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Mustafa Abdo,1 Frederik Trinkmann,2,3 Anne-Marie Kirsten,4 Heike Biller,1 Frauke Pedersen,1,4 Benjamin Waschki,1 Erika Von Mutius,5 Matthias Kopp,6,7 Gesine Hansen,8 Klaus F Rabe,1 Thomas Bahmer,1,9,&ast; Henrik Watz4,&ast; On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 3Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 4Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 5Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich, German Center for Lung Research (DZL), and Institute of Asthma and Allergy Prevention, Helmholtz Centre, Both Munich, Germany; 6Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 7Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 8Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 9University Hospital Schleswig-Holstein-Campus Kiel, department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany&ast;These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Grosshansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Small airway dysfunction (SAD) is a frequent feature of asthma that has been linked to disease severity and poor symptom control. However, little is known about the role of SAD in nocturnal asthma.Objective: To study the association between the severity of SAD and frequency of nocturnal symptoms compared to conventional lung function testing.Methods: We assessed the frequency of self-reported nocturnal symptoms through the asthma control test. We studied the impact of nocturnal asthma using the Asthma Quality of Life Questionnaire (AQLQ) and the Multidimensional Fatigue Inventory (MFI-20). We assessed the lung function using spirometry, body plethysmography, impulse oscillometry, single and multiple inert gas washout and measured markers of T2-inflammation (blood and sputum eosinophils; fractional exhaled nitric oxide (FeNo)). We stratified the patients according to the presence and frequency of nocturnal asthma.Results: A total of 166 asthma patients were enrolled in the analysis. Eighty-seven patients (52%) reported to have nocturnal symptoms at least once in the last four weeks. The odds ratio of nocturnal asthma correlated with the severity of all non-spirometric measures of SAD, yet neither with airflow obstruction (FEV1 and FEV/FVC) nor with large airway resistance (R20). Patients with frequent nocturnal asthma (n = 29) had a numerical increase of T2 markers and more severe SAD, as indicated by all non-spirometric measures of SAD (all p-values < 0.05), worse overall asthma control, increased fatigue and reduced quality of life (all p-values < 0.01) compared to patients with infrequent nocturnal asthma (n = 58) or patients without nocturnal asthma (n = 79). We identified 63 patients without airflow obstruction, nearly 43% of them (n = 27) had nocturnal asthma. In this subgroup, only markers of air trapping and ventilation heterogeneity were significantly elevated and correlated with the frequency of nocturnal symptoms: LCI (Spearman’s coefficient = − 0.42, p < 0.001), RV% (− 0.32, p = 0.02).Conclusion: SAD is closely associated to asthma with nocturnal symptoms. Spirometry might underestimate the broad spectrum of distal lung function impairments in this population of patients.Keywords: small airway dysfunction, nocturnal asthma, ventilation heterogeneity, air trapping

Mustafa Abdo,1 Benjamin Waschki,2 Anne-Marie Kirsten,3 Frederik Trinkmann,4,5 Heike Biller,1 Christian Herzmann,6 Erika von Mutius,7 Matthias Kopp,8,9 Gesine Hansen,10 Klaus F Rabe,1 Thomas Bahmer,1,11,* Henrik Watz3,* On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Cardiology and Pneumology at Hospital Itzehoe, Itzehoe, Germany; 3Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 4Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 5Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 6Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany; 7Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany; 8Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 9Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 10Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 11University Hospital Schleswig-Holstein-Campus Kiel, Department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany*These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Großhansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Asthma, obesity and physical activity (PA) are interrelated. However, longitudinal data with objective PA measures and direct assessment of body composition are still lacking.Objective: To study the impact of symptom control on PA and body composition.Methods: In a longitudinal cohort study of the German Center for Lung Research, we assessed the body composition of 233 asthma patients and 84 healthy controls using bioelectrical impedance analysis. PA (ie average daily steps and time of at least moderate activity, steps/min) was measured by accelerometry for one week. Asthma control was assessed by ACT score, ACQ-5 score and history of severe exacerbations. After two years of follow-up, we studied changes in physical activity and body composition in relation to asthma control.Results: Patients with uncontrolled asthma had increased fat mass and decreased muscle mass compared to patients with controlled asthma or healthy controls. Both fat mass and muscle mass correlated better with asthma control than the body mass index (BMI). In multivariate regressions adjusted for age and sex, asthma control and physical activity were independent predictors of body composition (R2 = 0.61, p

Kerri Lynn Schellenberg,1 Gregory Hansen2 1Department of Medicine, Division of Neurology, University of Saskatchewan, Saskatoon, SK, Canada; 2Department of Pediatrics, Division of Critical Care, University of Saskatchewan, Saskatoon, SK, Canada Purpose: Multidisciplinary clinics (MDC) have become the standard of care for management of amyotrophic lateral sclerosis (ALS). No studies however, have captured patients’ perspectives during a transition to ALS MDCs. Recently, an ALS MDC emerged from a single-physician clinic in Saskatoon, Canada, providing patients with a unique exposure to two different models of care. Patients and methods: Fifteen patients with ALS participated in semi-structured interviews that were digitally recorded and transcribed. Two independent researchers performed an inductive thematic analysis. Information was coded based on emerging and a priori themes. An iterative process followed involving discussion and reexamination of the themes until consensus was reached. Results: All patients cited the convenience of integrated care as an advantage. Other advantages included clinical expertise and advocacy potential. Travel and reduced mobility were the most commonly discussed barriers/disadvantages of MDC attendance. The impact of geography and weather appeared to augment both the appreciation of an integrated approach and the impediment of travel, compared to the existing literature. The need for individualized care was demonstrated by the conflicting viewpoints obtained from participants. Most patients felt additional practitioners and supports for both patients and caregivers were required. Conclusion: ALS patients transitioned to MDCs reported many of the advantages and disadvantages reported elsewhere. A novel perspective of a MDC’s advocacy potential was recognized, and the need for an innovative approach to meet demands for individualized care was highlighted. Keywords: amyotrophic lateral sclerosis, motor neuron disease, multidisciplinary care, qualitative research

David R Powell, Jason P Gay, Melinda Smith, Nathaniel Wilganowski, Angela Harris, Autumn Holland, Maricela Reyes, Laura Kirkham, Laura L Kirkpatrick, Brian Zambrowicz, Gwenn Hansen, Kenneth A Platt, Isaac van Sligtenhorst, Zhi-Ming Ding, Urvi Desai Metabolism Research, Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA Abstract: Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), encoded by fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for w3, w6, and w9 polyunsaturated fatty acids (PUFAs). Although PUFAs appear to be involved in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways is unclear. After generating >4,650 knockouts (KOs) of independent mouse genes and analyzing them in our high-throughput phenotypic screen, we found that Fads1 KO mice were among the leanest of 3,651 chow-fed KO lines analyzed for body composition and were among the most glucose tolerant of 2,489 high-fat-diet-fed KO lines analyzed by oral glucose tolerance test. In confirmatory studies, chow- or high-fat-diet-fed Fads1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 38% and 31% lower in Fads1 male and female KO mice, respectively. Fads1 KO mice also had lower glucose and insulin excursions during oral glucose tolerance tests along with lower fasting glucose, insulin, triglyceride, and total cholesterol levels. In additional studies using a vascular injury model, Fads1 KO mice had significantly decreased femoral artery intima/media ratios consistent with a decreased inflammatory response in their arterial wall. Based on this result, we bred Fads1 KO and WT mice onto an ApoE KO background and fed them a Western diet for 14 weeks; in this atherogenic environment, aortic trees of Fads1 KO mice had 40% less atheromatous plaque compared to WT littermates. Importantly, PUFA levels measured in brain and liver phospholipid fractions of Fads1 KO mice were consistent with decreased D5D activity and normal D6D activity. The beneficial metabolic phenotype demonstrated in Fads1 KO mice suggests that selective D5D inhibitors may be useful in the treatment of human obesity, diabetes, and atherosclerotic cardiovascular disease. Keywords: delta-5 desaturase, delta-6 desaturase, obesity, diabetes, atherosclerosis

Despite being a well-established research field, the detection and attribution of observed climate change to anthropogenic forcing is not yet provided as a climate service. One reason for this is the lack of a methodology for performing tailored detection and attribution assessments on a rapid time scale. Here we develop such an approach, based on the translation of quantitative analysis into the “confidence” language employed in recent Assessment Reports of the Intergovernmental Panel on Climate Change. While its systematic nature necessarily ignores some nuances examined in detailed expert assessments, the approach nevertheless goes beyond most detection and attribution studies in considering contributors to building confidence such as errors in observational data products arising from sparse monitoring networks. When compared against recent expert assessments, the results of this approach closely match those of the existing assessments. Where there are small discrepancies, these variously reflect ambiguities in the details of what is being assessed, reveal nuances or limitations of the expert assessments, or indicate limitations of the accuracy of the sort of systematic approach employed here. Deployment of the method on 116 regional assessments of recent temperature and precipitation changes indicates that existing rules of thumb concerning the detectability of climate change ignore the full range of sources of uncertainty, most particularly the importance of adequate observational monitoring.

Impacts of recent regional changes in climate on natural and human systems are documented across the globe, yet studies explicitly linking these observations to anthropogenic forcing of the climate are scarce. Here we provide a systematic assessment of the role of anthropogenic climate change for the range of impacts of regional climate trends reported in the IPCC's Fifth Assessment Report. We find that almost two-thirds of the impacts related to atmospheric and ocean temperature can be confidently attributed to anthropogenic forcing. In contrast, evidence connecting changes in precipitation and their respective impacts to human influence is still weak. Moreover, anthropogenic climate change has been a major influence for approximately three-quarters of the impacts observed on continental scales. Hence the effects of anthropogenic emissions can now be discerned not only globally, but also at more regional and local scales for a variety of natural and human systems.

Assessing past impacts of observed climate change on natural, human and managed systems requires detailed knowledge about the effects of both climatic and other drivers of change, and their respective interaction. Resulting requirements with regard to system understanding and long-term observational data can be prohibitive for quantitative detection and attribution methods, especially in the case of human systems and in regions with poor monitoring records. To enable a structured examination of past impacts in such cases, we follow the logic of quantitative attribution assessments, however, allowing for qualitative methods and different types of evidence. We demonstrate how multiple lines of evidence can be integrated in support of attribution exercises for human and managed systems. Results show that careful analysis can allow for attribution statements without explicit end-to-end modeling of the whole climate-impact system. However, care must be taken not to overstate or generalize the results and to avoid bias when the analysis is motivated by and limited to observations considered consistent with climate change impacts.

There is growing interest in assessing the role of climate change in observed extreme weather events. Recent work in this area has focused on estimating a measure called attributable risk. A statistical formulation of this problem is described and used to construct a confidence interval for attributable risk. The resulting confidence is shown to be surprisinglywide even in the case where the event of interest is unprecedented in the historical record.

Anthropogenic climate change has triggered impacts on natural and human systems world-wide, yet the formal scientific method of detection and attribution has been only insufficiently described. Detection and attribution of impacts of climate change is a fundamentally cross-disciplinary issue, involving concepts, terms, and standards spanning the varied requirements of the various disciplines. Key problems for current assessments include the limited availability of long-term observations, the limited knowledge on processes and mechanisms involved in changing environmental systems, and the widely different concepts applied in the scientific literature. In order to facilitate current and future assessments, this paper describes the current conceptual framework of the field and outlines a number of conceptual challenges. Based on this, it proposes workable cross-disciplinary definitions, concepts, and standards. The paper is specifically intended to serve as a baseline for continued development of a consistent cross-disciplinary framework that will facilitate integrated assessment of the detection and attribution of climate change impacts. © 2013 The Author(s).