the French National Sleep Apnea Registry between January 1997 and January 2017. Univariable and multivariable logistic regression models were used to compare OVS versus OSA alone on symptoms and cardiovascular health.Results46,786 patients had moderate-to-severe OSA. Valid spirometry was available for 16,466 patients: 14,368 (87%) had moderate-to-severe OSA alone and 2098 (13%) had OVS. A lower proportion of OVS patients complained of snoring, morning headaches and excessive daytime sleepiness compared to OSA alone (median Epworth Sleepiness Scale score: 9 [interquartile range (IQR) 6-13] versus 10 (IQR 6-13), respectively; P ConclusionsIn adults with moderate-to-severe OSA, OVS was minimally symptomatic, but exhibited higher odds for prevalent coronary heart disease, heart failure and peripheral arteriopathy.

Rationale Chronic intermittent hypoxia occurring in obstructive sleep apnea (OSA) is independently associated with nonalcoholic fatty liver disease (NAFLD). Chronic obstructive pulmonary disease (COPD) has also been suggested to be linked with liver disease. Objective In this individual participant data meta-analysis, we investigated the association between liver damage and OSA and COPD severity. Methods and measurements Patients suspected of OSA underwent polysomnography (PSG) or home sleep apnea testing (HSAT). Non-invasive tests were used to evaluate liver steatosis (Hepatic Steatosis Index) and fibrosis (Fibrotest or FibroMeter). An individual participant data meta-analysis approach was used to determine if the severity of OSA/COPD affects the type and severity of liver disease. Results were confirmed by multivariate and causal mediation analysis. Sub-group analyses were performed to investigate specific populations. Main results Among 2120 patients, 1584 had steatosis (75%). In multivariable analysis, risk factors for steatosis were an apnea-hypopnea index (AHI) > 5/h, body mass index (BMI) > 26 kg/m2, age, type 2 diabetes (all p-values 26 kg/m2, age, male gender, and type 2 diabetes (all p-values 30/h and COPD stage 1 was associated with an increased risk of steatosis. Conclusion This meta-analysis confirms the strong association between steatosis and the severity of OSA. The relation between OSA and fibrosis is mainly due to BMI as shown by causal mediation analysis.

Background: Very few studies have examined the association between long-term outdoor air pollution and rhinitis severity in adults. Objective: We sought to assess the cross-sectional association between individual long-term exposure to air pollution and severity of rhinitis. Methods: Participants with rhinitis from 2 multicenter European cohorts (Epidemiological Study on the Genetics and Environment on Asthma and the European Community Respiratory Health Survey) were included. Annual exposure to NO2, PM10, PM2.5, and PMcoarse (calculated by subtracting PM2.5 from PM10) was estimated using land-use regression models derived from the European Study of Cohorts for Air Pollution Effects project, at the participants' residential address. The score of rhinitis severity (range, 0-12), based on intensity of disturbance due to symptoms reported by questionnaire, was categorized into low (reference), mild, moderate, and high severity. Polytomous logistic regression models with a random intercept for city were used. Results: A total of 1408 adults with rhinitis (mean age, 52 years; 46% men, 81% from the European Community Respiratory Health Survey) were included. The median (1st quartile-3rd quartile) score of rhinitis severity was 4 (2-6). Higher exposure to PM10 was associated with higher rhinitis severity (adjusted odds ratio [95% CI] for a 10 μg/m3 increase in PM10: for mild: 1.20 [0.88-1.64], moderate: 1.53 [1.07-2.19], and high severity: 1.72 [1.23-2.41]). Similar results were found for PM2.5. Higher exposure to NO2 was associated with an increased severity of rhinitis, with similar adjusted odds ratios whatever the level of severity. Adjusted odds ratios were higher among participants without allergic sensitization than among those with, but interaction was found only for NO2. CONCLUSIONS: People with rhinitis who live in areas with higher levels of pollution are more likely to report more severe nasal symptoms. Further work is required to elucidate the mechanisms of this association. The following bodies funded the local studies in ECRHS III in this article: Belgium: Antwerp South, Antwerp City: Research Foundation Flanders (FWO), grant code G.0.410.08.N.10 (both sites); France: Ministère de la Santé , Programme Hospitalier de Recherche Clinique (PHRC) national 2010; Germany: Erfurt: German Research Foundation ( HE 3294/10-1 ); Spain: Fondo de Investigación Sanitaria ( PS09/02457 , PS09/00716 09/01511 , PS09/02185 , and PS09/03190 ), Servicio Andaluz de Salud, Sociedad Española de Neumología y Cirurgía Torácica ( SEPAR 1001/2010 ); Barcelona: Fondo de Investigación Sanitaria ( FIS PS09/00716 ); Galdakao: Fondo de Investigación Sanitaria ( FIS 09/01511 ); Huelva: Fondo de Investigación Sanitaria ( FIS PS09/02185 ) and Servicio Andaluz de Salud ; Oviedo: Fondo de Investigación Sanitaria ( FIS PS09/03190 ); United Kingdom: Medical Research Council (grant no. 92091 ). The Epidemiological Study on the Genetics and Environment on Asthma is funded in part by PHRC-Paris, PHRC-Grenoble, ANR 05-SEST-020-02/05-9-97, ANR-06-CEBS, ANR-CES-2009, Région Nord Pas-de-Calais, and Merck Sharp & Dohme. European Study of Cohorts for Air Pollution Effects Funding: The research leading to these results has received funding from the European Community’s Seventh Framework Program ( FP7/2007-2011 ; under grant agreement no. 211250 )

ObjectiveExposure to cigarette smoking during pregnancy has been robustly associated with cord blood DNA methylation. However, little is known about such effects on the placenta; in particular, whether cigarette smoking before pregnancy could also induce epigenetic alterations in the placenta of former smokers is unknown.Design and resultsPlacental DNA methylation levels were measured in 568 women and compared among non-smokers and women either smoking during their pregnancy or who had ceased smoking before pregnancy. An Epigenome Wide Association Study identified 344 Differentially Methylated Regions (DMRs) significantly associated with maternal smoking status. Among these 344 DMRs, 262 showed “reversible” alterations of DNA methylation, only present in the placenta of current smokers, whereas 44 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. This observation was further supported by a significant demethylation of LINE-1 sequences in the placentas of both current (−0.43 (−0.83 to −0.02)) and former smokers (−0.55 (−1.02 to −0.08)) compared to nonsmokers. A comparative analysis of the epigenome landscape based on the ENCODE placenta data demonstrated an enrichment of all 344 DMRs in enhancers histone marks. Additionally, smoking-associated DMRs were found near and/or overlapping with 13 imprinting gene clusters encompassing 18 imprinted genes.ConclusionsDNA methylation patterns alterations were found in 344 genomic regions in the placenta of women smoking during their pregnancy, including 44 DMRs and LINE-1 elements, where methylation changes persisted in former smokers, supporting the hypothesis of an “epigenetic memory” of exposure to cigarette smoking before pregnancy. Enhancers regions, including imprinting control regions were also particularly affected by placenta methylation changes associated to smoking, suggesting a biological basis for the sensitivity of these regions to tobacco exposure and mechanisms by which fetal development could be impacted.

One of the major challenges in treating OSA is to achieve adequate CPAP adherence. Telemonitoring has the potential to provide individualized management and early recognition of problems during treatment.What is the effect of a multimodal telemonitoring intervention on treatment adherence, quality of life, and functional status in symptomatic patients with OSA and low cardiovascular risk?In a multicenter, randomized controlled trial, patients newly diagnosed with OSA were randomly assigned to multimodal telemonitoring for 6 months vs usual care (UC). Telemonitoring consisted of built-in electronic alert algorithms for early adjustment of CPAP treatment in case of side effects, leaks, or persistent residual events. The primary outcome was CPAP adherence (in hours per night). Secondary outcomes included daily symptoms such as fatigue and sleepiness, and quality of life measured by using self-reported questionnaires.A total of 206 patients with OSA and a median age of 50.6 years (interquartile range [IQR], 42.1; 58.1 years) were included in the study; they were predominantly male (63%) with a median BMI of 30.6 kg/mIn patients with severe OSA and low cardiovascular risk, multimodal telemonitoring did not increase CPAP adherence. For both the telemonitoring and UC groups, similar improvements in daytime symptoms were achieved.ClinicalTrials.gov; No.: 01796769; URL: www.clinicaltrials.gov.

Introduction & background: Chronic intermittent hypoxia in obstructive sleep apnea (OSA) is associated with Nonalcoholic fatty liver disease (NAFLD). Aims & objectives: In this meta-analysis, we investigate the association between liver injuries, OSA and/or COPD indices of severity. Methods: Patients referred for OSA underwent a polysomnography or overnight respiratory polygraphy. Non-invasive tests were used to evaluate liver steatosis and fibrosis. An individual participant data meta-analysis approach was performed with subgroup analyses to determine if there are some differences between patient subgroups according to OSA or COPD severity. Results: Among 2,402 patients, 1,813 had steatosis (HSI>36). In multivariate analysis, risk factors for steatosis were apnea-hypopnea index (AHI)>30/h (OR: 6.93 [4.92;9.76]), hypertension (OR: 2.37 [1.87;3.01]) and type 2 diabetes (OR: 5.36 [3.32;8.64]). Concerning fibrosis, data were available for 2,526 patients. Among them, 517 patients exhibited liver fibrosis, including 330 (29%) in severe OSA. Risk factors associated with fibrosis were AHI>30/h (OR: 2.38 [1.44; 3.96]), age, male gender (OR: 2.92 [2.22; 3.84], hypertension (OR: 1.53 [1.19; 1.97]) and type 2 diabetes (OR: 4.64 [3.45; 6.24]). Conclusions: This meta-analysis confirms the strong association between OSA and liver diseases and the impact of COPD. Liver diseases should now be included in the list of comorbidities of both COPD and OSA.

BackgroundObstructive sleep apnea (OSA) is associated with cardiovascular co-morbidities and mortality. Arterial stiffness is an independent predictor of cardiovascular risk and mortality, and is influenced by the presence of OSA and related comorbidities. There is a paucity of data regarding long-term evolution of arterial stiffness in CPAP-treated OSA patients. We aimed to prospectively study long term PWV variations and determinants of PWV deterioration.MethodsIn a prospective obese OSA cohort, at time of diagnosis and after several years of follow-up we collected arterial stiffness measured by carotid-femoral pulse wave velocity (PWV), clinical and metabolic parameters, and CPAP adherence. Univariate and multivariate analyses were performed in order to determine contributing factors.ResultsSeventy two OSA patients (men: 52.8%, median age: 55.8 years and median BMI of 38.5 kg/m2) with a prevalence of hypertension: 58.3%, type 2 diabetes: 20.8%, hypercholesterolemia: 33.3%, current or past smoking: 59.7%, were evaluated after a median follow-up of 7.4 [5.8; 8.3] years. Over the period of follow-up, the median increase in PWV was 1.34 [0.10; 2.37] m/s. In multivariate analysis, the increase in PWV was associated with older age (10 extra years was associated with a 5.24 [1.35; 9.12] % increase in PWV) and hypertension (a significant increase in PWV of 8.24 [1.02; 15.57] %). No impact of CPAP adherence on PWV evolution was found.ConclusionPWV progression in CPAP-treated OSA patients is mainly related to pre-existing cardio-metabolic comorbidities and not influenced by CPAP adherence. In this high cardiovascular risk population, it is crucial to associated weight management and exercise with CPAP treatment.

Introduction Des donnees issues de la recherche fondamentale et clinique suggerent que le syndrome d’apnees hypopnees du sommeil (SAHOS) et la bronchopneumopathie chronique obstructive (BCPO) seraient associes au developpement de la maladie steatosique hepatique non alcoolique (non-alcoolic fatty liver disease [NAFLD]). Nous avons voulu etudier les liens entre ces deux maladies respiratoires et les marqueurs non-invasifs de la NAFLD en realisant une meta-analyse a partir de donnees individuelles issues de plusieurs cohortes cliniques. Methodes Les patients suivis pour une BPCO, d’une part, et les patients enregistres par polygraphie ventilatoire ou polysomnographie pour une suspicion clinique de SAHOS, d’autre part, ont ete inclus dans l’etude. Une ponction veineuse permettait d’effectuer le bilan metabolique et hepatique necessaire pour le calcul des tests non-invasifs de steatose hepatique (Hepatic Steatosis Index) et de fibrose (Fibrotest ou FibroMetre). Une meta-analyse a partir des donnees individuelles a ete realisee pour etudier si la presence et/ou la severite du SAHOS et/ou de la BPCO etaient associees a la presence et la severite de la NAFLD dans ces differentes composantes (steatose et fibrose). Resultats Parmi les 2120 patients analyses, 1584 presentaient une steatose (75 %). En analyse multivariee, les facteurs de risque de steatose etaient un index d’apnee-hypopnee (IAH) > 5/h, un indice de masse corporelle (IMC)> 26 kg/m2, l’âge, le diabete de type 2 (p 26 kg/m2, l’âge, le sexe masculin et le diabete de type 2 (p Conclusion Cette meta-analyse retrouve une association independante entre la steatose hepatique et la presence d’un SAHOS. Il existe une association entre le SAHOS et la fibrose hepatique mais celle-ci est principalement en rapport avec l’obesite des patients. Il n’existe pas de liens independants entre la NAFLD et la BPCO.

Chronic Obstructive Pulmonary Disease (COPD) and Non-Alcoholic Fatty Liver Disease (NAFLD) both independently increase cardiovascular risk. We hypothesized that NAFLD might increase the incidence of cardiovascular disease and death in COPD patients. The relationship between NAFLD, incident cardiovascular events, and death was assessed in a prospective cohort of COPD patients with 5-year follow-up. Noninvasive algorithms combining biological parameters (FibroMax®) were used to evaluate steatosis, non-alcoholic steatohepatitis (NASH) and liver fibrosis. Univariate and multivariate Cox regression models were used to assess the hazard for composite outcome at the endpoint (death or cardiovascular event) for each liver pathology. In 111 COPD patients, 75% exhibited liver damage with a prevalence of steatosis, NASH and fibrosis of 41%, 37% and 61%, respectively. During 5-year follow-up, 31 experienced at least one cardiovascular event and 7 died. In univariate analysis, patients with liver fibrosis had more cardiovascular events and higher mortality (Hazard ratio [95% CI]: 2.75 [1.26; 6.03]) than those with no fibrosis; this remained significant in multivariate analysis (Hazard ratio [95% CI]: 2.94 [1.18; 7.33]). We also found that steatosis and NASH were not associated with increased cardiovascular events or mortality. To conclude, early assessment of liver damage might participate to improve cardiovascular outcomes in COPD patients.

The management of patients with high cardiovascular risk and OSA must target not only improving adherence to CPAP, but should also include strategies aimed at reducing BP and increasing physical activity. The study aims to evaluate the effectiveness of an integrated intervention using remote patient telemonitoring in reducing BP in high cardiovascular risk patients with OSA.In a multicenter, open, randomized trial, patients with OSA were randomly assigned at CPAP initiation to usual care or multimodal telemonitoring for 6 months. Telemonitoring used electronic equipment collecting information about BP, symptoms, CPAP side effects, and physical activity with home care providers prespecified protocoled actions. The primary effectiveness outcome was assessed using home self-measured BP on 3 consecutive days. Secondary outcomes included CPAP compliance, symptoms, and physical activity.Of 306 patients with a median age of 61.3 years [interquartile range, 54.1; 66.1], who were predominantly men, 226 (74%) with a BMI of 32.0 [28.7; 35.6] kg/mIn OSA patients with high cardiovascular risk, multimodal telemonitoring was not superior to usual CPAP care for improving home BP; however, telemonitoring improved adherence and patient-centered outcomes.

Objectif L’hypoxie intermittente chronique associee au syndrome d’apnees obstructives du sommeil (SAOS) a ete decrite chez l’animal et chez l’homme comme pouvant favoriser la progression de la steatopathie metabolique (steatose, NASH, fibrose). Methodes Etablir un lien entre la severite du SAOS, de la steatose (score HSI) et de la fibrose (Fibrotest ou FibroMeter) hepatique en realisant une meta-analyse sur donnees individuelles avec ajustement des facteurs confondants a partir des donnees de 9 centres en France. Resultats Concernant la steatose, 2402 patients ont ete analyses, âge median : 60 [50 ; 68] ans, IAH : 28 [13 ; 44]/h, IMC : 29,7 [26,2 ; 34,4] kg/m2, HSI : 41 [36 ; 48]. Parmi ceux-ci, 1813 presentent une steatose. En analyse multivariee, les facteurs associes a une augmentation du risque d’avoir une steatose sont l’IAH > 30/h (OR : 6,93 [4,92 ; 9,76]), l’hypertension arterielle (HTA, OR : 2,37 [1,87 ; 3,01]) et le diabete de type 2 (DT2, OR : 5,36 [3,32 ; 8,64]). Concernant la fibrose, 2526 patients ont ete analyses, âge : 60 [50 ; 68] ans, IAH : 28 [13 ; 44]/h, IMC : 29,7 [26,1 ; 34,3] kg/m2 et 517 sont atteints de fibrose. Les facteurs associes a une fibrose sont l’IAH > 30/h (OR : 2,38 [1,44 ; 3,96]), l’âge, le sexe (2,92 [2,22 ; 3,84] pour les hommes), l’HTA (OR : 1,53 [1,19 ; 1,97]) et le DT2 (OR : 4,64 [3,45 ; 6,24]). Conclusion Le SAOS est une maladie multi-systemique associee au developpement de lesions hepatiques. Il est necessaire de considerer ce risque eleve de lesions hepatiques chez les patients SAOS.

Background: OSA management must target not only increasing adherence to continuous positive airway pressure (CPAP) but should also include strategies aimed at reducing blood pressure and increasing physical activity. Objective: To evaluate the effectiveness of an integrated intervention using remote patient monitoring (telemonitoring) in reducing arterial blood pressure (BP) in high cardiovascular risk OSA patients. Methods: In a multicenter, open, randomized trial, OSA patients were randomly assigned at time of CPAP initiation to usual care vs multimodal telemonitoring for 6 months. Telemonitoring used electronic equipment that collected information about BP, symptoms, CPAP side effects, oximetry and steps per day. Home care providers conducted telemonitoring reviews and protocolized actions. The primary effectiveness outcome was assessed using home self-measured BP (HBP) (3 consecutive days, 10 to 18 measurements). Secondary outcomes included CPAP compliance, symptoms and steps per day. Results: Of 306 patients (mean age 60 [SD, 9.5] years; 227 [74 %] men; mean BMI 33 [SD, 6.3] kg/m2; mean AHI 50/hour [SD, 20]), 149 received usual care and 157 telemonitoring. The intervention and usual care groups did not differ significantly in 6 months home self-measured BP. In secondary analyses, there were no significant differences in steps per day or symptoms, but there was a significant difference in CPAP compliance in favor of the telemonitoring arm (-0.53 hour (95% CI: -1.05; 0.00), p=0.05). Conclusion: In OSA patients with high cardiovascular risk, multimodal telemonitoring did not improve HBP but increase CPAP adherence.

Introduction: Arterial stiffness measured by carotid-femoral pulse wave velocity (PWV) is elevated in severe OSA. A 1m/s increase in PWV is associated with a 15% increased risk of mortality. There is a paucity of data regarding long term evolution of PWV in CPAP-treated OSA. Aims: To measure PWV evolution in CPAP-treated OSA. Methods: In a prospective obese OSA cohort, we collected PWV, clinical and biological metabolic data, incident cardiovascular events and CPAP adherence at time of diagnosis and after at least 5-year follow-up. Results: 72 OSA (men: 52.8%, median age: 55.8 years and median BMI of 38.5 kg/m2) with a high prevalence of hypertension: 58.3%, Type 2 diabetes: 20.8%, hypercholesterolemia: 33.3%, current and past smoking: 59.7%, were evaluated after a median follow-up of 7.4 [5.8; 8.3] years. The mean increase in PWV was 1.5 (SD: 2.2) m/s. OSA patients with an elevation of PWV ≥2m/s (n=27; 37.5%) exhibited a significantly higher prevalence of diabetes (p = 0.04), and COPD (p = 0.004) and a greater amount of nocturnal hypoxia (time spent with SaO2 Conclusions: The rate of increase in PWV in CPAP-treated OSA is high and mainly related to pre-existing cardio-metabolic comorbidities. Adherence to CPAP does not influence the increase in PWV. In this population at high cardiovascular risk, combining therapeutic modalities by including weight loss and physical activity is crucial beyond CPAP treatment.

the EDEN Mother–Child Cohort Study Group; International audience; Background: Phenols and phthalates may have immunomodulatory and proinflammatory effects and thereby adversely affect respiratory health.Objective: We estimated the associations between gestational exposure to select phthalates and phenols and respiratory health in boys.Methods: Among 587 pregnant women from the EDEN (Etude des Déterminants pré et post natals du développement et de la santé de l’Enfant) cohort who delivered a boy, 9 phenols and 11 phthalates metabolites were quantified in spot pregnancy urine samples. Respiratory outcomes were followed up by questionnaires until age 5, when forced expiratory volume in 1 s (FEV1) was measured by spirometry. Adjusted associations of urinary metabolites log–transformed concentrations with respiratory outcomes and FEV1 in percent predicted (FEV1%) were estimated by survival and linear regression models, respectively.Results: No phenol or phthalate metabolite exhibited clear deleterious associations simultaneously with several respiratory outcomes. Ethyl-paraben was associated with increased asthma rate [hazard rate (HR)=1.10; 95% confidence interval (CI): 1.00, 1.21] and tended to be negatively associated with FEV1% (beta=−0.59; 95% CI: −1.24, 0.05); bisphenol A tended to be associated with increased rates of asthma diagnosis (HR=1.23; 95% CI: 0.97, 1.55) and bronchiolitis/bronchitis (HR=1.13; 95% CI: 0.99, 1.30). Isolated trends for deleterious associations were also observed between 2,5-dichlorophenol and wheezing, and between monocarboxynonyl phthalate, a metabolite of di-isodecyl phthalate (DIDP), and wheezing.Conclusion: Ethyl-paraben, bisphenol A, 2,5-dichlorophenol, and DIDP tended to be associated with altered respiratory health, with ethyl-paraben and bisphenol A exhibiting some consistency across respiratory outcomes. The trends between bisphenol A pregnancy level and increased asthma and bronchiolitis/bronchitis rates in childhood were consistent with a previous cohort study.

Purpose The aim of this study was to apply a propensity score approach to assess the long-term benefits of inhaled corticosteroids (ICS) on respiratory health in asthma. Methods This analysis was conducted on adults with persistent asthma from the Epidemiological study on the Genetics and Environment of Asthma, a 12-year follow-up study. ICS exposure was assessed by questionnaire. Change in lung function over the follow-up period, asthma control, and health-related quality of life (asthma quality of life questionnaire) were assessed by standardized and validated methods. Results Among 245 adults with persistent asthma, 78 (31.8%) were regularly/continuously exposed to ICS (≥6 months/year, ICS++) and 167 never/irregularly exposed to ICS (

Introduction La bronchopneumopathie chronique obstructive (BPCO) est reconnue aujourd’hui comme un probleme de sante publique grandissant, a l’origine de couts de sante considerables et d’une surmortalite. La presence de comorbidites en particuliers cardiovasculaires est la premiere cause de mortalite. BPCO et steatose hepatique non alcoolique (NAFLD) sont associees a une augmentation du risque cardiovasculaire. L’objectif est d’etablir la relation entre NAFLD et incidence d’evenements cardiovasculaires/mortalite chez des patients BPCO. Methodes Dans une cohorte prospective de patients BPCO suivis sur une duree de 5 ans, la steatose et la steatohepatite non alcoolique (NASH) ainsi que la fibrose ont ete evaluees par des tests sanguins non-invasifs (FibroMax®). L’impact des hepatopathies sur le critere composite (evenements cardiovasculaires/deces) a ete etudie par des modeles de Cox univaries et multivaries. Resultats Sur 111 patients BPCO suivis, 75 % sont atteints d’hepatopathies (41 % de steatose, 37 % de NASH et 61 % de fibrose hepatique). Apres 5 ans de suivi, on observe la survenue d’evenements cardiovasculaires chez 31 patients et 7 deces. En analyse multivariee, le nombre d’evenements cardiovasculaires et de deces est plus eleve chez les patients fibrotiques que chez les non fibrotiques (HR [95 %CI] : 2,94 [1,18 ; 7,33]). La steatose ou la NASH ne sont pas associees a une augmentation de la survenue d’evenements cardiovasculaires ou de deces. Conclusion Cette etude longitudinale est la premiere a evaluer l’impact des hepatopathies sur le pronostic des patients BPCO. Les patients BPCO atteints de NAFLD montrent un risque accru d’evenements cardiovasculaires. La detection et la prise en charge des hepatopathies pourrait donc ameliorer le pronostic cardiovasculaire chez les patients BPCO.

Background: Errors in address geocodes may affect estimates of the effects of air pollution on health. Objective: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults. Methods: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant’s address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects. Results: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 μg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: –0.56, –6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: –0.14, –3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted –2.81 (95% CI: –0.26, –5.35) using NavTEQ, or 2.08 (95% CI –4.63, 0.47, p = 0.11) using Google Maps]. Conclusions: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model. Citation: Jacquemin B, Lepeule J, Boudier A, Arnould C, Benmerad M, Chappaz C, Ferran J, Kauffmann F, Morelli X, Pin I, Pison C, Rios I, Temam S, Künzli N, Slama R, Siroux V. 2013. Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function. Environ Health Perspect 121:1054–1060; http://dx.doi.org/10.1289/ehp.1206016

Nanoparticles are useful tools in oncology because of their capacity to passively accumulate in tumors in particular via the enhanced permeability and retention (EPR) effect. However, the importance and reliability of this effect remains controversial and quite often unpredictable. In this preclinical study, we used optical imaging to detect the accumulation of three types of fluorescent nanoparticles in eight different subcutaneous and orthotopic tumor models, and dynamic contrast-enhanced and vessel size index Magnetic Resonance Imaging (MRI) to measure the functional parameters of these tumors. The results demonstrate that the permeability and blood volume fraction determined by MRI are useful parameters for predicting the capacity of a tumor to accumulate nanoparticles. Translated to a clinical situation, this strategy could help anticipate the EPR effect of a particular tumor and thus its accessibility to nanomedicines.

Objectif Chez les patients SAOS, la prevalence de l’hypertension arterielle est elevee et la prise en charge therapeutique est similaire a celle des patients non SAOS, alors que leur reponse au traitement est potentiellement differente. L’objectif est d’identifier la strategie anti-hypertensive la plus appropriee chez les patients SAOS, a partir des donnees d’un essai randomise de tele-suivi des patients SAOS (OPTISAS 2 [NCT01505959] : 213 patients sous antihypertenseurs). Methodes Selection des patients avec traitement anti-hypertenseur et repartition en 3 categories (mono-, bi- ou tri-therapie). Analyses en sous-groupes en considerant (1) les differentes mono-therapies, (2) parmi les bi-therapies, celles associant au moins un diuretique. Une approche d’inference causale multivariee basee sur l’inverse de la probabilite de recevoir le traitement a ete utilisee. La pression arterielle (PA) est mesuree par le patient en auto-mesure (sur 3 jours consecutifs). Resultats Parmi les mono-therapies, aucun traitement particulier n’entraine de baisse significative de la PA ni de superiorite par rapport aux autres. Les patients sous bi-therapie comprenant ou non un diuretique (71 [33 %]) ont une PA systolique mieux controlee (−2,2 [−7,26–2,85] mmHg ; p = 0,07) compare aux patients sous mono-therapie (99 [46 %]) ou tri-therapie (43 [21 %]). Conclusion Nous confirmons que le taux de reponse aux mono-therapies anti-hypertensives est faible chez les patients SAOS. Les bi-therapies sont les plus adaptees pour reguler la PA et la tri-therapie n’apporte pas de reduction supplementaire. Ceci souligne la resistance des patients SAOS aux antihypertenseurs. Une strategie particuliere combinee doit donc etre developpee associant pression positive continue, anti-hypertenseurs et activite physique.

Objectif Une prise en charge integree du SAOS necessite d’obtenir une bonne observance de la PPC, mais aussi une reduction de la pression arterielle (PA) et une augmentation de l’activite physique quotidienne. L’objectif de cet essai randomise etait d’evaluer l’efficacite d’un tele-monitoring multimodal (PPC, PA, activite physique) sur l’evolution de la PA de SAOS a haut-risque cardiovasculaire par comparaison a un bras soins usuels. Methodes Essai multicentrique en ouvert, randomise lors de la mise sous PPC : suivi usuel versus tele-monitoring durant 6 mois. Le tele-monitoring est realise a l’aide d’equipements electroniques collectant des donnees de PA, symptomes, effets indesirables de la PPC, oxymetrie et nombre de pas par jour. Objectif primaire : suivi de la PA a domicile (3 jours consecutifs, 10 a 18 mesures). Objectifs secondaires : adherence a la PPC, symptomes et nombre de pas. Resultats Trois cent six patients (âge moyen 60 ans [SD, 9,5] ; 227 hommes [74 %] ; IMC moyen 33 kg/m2 [SD, 6,3] ; IAH moyen 50/heure [SD, 20]), 149 dans le groupe suivi usuel et 157 tele-monitores. Il n’y avait aucune difference sur la PA mesuree a domicile, le nombre de pas ou encore les symptomes a 6 mois. Cependant, on observait une difference significative en faveur du groupe tele-monitore sur l’observance de la PPC (−0,53 heure [95 % CI : −1,05 ; 0,00], p = 0,05). Conclusion Le tele-monitoring des patients SAOS a haut risque cardiovasculaire ameliore l’observance de la PPC mais pas la PA.

Introduction La rigidite arterielle mesuree par la vitesse de l’onde de pouls carotido-femorale (VOP) est elevee dans le SAOS severe. Une augmentation de 1 m/s de VOP est associee a un risque accru de 15 % de mortalite. Une diminution de la VOP a ete decrite apres quelques mois de traitement par pression positive continue (PPC), mais il existe peu de donnees concernant l’evolution a long terme de la VOP dans le SAOS traite par PPC [1] . L’objectif de l’etude est de mesurer l’evolution et les determinants de la VOP dans le SOAS traite par PPC. Methodes Dans une cohorte prospective d’obeses avec un SAOS, nous avons recueilli des donnees cliniques et biologiques ainsi que les donnees de VOP, d’evenements cardiovasculaires et d’observance au traitement par PPC, au moment du diagnostic et apres un suivi de 5 ans au moins. Resultats Au total, 72 patients avec SAOS (hommes : 52,8 %, âge median : 55,8 ans, IMC median : 38,5 kg/m 2 ) avec une prevalence elevee d’hypertension arterielle (HTA) : 58,3 %, diabete de type 2 : 20,8 %, hypercholesterolemie : 33,3 %, tabagisme actif et ancien : 59,7 %, ont ete evalues apres un suivi median de 7,5 [5,8 ; 8,3] ans. La VOP mediane au moment du diagnostic etait de 9,7 [8,5 ; 10,7] m/s. La VOP mediane apres suivi dans notre centre etait de 10,5 [9,6 ; 12,7] m/s. Et, l’augmentation mediane de VOP etait de 1,34 [0,10 ; 2,37] m/s. L’observance a la PPC etait de 72,2 %. Ces valeurs de VOP sont superieures a celle de la population saine d’age comparable [2] . En analyse univariee : l’HTA, le diabete et l’age etaient correles a une VOP plus elevee. En analyse multivariee, seul l’âge et l’HTA etaient correles a une augmentation de la VOP respectivement de 0,55 [0,16 ; 0,94] % par annees et de 8,54 [1,17 ; 15,91] % en cas d’HTA. Il n’y avait aucun effet de l’adherence au traitement par PPC sur la VOP. Conclusion La VOP est elevee chez les patients obeses traites pour un SAOS. L’augmentation de la VOP dans le SAOS traite par PPC est principalement lie a l’âge et a l’HTA en analyse multivariee. L’adherence a la PPC n’influence pas la VOP. Dans cette population a risque cardiovasculaire eleve, la combinaison des modalites therapeutiques est cruciale au-dela du traitement CPAP.

We studied the role of chronic exposure to ambiant air pollution on lung function level and evolution in lung transplant patients. The lung function of 525 lung transplant (LT) patients from the COLT cohort was followed-up. The 12-month average levels of air pollutants (Nitrogen dioxide (NO 2 ), fine particulate matters (PM 2.5 , PM 10 ) and ozone (O 3 )) were estimated at the home addresses of each patient. The effect of air pollutant exposure on FEV 1 level and change in FEV 1 both during the recovery and decline periodes were estimated using mixed linear regression models adjusted on recipient age, sex, smoking (donor and patient), body mass index, donor age, type of LT, underlying disease, sex and HLA mismatch, ischemia time, anti-HLA antibodies, Pseudomonas colonization, CMV infections, immunosuppression induction and acute rejection. The population included 54% of men and 81% of double LT (mean age 43yrs). The main underlying diseases were cystic fibrosis (40%), emphysema/COPD (34%) and pulmonary arterial hypertension (14%). Mean (sd) individual exposure levels were 15.2 (2.1), 22.1 (3.1), 18.1 (7.3) and 51.7 (8.2) µg/m 3 for PM 2.5 , PM 10 , NO 2 and O 3 , respectively. NO 2 exposure was significantly associated with lower FEV 1 levels measured during the recovery period and a non-significant trend was observed in the decline period (estimate (se) = -3.39(1.48) p=0.02 and -1.96(1.47) p=0.18). None of the air pollutants exposure was associated with change in FEV 1 . Our results suggest a potential deleterious effect of chronic exposure to NO 2 on FEV 1 level following LT and did not evidence an effect of air pollution on change in FEV 1 . Fundings: EU-FP7 SYSCLAD, Vaincre la Mucoviscidose, Association Gregory Lemarchal.

Background: Some endocrine disruptors, in particular from the phenols and phthalates families, are suspected of adverse effects on respiratory health. The biological plausibility of such an effect ...

The aim of this study was to apply a propensity score approach to assess the long-term benefits of inhaled corticosteroids (ICS) on respiratory health in asthma.This analysis was conducted on adults with persistent asthma from the Epidemiological study on the Genetics and Environment of Asthma, a 12-year follow-up study. ICS exposure was assessed by questionnaire. Change in lung function over the follow-up period, asthma control, and health-related quality of life (asthma quality of life questionnaire) were assessed by standardized and validated methods.Among 245 adults with persistent asthma, 78 (31.8%) were regularly/continuously exposed to ICS (≥6 months/year, ICS++ ) and 167 never/irregularly exposed to ICS (6 months/year, ICS+/- ) over the follow-up period. Compared with ICS+/- subjects, a nonsignificant trend for a slower lung function decline (mL/year) was observed in ICS++ subjects (β [95%CI] = -11.4 [-24.9; 2.0]). The ICS++ subjects did not have better controlled asthma and higher health-related quality of life as compared with ICS+/- subjects.Applying a propensity score method did not offer evidence of a statistical significant long-term benefit of ICS on respiratory health in adults with persistent asthma regularly or continuously exposed to ICS over a long period.

Drug-based therapy is usually the initial treatment for Graves' disease (GD) hyperthyroidism in children, but there is some debate about treatment duration.Our objective was to assess the effect of long-term carbimazole therapy on GD remission in children and its determinants.This was an observational prospective multicenter follow-up cohort study.Participants included 154 children newly diagnosed with GD between 1997 and 2002. The intention was to treat patients with three consecutive courses of carbimazole, each lasting 2 yr. Definitive treatment was performed in cases of poor compliance with antithyroid drug (ATD) treatment, thyrotoxicosis relapse, or major adverse effects of ATD treatment.The main outcome measure was remission for at least 18 months after the completion of each course of ATD treatment.The median duration of follow-up was 10.4 (9.0-12.1) yr. Overall estimated remission rates (95% confidence interval) 18 months after the withdrawal of ATD treatment increased with time and were 20 (13-26), 37 (29-45), 45 (35-54), and 49 (40-57)% after 4, 6, 8, and 10 yr follow-up, respectively. A multivariate competing risk model revealed an independent positive effect of less severe forms of hyperthyroidism at diagnosis [subhazard ratio of 1 for patients with free T(4)35 pmol/liter vs. 0.4 (0.20-0.80) for free T(4) ≥ 35 pmol/liter; P = 0.01] and of the presence of other autoimmune conditions [subhazard ratio of 2.23 (1.19-4.18); P = 0.01] on remission rate after medical treatment.About half the patients achieved remission after carbimazole discontinuation, and there seems to be a plateau in the incidence of remission achieved after 8-10 yr ATD therapy.

Additional file 2: Supplementary Figure S1. cellular heterogeneity estimated by the RefFreeEWAS method on 668 placenta samples from the EDEN cohort (A) contribution (%) of each latent variable (B) Pearson correlation between the 6 latent variables. Supplementary Figure S2. Q-Q plot, genomic inflation factor (lambda) and Bayesian inflation factor (BIF) for the association between each methylation site of the EWAS (425,878 CpGs) and tobacco smoking during pregnancy (current, never, former smoker). Results were adjusted for child sex, parity, education level, season of conception, study center, maternal body mass index before pregnancy, maternal age at delivery, gestational duration, paternal smoking status at conception, batch, plate and chip and estimated cellular heterogeneity. Supplementary Figure S3. H3K4me3 (A), H3K4me1 (B) and H3K27ac (C) ChIPSeq signal of 3 placenta replicates. The top panels represent the mean signal values centered on our 203 DMRs +/-2kb (blue) and the mean signal values centered on the 420 random regions +/-2kb (green). The center panels represent heatmaps of the corresponding ChIP-Seq signals centered on our 203 DMRs +/-2kb (upper heatmaps) or on the 420 random regions+/-2kb (lower heatmaps). Supplementary Figure S4. Expression of genes in normal human tissues from RNA-seq data. The barplots show average expression levels of the 16 imprinted genes overlapping our DMRs in normal tissues and development stages (adult, embryonic and fetal). For the sake of clarity, the plots are separated in two panels of 8 genes. Vertical lines on the top of the barplots represent standard deviations. Barplots representing expressions in placenta are in green. RNA-seq data in normal tissues were provided by GTEx portal and NCBI Sequence Read Archive (datasets PRJNA280600, PRJEB4337, PRJEB2445, PRJNA270632, GSE70741, GSE53096). The expression levels are represented in log-transformed RPKM (Read per Kilobase Million) values after addition of a pseudo count of 1, i.e. log-transformed RPKM = log2(1+RPKM). MIR675 has no expression in any of the analyzed samples. Figure S5. The methylation levels of 7 imprinted loci are consistently modified following exposure to cigarette smoking. The left, center and right panels are respectively centered on the DMRs associated with the NNAT locus +/- 2kb, the SGCE/PEG10 locus +/- 2kb and the H19/MIR675 locus +/- 2kb. The top panels show heatmaps respectively corresponding to H3K4me3, H3K4me1 and H3k27ac enrichments in placenta around the center of the region of interest +/- 2 kilobases. For each mark we downloaded triplicates from ENCODE data (see Methods). We computed the enrichment matrices from bigWig files using the deepTools software and displayed it using a custom R script. The middle panels show genes and CpG islands from the Illumina Infinium Human Methylation 450K BeadChip annotations, ICR from Pervjakova et al. [72], the DMR we identified and the corresponding Illumina probes of the region of interest. The lower panels show the methylation changes in smokers (S) (resp. Former Smokers (FS)) in red (resp. blue) compared to nonsmokers. The points represent the beta of the linear model and the error bars correspond to 2 standard deviations. The Y-axis represents the distributions of the variations of the regression coefficient (i.e. the associated change in DNA methylation level between 0 and 1) for each CpG within the DMRs selected by our analysis.

Additional file 2: Supplementary Figure S1. cellular heterogeneity estimated by the RefFreeEWAS method on 668 placenta samples from the EDEN cohort (A) contribution (%) of each latent variable (B) Pearson correlation between the 6 latent variables. Supplementary Figure S2. Q-Q plot, genomic inflation factor (lambda) and Bayesian inflation factor (BIF) for the association between each methylation site of the EWAS (425,878 CpGs) and tobacco smoking during pregnancy (current, never, former smoker). Results were adjusted for child sex, parity, education level, season of conception, study center, maternal body mass index before pregnancy, maternal age at delivery, gestational duration, paternal smoking status at conception, batch, plate and chip and estimated cellular heterogeneity. Supplementary Figure S3. H3K4me3 (A), H3K4me1 (B) and H3K27ac (C) ChIPSeq signal of 3 placenta replicates. The top panels represent the mean signal values centered on our 203 DMRs +/-2kb (blue) and the mean signal values centered on the 420 random regions +/-2kb (green). The center panels represent heatmaps of the corresponding ChIP-Seq signals centered on our 203 DMRs +/-2kb (upper heatmaps) or on the 420 random regions+/-2kb (lower heatmaps). Supplementary Figure S4. Expression of genes in normal human tissues from RNA-seq data. The barplots show average expression levels of the 16 imprinted genes overlapping our DMRs in normal tissues and development stages (adult, embryonic and fetal). For the sake of clarity, the plots are separated in two panels of 8 genes. Vertical lines on the top of the barplots represent standard deviations. Barplots representing expressions in placenta are in green. RNA-seq data in normal tissues were provided by GTEx portal and NCBI Sequence Read Archive (datasets PRJNA280600, PRJEB4337, PRJEB2445, PRJNA270632, GSE70741, GSE53096). The expression levels are represented in log-transformed RPKM (Read per Kilobase Million) values after addition of a pseudo count of 1, i.e. log-transformed RPKM = log2(1+RPKM). MIR675 has no expression in any of the analyzed samples. Figure S5. The methylation levels of 7 imprinted loci are consistently modified following exposure to cigarette smoking. The left, center and right panels are respectively centered on the DMRs associated with the NNAT locus +/- 2kb, the SGCE/PEG10 locus +/- 2kb and the H19/MIR675 locus +/- 2kb. The top panels show heatmaps respectively corresponding to H3K4me3, H3K4me1 and H3k27ac enrichments in placenta around the center of the region of interest +/- 2 kilobases. For each mark we downloaded triplicates from ENCODE data (see Methods). We computed the enrichment matrices from bigWig files using the deepTools software and displayed it using a custom R script. The middle panels show genes and CpG islands from the Illumina Infinium Human Methylation 450K BeadChip annotations, ICR from Pervjakova et al. [72], the DMR we identified and the corresponding Illumina probes of the region of interest. The lower panels show the methylation changes in smokers (S) (resp. Former Smokers (FS)) in red (resp. blue) compared to nonsmokers. The points represent the beta of the linear model and the error bars correspond to 2 standard deviations. The Y-axis represents the distributions of the variations of the regression coefficient (i.e. the associated change in DNA methylation level between 0 and 1) for each CpG within the DMRs selected by our analysis.