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Lung cancer patients are diagnosed at late stages when curative treatments are no longer possible; thus, molecular biomarkers for noninvasive detection are urgently needed. In this sense, we previously identified and validated an epigenetic 4-gene signature that yielded a high diagnostic performance in tissue and invasive pulmonary fluids. We analyzed DNA methylation levels using the ultrasensitive digital droplet PCR in noninvasive samples in a cohort of 83 patients. We demonstrated that BCAT1 is the candidate that achieves high diagnostic efficacy in circulating DNA derived from plasma (area under the curve: 0.85). Impact of potentially confounding variables was also explored.

Background Cardiac rehabilitation after acute myocardial infarction permits recovery of the heart function and enables secondary prevention programs in which changes in lifestyle habits are crucial. Cardiac rehabilitation often takes place in hospitals without coordination with primary healthcare and is not focused on individual patient preferences and goals, which is the core of the motivational interview. The objective of this study was to evaluate the efficacy of a cardiac rehabilitation program with a motivational interview in patients discharged from hospital after acute myocardial infarction. Methods/design A randomized, non-pharmacological clinical trial in six primary healthcare centers in Barcelona (Spain) will assess whether a tailored cardiac rehabilitation program consisting of four motivational interviews and visits with family physicians, primary healthcare nurses and a cardiologist, coordinated with the reference hospital, results in better cardiac rehabilitation than standard care. A minimum sample of 284 participants requiring cardiac rehabilitation after acute myocardial infarction will be randomized to a cardiac rehabilitation group with a motivational interview program or to standard primary healthcare. The main outcome will be physical function measured by the six-minute walk test, and the secondary outcome will be the effectiveness of secondary prevention: a composite outcome comprising control of blood pressure, cholesterol, diabetes mellitus, smoking and body weight. Results will be evaluated at 1,3 and 6 months. Discussion This is the first clinical trial to study the impact of a new primary healthcare cardiac rehabilitation program with motivational interviews for patients discharged from hospital after myocardial infarction. Changes in lifestyles and habits after myocardial infarction are a core element of secondary prevention and require patient-centered care strategies such as motivational interviews. Therefore, this study could clarify the impact of this approach on health indicators, such as functional capacity. Trial registration ClinicalTriasl.gov NCT05285969 registered on March 18, 2022.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) progression is variable and affects several disease domains, including decline in lung function, exercise capacity, muscle strength, and health status as well as changes in body composition. We aimed to assess the longitudinal association of physical activity (PA) with these a priori selected components of disease progression. METHODS: We studied 114 COPD patients from the PAC-COPD cohort (94% male, mean [SD], 70 yr [8 yr] of age, 54 [16] forced expiratory volume in 1 s % predicted) at baseline and 2.6 yr (0.6 yr) later. Baseline PA was assessed by accelerometry. Multivariable general linear models were built to assess the association between PA and changes in lung function, functional exercise capacity, muscle strength, health status, and body composition. All models were adjusted for confounders and the respective baseline value of each measure. RESULTS: Per each 1000 steps higher baseline PA, forced expiratory volume in 1 s declined 7 mL less (P < 0.01), forced vital capacity 9 mL less (P = 0.03) and carbon monoxide diffusing capacity 0.10 mL·min·mm Hg less (P = 0.04), while the St George's Respiratory Questionnaire symptom domain deteriorated 0.4 points less (P = 0.03), per year follow-up. Physical activity was not associated with changes in functional exercise capacity, muscle strength, other domains of health status or body composition. CONCLUSIONS: Higher PA is associated with attenuated decline in lung function and reduced health status (symptoms domain) deterioration in moderate-to-very severe COPD patients. ispartof: MEDICINE AND SCIENCE IN SPORTS AND EXERCISE vol:51 issue:5 pages:833-840 ispartof: location:United States status: published

This article provides an updated picture of the enormous consequences that the first wave of the COVID-19 pandemic (March–June 2020) had for older adults living in Spanish care homes. It aims to describe the regional variation in deaths among home care residents through a methodological triangulation of descriptive quantitative, ecological and documentary analysis. Figures of five different indicators of care home mortality are provided and some factors related to higher mortality rates are presented and analysed in the descriptive ecological analysis in order to depict trends and, in a linear regression, to determine their statistical significance. The clearest trend reflected by the data is that the higher the cumulative incidence and the number of care home beds in the surrounding area, the higher the COVID-19 care home mortality. We argue that the pandemic has brought to light the historical fragility and underdevelopment of the Spanish LTC sector, and that these factors have exacerbated the consequences of the pandemic. Finally, we conclude that publicly available and disaggregated data would allow a deeper and more accurate analysis of potentially explanatory factors such as the type of care home ownership and management, and that further qualitative research would shed more light on people’s experiences.

Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of recombinant EDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR-mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate tyrosine kinase inhibitor delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors. Significance: EDNR antagonists can be repurposed to improve drug delivery in VEGFA–secreting tumors, which normally respond to TKI treatment by secreting EDN1, promoting vasoconstriction, and limiting blood and drug delivery.

BACKGROUND Public patient involvement (PPI) generates knowledge about the health-illness process through the incorporation of people's experiences and priorities. The Babies Born Better (BBB) survey is a pan-European online questionnaire that can be used as a PPI tool for preliminary and consultative forms of citizens' involvement. The purpose of this research was to identify which practices support positive birth experiences and which ones women want changed. METHODS The BBB survey was distributed in virtual communities of practice and through social networks. The version launched in Spain was used to collect data in 2014 and 2015 from women who had given birth in the previous 5 years. A descriptive, quantitative analysis was applied to the sociodemographic data. Two open-ended questions were analyzed by qualitative content analysis using a deductive and inductive codification process. RESULTS A total of 2841 women participated. 41.1% of the responses concerned the category "Care received and experienced," followed by "Specific interventions and procedures" (26.6%), "Involved members of care team" (14.2%), and "Environmental conditions" (9%). Best practices were related to how care is provided and received, and the main areas for improvement referred to specific interventions and procedures. CONCLUSIONS This survey proved a useful tool to map the best and poorest practices reported. The results suggest a need for improvement in some areas of childbirth care. Women's reports on negative experiences included a wide range of routine clinical interventions, avoidable procedures, and the influence exerted by professionals on their decision-making.

Introduction The birth plan allows the woman to express her expectations and needs with regards to the childbearing continuum but its use has been debated in the clinical context and in published literature. The birth plan was first introduced in the Spanish Health Service in 2008 through the Strategy for the Care in Normal Childbirth. In Catalonia, the Normal Childbirth Care Programme has promoted the use of birth plans in hospitals participating in this Programme. Objective This works describes and analyses the birth plans produced by the participating hospitals in order to gather knowledge about the options available to women. Method Qualitative study in which the content of birth plans is systematically and quantitatively described in order to evaluate options available to women. The final sample includes all the birth plans provided by 30 Catalonian public hospitals. Following an initial assessment, it was decided to devise a grading scale which allowed to code and assign a value to each of the items contained in the birth plans. Results Three different types of birth plan are identified: a) those which present a list of items with no (or very little) associated explanations, b) list of items with some explanations and c) plans without items which only explain normal working practices in the hospital and/or protocols.

We assume that the construction of encounters that produce care is a participative practice in health. Drawing on different research that has explored care production from a micropolitical approach, we present a view of participation as embedded in everyday life and based on the construction of encounters and relationships. Our goal is to provide reflections for debate on participatory practice within different frames of action. Based on the analysis of different cartographic narratives generated by research on a reproductive health policy, we discuss some core elements for the construction of encounters that produce care. On the same lines as models of professional development based on professionals’ day-to-day experiences, we propose experimentation during the encounters and discussion about what happens in them, as both a reflective practices and forms of collective and participative knowledge production.

Background COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes.Objective We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results.Methods We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance.Results The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17-0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32-0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies.Conclusions Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.

Epigenetic information is able to interact with the cellular environment and could be especially useful for reprograming gene expression in response to a physiological perturbation. In fact the genes induced or repressed by osmotic stress undergo significant changes in terms of the levels of various histone modifications, especially in the acetylation levels of histone H3. Exposing yeast to high osmolarity results in the activation of stress-activated protein kinase Hog1, which plays a central role in gene expression control. We evaluated the connection between the presence of Hog1 and changes in histone H3 acetylation in stress-regulated genes. We found a parallel increase in the acetylation of lysines 9 and 14 of H3 in induced genes during stress, which was largely dependent on Hog1 at the genome-wide level. Conversely, we observed that acetylation decreased in repressed genes and was not dependent on Hog1. However, lack of Hog1 sometimes produced different, and even opposite, effects on the induction and acetylation of H3 of each gene. We also found that the acetylation state of lysine 9 of H3 was altered in the strains deficient in Nut1 HAT and Hos1 HDAC in the genes up-regulated during osmotic stress in an Msn2/Msn4-independent manner, while lysine 9 acetylation of H3 varied in the strains deficient in Sas2 HAT and Rpd3 HDAC for the Msn2/Msn4-dependent induced genes. The results presented here show new, unexpected participants in gene regulation processes in response to environmental perturbations.

Background: A mean annual decline in physical activity (PA) of 450 steps/d approximately has been reported in patients with COPD but it is not known if the evolution is the same for all patients. Aims: To identify PA trajectories and their determinants using a hypothesis-free approach. Methods: We pooled data from the PROactive initial validation (NCT01388218) study and the usual care arm of the Urban Training study (NCT01897298), including an objective measure of PA at baseline and 12 months. We identified clusters of individual PA trajectories (steps/d), using a k-means approach and compared baseline sociodemographic, interpersonal, clinical and psychological characteristics across clusters. Results: Based on 293 COPD patients (mean (SD) 68 (8) y, 82% male, FEV1 58% pred), we identified three distinct PA trajectories: inactive (59%), improvers (17%) and decliners (24%) (Fig 1). Being in the inactive group was associated with a lower proportion of patients still working and a worse general status (lower lung function, exercise capacity and quality of life, and higher dyspnoea and depression score) at baseline. While improvers and decliners were very similar in their baseline characteristics, improvers showed a significant reduction in weight during follow-up compared to decliners. Conclusions: The natural course of PA in patients with COPD was heterogeneous and one group improved PA over time.

OBJECTIVES: Physical activity is key to improve the prognosis of chronic obstructive pulmonary disease (COPD). To help to tailor future interventions we aimed to identify the baseline characteristics of COPD patients which predict 12-month completion and response to a behavioral physical activity intervention. METHODS: This is a 12-month cohort study of the intervention arm of the Urban Training randomized controlled trial (NCT01897298), an intervention proven to be efficacious to increase physical activity. We considered baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics as potential determinants of completion and response. We defined completion as attending the 12-month study visit. Among completers, we defined response as increasing physical activity ≥1100 steps/day from baseline to 12 months, measured by accelerometer. We estimated the factors independently for completion and response using multivariable logistic regression models. RESULTS: Of a total of 202 patients (m (SD) 69 (9) years, 84% male), 132 (65%) completed the study. Among those, 37 (28%) qualified as responders. Higher numbers of baseline steps/day (OR [95% CI] 1.11 [1.02-1.21] per increase of 1000 steps, p

International audience; The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

e15042 Background: Inhibitors of immune checkpoint PD-1/PD-L1 (ICI) have become a care standard in non-small cell lung cancer (NSCLC). Despite promising results, some patients cannot take advantage of immunotherapy effects. Nowadays, neither predictive nor prognostic circulating biomarkers have been found in order to select patients or to predict response to ICI. Myeloid-derived suppressor cells (MDSC) are potent immunity suppressors and may represent both a potential prognostic and a predictive biomarker. We aimed to assess the role of pretreatment circulating MDSC subpopulations on ICI outcomes in NSCLC patients. Methods: 86 NSCLC patients treated with ICI and 10 healthy donors in 3 centers between 02/2018 and 10/2019 were eligible. Pretreatment immunophenotyping of monocytes, early-MDSC (e-MDSC: CD14-/CD15-/HLA-DR-/CD33+/CD11b+), monocytic-MDSC (M-MDSC: CD14+/CD15-/HLA-DR-/CD33+/CD11b+) and polymorphonuclear-MDSC (PMN-MDSC: CD14-/CD15+/HLA-DR-/CD33+/CD11b+) was prospectively performed by flow cytometry in fresh whole blood. Correlation between baseline circulating MDSC subpopulations and Neutrophils/Lymphocytes Ratio (NLR) was evaluated as well as their impact on outcomes. Results: 86 patients who received at least one previous platinum based combination chemotherapy for stage III-IV NSCLC were prospectively included; 82 (95%) smokers, median age 62 years; 52 (60%) non-squamous; 69 (93%) ECOG PS 0-1; 43 (50%) PDL1 ≥ 1% and 65 (76%) were treated in a second line setting. Median PFS (mPFS) was 2.79 months (m) [95% CI, 1.3-4.2] and mOS 11.6 m [9.3-13.9]. Overall, 3m-death rate was 18.6%. Pretreatment high-NLR (NLR > 3) (62/86; 72%) was correlated with poor PFS (p = 0.03), OS (p = 0.01) and a 3m-death rate of 22.6%. High level of global MDSC before anti-PD-1/PD-L1 therapy, defined by the median value as a cut-off ( > 6.3%), was associated with poor OS (p = 0.03). Pretreatment low e-MDSC ( < 21.7%), were also associated with poor PFS (p = 0.01), OS (p = 0.006) and a 3m-death rate of 23.8%. There was not correlation between M-MDSC and PMN-MDSC and clinical outcomes. Conclusions: Our study suggests that a baseline circulating low level of e-MDSC and high-NLR are associated with early failure to ICI and poorer survival. The role of e-MDSC appears interesting as a potential predictive and prognostic biomarker in NSCLC patients treated with anti-PD1/PD-L1. Dynamic assessment of MDSC levels over time and further validation with longer follow up in larger cohorts are needed.

Background: Reports on the determinants of health-related quality of life (HRQoL) in COPD patients have mostly been focused on clinical factors. Aim: To assess the relationship between interpersonal and environmental factors, and HRQoL in COPD patients. Methods: In this cross-sectional study recruiting 407 moderate-to-severe COPD patients from five Catalan municipalities, HRQoL was assessed using COPD Assessment Test (CAT). Interpersonal factors such as number of people in the household, grandparenting and walking the dog, were assessed by questionnaire. Neighbourhood deprivation was assessed using the census-based Urban Vulnerability Index 2001. Residential surrounding greenness was determined using satellite-derived Normalized Difference Vegetation Index (NDVI). Residential proximity was defined for those living within a recommended 300 m distance to green or blue spaces. Results: 85% patients were male (mean age 69±9 years) with a post-bronchodilator FEV1 of 56±17 %pred. In the linear model adjusted for body mass index (BMI), FEV1%pred and 6-min walk distance, living alone was related to a worse HRQoL (coefficient β: 2.85; 95% confidence interval (CI): 0.75, 4.95) and living close to a green or blue space was marginally associated with a better HRQoL (β: -1.2; 95%CI: -2.6, 0.12). Other interpersonal and environmental determinants were not associated with HRQoL in COPD. Conclusions: Living alone and lack of proximity to green or blue space can negatively affect the HRQoL in COPD patients.

Lower levels of lung function have been related to lower physical activity (PA) levels in patients with COPD. However, the characterization of COPD patients with severe lung function and high PA remains still unknown. Aim: To identify the socio-environmental, clinical and functional characteristics of patients with severe lung function and high levels of PA. Methods: We recruited 407 COPD patients from primary care and hospitals of 5 Catalan cities and collected sociodemographic, smoking history, symptoms and medical history, health related quality of life (HRQoL), forced spirometry, exercise capacity (6MWT) and environmental data. We defined ‘severe COPD’ as postBD FEV1 Results: Patients with severe COPD (37%) had lower PA than those with mild-to-moderate airflow limitation (6840 vs 7965 steps/d, p Conclusions: Although more severity of airflow limitation is associated with low PA, there is a subset of COPD patients that has severe COPD and high PA. In our cohort, these patients were characterized by lower dyspnoea, better HRQoL and higher exercise capacity.

Maintaining good oral hygiene in patients wearing fixed appliances is a challenge for orthodontics. Conventional education has been demonstrated to be insufficient for the promotion of good oral habits, while motivational interviewing has the potential to facilitate health behavior change. The present randomized controlled trial with 130 patients aimed to evaluate the effectiveness of a single session of motivational interviewing in enhancing oral hygiene in orthodontic patients compared with conventional education alone. Results revealed an immediate improvement in oral hygiene which remained stable throughout the 6-month follow-up.

Resumen: Objetivo: Analizar la implementación de las estrategias de salud reproductiva en las actividades cotidianas de los servicios y la transformación de las prácticas de profesionales y usuarias. Método: Investigación cartográfica de tipo etnográfico multilocal orientada a captar los procesos de transformación. Técnicas de generación de datos: observación participante y entrevistas situadas. Análisis del discurso del corpus textual a partir de tres líneas de acción promovidas por las estrategias. Resultados: Se observan elementos de transformación en: 1) desmedicalización: aumento de la competencia y autonomía de la matrona, cambios en las episiotomías y facilitación de prácticas de vínculo; 2) calidez en la atención: incorporación de las necesidades y expectativas de la mujer y mejoras en la confortabilidad de los espacios en partos fisiológicos; y 3) participación: acciones que favorecen la toma de decisiones compartida y mayor implicación de la persona acompañante. Conclusiones: La transformación se visibiliza sobre todo en la incorporación de nuevas actitudes, nuevas sensibilidades y nuevas praxis que empiezan alrededor de las viejas estructuras, especialmente en la atención al parto fisiológico. Los espacios más tecnificados han sido menos permeables al cambio. La gestión del riesgo en la toma de decisiones y el abordaje de la diversidad se identifican como campos en los que la transformación es menos evidente. Abstract: Objective: We analyse how reproductive health strategies have been incorporated into the everyday activities of the services and the resulting transformation of professional and user practices. Method: Cartographic research taking a multi-sited ethnographic approach that seeks to reveal the processes of transformation. Data generation techniques featuring participant observation and situated interviews. Discourse analysis of the text corpus using three analytical axes based on three main lines of action promoted by the strategies. Results: We identified transformations in: 1) demedicalisation: an increase in midwives’ know-how and autonomy, changes in episiotomy practice and the facilitation of bonding practices; 2) warmth of care: incorporation of women's needs and expectations and improvements in the comfortableness of birth settings, especially in assistance at physiological birth; and 3) participation: actions that foster shared decision-making and the involvement of the persons accompanying women in labour. Conclusions: Above all, transformation is visible in the incorporation of new attitudes, sensibilities and practices that have developed around the old structures, especially during physiological childbirth. The more technological areas have been less permeable to change. Risk management in decision-making and addressing diversity are identified as areas where transformation is less evident. Palabras clave: Política pública, Servicios de salud reproductiva, Parto humanizado, Participación del paciente, Investigación en servicios de salud, Investigación cualitativa, Etnografía, Keywords: Public policy, Reproductive health services, Humanizing delivery, Patient participation, Health services research, Qualitative research, Ethnography

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.

The PAC-COPD Study is funded by grants from Fondo de Investigacion Sanitaria (FIS PI020541), Ministry of Health, Spain; Agencia d’Avaluacio de Tecnologia i Recerca Mediques (AATRM 035/20/02), Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2002/137); Catalan Foundation of Pneumology (FUCAP 2003 Beca Maria Rava); Red RESPIRA (RTIC C03/11); Red RCESP (RTIC C03/09), Fondo de Investigacion Sanitaria (PI052486); Fondo de Investigacion Sanitaria (PI052302); Fundacio La Marato de TV3 (num. 041110); DURSI (2005SGR00392); and unrestricted educational grants from Novartis Farmaceutica, Spain, and AstraZeneca Farmaceutica, Spain. CIBERESP and CIBERES are funded by the Instituto de Salud Carlos III, Ministry of Health, Spain.

Scope Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. Methods and results We used an in vivo model based on methionine- and choline-deficient (MCD) diet-fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake- and trafficking-related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K-inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism-related genes displayed a tendency to normalize in both in vivo and in vitro models. Conclusion These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.

Body: There is a need to design interventions that increase physical activity (PA) in COPD patients at the long term. Aim: To assess the effectiveness of the Urban Training intervention on PA after 12 months in COPD patients. Methods: We recruited 410 COPD patients from 33 primary care centers and 5 hospitals from Catalonia in 2013-2015 and allocated them randomly 1:1 to Urban Training or Usual Care. The Urban Training intervention combined behavioral strategies (motivational interviewing, pedometers, calendars, text messages, and walking groups) and unsupervised walking in trails from outdoor public spaces specifically designed for COPD (PLoSOne 14;11(1):e0146705). Primary outcome: steps/day by accelerometer; secondary: hospital admissions, exercise capacity, body composition, health-related quality of life, anxiety and depression. Modified intention to treat (MITT) and per protocol (PP) populations were analyzed, the latter including patients adherent to their corresponding intervention. Results: Patients were 85% male, had age 69 (8.5) years, and FEV1 56 (16) % pred. 284 patients completed the follow-up. In MITT there was no difference in the number of steps, but a large difference was observed in PP approach (Table 1). There were no differences in secondary outcomes. Conclusions: The Urban Training intervention increased PA after 12 months of follow-up in adherent patients.

Background Childhood recurrent wheezing and consequently asthma corresponds to various phenotypes. Our aim was to link genetic variants of asthma candidate genes to the phenotypes of early onset wheezing. Study design We included very young consecutive children presenting with recurrent wheezing who had been evaluated for the severity of wheezing, associated atopic comorbidities, and tested for biomarkers of atopy and inflammation. All were genotyped for 16 single nucleotide polymorphisms (SNPs) linked with asthma or atopy. An unsupervised hierarchical bottom-up method was used for clustering the phenotypes and a multinomial logistic regression was performed for each individual SNP. Results We replicated the three phenotypes previously described Trousseau Asthma Program in 317 children aged 21.5 ± 7.9 months: cluster 1 (nonatopic uncontrolled severe wheeze), n = 207, a severe viral-induced wheeze, cluster 2 (atopic multiple trigger wheeze), n = 61, with multiple allergic comorbidities, and cluster 3 (episodic viral wheeze), n = 49, a mild viral-induced wheeze. The TT-genotype of the IL-4 rs2070874 polymorphism was significantly associated with the nonatopic uncontrolled severe wheeze compared to the episodic viral wheeze (OR 7.9; CI95% [2.5-25.3]; P = 0.001). Conclusion Association between the TT-genotype of IL-4 rs2070874 polymorphism and a severe phenotype of viral-induced wheeze further underlines the role IL-4 plays in the inflammation pathway leading to viral respiratory infections.

We analyse how reproductive health strategies have been incorporated into the everyday activities of the services and the resulting transformation of professional and user practices.Cartographic research taking a multi-sited ethnographic approach that seeks to reveal the processes of transformation. Data generation techniques featuring participant observation and situated interviews. Discourse analysis of the text corpus using three analytical axes based on three main lines of action promoted by the strategies.We identified transformations in: 1) demedicalisation: an increase in midwives' know-how and autonomy, changes in episiotomy practice and the facilitation of bonding practices; 2) warmth of care: incorporation of women's needs and expectations and improvements in the comfortableness of birth settings, especially in assistance at physiological birth; and 3) participation: actions that foster shared decision-making and the involvement of the persons accompanying women in labour.Above all, transformation is visible in the incorporation of new attitudes, sensibilities and practices that have developed around the old structures, especially during physiological childbirth. The more technological areas have been less permeable to change. Risk management in decision-making and addressing diversity are identified as areas where transformation is less evident.

Summary Background Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4–8 years. Methods In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years. Findings We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8–48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7–78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years. Interpretation Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone—both in the presence and absence of IgE sensitisation—suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases. Funding EU Seventh Framework Programme.

Liver fatty acid binding protein (FABP1) prevents lipotoxicity of free fatty acids and regulates fatty acid trafficking and partition. Our objective is to investigate the transcription factors controlling the human FABP1 gene and their regulation in nonalcoholic fatty liver disease (NAFLD). Adenovirus-mediated expression of multiple transcription factors in HepG2 cells and cultured human hepatocytes demonstrated that FOXA1 and PPARα are among the most effective activators of human FABP1, whereas C/EBPα is a major dominant repressor. Moreover, FOXA1 and PPARα induced re-distribution of FABP1 protein and increased cytoplasmic expression. Reporter assays demonstrated that the major basal activity of the human FABP1 promoter locates between -96 and -229bp, where C/EBPα binds to a composite DR1-C/EBP element. Mutation of this element at -123bp diminished basal reporter activity, abolished repression by C/EBPα and reduced transactivation by HNF4α. Moreover, HNF4α gene silencing by shRNA in HepG2 cells caused a significant down-regulation of FABP1 mRNA expression. FOXA1 activated the FABP1 promoter through binding to a cluster of elements between -229 and -592bp, whereas PPARα operated through a conserved proximal element at -59bp. Finally, FABP1, FOXA1 and PPARα were concomitantly repressed in animal models of NAFLD and in human nonalcoholic fatty livers, whereas C/EBPα was induced or did not change. We conclude that human FABP1 has a complex mechanism of regulation where C/EBPα displaces HNF4α and hampers activation by FOXA1 and PPARα. Alteration of expression of these transcription factors in NAFLD leads to FABP1 gen repression and could exacerbate lipotoxicity and disease progression.

To understand how cells regulate each step in the flow of gene expression is one of the most fundamental goals in molecular biology. In this work, we have investigated several protein turnover-related steps in the context of gene expression regulation in response to changes in external temperature in model yeast Saccharomyces cerevisiae. We have found that the regulation of protein homeostasis is stricter than mRNA homeostasis. Although global translation and protein degradation rates are found to increase with temperature, the increase of the catalytic activity of ribosomes is higher than the global translation rate suggesting that yeast cells adapt the amount of translational machinery to the constraints imposed by kinetics in order to minimize energy costs. Even though the transcriptional machinery is subjected to the same constraints, we observed interesting differences between transcription and translation, which may be related to the different energy costs of the two processes as well as the differential functions of mRNAs and proteins.

Socio-ecological determinants may affect the physical activity (PA) in COPD patients, but knowledge on this topic is still scarce. Aim: To assess the association between patients9 social and environmental characteristics, and PA amount and intensity. Methods: 411 COPD patients were recruited in 5 cities from Catalonia in 2015. Social (work, marital, and socioeconomic status (SES), dog walking, grandchildren care and having lift) and environmental characteristics (surrounding greenness and distance to green or blue spaces) were collected. PA variables (walking time, time in any-intensity (>1.5 METs) and moderate-to-vigorous (>3 METs) PA and VMU/min) were measured by the MoveMonitor accelerometer during 1 week. We built multivariable linear regression models. Results: Patients were 85% male, had mean(SD) age 69(9)y, FEV 1 76(17)%pred and BMI 28(5)kg/m 2 . Walking the dog was significantly associated with higher PA amount, low SES related to spending more time in any-intensity PA, and taking care of grandchildren associated with higher PA intensity Environmental variables did not show significant relationships with PA amount or intensity. Conclusions: COPD patients who walk the dog have higher levels of PA and those taking care of grandchildren have higher PA intensity. Social characteristics should be considered when designing future PA interventions.

Background: During the last decades, a large number of phenotypes and disease classifications of allergic diseases have been proposed. Despite the heterogeneity across studies, no systematic review has been conducted on phenotype classification and the criteria that define allergic diseases. We aimed to identify clinically expressed, population-based phenotypes of allergic diseases and their interrelationships, to explore disease heterogeneity and to evaluate the measurements employed in disease diagnosis. Methods: We conducted a search of MEDLINE up to December 2012, to identify relevant original studies published in the English language that examine at least one objective of this systematic review in subjects aged 0-18 years. The screening of titles and abstracts and the extraction of data were conducted independently by two reviewers. Results: From a total of 13,767 citations, 197 studies met the criteria for inclusion, with 54% being cohort studies. Allergic diseases were studied as a single entity in 55% (109/197) of the studies or in the context of multimorbidity in 45%. Asthma accounted for 81.7% of the studies examining single diseases. Overall, up to 33 different phenotypes of allergic disease were reported. Transient early, late-onset and persistent wheeze were the most frequently reported phenotypes. Most studies (78%) used questionnaires. The skin-prick test was the preferred measurement of sensitization (64%). Spirometry and bronchial hyperresponsiveness were assessed in one third of the studies, peak flow rate in 8.6% and disease severity in 35%. Conclusions: Studies reporting phenotypes of allergic diseases in children are highly heterogeneous and often lack objective phenotypical measures. A concerted effort to standardize methods and terminology is necessary.

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

The transcription of tissue-specific and inducible genes is usually subject to the dynamic control of multiple activators. Dedifferentiated hepatic cell lines lose the expression of tissue-specific activators and many characteristic hepatic genes, such as drug-metabolizing cytochrome P450. Here we demonstrate that by combining adenoviral vectors for CCAAT/enhancer-binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), and constitutive androstane receptor, the CYP2B6 expression and inducibility by CITCO are restored in human hepatoma HepG2 cells at levels similar to those in cultured human hepatocytes. Moreover, several other phase I and II genes are simultaneously activated, which suggests that this is an effective approach to endow dedifferentiated human hepatoma cells with a particular metabolic competence and response to inducers. In order to gain insight into the molecular mechanism, we examined the cooperation of these three transcription factors on the CYP2B6 5′-flanking region. We show new CYP2B6-responsive sequences for C/EBPα and HNF4α and a novel synergistic regulatory mechanism whereby C/EBPα, HNF4α, and constitutive androstane receptor bind and cooperate through proximal and distal response elements to confer a maximal level of expression. The results obtained from human liver also suggest that important differences in the expression and binding of C/EBPα and HNF4α could account for the large interindividual variability of the hepatic CYP2B6 enzyme, which metabolizes commonly used drugs.

Resumen Introduccion y objetivos el estudio Caracterizacion Fenotipica y Evolucion de la Enfermedad Pulmonar Obstructiva Cronica (PAC-COPD) pretende mejorar la comprension de la heterogeneidad fenotipica de esta enfermedad y el grado en que dicha heterogeneidad se relaciona con su evolucion. Los principales objetivos son: a) caracterizar la variabilidad fenotipica de las personas que ingresan por primera vez por agudizacion de la enfermedad pulmonar obstructiva cronica (EPOC) y proponer una clasificacion en subtipos, y b) estimar la asociacion entre los subtipos definidos y la evolucion clinica y funcional de la EPOC. Pacientes y metodo el diseno de investigacion incluye un estudio transversal y un estudio de seguimiento de una cohorte de 342 pacientes con EPOC procedentes de 9 hospitales terciarios de 3 comunidades autonomas. El periodo de seguimiento abarca un minimo de 5 anos. Las principales medidas que se determinaran son las siguientes: sintomas respiratorios, tabaco, alcohol, actividad fisica, utilizacion de servicios sanitarios, atencion medica, tratamientos recibidos, actividades de la vida diaria, comorbilidades, somnolencia, ansiedad y depresion, calidad de vida, espirometria forzada y prueba broncodilatadora, pletismografia corporal con volumenes pulmonares y capacidad inspiratoria, capacidad de transferencia del monoxido de carbono, gasometria arterial basal, funcion de musculos respiratorios y perifericos, electrocardiograma, peso y composicion nutricional mediante impedanciometria bioelectrica, radiografia de torax, pruebas cutaneas de alergia, capacidad de ejercicio segun la prueba de la marcha de 6 min y prueba de ejercicio cardiopulmonar, esputo inducido (para cultivo microbiologico cuantitativo y determinacion de marcadores de inflamacion), pulsioximetria nocturna, tomografia computarizada pulmonar y ecocardiografia. Ademas, se obtienen muestras de suero y plasma para la medicion de marcadores inflamatorios y de estres oxidativo, analisis geneticos y otras posibles mediciones que puedan plantearse en el futuro. Para el analisis estadistico de los resultados se combinara el analisis factorial con modelos de supervivencia como la regresion de Cox. El proyecto permitira replantear la definicion y clasificacion de la EPOC, asi como comprender mejor los factores asociados a su evolucion.