Search

Objective: The existence of catch-up lung function growth and its predictors is uncertain. We aimed to identify lung function trajectories and their predictors in a population-based birth cohort., Methods: We applied group-based trajectory modelling to z-scores of forced expiratory volume in 1 second (zFEV 1 ) and z-scores of forced vital capacity (zFVC) from 1151 children assessed at around 4, 7, 9, 10, 11, 14 and 18 years. Multinomial logistic regression models were used to test whether potential prenatal and postnatal predictors were associated with lung function trajectories., Results: We identified four lung function trajectories: a low (19% and 19% of the sample for zFEV 1 and zFVC, respectively), normal (62% and 63%), and high trajectory (16% and 13%) running in parallel, and a catch-up trajectory (2% and 5%) with catch-up occurring between 4 and 10 years. Fewer child allergic diseases and higher body mass index z-score (zBMI) at 4 years were associated with the high and normal compared with the low trajectories, both for zFEV 1 and zFVC. Increased children's physical activity during early childhood and higher zBMI at 4 years were associated with the catch-up compared with the low zFEV 1 trajectory (relative risk ratios: 1.59 per physical activity category (1.03-2.46) and 1.47 per zBMI (0.97-2.23), respectively). No predictors were identified for zFVC catch-up growth., Conclusion: We found three parallel-running and one catch-up zFEV 1 and zFVC trajectories, and identified physical activity and body mass at 4 years as predictors of zFEV 1 but not zFVC catch-up growth., Competing Interests: Competing interests: JGA has received payment for lectures from AstraZeneca, Esteve and Chiesi., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Wrist-worn inertial sensors are used in digital health for evaluating mobility in real-world environments. Preceding the estimation of spatiotemporal gait parameters within long-term recordings, gait detection is an important step to identify regions of interest where gait occurs, which requires robust algorithms due to the complexity of arm movements. While algorithms exist for other sensor positions, a comparative validation of algorithms applied to the wrist position on real-world data sets across different disease populations is missing. Furthermore, gait detection performance differences between the wrist and lower back position have not yet been explored but could yield valuable information regarding sensor position choice in clinical studies., Objective: The aim of this study was to validate gait sequence (GS) detection algorithms developed for the wrist position against reference data acquired in a real-world context. In addition, this study aimed to compare the performance of algorithms applied to the wrist position to those applied to lower back-worn inertial sensors., Methods: Participants with Parkinson disease, multiple sclerosis, proximal femoral fracture (hip fracture recovery), chronic obstructive pulmonary disease, and congestive heart failure and healthy older adults (N=83) were monitored for 2.5 hours in the real-world using inertial sensors on the wrist, lower back, and feet including pressure insoles and infrared distance sensors as reference. In total, 10 algorithms for wrist-based gait detection were validated against a multisensor reference system and compared to gait detection performance using lower back-worn inertial sensors., Results: The best-performing GS detection algorithm for the wrist showed a mean (per disease group) sensitivity ranging between 0.55 (SD 0.29) and 0.81 (SD 0.09) and a mean (per disease group) specificity ranging between 0.95 (SD 0.06) and 0.98 (SD 0.02). The mean relative absolute error of estimated walking time ranged between 8.9% (SD 7.1%) and 32.7% (SD 19.2%) per disease group for this algorithm as compared to the reference system. Gait detection performance from the best algorithm applied to the wrist inertial sensors was lower than for the best algorithms applied to the lower back, which yielded mean sensitivity between 0.71 (SD 0.12) and 0.91 (SD 0.04), mean specificity between 0.96 (SD 0.03) and 0.99 (SD 0.01), and a mean relative absolute error of estimated walking time between 6.3% (SD 5.4%) and 23.5% (SD 13%). Performance was lower in disease groups with major gait impairments (eg, patients recovering from hip fracture) and for patients using bilateral walking aids., Conclusions: Algorithms applied to the wrist position can detect GSs with high performance in real-world environments. Those periods of interest in real-world recordings can facilitate gait parameter extraction and allow the quantification of gait duration distribution in everyday life. Our findings allow taking informed decisions on alternative positions for gait recording in clinical studies and public health., Trial Registration: ISRCTN Registry 12246987; https://www.isrctn.com/ISRCTN12246987., International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2021-050785., (©Felix Kluge, Yonatan E Brand, M Encarna Micó-Amigo, Stefano Bertuletti, Ilaria D'Ascanio, Eran Gazit, Tecla Bonci, Cameron Kirk, Arne Küderle, Luca Palmerini, Anisoara Paraschiv-Ionescu, Francesca Salis, Abolfazl Soltani, Martin Ullrich, Lisa Alcock, Kamiar Aminian, Clemens Becker, Philip Brown, Joren Buekers, Anne-Elie Carsin, Marco Caruso, Brian Caulfield, Andrea Cereatti, Lorenzo Chiari, Carlos Echevarria, Bjoern Eskofier, Jordi Evers, Judith Garcia-Aymerich, Tilo Hache, Clint Hansen, Jeffrey M Hausdorff, Hugo Hiden, Emily Hume, Alison Keogh, Sarah Koch, Walter Maetzler, Dimitrios Megaritis, Martijn Niessen, Or Perlman, Lars Schwickert, Kirsty Scott, Basil Sharrack, David Singleton, Beatrix Vereijken, Ioannis Vogiatzis, Alison Yarnall, Lynn Rochester, Claudia Mazzà, Silvia Del Din, Arne Mueller. Originally published in JMIR Formative Research (https://formative.jmir.org), 01.05.2024.)

This study aimed to validate a wearable device's walking speed estimation pipeline, considering complexity, speed, and walking bout duration. The goal was to provide recommendations on the use of wearable devices for real-world mobility analysis. Participants with Parkinson's Disease, Multiple Sclerosis, Proximal Femoral Fracture, Chronic Obstructive Pulmonary Disease, Congestive Heart Failure, and healthy older adults (n = 97) were monitored in the laboratory and the real-world (2.5 h), using a lower back wearable device. Two walking speed estimation pipelines were validated across 4408/1298 (2.5 h/laboratory) detected walking bouts, compared to 4620/1365 bouts detected by a multi-sensor reference system. In the laboratory, the mean absolute error (MAE) and mean relative error (MRE) for walking speed estimation ranged from 0.06 to 0.12 m/s and - 2.1 to 14.4%, with ICCs (Intraclass correlation coefficients) between good (0.79) and excellent (0.91). Real-world MAE ranged from 0.09 to 0.13, MARE from 1.3 to 22.7%, with ICCs indicating moderate (0.57) to good (0.88) agreement. Lower errors were observed for cohorts without major gait impairments, less complex tasks, and longer walking bouts. The analytical pipelines demonstrated moderate to good accuracy in estimating walking speed. Accuracy depended on confounding factors, emphasizing the need for robust technical validation before clinical application.Trial registration: ISRCTN - 12246987., (© 2024. The Author(s).)

Background: Understanding the natural history of abnormal spirometric patterns at different stages of life is critical to identify and optimise preventive strategies. We aimed to describe characteristics and risk factors of restrictive and obstructive spirometric patterns occurring before 40 years (young onset) and between 40 and 61 years (mid-adult onset)., Methods: We used data from the population-based cohort of the European Community Respiratory Health Survey (ECRHS). Prebronchodilator forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) were assessed longitudinally at baseline (ECRHS1, 1993-1994) and again 20 years later (ECRHS3, 2010-2013). Spirometry patterns were defined as: restrictive if FEV 1 /FVC≥LLN and FVC<10th percentile, obstructive if FEV 1 /FVC

Background: We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements., Methods: Participants (20-68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991-2013 and 1997-2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV 1 , FVC and height at baseline, accounting for personal smoking., Findings: Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV 1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV 1 2.6 ml/year; 0.9, 4.4) (FEV 1 /FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV 1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found., Interpretation: Mothers' smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV 1 and FVC later in life comparable to smoking 10 pack-years., Funding: European Union's Horizon 2020; Research Council of Norway; Academy of Finland; University Hospital Oulu; European Regional Development Fund; Spanish Ministry of Science and Innovation; Generalitat de Catalunya., Competing Interests: SCD and CJL have received an investigator-initiated grant from GSK and a partnership grant from AZ for unrelated work. All other authors declare no conflict of interest., (© 2023 The Authors.)

Introduction: The clinical assessment of mobility, and walking specifically, is still mainly based on functional tests that lack ecological validity. Thanks to inertial measurement units (IMUs), gait analysis is shifting to unsupervised monitoring in naturalistic and unconstrained settings. However, the extraction of clinically relevant gait parameters from IMU data often depends on heuristics-based algorithms that rely on empirically determined thresholds. These were mainly validated on small cohorts in supervised settings., Methods: Here, a deep learning (DL) algorithm was developed and validated for gait event detection in a heterogeneous population of different mobility-limiting disease cohorts and a cohort of healthy adults. Participants wore pressure insoles and IMUs on both feet for 2.5 h in their habitual environment. The raw accelerometer and gyroscope data from both feet were used as input to a deep convolutional neural network, while reference timings for gait events were based on the combined IMU and pressure insoles data., Results and Discussion: The results showed a high-detection performance for initial contacts (ICs) (recall: 98%, precision: 96%) and final contacts (FCs) (recall: 99%, precision: 94%) and a maximum median time error of -0.02 s for ICs and 0.03 s for FCs. Subsequently derived temporal gait parameters were in good agreement with a pressure insoles-based reference with a maximum mean difference of 0.07, -0.07, and <0.01 s for stance, swing, and stride time, respectively. Thus, the DL algorithm is considered successful in detecting gait events in ecologically valid environments across different mobility-limiting diseases., Competing Interests: AM and FK are employees of, and may hold stock in, Novartis. BE reports consulting activities with, Siemens AG, Siemens Healthineers AG, WS Audiology GmbH outside of the study. He is a shareholder in Portabiles HealthCare Technologies GmbH. In addition, BE holds a patent related to gait assessment. MF is an employee of Grünenthal. LP and LC are co-founders and own shares of mHealth Technologies (https://mhealthtechnologies.it/). LS and CB are consultants of Philips Healthcare, Bosch Healthcare, Eli Lilly, and Gait Up. JH reports having submitted a patent for assessment of mobility using wearable sensors in Parkinson's disease. The intellectual property rights are held by the Tel Aviv Medical Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Romijnders, Salis, Hansen, Küderle, Paraschiv-Ionescu, Cereatti, Alcock, Aminian, Becker, Bertuletti, Bonci, Brown, Buckley, Cantu, Carsin, Caruso, Caulfield, Chiari, D'Ascanio, Del Din, Eskofier, Fernstad, Fröhlich, Garcia Aymerich, Gazit, Hausdorff, Hiden, Hume, Keogh, Kirk, Kluge, Koch, Mazzà, Megaritis, Micó-Amigo, Müller, Palmerini, Rochester, Schwickert, Scott, Sharrack, Singleton, Soltani, Ullrich, Vereijken, Vogiatzis, Yarnall, Schmidt and Maetzler.)

Background: Although digital mobility outcomes (DMOs) can be readily calculated from real-world data collected with wearable devices and ad-hoc algorithms, technical validation is still required. The aim of this paper is to comparatively assess and validate DMOs estimated using real-world gait data from six different cohorts, focusing on gait sequence detection, foot initial contact detection (ICD), cadence (CAD) and stride length (SL) estimates., Methods: Twenty healthy older adults, 20 people with Parkinson's disease, 20 with multiple sclerosis, 19 with proximal femoral fracture, 17 with chronic obstructive pulmonary disease and 12 with congestive heart failure were monitored for 2.5 h in the real-world, using a single wearable device worn on the lower back. A reference system combining inertial modules with distance sensors and pressure insoles was used for comparison of DMOs from the single wearable device. We assessed and validated three algorithms for gait sequence detection, four for ICD, three for CAD and four for SL by concurrently comparing their performances (e.g., accuracy, specificity, sensitivity, absolute and relative errors). Additionally, the effects of walking bout (WB) speed and duration on algorithm performance were investigated., Results: We identified two cohort-specific top performing algorithms for gait sequence detection and CAD, and a single best for ICD and SL. Best gait sequence detection algorithms showed good performances (sensitivity > 0.73, positive predictive values > 0.75, specificity > 0.95, accuracy > 0.94). ICD and CAD algorithms presented excellent results, with sensitivity > 0.79, positive predictive values > 0.89 and relative errors < 11% for ICD and < 8.5% for CAD. The best identified SL algorithm showed lower performances than other DMOs (absolute error < 0.21 m). Lower performances across all DMOs were found for the cohort with most severe gait impairments (proximal femoral fracture). Algorithms' performances were lower for short walking bouts; slower gait speeds (< 0.5 m/s) resulted in reduced performance of the CAD and SL algorithms., Conclusions: Overall, the identified algorithms enabled a robust estimation of key DMOs. Our findings showed that the choice of algorithm for estimation of gait sequence detection and CAD should be cohort-specific (e.g., slow walkers and with gait impairments). Short walking bout length and slow walking speed worsened algorithms' performances. Trial registration ISRCTN - 12246987., (© 2023. The Author(s).)

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 ≤0.02 m, walking speed ≤0.02 m/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 0.04-0.06 m, walking speed 0.03-0.05 m/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., Competing Interests: AM and FK are employees of, and may hold stock in, Novartis. BME reports consulting activities with adidas AG, Siemens AG, SiemensHealthineers AG, WSAudiology GmbH outside of the study. He is a shareholder in Portabiles HealthCare Technologies GmbH. In addition, BME holds a patent related to gait assessment. LP and LC are co-founders and own shares of mHealth Technologies (https://mhealthtechnologies.it/). LS and CB are consultants of Philipps Healthcare, Bosch Healthcare, Eli Lilly, Gait-up. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salis, Bertuletti, Bonci, Caruso, Scott, Alcock, Buckley, Gazit, Hansen, Schwickert, Aminian, Becker, Brown, Carsin, Caulfield, Chiari, D’Ascanio, Del Din, Eskofier, Garcia-Aymerich, Hausdorff, Hume, Kirk, Kluge, Koch, Kuederle, Maetzler, Micó-Amigo, Mueller, Neatrour, Paraschiv-Ionescu, Palmerini, Yarnall, Rochester, Sharrack, Singleton, Vereijken, Vogiatzis, Della Croce, Mazzà and Cereatti and for the Mobilise-D consortium.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. Methods: We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory 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 CK (creatine kinase) 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 the 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 (adjusted odds ratio, 95% confidence interval: 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 and CKB ) were underexpressed in blood from asthmatics compared with control subjects ( P  = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: Circulating concentrations 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 airway hyperresponsiveness and reduction of airway mucin.

Introduction: Obesity 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., Methods: We 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/m 2 ) individuals at visit t . The relative risk (RR) of obesity at t+1 associated with asthma at t was 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., Results: We 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., Conclusion: This 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., Competing Interests: Competing interests: SM reports Long-Term Research fellowship and Young Scientist Sponsorship from the European Respiratory Society, outside the submitted work. MJA holds investigator-initiated grants for unrelated research from Pfizer and Boehringer-Ingelheim. He has undertaken an unrelated consultancy for and received assistance with conference attendance from Sanofi and has also received a speaker’s fee from GSK, outside the submitted work. PD reports personal fees from ALK, Stallergenes Greer, IQVIA, Chiesi, AstraZeneca, Thermo Fisher Scientific, Ménarini, Bausch & Lomb, Mylan, ASIT Biotech, Novartis, Sanofi, Regeneron, outside the submitted work. RJ reports grants from Estonian Research Council Personal Research Grant no 562, during the conduct of the study; personal fees from Consultancy, grants from Grants/grants pending, personal fees from Payment for lectures, personal fees from Travel/accommodations/meeting expenses, outside the submitted work. CR-S reports personal fees from ALK, Astra Zeneca, GSK, Novartis, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. Crown.)

Background: We previously reported an association of high fat mass levels from age 9 to 15 years with lower forced expiratory flow in 1 s (FEV 1 )/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., Methods: We 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 FEV 1 /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., Results: Compared to children in the "low" FMI trajectory, children in the "medium-high" and "high" FMI trajectories had lower FEV 1 /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., Conclusion: The association between mid-childhood fat mass and FEV 1 /FVC ratio at 15 years may be partially mediated by insulin resistance., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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 (NO 2 ) and particulate matter (PM 2.5 ). 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 NO 2 levels related with more sedentary time and more difficulty in physical activity. PM 2.5 and noise were not associated with physical activity or exercise capacity., Discussion: Population density, pedestrian street length, slope and NO 2 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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 2t -IsoP) using ELISA technique. Residential and scholastic greenness were defined by the Normalized Difference Vegetation Index (NDVI) in buffers with 100, 250, 300, 500 and 1000 m radii, and vegetated portion was also estimated. Multisite exposures were derived accounting for NDVI around home and school, weighted for time spent in each location. Linear mixed models, age-adjusted, with schools as random intercept, tested the association between 500 m-radius buffer multisite grenness variables and log (15-F 2t -IsoP), reporting decreased oxidative stress per interquartile range (IQR) increase in multisite NDVI (β: 012, 95%CI -0.240 to 0.004) and multisite vegetated portion (β: 0.14, 95%CI -0.270 to -0.006). The mediation analysis did not support the hypothesis that physical activity frequency could mediate these associations. Multisite greenness exposure is associated with decreased oxidative stress in children and our data did not support the mediating role of physical activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The effectiveness of noninvasive respiratory support in severe COVID-19 patients is still controversial. We aimed to compare the outcome of patients with COVID-19 pneumonia and hypoxemic respiratory failure treated with high-flow oxygen administered via nasal cannula (HFNC), continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV), initiated outside the intensive care unit (ICU) in 10 university hospitals in Catalonia, Spain. We recruited 367 consecutive patients aged ≥ 18 years who were treated with HFNC (155, 42.2%), CPAP (133, 36.2%) or NIV (79, 21.5%). The main outcome was intubation or death at 28 days after respiratory support initiation. After adjusting for relevant covariates and taking patients treated with HFNC as reference, treatment with NIV showed a higher risk of intubation or death (hazard ratio 2.01; 95% confidence interval 1.32-3.08), while treatment with CPAP did not show differences (0.97; 0.63-1.50). In the context of the pandemic and outside the intensive care unit setting, noninvasive ventilation for the treatment of moderate to severe hypoxemic acute respiratory failure secondary to COVID-19 resulted in higher mortality or intubation rate at 28 days than high-flow oxygen or CPAP. This finding may help physicians to choose the best noninvasive respiratory support treatment in these patients.Clinicaltrials.gov identifier: NCT04668196., (© 2022. The Author(s).)

Objective: To investigate the association between maternal sleep duration (an important health indicator) and neonate birth weight., Methods: The study included 2536 mother-neonate 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 neonate birth weight score (g) standardized to 40 weeks of gestation., Results: In women sleeping for <7 h/day before pregnancy, each additional hour of sleep increased birth weight 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 for more than 9 h/day decreased birth weight score by 39.2 g per additional hour (P = 0.001). Findings were similar after adjusting for several sociodemographic confounders and maternal depression-anxiety clinical history as an intermediate factor. Similar but attenuated associations were observed with sleep duration in the second trimester of pregnancy., Conclusion: The relationship between maternal sleep duration before and during pregnancy and neonate birth weight is an inverse U-shaped curve. Excessive sleep duration may adversely affect neonate health through its impact on birth weight., (© 2021 International Federation of Gynecology and Obstetrics.)

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)., Competing Interests: Competing interests: FC is CEO and shareholder of Aeqora Ltd, of which VL is director and shareholder. HS is an employee of AstraZeneca. BE is co-founder and owns shares of Portabiles HealthCare Technologies GmbH. McRoberts is the manufacturer of the DynaPort. MN, JE, and LPl are employees of McRoberts. AM is an employee of Novartis and holds stock in Novartis. LS and CB are consultants of Philipps Healthcare, Bosch Healthcare, Eli Lilly, Gait-up. JMH reports having submitted a patent for assessment of mobility using wearable sensors in 400 Parkinson’s disease; the intellectual property rights 401 are held by the Tel Aviv Medical Center. LPa and LC are co-founders and own shares of mHealth Technologies., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although there are many health benefits from being active, there was no benefit observed in this study from vigorous physical activity in reducing the risk of asthma onset in middle-aged adults https://bit.ly/3bEtHDn., Competing Interests: Conflict of interest: M.A. Russell has nothing to disclose. Conflict of interest: S. Dharmage has nothing to disclose. Conflict of interest: E. Fuertes has nothing to disclose. Conflict of interest: A. Marcon has nothing to disclose. Conflict of interest: A-E. Carsin has nothing to disclose. Conflict of interest: S. Pascual Erquicia has nothing to disclose. Conflict of interest: J. Heinrich has nothing to disclose. Conflict of interest: A. Johannessen has nothing to disclose. Conflict of interest: M.J. Abramson has nothing to disclose. Conflict of interest: A.F.S. Amaral has nothing to disclose. Conflict of interest: I. Cerveri has nothing to disclose. Conflict of interest: P. Demoly reports board fees from Chiesi, IQVIA, Ménarini and Sanofi; board and speaker bureau fees from AstraZeneca, Bausch & Lomb and ThermoFisher Scientific; and speaker fees from Mylan and Novartis, all outside the submitted work. Conflict of interest: V. Garcia-Larsen has nothing to disclose. Conflict of interest: D. Jarvis has nothing to disclose. Conflict of interest: J. Martinez-Moratalla has nothing to disclose. Conflict of interest: D. Nowak has nothing to disclose. Conflict of interest: L. Palacios-Gómez has nothing to disclose. Conflict of interest: G. Squillacioti has nothing to disclose. Conflict of interest: W. Raza has nothing to disclose. Conflict of interest: M. Emtner has nothing to disclose. Conflict of interest: J. Garcia-Aymerich has nothing to disclose., (Copyright ©The authors 2021.)

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 (FEV 1 ) 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 FEV 1 and the FEV 1 /FVC ratio for exposure to biological dust, mineral dust, and metals (FEV 1  = -15.1 ml, -14.4 ml, and -18.7 ml, respectively; and FEV 1 /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.

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 <80% predicted) using modified Poisson regression, adjusting for relevant confounders. After 10 years of follow-up, 3.3% of participants had developed restrictive spirometry pattern. Being physically active was associated with a lower risk of developing this phenotype (relative risk = 0.76, 95% confidence interval: 0.59, 0.98). This association was stronger among those who were overweight and obese than among those of normal weight (P for interaction = 0.06). In 2 large European studies, adults practicing regular physical activity were at lower risk of developing restrictive spirometry pattern over 10 years., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: Conflict of interest: P. Haldar has nothing to disclose. Conflict of interest: A-E. Carsin has nothing to disclose. Conflict of interest: S. Debnath has nothing to disclose. Conflict of interest: S.G. Maity has nothing to disclose. Conflict of interest: I. Annesi-Maesano has nothing to disclose. Conflict of interest: J. Garcia-Aymerich has nothing to disclose. Conflict of interest: A. Bandyopadhyay has nothing to disclose. Conflict of interest: Saibal Moitra has nothing to disclose. Conflict of interest: M. Kogevinas has nothing to disclose. Conflict of interest: Subhabrata Moitra reports a Young Scientist sponsorship and a long-term fellowship from the European Respiratory Society, and nonfinancial support from Oxford Publications, outside the submitted work., (Copyright ©ERS 2020.)

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 (<-0.25 kg/year) exhibited an attenuation of FVC and FEV 1 declines. We found no association between weight change profiles and FEV 1 /FVC decline., Conclusion: Moderate and high weight gain over 20 years was associated with accelerated lung function decline, while weight loss was related to its attenuation. Control of weight gain is important for maintaining good lung function in adult life., Competing Interests: Competing interests: JG-A reports personal fees from Esteve, Chiesi and AstraZeneca, outside the submitted work. MJA reports grants from Pfizer, grants from Boehringer-Ingelheim and personal fees from Sanofi, outside the submitted work. PD reports personal fees from ALK, Stallergenes Greer, IQVIA, Chiesi, AstraZeneca, Thermo Fisher Scientific, Menarini, Bausch & Lomb, Mylan, ASIT Biotech, Novartis, Sanofi and Regeneron, outside the submitted work. RJ reports grants from Estonian Research Council (Personal Research Grant no 562) and personal fees from GSK, Boehringer and Novartis, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

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 NO 2 , PM 10 , PM 2.5 , and PM coarse (calculated by subtracting PM 2.5 from PM 10 ) 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 PM 10 was associated with higher rhinitis severity (adjusted odds ratio [95% CI] for a 10 μg/m 3 increase in PM 10 : 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 PM 2.5 . Higher exposure to NO 2 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 NO 2. 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., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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 (AO post-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 AO post-BD was 59.1% (52.0-66.2%) in men and 42.6% (35.1-50.1%) in women. AO post-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. AO post-BD incidence is expected to be half of AO incidence.

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., Competing Interests: The authors have declared that no competing interests exist.

This longitudinal study investigated whether smoking bans influence passive smoking at work and/or at home in the same subjects. Passive smoking at work and/or at home was investigated in random population samples (European Community Respiratory Health Survey) in 1990-1995, with follow-up interviews in 1998-2003 and 2010-2014. National smoking bans were classified as partial (restricted to public workplaces) or global (extended to private workplaces). Multivariable analysis was accomplished by three-level logistic regression models, where level-1, level-2, and level-3 units were, respectively, questionnaire responses, subjects, and centers. Passive smoking at work was reported by 31.9% in 1990-1995, 17.5% in 1998-2003, and 2.5% in 2010-2014. Concurrently, passive smoking at home decreased from 28.9% to 18.2% and 8.8%. When controlling for sex, age, education, smoking status, and ECHRS wave, the odds of passive smoking at work was markedly reduced after global smoking bans (OR = 0.45, 95% CI 0.25-0.81), particularly among non-smokers, while the protective effect of global smoking bans on passive smoking at home was only detected in non-smokers. Smoking bans both in public and private workplaces were effective in reducing passive smoking at work in Europe. However, given the inefficacy of smoking bans in current smokers' dwellings, better strategies are needed to avoid smoking indoors., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Ambient air pollution is a leading environmental risk factor and its broad spectrum of adverse health effects includes a decrease in lung function. Socioeconomic status (SES) is known to be associated with both air pollution exposure and respiratory function. This study assesses the role of SES either as confounder or effect modifier of the association between ambient air pollution and lung function. Cross-sectional data from three European multicenter adult cohorts were pooled to assess factors associated with lung function, including annual means of home outdoor NO 2 . Pre-bronchodilator lung function was measured according to the ATS-criteria. Multiple mixed linear models with random intercepts for study areas were used. Three different factors (education, occupation and neighborhood unemployment rate) were considered to represent SES. NO 2 exposure was negatively associated with lung function. Occupation and neighborhood unemployment rates were not associated with lung function. However, the inclusion of the SES-variable education improved the models and the air pollution-lung function associations got slightly stronger. NO 2 associations with lung function were not substantially modified by SES-variables. In this multicenter European study we could show that SES plays a role as a confounder in the association of ambient NO 2 exposure with lung function.

Objectives: Chronic bronchitis (CB) is an important chronic obstructive pulmonary disease (COPD)-related phenotype, with distinct clinical features and prognostic implications. Occupational exposures have been previously associated with increased risk of CB but few studies have examined this association prospectively using objective exposure assessment. We examined the effect of occupational exposures on CB incidence in the European Community Respiratory Health Survey., Methods: Population samples aged 20-44 were randomly selected in 1991-1993, and followed up twice over 20 years. Participants without chronic cough or phlegm at baseline were analysed. Coded job histories during follow-up were linked to the ALOHA Job Exposure Matrix, generating occupational exposure estimates to 12 categories of chemical agents. Their association with CB incidence over both follow-ups was examined with Poisson models using generalised estimating equations., Results: 8794 participants fulfilled the inclusion criteria, contributing 13 185 observations. Only participants exposed to metals had a higher incidence of CB (relative risk (RR) 1.70, 95% CI 1.16 to 2.50) compared with non-exposed to metals. Mineral dust exposure increased the incidence of chronic phlegm (RR 1.72, 95% CI 1.43 to 2.06). Incidence of chronic phlegm was increased in men exposed to gases/fumes and to solvents and in women exposed to pesticides., Conclusions: Occupational exposures are associated with chronic phlegm and CB, and the evidence is strongest for metals and mineral dust exposure. The observed differences between men and women warrant further investigation., Competing Interests: Competing interests: DJ reports grants from European Commission during the conduct of the study. VS reports grants from the Wood Dust Foundation (Project No 444508795) during the conduct of the study. IP reports non-financial support and other from Novartis, personal fees and other from Astra Zeneca, non-financial support and other from Chiesi, outside the submitted work. PD reports personal fees from ALK, Stallergènes Greer, Chiesi, Thermo Fisher Scientific, Ménarini, Bausch&Lomb and Mylan, outside the submitted work. RJ reports grants from Estonian Research Council (personal research grant number 562) during the conduct of the study, personal fees and non-financial support from GSK, personal fees from Novartis and Boehringer, outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

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-κB 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.

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 FEV 1 /FVC ≥ Lower Limit of Normal and a FVC<80% predicted in two population-based studies (ECRHS-III and SAPALDIA3). Physical activity was measured using the International Physical Activity Questionnaire. The odds of having low physical activity (<1st study-specific tertile) was evaluated using adjusted logistic regression models., Results: Subjects with a restrictive spirometry pattern (n = 280/4721 in ECRHS, n = 143/3570 in SAPALDIA) reported lower levels of physical activity than those with normal spirometry (median of 1770 vs 2253 MET·min/week in ECRHS, and 3519 vs 3945 MET·min/week in SAPALDIA). Subjects with a restrictive spirometry pattern were more likely to report low physical activity (meta-analysis odds ratio: 1.41 [95%CI 1.07-1.86]) than those with a normal spirometry. Obesity, respiratory symptoms, co-morbidities and previous physical activity levels did not fully explain this finding., Conclusion: Adults with a restrictive spirometry pattern were more likely to report low levels of physical activity than those with normal spirometry. These results highlight the need to identify and act on this understudied but prevalent condition., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Occupational exposures have been associated with an increased risk of COPD. However, few studies have related objectively assessed occupational exposures to prospectively assessed incidence of COPD, using postbronchodilator lung function tests. Our objective was to examine the effect of occupational exposures on COPD incidence in the European Community Respiratory Health Survey., Methods: General population samples aged 20-44 were randomly selected in 1991-1993 and followed up 20 years later (2010-2012). Spirometry was performed at baseline and at follow-up, with incident COPD defined using a lower limit of normal criterion for postbronchodilator FEV1/FVC. Only participants without COPD and without current asthma at baseline were included. Coded job histories during follow-up were linked to a Job-Exposure Matrix, generating occupational exposure estimates to 12 categories of agents. Their association with COPD incidence was examined in log-binomial models fitted in a Bayesian framework., Findings: 3343 participants fulfilled the inclusion criteria; 89 of them had COPD at follow-up (1.4 cases/1000 person-years). Participants exposed to biological dust had a higher incidence of COPD compared with those unexposed (relative risk (RR) 1.6, 95% CI 1.1 to 2.3), as did those exposed to gases and fumes (RR 1.5, 95% CI 1.0 to 2.2) and pesticides (RR 2.2, 95% CI 1.1 to 3.8). The combined population attributable fraction for these exposures was 21.0%., Interpretation: These results substantially strengthen the evidence base for occupational exposures as an important risk factor for COPD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The vicious circle of dyspnoea-inactivity has been proposed, but never validated empirically, to explain the clinical course of chronic obstructive pulmonary disease (COPD). We aimed to develop and validate externally a comprehensive vicious circle model.We utilised two methods. 1) Identification and validation of all published vicious circle models by a systematic literature search and fitting structural equation models to longitudinal data from the Spanish PAC-COPD (Phenotype and Course of COPD) cohort (n=210, mean age 68 years, mean forced expiratory volume in 1 s (FEV 1 ) 54% predicted), testing both the hypothesised relationships between variables in the model ("paths") and model fit. 2) Development of a new model and external validation using longitudinal data from the Swiss and Dutch ICE COLD ERIC (International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts) cohort (n=226, mean age 66 years, mean FEV 1 57% predicted).We identified nine vicious circle models for which structural equation models confirmed most hypothesised paths but showed inappropriate fit. In the new model, airflow limitation, hyperinflation, dyspnoea, physical activity, exercise capacity and COPD exacerbations remained related to other variables and model fit was appropriate. Fitting it to ICE COLD ERIC, all paths were replicated and model fit was appropriate.Previously published vicious circle models do not fully explain the vicious circle concept. We developed and externally validated a new comprehensive model that gives a more relevant role to exercise capacity and COPD exacerbations., Competing Interests: Conflict of interest: A. Agustí reports receiving grants and personal fees from AstraZeneca, GSK and Menarini, grants from MSD, and personal fees from Novartis, Teva and Chiesi, outside the submitted work. Conflict of interest: R. Rodriguez-Roisin reports receiving grants from Almirall and Menarini, personal fees for service on an advisory board from Boehringer Ingelheim, Pearl Therapeutics and Teva, and lecture fees from Novartis and Takeda, during the conduct of the study, all related to COPD. Conflict of interest: J. Garcia-Aymerich reports payments to her institution for consulting and lecturing from AstraZeneca, and receiving lecture fees from Esteve and Chiesi, outside the submitted work., (Copyright ©ERS 2018.)

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., Funding: European Union (Horizon 2020, GA-633212).

Background: The association between air pollution and rhinitis is not well established., Aim: The aim of this longitudinal analysis was to study the association between modeled air pollution at the subjects' home addresses and self-reported incidence of rhinitis., Methods: We used data from 1533 adults from two multicentre cohorts' studies (EGEA and ECRHS). Rhinitis incidence was defined as reporting rhinitis at the second follow-up (2011 to 2013) but not at the first follow-up (2000 to 2007). Annual exposure to NO 2 , PM 10 and PM 2.5 at the participants' home addresses was estimated using land-use regression models developed by the ESCAPE project for the 2009-2010 period. Incidence rate ratios (IRR) were computed using Poisson regression. Pooled analysis, analyses by city and meta-regression testing for heterogeneity were carried out., Results: No association between long-term air pollution exposure and incidence of rhinitis was found (adjusted IRR (aIRR) for an increase of 10 μg·m -3 of NO 2: 1.00 [0.91-1.09], for an increase of 5 μg·m -3 of PM 2.5 : 0.88 [0.73-1.04]). Similar results were found in the two-pollutant model (aIRR for an increase of 10 μg·m -3 of NO 2: 1.01 [0.87-1.17], for an increase of 5 μg·m -3 of PM 2.5 : 0.87 [0.68-1.08]). Results differed depending on the city, but no regional pattern emerged for any of the pollutants., Conclusions: This study did not find any consistent evidence of an association between long-term air pollution and incident rhinitis., (Copyright © 2018. Published by Elsevier Ltd.)

Rationale: Cleaning tasks may imply exposure to chemical agents with potential harmful effects to the respiratory system, and increased risk of asthma and respiratory symptoms among professional cleaners and in persons cleaning at home has been reported. Long-term consequences of cleaning agents on respiratory health are, however, not well described., Objectives: This study aimed to investigate long-term effects of occupational cleaning and cleaning at home on lung function decline and airway obstruction., Methods: The European Community Respiratory Health Survey (ECRHS) investigated a multicenter population-based cohort at three time points over 20 years. A total of 6,235 participants with at least one lung function measurement from 22 study centers, who in ECRHS II responded to questionnaire modules concerning cleaning activities between ECRHS I and ECRHS II, were included. The data were analyzed with mixed linear models adjusting for potential confounders., Measurements and Main Results: As compared with women not engaged in cleaning (ΔFEV 1  = -18.5 ml/yr), FEV 1 declined more rapidly in women responsible for cleaning at home (-22.1; P = 0.01) and occupational cleaners (-22.4; P = 0.03). The same was found for decline in FVC (ΔFVC = -8.8 ml/yr; -13.1, P = 0.02; and -15.9, P = 0.002; respectively). Both cleaning sprays and other cleaning agents were associated with accelerated FEV 1 decline (-22.0, P = 0.04; and -22.9, P = 0.004; respectively). Cleaning was not significantly associated with lung function decline in men or with FEV 1 /FVC decline or airway obstruction., Conclusions: Women cleaning at home or working as occupational cleaners had accelerated decline in lung function, suggesting that exposures related to cleaning activities may constitute a risk to long-term respiratory health.

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: FEV 1 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 FEV 1 and FVC., Results: Physical activity frequency and duration increased over the study period. In adjusted models, active individuals at the first examination had higher FEV 1 (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, FEV 1 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 FEV 1 and FVC over a 10-year period among current smokers, but not with FEV 1 and FVC decline., Competing Interests: Competing interests: PD reports consulting fees from ALK, Stallergènes Greer, Circassia, Chiesi, Thermofisher Scientific and Ménarini, and AGC reports grants from Chiesi Farmaceutici and from GlaxoSmithKline Italy, during the conduct of the study. Other authors declare no competing interests related to this work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., Competing Interests: Conflict of interest: J. Bousquet has received personal fees for acting on scientific and advisory boards from Almirall, Meda, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach; and personal fees for lecturing from Almirall, AstraZeneca, Chiesi, GSK, Meda, Menarini, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach, outside the submitted work. Conflict of interest: R.J.P. van der Valk received a grant from the Dutch Lung Foundation during the conduct of the study; and is a Dutch Medical Affairs employee of GlaxoSmithKline (since June 2015), but does not hold stocks and is not involved in conducting any R&D activities for GlaxoSmithKline. Conflict of interest: M.C. Nawijn received a supporting grant to his institution for the submitted work from the Lung Foundation Netherlands during the conduct of the study. Conflict of interest: S. Guerra received a grant from European Commission's Seventh Framework Programme during the conduct of the study. Conflict of interest: D.S. Postma: The University of Groningen received grants for research from AstraZeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. Conflict of interest: G.H. Koppelman has received institutional grants from the Netherlands Lung Foundation, Ubbo Emmius Foundation and the European Commission during the conduct of the study; and grants from the Netherlands Lung Foundation, TEVA (the Netherlands) and Stichting Astma Bestrijding outside the submitted work., (Copyright ©ERS 2018.)

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., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Sleep length has been associated with obesity and various adverse health outcomes. The possible association of sleep length and respiratory symptoms has not been previously described. The aim of this study was to investigate the association between sleep length and respiratory symptoms and whether such an association existed independent of obesity., Methods: This is a multicentre, cross-sectional, population-based study performed in 23 centres in 10 different countries. Participants (n=5079, 52.3% males) were adults in the third follow-up of the European Community Respiratory Health Survey III. The mean±SD age was 54.2±7.1 (age range 39-67 years). Information was collected on general and respiratory health and sleep characteristics., Results: The mean reported nighttime sleep duration was 6.9±1.0 hours. Short sleepers (<6 hours per night) were n=387 (7.6%) and long sleepers (≥9 hours per night) were n=271 (4.3%). Short sleepers were significantly more likely to report all respiratory symptoms (wheezing, waking up with chest tightness, shortness of breath, coughing, phlegm and bronchitis) except asthma after adjusting for age, gender, body mass index (BMI), centre, marital status, exercise and smoking. Excluding BMI from the model covariates did not affect the results. Short sleep was related to 11 out of 16 respiratory and nasal symptoms among subjects with BMI ≥30 and 9 out of 16 symptoms among subjects with BMI <30. Much fewer symptoms were related to long sleep, both for subjects with BMI <30 and ≥30., Conclusions: Our results show that short sleep duration is associated with many common respiratory symptoms, and this relationship is independent of obesity., Competing Interests: Competing interests: None declared.

Background: Currently, the 5-year survival rate for rectal cancer remains at <60%. The identification of potentially modifiable prognostic factors would be of considerable public health importance. A few studies have suggested associations between smoking and survival in rectal cancer; however, the evidence is inconsistent, and most of these studies were relatively small. In a large population-based cohort study, we investigated whether smoking at diagnosis is an independent prognostic factor for cancer-specific survival in rectal cancer and whether the association varies by sex, age, or treatment., Methods: Rectal cancers (ICD10 C19-20) diagnosed between 1994 and 2012 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, 2012. Multivariable Cox proportional hazards models were used to compare cancer-specific death rates in current smokers, ex-smokers, and never smokers. Subgroup analyses by age at diagnosis, sex, and treatment were conducted., Results: A total of 10,794 rectal cancers were diagnosed. At diagnosis, 25% were current smokers, 24% were ex-smokers, and 51% were never smokers. Compared with never smokers, current smokers had a significantly greater rate of death from cancer (multivariable hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.06-1.24), but ex-smokers did not (HR, 1.02; 95% CI, 0.94-1.11). The association was slightly stronger in men (current versus never smokers: HR = 1.13, 95% CI, 1.02-1.24) than females (HR, 1.05; 95% CI, 0.90-1.23), but the test for interaction was not significant (P = .75). The effect of smoking was not modified by age or receipt of tumor-directed surgery, radiotherapy, or chemotherapy., Conclusions: Rectal cancer patients who smoke at diagnosis have a statistically significant increased cancer death rate. Elucidation of the underlying mechanisms is urgently required. Cancer 2017;123:2543-50. © 2017 American Cancer Society., (© 2017 American Cancer Society.)