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Introduction:Accurately assessing people’s gait, especially in real-world conditions and in case of impaired mobility, is still a challenge due to intrinsic and extrinsic factors resulting in gait complexity. To improve the estimation of gait-related digital mobility outcomes (DMOs) in real-world scenarios, this study presents a wearable multi-sensor system (INDIP), integrating complementary sensing approaches (two plantar pressure insoles, three inertial units and two distance sensors). Methods:The INDIP technical validity was assessed against stereophotogrammetry during a laboratory experimental protocol comprising structured tests (including continuous curvilinear and rectilinear walking and steps) and a simulation of daily-life activities (including intermittent gait and short walking bouts). To evaluate its performance on various gait patterns, data were collected on 128 participants from seven cohorts: healthy young and older adults, patients with Parkinson’s disease, multiple sclerosis, chronic obstructive pulmonary disease, congestive heart failure, and proximal femur fracture. Moreover, INDIP usability was evaluated by recording 2.5-h of real-world unsupervised activity. Results and discussion:Excellent absolute agreement (ICC >0.95) and very limited mean absolute errors were observed for all cohorts and digital mobility outcomes (cadence ≤0.61 steps/min, stride length ≤0.02m, walking speed ≤0.02m/s) in the structured tests. Larger, but limited, errors were observed during the daily-life simulation (cadence 2.72–4.87 steps/min, stride length 0.04–0.06m, walking speed 0.03–0.05m/s). Neither major technical nor usability issues were declared during the 2.5-h acquisitions. Therefore, the INDIP system can be considered a valid and feasible solution to collect reference data for analyzing gait in real-world conditions.

Background: Some studies suggest smoking may result in poorer clinical outcomes in head and neck cancer, but the evidence is heterogeneous and some of it is poor quality. In a large, population-based, study we investigated: (i) whether smoking at diagnosis is an independent prognostic factor for cancer-specific survival in head and neck cancer; and (ii) whether the association varies by site and treatment.Methods: Head and neck cancers (ICD10 C01-C14, and C30–32) diagnosed from 1994 to 2009 were abstracted from the National Cancer Registry Ireland, and classified by smoking status at diagnosis. Follow-up was for 5 years or until December 31, 2010. Multivariate Cox proportional hazards models were used to compare cancer-specific death rates in current, ex-, and never smokers. Subgroup analyses by site and treatment were conducted.Results: In total, 5,652 head and neck cancers were included. At diagnosis, 24% were never smokers, 20% ex-smokers, and 56% current smokers. Compared with never smokers, current smokers had a significantly raised death rate from cancer [multivariate HR, 1.36; 95% confidence interval (CI), 1.21–1.53]. The association was similar after restriction to squamous cell tumors. A significantly increased cancer-related death rate was seen for current smokers with oral cavity, pharyngeal, and laryngeal cancers. The association was stronger in surgically treated patients [HR, 1.49; 95% CI, 1.25–1.79; P(interaction) = 0.01]. Neither radiotherapy nor chemotherapy modified the effect of smoking.Conclusions: Patients with head and neck cancer who smoke at diagnosis have a significantly increased cancer death rate.Impact: Greater efforts are needed to encourage and support smoking cessation in those at risk of, and diagnosed with, head and neck cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2579–90. ©2014 AACR.

Supplementary table 3: supplemental analysis, demographic, tumour and treatment characteristics

Supplementary table 2: post-hoc analysis of associations between smoking status and survival by treatment(s) received

Supplementary table 4: supplemental analysis, Cox model for all head and neck cancers

Supplementary table 1: details of imputation modelling

RATIONALE: The identification of novel molecules associated with asthma may provide insights into mechanisms of disease and their potential clinical implications.OBJECTIVES: To conduct a screening of circulating proteins in childhood asthma and to study proteins emerged from human studies in a mouse model of asthma.METHODS: We included 2,264 children from eight birth cohorts from the MeDALL project and the Tucson TCRS Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As creatine kinase (CK) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma (n=249) and used a house dust mite (HDM) challenged mouse model to gain insights into CK lung expression and its role in resolution of asthma phenotypes.MEASUREMENTS AND MAIN RESULTS: As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjOR: 0.31, 0.15-0.65; p=0.002), validation (0.63, 0.42-0.95; p=0.03), and replication (0.40, 0.16-0.97; p = 0.04) stages. Both cytosolic CK forms (CKM, CKB) were under-expressed in blood from asthmatics compared to controls (p=0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced and, following HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness (AHR) and reduction of airway mucin.CONCLUSIONS: Circulating levels and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of AHR and reduction of airway mucin.

Accurately assessing people’s gait, especially in real-world conditions and in case of impaired mobility, is still a challenge due to intrinsic and extrinsic factors resulting in gait complexity. To improve the estimation of gait-related digital mobility outcomes (DMOs) in real-world scenarios, this study presents a wearable multi-sensor system (INDIP), integrating complementary sensing approaches (two plantar pressure insoles, three inertial units and two distance sensors). The INDIP technical validity was assessed against stereophotogrammetry during a laboratory experimental protocol comprising structured tests (including continuous curvilinear and rectilinear walking and steps) and a simulation of daily-life activities (SDA, including intermittent gait and short walking bouts). To evaluate its performance on various gait patterns, data were collected on 128 participants from seven cohorts: healthy young and older adults, patients with Parkinson’s disease, multiple sclerosis, chronic obstructive pulmonary disease, congestive heart failure, and proximal femur fracture. Moreover, INDIP usability was evaluated by recording 2.5-hours of real-world unsupervised activity. Excellent absolute agreement (ICC > 0.95) and very limited mean absolute errors were observed for all cohorts and DMOs (cadence ≤ 0.61 steps/min, stride length ≤ 0.02 m, walking speed ≤ 0.02 m/s) in the structured tests. Larger, but limited, errors were observed during the SDA (cadence 2.72–4.87 steps/min, stride length 0.04–0.06 m, walking speed 0.03–0.05 m/s). Neither major technical nor usability issues were declared during the 2.5-hours acquisitions. Therefore, the INDIP system can be considered a valid and feasible solution to collect reference data for analyzing gait in real-world conditions.

Key MessageAlthough obesity measures have been consistently associated with a lower FEV1/FVC ratio in adolescents, no previous study has assessed the underlying mechanisms of this association This population-based study assessed whether insulin resistance and CRP levels at 15 years partially mediate the association between fat mass and FEV1/FVC using a causal mediation analysis approach. The findings suggest that insulin resistance at 15 years may mediate over 20% of this association, but no evidence of a mediating role of CRP was found. Further, longitudinal studies that evaluate other biomarkers of systemic inflammation and examine other potential mechanisms are needed to better understand the pathways linking obesity and respiratory health in adolescence. This is key for public health interventions and targeting clinical interventions.AbstractBackgroundWe previously reported an association of high fat mass levels from age 9 to 15 years with lower forced expiratory flow in 1 s (FEV1)/forced vital capacity (FVC) ratio (i.e., increased risk of airflow limitation) at 15 years. Here, we aimed to assess whether insulin resistance and C-reactive protein (CRP) at 15 years partially mediate this association.MethodsWe included 2263 children from the UK Avon Longitudinal Study of Parents and Children population-based cohort (ALSPAC). Four fat mass index (FMI) trajectories (“low,” “medium-low,” “medium-high,” “high”) from 9 to 15 years were previously identified using Group-Based Trajectory Modeling. Data on CRP, glucose, insulin, and post-bronchodilator FEV1/FVC were available at 15 years. We defined insulin resistance by the homeostasis model assessment-estimated insulin resistance index (HOMA-IR). We used adjusted linear regression models and a causal mediation analysis to assess the mediating role of HOMA-IR and CRP.ResultsCompared to children in the “low” FMI trajectory, children in the “medium-high” and “high” FMI trajectories had lower FEV1/FVC at 15 years. The percentage of the total effect explained by HOMA-IR was 19.8% [−114.1 to 170.0] and 20.4% [1.6 to 69.0] for the “medium-high” and “high” trajectories, respectively. In contrast, there was little evidence for a mediating role of CRP.ConclusionThe association between mid-childhood fat mass and FEV1/FVC ratio at 15 years may be partially mediated by insulin resistance.

Background: Measuring mobility in daily life entails dealing with confounding factors arising from multiple sources, including pathological characteristics, patient specific walking strategies, environment/context, and purpose of the task. The primary aim of this study is to propose and validate a multi-task and multi-phase protocol for simulating real-world gait accounting for all these factors within a single set of observations carried out within a limited laboratory space, while ensuring minimisation of participant burden and safety.Methods: The protocol included eight motor tasks at varying speed, incline/steps, surface, path shape, cognitive demand, and included postures that may abruptly alter the participants’ strategy of walking. It was deployed in a convenience sample of 108 participants recruited from six cohort groups that included older healthy adults (HA) and participants with potentially altered mobility due to Parkinson’s Disease (PD), Multiple Sclerosis (MS), Proximal Femoral Fracture (PFF), Chronic Obstructive Pulmonary Disease (COPD) or Congestive Heart Failure (CHF). A novelty introduced in the protocol was the tiered approach to increase difficulty both within the same task (e.g., by allowing use of aids or armrests) and across tasks.Results: The protocol proved to be safe and feasible and the addition of the more complex tasks allowed a much greater spread in walking speeds to be achieved compared to standard straight walking trials. Furthermore, it allowed a relatively realistic representation of daily life relevant mobility aspects and can therefore be used for the validation of monitoring devices used in real life.Conclusions: The suitability of the protocol for measuring gait in a variety of pathological conditions suggests that it can also be used to detect changes in gait due to, for example, the onset or progression of a disease, or due to therapy.Trial registration: ISRCTN – 12246987.

IntroductionObesity is a known risk factor for asthma. Although some evidence showed asthma causing obesity in children, the link between asthma and obesity has not been investigated in adults.MethodsWe used data from the European Community Respiratory Health Survey (ECRHS), a cohort study in 11 European countries and Australia in 3 waves between 1990 and 2014, at intervals of approximately 10 years. We considered two study periods: from ECRHS I (t) to ECRHS II (t+1), and from ECRHS II (t) to ECRHS III (t+1). We excluded obese (body mass index≥30 kg/m2) individuals at visitt. The relative risk (RR) of obesity att+1associated with asthma attwas estimated by multivariable modified Poisson regression (lag) with repeated measurements. Additionally, we examined the association of atopy and asthma medication on the development of obesity.ResultsWe included 7576 participants in the period ECRHS I-II (51.5% female, mean (SD) age of 34 (7) years) and 4976 in ECRHS II-III (51.3% female, 42 (8) years). 9% of participants became obese in ECRHS I-II and 15% in ECRHS II—III. The risk of developing obesity was higher among asthmatics than non-asthmatics (RR 1.22, 95% CI 1.07 to 1.38), and particularly higher among non-atopic than atopic (1.47; 1.17 to 1.86 vs 1.04; 0.86 to 1.27), those with longer disease duration (1.32; 1.10 to 1.59 in >20 years vs 1.12; 0.87 to 1.43 in ≤20 years) and those on oral corticosteroids (1.99; 1.26 to 3.15 vs 1.15; 1.03 to 1.28). Physical activity was not a mediator of this association.ConclusionThis is the first study showing that adult asthmatics have a higher risk of developing obesity than non-asthmatics, particularly those non-atopic, of longer disease duration or on oral corticosteroids.

The potential effect of gestational exposure to phthalates on the lung function levels during childhood is unclear. Therefore, we examined this association at different ages (from 4 to 11 years) and over the whole childhood. Specifically, we measured 9 phthalate metabolites (MEP, MiBP, MnBP, MCMHP, MBzP, MEHHP, MEOHP, MECPP, MEHP) in the urine of 641 gestating women from the INMA study (Spain) and the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC in their offspring at ages 4, 7, 9 and 11. We used linear regression and mixed linear regression with a random intercept for subject to assess the association between phthalates and lung function at each study visit and for the overall childhood, respectively. We also assessed the phthalate metabolites mixture effect on lung function using a Weighted Quantile Sum (WQS) regression. We observed that the phthalate metabolites gestational levels were consistently associated with lower FVC and FEV1 at all ages, both when assessed individually and jointly as a mixture, although most associations were not statistically significant. Of note, a 10% increase in MiBP was related to lower FVC (-0.02 (-0.04, 0)) and FEV1 z-scores (-0.02 (-0.04,-0.01) at age 4. Similar significant reductions in FVC were observed at ages 4 and 7 associated with an increase in MEP and MnBP, respectively, and for FEV1 at age 4 associated with an increase in MBzP. WQS regression consistently identified MBzP as an important contributor to the phthalate mixture effect. We can conclude that the gestational exposure to phthalates was associated with children's lower FVC and FEV1, especially in early childhood, and in a statistically significant manner for MEP, MiBP, MBzP and MnBP. Given the ubiquity of phthalate exposure and its established endocrine disrupting effects in children, our findings support current regulations that limit phthalate exposure. The INMA study was funded by grants from the European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) , and from Spain: Instituto de Salud Carlos III and Ministry of Health (Red INMA G03/176; CB06/02/0041; PI041436, PI081151, PI06/0867, PS09/00090, PI13/02187; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI12/01890, PI13/1944, PI13/2032, PI14/00891, PI14/1687, PI17/01194, and PI17/00663; MV16/00015; predoctoral grant PFIS - FI14/00099, pre-doctoral grant PFIS FIS-FSE: 17/00260, FIS19/1338, MV16/00015, Miguel Servet-FEDER: CP11/0178, and Miguel Servet-FSE: MS13/00054, MSII16/00051, and MS16/00128) , CIBERESP; Department of Health of the Basque Government (2005111093 and 2009111069) ; the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001) ; and the Generalitat de Catalunya-CIRIT (1999SGR 00241) . ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX 2018-000806-S) , and support from the Generalitat de Catalunya through the CERCA Program.

Background The study of impact of lockdowns on individual health-related behaviors has produced divergent results. Purpose To identify patterns of change in multiple health-related behaviors analyzed as a whole, and their individual determinants. Methods Between March and August 2020, we collected data on smoking, alcohol, physical activity, weight, and sleep in a population-based cohort from Catalonia who had available pre-pandemic data. We performed multiple correspondence and cluster analyses to identify patterns of change in health-related behaviors and built multivariable multinomial logistic regressions to identify determinants of behavioral change. Results In 10,032 participants (59% female, mean (SD) age 55 (8) years), 8,606 individuals (86%) modified their behavior during the lockdown. We identified five patterns of behavioral change that were heterogeneous and directed both towards worsening and improvement in diverse combinations. Patterns ranged from “global worsening” (2,063 participants, 21%) characterized by increases in smoking, alcohol consumption, and weight, and decreases in physical activity levels and sleep time, to “improvement” (2,548 participants, 25%) characterized by increases in physical activity levels, decreases in weight and alcohol consumption, and both increases and decreases in sleep time. Being female, of older age, teleworking, having a higher education level, assuming caregiving responsibilities, and being more exposed to pandemic news were associated with changing behavior (all p < .05), but did not discriminate between favorable or unfavorable changes. Conclusions Most of the population experienced changes in health-related behavior during lockdowns. Determinants of behavior modification were not explicitly associated with the direction of changes but allowed the identification of older, teleworking, and highly educated women who assumed caregiving responsibilities at home as susceptible population groups more vulnerable to lockdowns.

Background: Physical activity and exercise capacity are key prognostic factors in chronic obstructive pulmonary disease (COPD) but their environmental determinants are unknown. Objectives: To test the association between urban environment and objective physical activity, physical activity experience and exercise capacity in COPD. Methods: We studied 404 patients with mild-to-very severe COPD from a multi-city study in Catalonia, Spain. We measured objective physical activity (step count and sedentary time) by the Dynaport MoveMonitor, physical activity experience (difficulty with physical activity) by the Clinical visit-PROactive (C-PPAC) instrument, and exercise capacity by the 6-min walk distance (6MWD). We estimated individually (geocoded to the residential address) population density, pedestrian street length, slope of terrain, and long-term (i.e., annual) exposure to road traffic noise, nitrogen dioxide (NO2) and particulate matter (PM2.5). We built single- and multi-exposure mixed-effects linear regressions with a random intercept for city, adjusting for confounders. Results: Patients were 85% male, had mean (SD) age 69 (9) years and walked 7524 (4045) steps/day. In multi-exposure models, higher population density was associated with fewer steps, more sedentary time and worse exercise capacity (−507 [95% CI: 1135, 121] steps, +0.2 [0.0, 0.4] h/day and −13 [-25, 0] m per IQR). Pedestrian street length related with more steps and less sedentary time (156 [9, 304] steps and −0.1 [-0.1, 0.0] h/day per IQR). Steeper slope was associated with better exercise capacity (15 [3, 27] m per IQR). Higher NO2 levels related with more sedentary time and more difficulty in physical activity. PM2.5 and noise were not associated with physical activity or exercise capacity. Discussion: Population density, pedestrian street length, slope and NO2 exposure relate to physical activity and capacity of COPD patients living in highly populated areas. These findings support the consideration of neighbourhood environmental factors during COPD management and the attention to patients with chronic diseases when developing urban and transport planning policies. info:eu-repo/semantics/publishedVersion

Residential greenness exposure has been reported to positively impact health mainly by reducing overweight/obesity risk, improving mental health and physical activity. Less is known on biological pathways involved in these health benefits. We aimed to investigate the association between multisite greenness exposure and oxidative stress in children and explore the potential mediating role of physical activity in this association. This cross-sectional study involved 323 healthy subjects (8-11 y) from five schools in Asti (Italy). Children's parents filled a questionnaire providing the residential address, parental education, and physical activity frequency. Oxidative stress was quantified in spot urine by isoprostane (15-F

Background: Measuring mobility in daily life entails dealing with confounding factors arising from multiple sources, including pathological characteristics, patient specific walking strategies, environment/context, and purpose of the task. The primary aim of this study is to propose and validate a protocol for simulating real-world gait accounting for all these factors within a single set of observations, while ensuring minimisation of participant burden and safety. Methods: The protocol included eight motor tasks at varying speed, incline/steps, surface, path shape, cognitive demand, and included postures that may abruptly alter the participants' strategy of walking. It was deployed in a convenience sample of 108 participants recruited from six cohorts that included older healthy adults (HA) and participants with potentially altered mobility due to Parkinson's disease (PD), multiple sclerosis (MS), proximal femoral fracture (PFF), chronic obstructive pulmonary disease (COPD) or congestive heart failure (CHF). A novelty introduced in the protocol was the tiered approach to increase difficulty both within the same task (e.g., by allowing use of aids or armrests) and across tasks. Results: The protocol proved to be safe and feasible (all participants could complete it and no adverse events were recorded) and the addition of the more complex tasks allowed a much greater spread in walking speeds to be achieved compared to standard straight walking trials. Furthermore, it allowed a representation of a variety of daily life relevant mobility aspects and can therefore be used for the validation of monitoring devices used in real life. Conclusions: The protocol allowed for measuring gait in a variety of pathological conditions suggests that it can also be used to detect changes in gait due to, for example, the onset or progression of a disease, or due to therapy. Trial registration: ISRCTN-12246987. This work was supported by the Mobilise-D project that has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 820820. This JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This study was also supported by the National Institute for Health Research (NIHR) through the Sheffield Biomedical Research Centre (BRC, Grant Number IS-BRC-1215–20017). AY, LA, LR and SDD are also supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Center (BRC) based at Newcastle Upon Tyne Hospital NHS Foundation Trust and Newcastle University. AY, LA, LR and SDD are also supported by the NIHR/Wellcome Trust Clinical Research Facility (CRF) infrastructure at Newcastle upon Tyne Hospitals NHS Foundation Trust. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and from the Generalitat de Catalunya through the CERCA Program. All opinions are those of the authors and not the funders. Neither IMI nor the European Union, EFPIA, NHS, NIHR, DHSC or any Associated Partners are responsible for any use that may be made of the information contained herein.

Objective Sleep duration is an important health indicator. Our aim was to investigate the association between maternal sleep duration and infant birthweight. Methods The study included 2,536 mother-infant pairs of a Spanish birth cohort (2004-2006, INMA project). The exposures were questionnaire-based measures of sleep duration before and during pregnancy. The primary outcome was infant birthweight score (g) standardized to 40 weeks of gestation. Results In women sleeping less than 7 hours per day before pregnancy, each additional hour of sleep increased birthweight score by 44.7 g (p = 0.049) in the minimally-adjusted model, although findings were not statistically significant after considering other potential confounders (p > 0.05). However, increasing sleep duration for the group of mothers who slept more than 9 hours per day decreased birthweight score by 39.2 g per additional hour (p = 0.001). Findings were similar after adjusting for several socio-demographic confounders and maternal depression-anxiety clinical history as an intermediate factor. Similar but attenuated associations were observed with sleep duration in the second pregnancy trimester. Conclusion The relationship between maternal sleep duration before and during pregnancy and infant birthweight is an inverse U-shaped curve. Excessive sleep duration may adversely affect infant health through its impact on birthweight.

International audience; Rationale: Few longitudinal studies have assessed the relationship between occupational exposures and lung-function decline in the general population with a sufficiently long follow-up.Objectives: To examine the potential association in two large cohorts: the ECRHS (European Community Respiratory Health Survey) and the SAPALDIA (Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults).Methods: General-population samples of individuals aged 18 to 62 were randomly selected in 1991-1993 and followed up approximately 10 and 20 years later. Spirometry (without bronchodilation) was performed at each visit. Coded complete job histories during follow-up visits were linked to a job-exposure matrix, generating cumulative exposure estimates for 12 occupational exposures. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were jointly modeled in linear mixed-effects models, fitted in a Bayesian framework, taking into account age and smoking.Results: A total of 40,024 lung-function measurements from 17,833 study participants were analyzed. We found accelerated declines in FEV1 and the FEV1/FVC ratio for exposure to biological dust, mineral dust, and metals (FEV1 = -15.1 ml, -14.4 ml, and -18.7 ml, respectively; and FEV1/FVC ratio = -0.52%, -0.43%, and -0.36%, respectively; per 25 intensity-years of exposure). These declines were comparable in magnitude with those associated with long-term smoking. No effect modification by sex or smoking status was identified. Findings were similar between the ECRHS and the SAPALDIA cohorts.Conclusions: Our results greatly strengthen the evidence base implicating occupation, independent of smoking, as a risk factor for lung-function decline. This highlights the need to prevent or control these exposures in the workplace.

Introduction: Existing mobility endpoints based on functional performance, physical assessments and patient self-reporting are often affected by lack of sensitivity, limiting their utility in clinical practice. Wearable devices including inertial measurement units (IMUs) can overcome these limitations by quantifying digital mobility outcomes (DMOs) both during supervised structured assessments and in real-world conditions. The validity of IMU-based methods in the real-world, however, is still limited in patient populations. Rigorous validation procedures should cover the device metrological verification, the validation of the algorithms for the DMOs computation specifically for the population of interest and in daily life situations, and the users' perspective on the device. Methods and analysis: This protocol was designed to establish the technical validity and patient acceptability of the approach used to quantify digital mobility in the real world by Mobilise-D, a consortium funded by the European Union (EU) as part of the Innovative Medicine Initiative, aiming at fostering regulatory approval and clinical adoption of DMOs.After defining the procedures for the metrological verification of an IMU-based device, the experimental procedures for the validation of algorithms used to calculate the DMOs are presented. These include laboratory and real-world assessment in 120 participants from five groups: healthy older adults; chronic obstructive pulmonary disease, Parkinson's disease, multiple sclerosis, proximal femoral fracture and congestive heart failure. DMOs extracted from the monitoring device will be compared with those from different reference systems, chosen according to the contexts of observation. Questionnaires and interviews will evaluate the users' perspective on the deployed technology and relevance of the mobility assessment. Ethics and dissemination: The study has been granted ethics approval by the centre's committees (London-Bloomsbury Research Ethics committee; Helsinki Committee, Tel Aviv Sourasky Medical Centre; Medical Faculties of The University of Tübingen and of the University of Kiel). Data and algorithms will be made publicly available. Trial registration number: ISRCTN (12246987). We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. SDD, AY and LRo are also supported by the Newcastle Biomedical Research Centre (BRC) based at Newcastle upon Tyne and Newcastle University. CM, BS, LVG and EB are also supported by the Sheffield Biomedical Research Centre (BRC) based at the Sheffield Teaching Hospital and the University of Sheffield. The work was also supported by the NIHR/Wellcome Trust Clinical Research Facility (CRF) infrastructure at Newcastle upon Tyne Hospitals NHS Foundation Trust and the CRF at the Sheffield Teaching Hospital. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care or the funders.This study was co-funded by the European Union’s Horizon 2020 research and innovation programme and EFPIA via the Innovative Medicine Initiative 2 (Mobilise-D project, grant number IMI22017-13-7-820820). The views expressed are those of the authors and not necessarily those of the IMI, the European Union, the EFPIA, or any Associated Partners. We acknowledge the support of Grünenthal GmbH via the funding of a PhD scholarship directly dedicated to the technical validation protocol.

Circadian rhythm is an endogenously driven cyclical process that regulates most of our bodily functions, such as sleep–wakefulness cycle, metabolism, and a wide range of cellular, molecular and behavioural processes. Chronotype, or an individual's preferred time of sleep and activity, is one of the major internal cues that helps to harmonise one's biological events according to its circadian timing [1]. Three major variations of chronotype exist among humans, those who prefer to wake up early and sleep early at night (known as morning types or “larks”), those who prefer late sleep at night and late waking up in the morning (referred to as evening type or “owls”) and those who remain in between (intermediate type) [1]., Individual preference of sleep and activity (chronotype) might play an important role on asthma and allergic diseases in adolescents: this link underscores a potential plausible behavioural intervention for asthma and allergic diseases in young population https://bit.ly/2THta9I

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 )

We estimated the association between regular physical activity and the incidence of restrictive spirometry pattern. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and physical activity were assessed in 2 population-based European cohorts (European Community Respiratory Health Survey: n = 2,757, aged 39-67 years; and Swiss Study on Air Pollution and Lung and Heart Diseases in Adults: n = 2,610, aged 36-82 years) first in 2000-2002 and again approximately 10 years later (2010-2013). Subjects with restrictive or obstructive spirometry pattern at baseline were excluded. We assessed the association of being active at baseline (defined as being physically active at least 2-3 times/week for ≥1 hour) with restrictive spirometry pattern at follow-up (defined as a postbronchodilation FEV1/FVC ratio of at least the lower limit of normal and FVC of

Investigating COPD trends may help healthcare providers to forecast future disease burden. We estimated sex- and smoking-specific incidence trends of pre-bronchodilator airflow obstruction (AO) among adults without asthma from 11 European countries within a 20-year follow-up (ECRHS and SAPALDIA cohorts). We also quantified the extent of misclassification in the definition based on pre-bronchodilator spirometry (using post-bronchodilator measurements from a subsample of subjects) and we used this information to estimate the incidence of post-bronchodilator AO (AOpost-BD), which is the primary characteristic of COPD. AO incidence was 4.4 (95% CI: 3.5-5.3) male and 3.8 (3.1-4.6) female cases/1,000/year. Among ever smokers (median pack-years: 20, males; 12, females), AO incidence significantly increased with ageing in men only [incidence rate ratio (IRR), 1-year increase: 1.05 (1.03-1.07)]. A strong exposure-response relationship with smoking was found both in males [IRR, 1-pack-year increase: 1.03 (1.02-1.04)] and females [1.03 (1.02-1.05)]. The positive predictive value of AO for AOpost-BD was 59.1% (52.0-66.2%) in men and 42.6% (35.1-50.1%) in women. AOpost-BD incidence was 2.6 (1.7-3.4) male and 1.6 (1.0-2.2) female cases/1,000/year. AO incidence was considerable in Europe and the sex-specific ageing-related increase among ever smokers was strongly related to cumulative tobacco exposure. AOpost-BD incidence is expected to be half of AO incidence. ALEC has received funding from the European Union’s Horizon 2020 research and innovation programme [Grant Agreement No. 633212]. The co-ordination of the ECRHS was supported by the European Commission (phases 1 and 2) and the Medical Research Council (phase 3). The SAPALDIA cohort was funded by The State Secretariat for Education, Research and Innovation (SERI), Switzerland. The principal investigators and team members of the ECRHS and SAPALDIA studies, and the national funders who supported data collection in the ECRHS and SAPALDIA studies are listed in the appendix available in the Supplementary Information.

Publisher's version (útgefin grein), Background: Previous studies have reported an association between weight increase and excess lung function decline in young adults followed for short periods. We aimed to estimate lung function trajectories during adulthood from 20-year weight change profiles using data from the population-based European Community Respiratory Health Survey (ECRHS). Methods: We included 3673 participants recruited at age 20-44 years with repeated measurements of weight and lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1)) in three study waves (1991-93, 1999-2003, 2010-14) until they were 39-67 years of age. We classified subjects into weight change profiles according to baseline body mass index (BMI) categories and weight change over 20 years. We estimated trajectories of lung function over time as a function of weight change profiles using population-averaged generalised estimating equations. Results: In individuals with normal BMI, overweight and obesity at baseline, moderate (0.25-1 kg/year) and high weight gain (>1 kg/year) during follow-up were associated with accelerated FVC and FEV 1 declines. Compared with participants with baseline normal BMI and stable weight (±0.25 kg/year), obese individuals with high weight gain during follow-up had -1011 mL (95% CI -1.259 to -763) lower estimated FVC at 65 years despite similar estimated FVC levels at 25 years. Obese individuals at baseline who lost weight (, Funding The present analyses are part of the ageing lungs in european cohorts (alec) study (www.alecstudy.org), which has received funding from the european Union’s horizon 2020 research and innovation programme under grant agreement no. 633212. The local investigators and funding agencies for the european community respiratory health survey are reported in the online supplement. isglobal is a member of the cerca Programme, generalitat de catalunya.

Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991-1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999-2003, and ECRHS III in 2010-2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean β (95% CI), comparing active versus non-active individuals: 58 mL (21-95) for forced expiratory volume in one second and 83 mL (36-130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding. The present analyses are part of the Ageing Lungs in European Cohorts (ALEC) Study (www.alecstudy.org), which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 633212.

A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis that inflammation and/or innate immunity plays a role in the obesity-asthma link. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (p = 0.0023), MAPK signaling (p = 0.013), NF-&kappa, B signaling (p = 0.031), and PI3K/AKT signaling (p = 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (p = 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.

Objective: Regular physical activity may be associated with improved lung function via reduced systemic inflammation, although studies exploring this mechanism are rare. We evaluated the role of C-reactive protein in blood, which is a common marker of systemic inflammation, on the association of physical activity with forced expiratory volume in one second and forced vital capacity. Methods: Cross-sectional data on spirometry, C-reactive protein levels and self-reported physical activity (yes/no; ≥2 times and ≥1hr per week of vigorous physical activity) were available in the European Community Respiratory Health Survey (N = 2347 adults, 49.3% male, 28–56 years-old). A subsample was also assessed 10 years later using the International Physical Activity Questionnaire, and tertiles of Metabolic Equivalent of Task—minutes per week spent in vigorous, moderate and walking activities were calculated (N = 671, 49.6% male, 40–67 years-old). Adjusted cross-sectional mixed linear regression models and the “mediate” package in “R” were used to assess the presence of mediation. Results: Despite positive significant associations between nearly all physical activity metrics with forced expiratory volume in one second and forced vital capacity, there was no evidence that C-reactive protein levels played a role. An influence of C-reactive protein levels was only apparent in the smaller subsample when comparing the medium to low tertiles of moderate activity (mean difference [95% CIs]: 21.1ml [5.2, 41.9] for forced expiratory volume in one second and 17.3ml [2.6, 38.0] for forced vital capacity). Conclusions: In a population of adults, we found no consistent evidence that the association of physical activity with forced expiratory volume in one second or forced vital capacity is influenced by the level of C-reactive protein in blood. The results reported herein correspond to the specific aims of the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Individual Fellowship scheme (H2020-MSCA-IF-2015; proposal number 704268; https://ec.europa.eu/research/mariecurieactions/actions/individual-fellowships_en), awarded to the Principal Investigator EF. These results also correspond to the specific aims of the Ageing Lungs in European Cohorts (ALEC) Study (www.alecstudy.org), awarded to the Principal Investigator DJ, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 633212 (https://ec.europa.eu/programmes/horizon2020/). The local investigators and funding agencies for the participating European Community Respiratory Health Survey (ECRHS II and ECRHS III) centres are reported in the Supplementary File. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction: Restrictive spirometry pattern is an under-recognised disorder with a poor morbidity and mortality prognosis. We compared physical activity levels between adults with a restrictive spirometry pattern and with normal spirometry. Methods: Restrictive spirometry pattern was defined as a having post-bronchodilator FEV1/FVC ≥ Lower Limit of Normal and a FVC

Background Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3–like 1 [CHI3L1] ) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown. Objective We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers ( CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood. Methods We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4 years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age by using multivariable logistic regression. Results YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. Conclusions The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs or methylation levels, were associated with childhood asthma.

Interleukin-1 receptor–like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10−16) and serum IL1RL1-a levels (p=2.8×10−56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.

Publisher's version (útgefin grein), Background Mothers’ smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers’ smoking may have a similar effect, and biological plausibility that fathers’ smoking during adolescence may influence offspring’s health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma. Methods Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged ≤51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents’ (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Results Fathers’ smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01–2.01] and mothers’ smoking during pregnancy (RRR = 1.27, 95% CI: 1.01–1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers’ smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17–2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02–1.55). Conclusions Fathers’ smoking during early adolescence and grandmothers’ and mothers’ smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception., The present analyses are part of the Ageing Lungs in European Cohorts (ALEC) Study [www.alecstudy.org], which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 633212. The coordination of the European Community Respiratory Health Survey (ECRHS) was supported by the European Commission (phases 1 and 2) and the Medical Research Council (phase 3). Local funding agencies for the ECRHS are reported in the Supplementary Appendix, available as Supplementary data at IJE online. Conflict of interest: J.W.H. reports grants from the European Union’s Horizon 2020 programme (633212), the Medical Research Council UK (MC_PC_15078) and the National Institutes of Health USA (R01 AI091905, R01 AI121226) during the conduct of the study. R.J. reports grants from the Estonian Research Council (personal grant No. 562) during the conduct of the study, grants/grants pending from the Estonian Research Council (personal research grant No. 562), personal fees for consulting and lecturing from GlaxoSmithKline, Boehringer and Novartis and travel/accommodation/meeting expenses paid by GlaxoSmithKline and Boehringer, outside the submitted work. C.R. reports personal fees for consulting and lecturing from ALK, Astra Zeneca, GSK, Boheringer and Novartis, outside the submitted work. A.G.C. reports grants from Chiesi Farmaceutici and GlaxoSmithKline Italy, during the conduct of the study. P.D. reports personal fees for consulting and lecturing from ALK and Stallergenes Greer and personal fees for consulting from Circassia, Chiesi Farmaceutici, ThermofisherScientific and Menarini, outside the submitted work. D.J. reports grants from the Medical Research Council and the European Union’s Horizon 2020 programme, during the conduct of the study. All other authors declare no competing interests.

OBJECTIVE: We assessed associations between physical activity and lung function, and its decline, in the prospective population-based European Community Respiratory Health Survey cohort. METHODS: FEV1 and FVC were measured in 3912 participants at 27-57 years and 39-67 years (mean time between examinations=11.1 years). Physical activity frequency and duration were assessed using questionnaires and used to identify active individuals (physical activity ≥2 times and ≥1 hour per week) at each examination. Adjusted mixed linear regression models assessed associations of regular physical activity with FEV1 and FVC. RESULTS: Physical activity frequency and duration increased over the study period. In adjusted models, active individuals at the first examination had higher FEV1 (43.6 mL (95% CI 12.0 to 75.1)) and FVC (53.9 mL (95% CI 17.8 to 89.9)) at both examinations than their non-active counterparts. These associations appeared restricted to current smokers. In the whole population, FEV1 and FVC were higher among those who changed from inactive to active during the follow-up (38.0 mL (95% CI 15.8 to 60.3) and 54.2 mL (95% CI 25.1 to 83.3), respectively) and who were consistently active, compared with those consistently non-active. No associations were found for lung function decline. CONCLUSION: Leisure-time vigorous physical activity was associated with higher FEV1 and FVC over a 10-year period among current smokers, but not with FEV1 and FVC decline. This project has received funding from the european Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-curie individual Fellowship scheme (elaine Fuertes, H2020- MSca-iF-2015; proposal number 704268). the present analyses are part of the ageing lungs in european cohorts (alec) Study (www.alecstudy.org), which has also received funding from the european Union's Horizon 2020 research and innovation programme under grant agreement no 633212. the local investigators and funding agencies for the european community respiratory Health Survey (ecrHS ii and ecrHS iii) are reported in the online supplementary file.

Introduction: A restrictive spirometry pattern is associated with high morbidity and mortality. Whether regular physical activity (PA) protects against this pattern has never been studied.Objective ...