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DNA labeling is a tool in molecular biology and biotechnology to visualize, detect, and study DNA at the molecular level. In this process, a DNA molecule is labeled by a set of specific patterns, referred to as labels, and is then imaged. The resulting image is modeled as an $(\ell+1)$-ary sequence, where $\ell$ is the number of labels, in which any non-zero symbol indicates the appearance of the corresponding label in the DNA molecule. The labeling capacity refers to the maximum information rate that can be achieved by the labeling process for any given set of labels. The main goal of this paper is to study the minimum number of labels of the same length required to achieve the maximum labeling capacity of 2 for DNA sequences or $\log_2q$ for an arbitrary alphabet of size $q$. The solution to this problem requires the study of path unique subgraphs of the de Bruijn graph with the largest number of edges and we provide upper and lower bounds on this value.

Nanophotonics is the study of interactions between nanoscale structures and light. It has greatly expanded the fields of application over the past decades, taking advantage of the advancement in MEMS technology. The most common nanophotonic structures consist of either dielectrics, metals, or both. When a nanophotonic structure contains metals, it is considered as a plasmonic structure. Plasmonics is a field of light-metal interactions. Due to the negative permittivity of metals, the electromagnetic energy of light is focused at the metal-dielectric interface and creates plasmons-a collective motion of electrons in the conduction band of metals. By shaping metals into different structures to achieve a desired performance, plasmonics have been successfully applied to many fields including photovoltaics, spectroscopy, and biomedical devices. This thesis provides 3 different applications of biomedical devices in which nanophotonics-articularly plasmonics-was applied. Chapter 1 discusses the application of nanophotonics to molecular sensing. In this chapter, an open-top, tapered waveguide that serves as a 3-dimensional plasmon cavity is demonstrated and achieves a near or single molecular detection. Chapter 2 discusses the application of nanophotonics to an implantable intraocular pressure sensor. In this chapter, an array of gold nanodots are introduced on a flexible membrane to optimize the performance of the sensor. Chapter 3 discusses the application of nanophotonics to angle-and-polarization independent pressure or strain sensing, which reduces the need for precise alignment or a trained technician, and therefore can be easily applied to moving subjects in diverse environments. Inspired by the geometry and optical principles of butterfly corneas, an array of gold paraboloids is designed to support a surface plasmon resonance that is angle-and-polarization independent. This array is integrated onto a hermetically sealed cavity with a flexible membrane and

La crise du Covid se révèle dans le secteur du luxe un formidable accélérateur des transformations commencées avant la pandémie. Comment l’empire du luxe répond-il aux nombreux défis qu’il rencontre : nouveaux modes de consommation et de distribution, digitalisation généralisée, importance du développement durable et de l’économie circulaire, entrée fracassante du gaming, irruption du métaverse et des NFT, notamment ? Comment ce secteur a-t-il su rebondir à travers le monde ? La hiérarchie mondiale des groupes de luxe est-elle confirmée ou voit-on l’émergence de nouveaux acteurs qui instaurent une nouvelle concurrence ?Très documenté et enrichi de nombreux témoignages d’acteurs clés, ce livre nous immerge dans l’univers fascinant du luxe. Indispensable pour comprendre les enjeux et les stratégies de ce secteur clé de l’économie mondiale, il rend compte de l’avènement d’un « nouveau normal » engendrant de nouvelles demandes, règles et standards.Il fait suite au livre des auteurs Le Luxe demain : les nouvelles règles du jeu, publié en janvier 2019.Préfacé par Laurent Boillot, P.-D.G. d’Hennessy et Cyril Chapuy, président de L’Oréal Luxe

Génération montante des Millennials, révolution digitale, influenceurs professionnels, révolution de la distribution, nouveaux écosystèmes de marque, secteur de l’ultraluxe en plein boum, célébrités qui lancent leur propre marque… Le luxe fait face à de nombreux challenges simultanés et il se réinvente sous nos yeux. Dans cette période où les consommateurs cherchent un sens à leur consommation, mais ne sont pas à une contradiction près lorsqu’il s’agit de luxe, le secteur vit de nombreux paradoxes qu’il doit prendre en compte pour résister au temps et ne pas être pris de court par le futur. Ce livre fourmille d’exemples, tant de grandes marques que de jeunes start-ups créatives qui illustrent, profilent et anticipent le luxe de demain. Un ouvrage indispensable pour comprendre les enjeux et les stratégies de ce secteur qui pèse autant dans l’économie française que l'automobile ou que l'aéronautique.Lauréat du prix DCF du Livre (Dirigeants Commerciaux de France) en 2020 (catégorie Expériences Ventes et Marketing)

Contains fulltext : 297145.pdf (Publisher’s version ) (Closed access), INTRODUCTION: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry. METHODS: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD. RESULTS: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated. CONCLUSIONS: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.

Mario Cazzola,1 Nicola A Hanania,2 Clive P Page,3 Maria Gabriella Matera4 1Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK; 4Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy, Email mario.cazzola@uniroma2.itAbstract: Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4+ and CD8+ T lymphocytes are key players in this process, although the extent of their participation varies according to the patient’s endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.Keywords: anti-inflammatory drugs, COPD, inflammation, treatment

Nicola A Hanania,1 Scott H Bunner,2 Lindsay GS Bengtson,2 Afisi S Ismaila,3,4 Michael Bogart5 1Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2Optum, Eden Prairie, MN, USA; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 5US Value Evidence & Outcomes, GSK, Research Triangle Park, NC, USACorrespondence: Afisi S Ismaila, Value Evidence and Outcomes, GSK, 1250 S. Collegeville Road, Collegeville, PA, 19426-0989, USA, Tel +1 919-3158229, Email afisi.s.ismaila@gsk.comPurpose: To examine the impact of initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in a single device on chronic obstructive pulmonary disease (COPD) exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related healthcare resource utilization (HCRU) and costs in patients with COPD.Methods: Retrospective database analysis of patients with COPD aged ≥ 40 years who initiated FF/UMEC/VI between September 1, 2017, and December 31, 2018 (index date: first pharmacy claim for FF/UMEC/VI), following evidence of multiple-inhaler triple therapy (MITT) (≥ 30 consecutive days) in the year prior to index. COPD exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related HCRU and costs were compared between the baseline period (12 months prior to and including index) and follow-up period (12 months following index).Results: Data from 912 patients (mean [SD] age: 71.2 [8.1], 51.2% female) were included in the analyses. Among the overall cohort, mean count of total COPD exacerbations (moderate or severe) per patient was statistically significantly lower in the follow-up period compared to baseline (1.2 vs 1.4, p=0.001). The proportion of patients with ≥ 1 COPD exacerbation (moderate or severe) was also statistically significantly lower in the follow-up period compared to baseline (56.4% vs 62.4%, p=0.00

Jorge F Maspero,1 Claus Bachert,2,3 Fernando J Martinez,4 Nicola A Hanania,5 Benjamin Ortiz,6 Naimish Patel,7 Leda P Mannent,8 Amy Praestgaard,7 Nami Pandit-Abid,9 Shahid Siddiqui,6 Megan Hardin7 1Allergy and Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina; 2Upper Airway Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium; 3Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; 4Division of Pulmonary and Critical Care, Weill Cornell Medical College, New York, NY, USA; 5Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 6Immunology and Allergy Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 7Immunology and Inflammation, Sanofi, Cambridge, MA, USA; 8Global Clinical Development, Sanofi, Chilly-Mazarin, France; 9Immunology and Inflammation, Sanofi, Bridgewater, NJ, USACorrespondence: Jorge F Maspero, Allergy and Respiratory Research Unit, Fundación CIDEA, Paraguay 2035, Buenos Aires, C1121ABE, Argentina, Tel +54 91141837294, Email jorge.maspero@fundacioncidea.org.arPurpose: To provide a descriptive summary of clinical efficacy and health-related quality of life (HRQoL) measures in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and clinical features of obstructive lung disease in the Phase III dupilumab studies SINUS-24 and SINUS-52 (NCT02912468, NCT02898454).Patients and Methods: Patients met a “broad” definition of having clinical features of obstructive lung disease with any of 3 criteria: (i) pre-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 0.70 and smoking history; (ii) patient-reported medical history of chronic obstructive pulmonary disease (COPD); or (iii) asthma with > 10 pack-years’ smoking history. A “narrow” definition including criteria (i) or (ii) was also analyzed. CRSwNP and HRQoL measures were evaluated in all patients and lu

DNA labeling is a powerful tool in molecular biology and biotechnology that allows for the visualization, detection, and study of DNA at the molecular level. Under this paradigm, a DNA molecule is being labeled by specific k patterns and is then imaged. Then, the resulted image is modeled as a (k + 1)- ary sequence in which any non-zero symbol indicates on the appearance of the corresponding label in the DNA molecule. The primary goal of this work is to study the labeling capacity, which is defined as the maximal information rate that can be obtained using this labeling process. The labeling capacity is computed for any single label and several results are provided for multiple labels as well. Moreover, we provide the optimal minimal number of labels of length one or two that are needed in order to gain labeling capacity of 2.

T1 mapping is a quantitative magnetic resonance imaging (qMRI) technique that has emerged as a valuable tool in the diagnosis of diffuse myocardial diseases. However, prevailing approaches have relied heavily on breath-hold sequences to eliminate respiratory motion artifacts. This limitation hinders accessibility and effectiveness for patients who cannot tolerate breath-holding. Image registration can be used to enable free-breathing T1 mapping. Yet, inherent intensity differences between the different time points make the registration task challenging. We introduce PCMC-T1, a physically-constrained deep-learning model for motion correction in free-breathing T1 mapping. We incorporate the signal decay model into the network architecture to encourage physically-plausible deformations along the longitudinal relaxation axis. We compared PCMC-T1 to baseline deep-learning-based image registration approaches using a 5-fold experimental setup on a publicly available dataset of 210 patients. PCMC-T1 demonstrated superior model fitting quality (R2: 0.955) and achieved the highest clinical impact (clinical score: 3.93) compared to baseline methods (0.941, 0.946 and 3.34, 3.62 respectively). Anatomical alignment results were comparable (Dice score: 0.9835 vs. 0.984, 0.988). Our code and trained models are available at https://github.com/eyalhana/PCMC-T1., Comment: Accepted to MICCAI 2023

Nicola A Hanania,1 Jorge F Maspero,2 David MG Halpin,3 David J Jackson,4,5 Reynold A Panettieri,6 Mario Castro,7 Christian Domingo,8 Nadia Daizadeh,9 Rebecca Gall,10 Juby A Jacob-Nara,11 Benjamin Ortiz,10 Michel Djandji,9 Paul J Rowe,11 Yamo Deniz10 1Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2Fundación CIDEA, Buenos Aires, Argentina; 3University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 4School of Immunology and Microbial Sciences, King’s College London, London, UK; 5Guy’s Severe Asthma Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 6Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 7University of Kansas School of Medicine, Kansas City, KS, USA; 8Pulmonary Service, Corporació Sanità ria Parc Taulí, Sabadell, Autonomous University of Barcelona, Barcelona, Spain; 9Sanofi, Cambridge, MA, USA; 10Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 11Sanofi, Bridgewater, NJ, USACorrespondence: Nicola A Hanania, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA, Tel +1 713 798-2400, Email hanania@bcm.edu

Penelitian ini bertujuan untuk mengetahui tingkat aktivitas fisik dan motorik kasar anak prasekolah di wilayah pesisir Kabupaten Trenggalek. Rancangan penelitian ini menggunakan metode survei dengan pendekatan kuantitatif serta menggunakan International Physical Activity Questionnaire (IPAQ) dan Test Gross Motor Development Second Edition (TGMD-2) sebagai instrumen penelitian. Populasi penelitian ini adalah seluruh siswa RA Darussalam Desa Kertosono Kecamatan Panggul Kabupaten Trenggalek dengan sampel 13 anak usia 3-5 tahun. Teknik analisis data yang digunakan adalah deskriptif statistik untuk mengetahui nilai minimum maksimum rata-rata dan persentase. Penelitian ini menunjukkan hasil bahwa sebagian besar keterampilan motorik kasar anak di wilayah pesisir Kabupaten Trenggalek dengan kategori average (rata-rata) atau 76% dengan rentang nilai GMQ 79-124. Sedangkan tingkat aktivitas fisiknya termasuk dalam kategori aktivitas fisik tinggi nbsp 46% nbsp dan aktivitas fisik sedang 56% dengan rentang nilai minimum maksimum yaitu 1173-4564 MET menit/minggu. Anak prasekolah di wilayah pesisir Kabupaten Trenggalek telah memenuhi standar rekomendasi aktivitas fisik dari WHO dengan intensitas sedang sampai tinggi namun masih perlu meningkatkan keterampilan motorik kasar.

Climate change is one of the most pressing challenges of our time, requiring rapid action across society. As artificial intelligence tools (AI) are rapidly deployed, it is therefore crucial to understand how they will impact climate action. On the one hand, AI can support applications in climate change mitigation (reducing or preventing greenhouse gas emissions), adaptation (preparing for the effects of a changing climate), and climate science. These applications have implications in areas ranging as widely as energy, agriculture, and finance. At the same time, AI is used in many ways that hinder climate action (e.g., by accelerating the use of greenhouse gas-emitting fossil fuels). In addition, AI technologies have a carbon and energy footprint themselves. This symposium brought together participants from across academia, industry, government, and civil society to explore these intersections of AI with climate change, as well as how each of these sectors can contribute to solutions.

A review of the development of self and empathy in infancy in general is followed by discussion of atypical development, noting that autistic children have a general deficit in development of empathic capacity and physical and representational sense of self. Specific interventions to enhance the development of both sense of self and empathic responses are suggested. (Contains extensive references.) (Author/DB)

Génération montante des Millennials, révolution digitale, influenceurs professionnels, révolution de la distribution, nouveaux écosystèmes de marque, secteur de l’ultraluxe en plein boum, célébrités qui lancent leur propre marque… Le luxe fait face à de nombreux challenges simultanés et il se réinvente sous nos yeux. Dans cette période où les consommateurs cherchent un sens à leur consommation, mais ne sont pas à une contradiction près lorsqu’il s’agit de luxe, le secteur vit de nombreux paradoxes qu’il doit prendre en compte pour résister au temps et ne pas être pris de court par le futur. Ce livre fourmille d’exemples, tant de grandes marques que de jeunes start-ups créatives qui illustrent, profilent et anticipent le luxe de demain. Un ouvrage indispensable pour comprendre les enjeux et les stratégies de ce secteur qui pèse autant dans l’économie française que l'automobile ou que l'aéronautique.

Severe asthma imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, comorbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include selection of a certain biological (as they all target overlapping disease phenotypes), the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based) and its cost‐effectiveness. The EAACI Guidelines on the use of biologicals in severe asthma follow the GRADE approach in formulating recommendations for each biological and each outcome. In addition, a management algorithm for the use of biologicals in the clinic is proposed, together with future approaches and research priorities.

Background: The InforMing the Pathway of COPD Treatment (IMPACT) trial demonstrated lower moderate/severe exacerbation rates with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI or UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. Since IMPACT was a global study, post-hoc analyses were conducted by geographic region to investigate potential differences in overall findings.Methods: IMPACT was a 52-week, randomized, double-blind trial. Patients with symptomatic COPD and >= 1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25 mu g, FF/VI 100/25 mu g, or UMEC/VI 62.5/25 mu g. Endpoints assessed in the overall, Western Europe and North America populations included on-treatment moderate/severe exacerbation (rates and time-to-first), trough forced expiratory volume in 1 second and St George's Respiratory Questionnaire (SGRQ) total score. Safety was assessed.Results: Overall, 10,355 patients were enrolled, 3164 from Western Europe, 2639 from North America. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in Western Europe (rate ratios 0.82 [95% CI 0.74 0.91], PConclusions: Consistent with intent-to-treat results, FF/UMEC/VI reduced moderate severe exacerbation rate and risk and improved lung function in Western Europe and North America; however, between-regions differences were seen for SGRQ total score and pneumonia incidence.

Hilary C Strollo,1 Seyed M Nouraie,1 Karin F Hoth,2 Craig M Riley,3 Chad Karoleski,1 Yingze Zhang,1 Nicola A Hanania,4 Russell P Bowler,5,6 Jessica Bon,1 Frank C Sciurba1 1University of Pittsburgh Medical Center, Department of Medicine, Department of Pulmonary Allergy and Critical Care Medicine, Pittsburgh, PA, USA; 2University of Iowa Carver College of Medicine, Department of Psychiatry, Iowa City, IA, USA; 3Chester County Hospital, University of Pennsylvania Health System, West Chester, PA, USA; 4Baylor College of Medicine, Department of Pulmonary, Critical Care and Sleep Medicine, Houston, TX, USA; 5National Jewish Health, Department of Medicine, Denver, CO, USA; 6University of Colorado School of Medicine, Denver, CO, USACorrespondence: Hilary C StrolloUniversity of Pittsburgh Medical Center, Department of Medicine, Department of Pulmonary Allergy and Critical Care Medicine, NW 628 UPMC Montefiore, 3459 Fifth Avenue, Pittsburgh, PA, 15213, USATel +1 412-692-2210Fax +1 412-692-4842Email strolloh2@upmc.eduRationale: Depression is a prevalent comorbidity of chronic obstructive pulmonary disease (COPD) that, along with COPD, has been associated with inflammation. An association between inflammation and depression in COPD has not been validated in a large COPD cohort.Methods: Individuals from the University of Pittsburgh SCCOR cohort and the COPDGene cohort with tobacco use history and airway obstruction (FEV1/FVC < 0.7) were evaluated using the Beck Depression Inventory II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Participants completed symptom-related questionnaires and plasma IL-6 measurements. T-test, Fisher’s Exact tests and logistic regression were used for statistical analysis.Results: The SCCOR cohort included 220 obstructed participants: 44% female and 21.4% with elevated depressive symptoms. GOLD staging distribution was predominantly stage I and II. The COPDGene cohort included 745 obstructed participants: 44% female

Arzu Ari,1 Karen Blain,2 Said Soubra,1 Nicola A Hanania3 1Department of Respiratory Care, Texas State University, Round Rock, TX, USA; 2Department of Respiratory Therapy, University of North Carolina Wilmington, Wilmington, NC, USA; 3Airways Clinical Research Center, Baylor College of Medicine, Houston, TX, USACorrespondence: Arzu Ari Email arzuari@txstate.eduAbstract: COVID-19 has affected millions of patients, caregivers, and clinicians around the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads via droplets and close contact from person to person, and there has been an increased concern regarding aerosol drug delivery due to the potential aerosolizing of viral particles. To date, little focus has been given to aerosol drug delivery to patients with COVID-19 treated at home to minimize their hospital utilization. Since most hospitals were stressed with multiple admissions and experienced restricted healthcare resources in the era of COVID-19 pandemic, treating patients with COPD at home became essential to minimize their hospital utilization. However, guidance on how to deliver aerosolized medications safely and effectively to this patient population treated at home is still lacking. In this paper, we provide some strategies and rationales for device and interface selection, delivery technique, and infection control for patients with COPD who are being treated at home in the era of COVID-19 and beyond.Keywords: coronavirus, COVID-19, SARS-CoV-2, aerosols, nebulizers, inhalers, homecare, infection control

Breast cancer is the most common malignancy in women. Mammographic findings such as microcalcifications and masses, as well as morphologic features of masses in sonographic scans, are the main diagnostic targets for tumor detection. However, improved specificity of these imaging modalities is required. A leading alternative target is neoangiogenesis. When pathological, it contributes to the development of numerous types of tumors, and the formation of metastases. Hence, demonstrating neoangiogenesis by visualization of the microvasculature may be of great importance. Super resolution ultrasound localization microscopy enables imaging of the microvasculature at the capillary level. Yet, challenges such as long reconstruction time, dependency on prior knowledge of the system Point Spread Function (PSF), and separability of the Ultrasound Contrast Agents (UCAs), need to be addressed for translation of super-resolution US into the clinic. In this work we use a deep neural network architecture that makes effective use of signal structure to address these challenges. We present in vivo human results of three different breast lesions acquired with a clinical US scanner. By leveraging our trained network, the microvasculature structure is recovered in a short time, without prior PSF knowledge, and without requiring separability of the UCAs. Each of the recoveries exhibits a different structure that corresponds with the known histological structure. This study demonstrates the feasibility of in vivo human super resolution, based on a clinical scanner, to increase US specificity for different breast lesions and promotes the use of US in the diagnosis of breast pathologies., Comment: to be published in MICCAI 2021 proceedings

Nicola A Hanania,1 Abebaw M Yohannes,2 Ayca Ozol-Godfrey,3 Michael Tocco,3 Thomas Goodin,3 Sanjay Sharma,3 Shahin Sanjar3 1Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, 77030, USA; 2Department of Physical Therapy, Azusa Pacific University, Azusa, CA, USA; 3Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Nicola A HananiaSection of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USATel +1 713-873-3454Email hanania@bcm.eduBackground: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited.Methods: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 μg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV1) and health-related quality of life determined by St George’s Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [–]) were examined following 12 weeks of GLY 25 μg twice-daily (BID) or placebo treatment.Results: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (–) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p< 0.0001), in the A/D (+) and A/D (–) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was &a

Nicola A Hanania,1 Scott Caveney,2 Tedi Soule,2 Lee Tombs,3 Sally Lettis,4 Courtney Crim,5,6 David M Mannino,7 Hitesh Patel,2 Isabelle H Boucot4 1Airways Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2US Medical Affairs, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Precise Approach Ltd, Contingent Worker on Assignment at GlaxoSmithKline, Brentford, Middlesex, UK; 4Statistics, GlaxoSmithKline, Brentford, Middlesex, UK; 5R&D, GlaxoSmithKline, Research Triangle Park, NC, USA; 6Internal Medicine - Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 7Department of Preventive Medicine and Environmental Health, University of Kentucky, College of Public Health, Lexington, KY, USACorrespondence: Nicola A HananiaAirways Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USAEmail hanania@bcm.eduIntroduction: Concerns have been raised about the practical use and clinical benefits of medications and inhalers in older patients with chronic obstructive pulmonary disease (COPD). Here, we report analyses according to age from five clinical trials evaluating medications administered using the ELLIPTA dry-powder inhaler (DPI).Methods: Efficacy and safety according to age groups (< 65 and ≥ 65 years) were assessed using data from five clinical trials in patients ≥ 40 years of age with symptomatic COPD. There was a mix of pre-specified and post hoc analyses of two 24-week trials with fluticasone furoate (FF)/vilanterol (VI) 100/25 μg; one 24-week trial with umeclidinium (UMEC) 62.5 μg; and two 12-week trials with UMEC 62.5 μg + FF/VI 100/25 μg. The primary endpoint was trough forced expiratory volume in 1 second (FEV1) obtained 23 and 24 hours after dosing on the last day of the study.Results: A total of 2876 patients < 65 years of age and 2148 patients ≥ 65 y

Why and under what circumstances do people support aggressive action in the international system? And can political psychology actually give us insights into state behavior? This dissertation argues against conventional accounts that hold that the public is rational and strategic with the regards to the use of power. Relying on the concepts of the cognitive miser and rational ignorance among the voting public, the author uses experimental methods to show that with regards to foreign policy individuals are motivated by the same prejudices and moral intuitions that guide domestic political behavior. The first chapter argues against folk realist theories and shows that constructivist theories based on the need to maintain a positive self-image do a better job of predicting when Americans support the use of force abroad. Another chapter shows that when Americans consider altruistic policies, hearing that the policy in question can financially benefit the United States makes them less likely to support it. Furthermore, the implications of differences between conservatives and liberals are explored. When conservatives are considering whether to support humanitarian intervention, they show a bias towards helping Christians over Muslims, but no racial prejudice. Liberals, in contrast, show little to no religious prejudice but are more likely to want to intervene in the scenario where whites are oppressing blacks rather than the other way around. Prejudice can even influence more abstract moral values, as when conservatives heard about Christians being killed by Muslims, they were not only more likely to support humanitarian intervention, but also to say that the United States had a general moral obligation to help foreign populations facing government persecution. The final chapter explores whether psychological differences between conservatives and liberals matter with regards to the making of foreign policy. Relying on measures of affinity, or S-scores, the author uses Un

Santiago Quirce,1 Enrico Heffler,2 Natalia Nenasheva,3 Pascal Demoly,4 Andrew Menzies-Gow,5 Ana Moreira-Jorge,6 Francis Nissen,7 Nicola A Hanania8 1Department of Allergy, La Paz University Hospital, IdiPAZ and Universidad Autónoma de Madrid, Madrid, Spain; 2Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, MI, Italy; 3Department of Allergology and Immunology of Russian Medical Academy for Continuous Medical Education, Moscow, Russian Federation; 4Department of Pulmonology, Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, France; 5Department of Respiratory Medicine, Royal Brompton Hospital, London, UK; 6Novartis Farmaceutica, S.A., Barcelona, Spain; 7London School of Hygiene and Tropical Medicine, London, UK; 8Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USACorrespondence: Santiago QuirceHospital Universitario La Paz, P. La Castellana, 261, Madrid, 28046 SpainEmail squirce@gmail.comAbstract: The Global Initiative for Asthma (GINA) 2020 defines late-onset asthma (LOA) as one of the clinical phenotypes of asthma wherein patients, particularly women, present with asthma for the first time in adult life, tend to be non-allergic and often require higher doses of inhaled corticosteroids (ICS) or are relatively refractory to corticosteroid treatment. In this review, we examine the published literature improve the understanding of the following aspects of LOA: 1) the age cut-off for its diagnosis; 2) its distinct clinical phenotypes, characteristics and risk factors; and 3) its association with allergic comorbidities and conditions. Overall, our review reveals that clinicians and researchers have used multiple age cut-offs to define LOA, with cut-off ages ranging from > 12 years to ≥ 65 years. LOA has also been classified into several distinct phenotypes, some of which drastically differ in their c

BackgroundRisk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.MethodsWe obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene®) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.ResultsOf 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.ConclusionsCurrent and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions t

Managing patients with severe asthma during the coronavirus pandemic and COVID-19 is a challenge. Authorities and physicians are still learning how COVID-19 affects people with underlying diseases, and severe asthma is not an exception. Unless relevant data emerge that change our understanding of the relative safety of medications indicated in patients with asthma during this pandemic, clinicians must follow the recommendations of current evidence-based guidelines for preventing loss of control and exacerbations. Also, with the absence of data that would indicate any potential harm, current advice is to continue the administration of biological therapies during the COVID-19 pandemic in patients with asthma for whom such therapies are clearly indicated and have been effective. For patients with severe asthma infected by SARS-CoV-2, the decision to maintain or postpone biological therapy until the patient recovers should be a case-by-case based decision supported by a multidisciplinary team. A registry of cases of COVID-19 in patients with severe asthma, including those treated with biologics, will help to address a clinical challenge in which we have more questions than answers.

PURPOSE OF REVIEW: To provide an update on the implementation of precision medicine, based on treatable traits and mechanisms, in the daily clinical management of chronic airways diseases.RECENT FINDINGS: Recent insights into the complex and heterogeneous nature of chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma identified several clinical and inflammatory phenotypes. This shifted the management focus of these diseases away from the prototypic disease labels and paved the way for developing novel targeted therapies.The concept of precision medicine aims to link the right patient to the right treatment, while minimizing the risk of adverse effects. Several treatable features ('treatable traits') have now been identified for these chronic airway diseases, including pulmonary, extra-pulmonary, and psychological/lifestyle/environmental traits. As the next step, innovative detection techniques should clarify underlying mechanisms and molecular pathways of these treatable traits and novel reliable point-of-care (composite) biomarkers to help predict responders to targeted therapies must be developed.SUMMARY: Precision medicine links the right patient to the right treatment. Identification of treatable traits in asthma and COPD will help optimize the treatment approach in these heterogeneous diseases. Furthermore, in-depth identification of underlying molecular pathways and reliable biomarkers in chronic airways diseases to guide targeted treatment in individual patients is in progress.

Génération montante des Millennials, révolution digitale, influenceurs professionnels, révolution de la distribution, nouveaux écosystèmes de marque, secteur de l’ultraluxe en plein boum, célébrités qui lancent leur propre marque… Le luxe fait face à de nombreux challenges simultanés et il se réinvente sous nos yeux. Dans cette période où les consommateurs cherchent un sens à leur consommation, mais ne sont pas à une contradiction près lorsqu’il s’agit de luxe, le secteur vit de nombreux paradoxes qu’il doit prendre en compte pour résister au temps et ne pas être pris de court par le futur. Ce livre fourmille d’exemples, tant de grandes marques que de jeunes start-ups créatives qui illustrent, profilent et anticipent le luxe de demain. Un ouvrage indispensable pour comprendre les enjeux et les stratégies de ce secteur qui pèse autant dans l’économie française que l'automobile ou que l'aéronautique.

Scholars argue that culture can be considered a fourth pillar in sustainable development, however culture is often overlooked in contemporary sustainability discourses and practice. By considering water management and heritage together, practitioners can begin to address this lacuna. It is important to recognize the aesthetic and social importance of water as well as its technical and economic contribution to historical urban development. Presenting two European case studies, this article examines the way in which water management has shaped the design of urban areas and people’s interactions with those areas. In the first case, in Rochdale, Manchester (UK), a project that included the deculverting of the River Roch in order to reduce flood risk provided other environmental and social benefits. In the second case, the city of Wrocław, a major flood has led to rethinking the form and function of the city and how citizens engage with it. Lessons from the two cases make it possible to offer recommendations for practice. In an era when climate change demands greater resilience, more attention must be paid to the intimate relationships between water and heritage.

BackgroundChronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.MethodsFour key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.ResultsUsing smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD group

Fragile X Syndrome (FXS) is a leading cause of heritable intellectual disability and autism. Humans with FXS show anxiety, sensory hypersensitivity and impaired learning. The mechanisms of learning impairments can be studied in the mouse model of FXS, the Fmr1 KO mouse, using tone-associated fear memory paradigms. Our previous study reported impaired development of parvalbumin (PV) positive interneurons and perineuronal nets (PNN) in the auditory cortex of Fmr1 KO mice. A recent study suggested PNN dynamics in the auditory cortex following tone-shock association is necessary for fear expression. Together these data suggest that abnormal PNN regulation may underlie tone-fear association learning deficits in Fmr1 KO mice. We tested this hypothesis by quantifying PV and PNN expression in the amygdala, hippocampus and auditory cortex of Fmr1 KO mice following fear conditioning. We found impaired tone-associated memory formation in Fmr1 KO mice. This was paralleled by impaired learning-associated regulation of PNNs in the superficial layers of auditory cortex in Fmr1 KO mice. PV cell density decreased in the auditory cortex in response to fear conditioning in both WT and Fmr1 KO mice. Learning-induced increase of PV expression in the CA3 hippocampus was only observed in WT mice. We also found reduced PNN density in the amygdala and auditory cortex of Fmr1 KO mice in all conditions, as well as reduced PNN intensity in CA2 hippocampus. There was a positive correlation between tone-associated memory and PNN density in the amygdala and auditory cortex, consistent with a tone-association deficit. Altogether our studies suggest a link between impaired PV and PNN regulation within specific regions of the fear conditioning circuit and impaired tone memory formation in Fmr1 KO mice.

Elizabeth A Brooks,1 Marc Massanari,2 Nicola A Hanania,3 Daniel J Weiner11TTi Health Research & Economics, Health Research & Economics, Westminster, MD, USA; 2Circassia Pharmaceuticals, Global Medical Affairs, Morrisville, NC, USA; 3Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USAPurpose: To use a modeled analysis to examine the cost-effectiveness of utilizing fractional exhaled nitric oxide (FeNO) as a biomarker to aid in the identification of omalizumab responders in patients with moderate-to-severe allergic asthma. Omalizumab is a biological drug used to treat asthma in adults and children 12 years and older.Patients and methods: We conducted a decision analysis in which two alternative strategies for predicting omalizumab response were assessed: 1) testing response via a 12-week trial of omalizumab and 2) using FeNO measurement to screen patients for likely omalizumab response prior to initiating a 12-week trial of omalizumab. In the standard of care arm, trial omalizumab responders continue on to receive 12 months of continuous omalizumab therapy. In the FeNO measurement predictor arm, patients with FeNO measurements >19.5 ppb are started on a trial of omalizumab. Trial omalizumab responders in this arm are then also tracked for 12 months of continuous omalizumab therapy.Results: Per-patient costs during the trial and initial treatment periods total $10,943 for FeNO + omalizumab and $13,703 for omalizumab only. The expected cost per responder during the trial period is $4,326 for FeNO + omalizumab and $7,786 for omalizumab only.Conclusion: Use of FeNO measurement to identify omalizumab responders decreases the expected per-patient cost by nearly 50% during the trial period and continues to show cost savings through the initial treatment period of 12 months. Our analysis may serve as a model for policy and clinical practice regarding the use of FeNO to determine omalizumab response and has wides

Nicola A Hanania,1 Denis E O’Donnell21Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine, Houston, TX, USA; 2Division of Respirology, Department of Medicine, Queen’s University, Kingston, Ontario, CanadaAbstract: Dyspnea is a distressing, debilitating, and near-ubiquitous symptom affecting patients with COPD. In addition to the functional consequences of dyspnea, which include activity limitation and reduced exercise tolerance, it is important to consider its psychological impact on patients with COPD, such as onset of depression or anxiety. Moreover, the anticipation of dyspnea itself can have a significant effect on patients’ emotions and behavior, with patients frequently self-limiting physical activity to avoid what has become the hallmark symptom of COPD. Dyspnea is, therefore, a key target for COPD treatments. Pharmacologic treatments can optimize respiratory mechanics, provide symptom relief, and reduce patients’ increased inspiratory neural drive to breathe. However, it is important to acknowledge the value of non-pharmacologic interventions, such as pulmonary rehabilitation and patient self-management education, which have proven to be invaluable tools for targeting the affective components of dyspnea. Furthermore, it is important to encourage maintenance of physical activity to optimize long-term patient outcomes. Here, we review the physiological and psychological consequences of activity-related dyspnea in COPD, assess the efficacy of modern management strategies in improving this common respiratory symptom, and discuss key unmet clinical and research needs that warrant further immediate attention.Keywords: dyspnea, chronic obstructive pulmonary disease, psychology, physiology, management

Dharani K Narendra, Nicola A HananiaSection of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USAAbstract: Many patients with chronic obstructive pulmonary disease (COPD) continue to experience exacerbations despite receiving standard-of-care treatments. Novel approaches to COPD treatment focus on understanding and targeting molecular mechanisms of airway inflammation, airway obstruction, remodeling and lung destruction. Several identified phenotypes and endotypes of COPD will pave the future path for a more personalized approach to therapy. Although well known to be associated with neutrophilic inflammation, COPD may also be driven by eosinophilic inflammation both at stable states and during exacerbation. Targeting eosinophilic inflammation has been successful in managing severe eosinophilic asthma and may hold promise in certain phenotypes of COPD. The most promising biologic treatments at an advanced stage of development are agents blocking interleukin (IL)-5 or its receptor. This review examines our current understanding of the eosinophilic inflammation in COPD and the rationale for IL-5 targeting agents.Keywords: COPD, airway inflammation, eosinophils, IL-5, mepolizumab, benralizumab

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Genes 9 (2018): 197, doi:10.3390/genes9040197., Xenopus laevis embryos are an established model for studying kidney development. The nephron structure and genetic pathways that regulate nephrogenesis are conserved between Xenopus and humans, allowing for the study of human disease-causing genes. Xenopus embryos are also amenable to large-scale screening, but studies of kidney disease-related genes have been impeded because assessment of kidney development has largely been limited to examining fixed embryos. To overcome this problem, we have generated a transgenic line that labels the kidney. We characterize this cdh17:eGFP line, showing green fluorescent protein (GFP) expression in the pronephric and mesonephric kidneys and colocalization with known kidney markers. We also demonstrate the feasibility of live imaging of embryonic kidney development and the use of cdh17:eGFP as a kidney marker for secretion assays. Additionally, we develop a new methodology to isolate and identify kidney cells for primary culture. We also use morpholino knockdown of essential kidney development genes to establish that GFP expression enables observation of phenotypes, previously only described in fixed embryos. Taken together, this transgenic line will enable primary kidney cell culture and live imaging of pronephric and mesonephric kidney development. It will also provide a simple means for high-throughput screening of putative human kidney disease-causing genes., These studies were supported by a postdoctoral fellowship from the National Kidney Foundation (FLB1628 to R.K.M), a National Institutes of Health (NIH) KO1 grant (K01DK092320 to R.K.M.), and startup funding from UTHealth McGovern Medical School’s Department of Pediatrics (to R.K.M.).

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here by permission of Genetics Society of America for personal use, not for redistribution. The definitive version was published in Genetics 208 (2018): 673-686, doi:10.1534/genetics.117.300468., Studying genes involved in organogenesis is often difficult because many of these genes are also essential for early development. The allotetraploid frog, Xenopus laevis, is commonly used to study developmental processes, but because of the presence of two homeologs for many genes, it has been difficult to use as a genetic model. Few studies have successfully used CRISPR in amphibians, and currently there is no tissue-targeted knockout strategy described in Xenopus. The goal of this study is to determine whether CRISPR/Cas9-mediated gene knockout can be targeted to the Xenopus kidney without perturbing essential early gene function. We demonstrate that targeting CRISPR gene editing to the kidney and the eye of F0 embryos is feasible. Our study shows that knockout of both homeologs of lhx1 results in the disruption of kidney development and function but does not lead to early developmental defects. Therefore, targeting of CRISPR to the kidney may not be necessary to bypass the early developmental defects reported upon disruption of Lhx1 protein expression or function by morpholinos, antisense RNA, or dominant negative constructs. We also establish a control for CRISPR in Xenopus by editing a gene (slc45a2) that when knocked out results in albinism without altering kidney development. This study establishes the feasibility of tissue-specific gene knockout in Xenopus, providing a cost effective and efficient method for assessing the roles of genes implicated in developmental abnormalities that is amenable to high-throughput gene or drug screening techniques., These studies were supported by a National Institutes of Health (NIH) KO1 grant (K01DK092320 to R.K.M.), startup funding from the Department of Pediatrics 424 Pediatric Research Center at the University of Texas McGovern Medical School (to R.K.M.), an NIH National Xenopus Resource Center grant (P40OD010997 to M.E.H.), and an NIH R01 grant (R01HD084409 to M.E.H.).

Rationale: Anxiety is a common comorbidity of chronic obstructive pulmonary disease (COPD) that is associated with higher morbidity and mortality. We evaluated three anxiety screening questionnaires: the Generalized Anxiety Disorder 7-Item Scale (GAD-7), the Hospital Anxiety and Depression Scale Anxiety subscale (HADS-A), and the Anxiety Inventory for Respiratory Disease (AIR).Objectives: To evaluate and compare the test performance characteristics of three anxiety screening questionnaires, using the Mini-International Neuropsychiatric Interview (MINI), version 7.0, as the "gold standard."Methods: Individuals with COPD were recruited at 16 centers. The MINI and questionnaires were administered by trained research coordinators at an in-person visit and readministered by telephone 2-4 weeks later. A composite score for the presence of any Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) anxiety disorder was computed, based on the MINI as the gold standard, compared with a participant screening positive on self-report measures for these analyses.Results: Two hundred and twenty eligible individuals with COPD were enrolled; 219 completed the study. Eleven percent were identified as having a DSM-V anxiety disorder, based on the MINI. Elevated anxiety symptoms based on questionnaires were 38% for the AIR, 30% for the GAD-7, and 20% for the HADS-A. Area under the receiver operating characteristic curve (AUC) was highest for the GAD-7 (0.78; 95% confidence interval [CI], 0.69-0.87), followed by the HADS-A (0.74; 95% CI, 0.64-0.84) and the AIR (0.66; 95% CI, 0.56-0.76). The AUC for the GAD-7 was significantly greater than for the AIR (P = 0.014). Sensitivity was not statistically different among the questionnaires: 77% for the GAD-7, 63% for the HADS-A, and 66% for the AIR. The HADS-A had the highest specificity, 85%, which was significantly higher than that of the GAD-7 (77%; P < 0.001) and the AIR (65%; P < 0.001); GAD-7 specificity was highe

Nicola A Hanania,1 Sanjay Sethi,2 Arkady Koltun,3 Jonathan K Ward,4 Jacqui Spanton,4 Dik Ng4 1Asthma Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2Pulmonary, Critical Care, and Sleep Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA; 3Global Medical Affairs, Mylan Inc., Canonsburg, PA, USA; 4Mylan Global Respiratory Group, Mylan Pharma UK Ltd., Sandwich, Kent, UK Background: Formoterol fumarate inhalation solution (FFIS; Perforomist®) is a long-acting β2-agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was <1.5. Secondary end points included spirometry. Results: The planned 1-year treatment period was completed by 520 patients; 551 discontinued prematurely (FFIS: 45.7%; placebo: 57.4%). The median treatment duration was approximately 10 and 7 months for FFIS and placebo, respectively. Among 1,071 randomized patients, 121 had ≥1 primary event (FFIS: 11.8%; placebo: 10.8%). The estimated HR of a primary event with FFIS vs placebo was 0.965 (90% CI: 0.711, 1.308), demonstrati

Anthony D D’Urzo,1 Mario Cazzola,2 Nicola A Hanania,3 Roland Buhl,4 M Reza Maleki-Yazdi5 1Department of Family and Community Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy; 3Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 4Pulmonary Department, Mainz University Hospital, Mainz, Germany; 5Division of Respiratory Medicine, Women’s College Hospital, University of Toronto, Toronto, ON, Canada Abstract: COPD causes considerable health and economic burden worldwide, with incidence of the disease expected to continue to rise. Inhaled bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), are central to the maintenance treatment of patients with COPD. Clinical studies have demonstrated that combined LAMA + LABA therapies improve efficacy while retaining a safety profile similar to LAMA or LABA alone. This has led to the development of several LAMA/LABA fixed-dose combination (FDC) therapies, which provide patients with the convenience of two active compounds in a single inhaler. GFF MDI (Bevespi Aerosphere®) is an FDC of glycopyrrolate/formoterol fumarate 18/9.6 µg formulated using innovative co-suspension delivery technology for administration via metered dose inhaler (MDI). GFF MDI was developed to make a treatment option available for patients who have a requirement or preference to use an MDI, rather than a dry powder or soft mist inhaler. Now that several LAMA/LABA FDCs have been approved for use in COPD, we review the impact of dual-bronchodilator treatment on COPD therapy and discuss recent clinical studies that are helping to develop a more comprehensive understanding of how LAMA/LABA FDCs can improve patient outcomes. Keywords: long-acting bronchodilator, LAMA, LABA, chronic obstructive pulmonary disease

James F Donohue,1 Vamsi K Bollu,2 Donald E Stull,3 Lauren M Nelson,4 Valerie SL Williams,4 Michael D Stensland,5 Nicola A Hanania6 1Department of Pulmonary Diseases and Critical Care Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 2Worldwide Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, 3Data Analytics and Design Strategy, 4Psychometrics, RTI Health Solutions, Research Triangle Park, NC, 5Agile Outcomes Research, Inc., Rochester, MN, 6Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George’s Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles. Methods: We examined data from a randomized, double-blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 µg (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores. Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (P=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, P=0.031) and Impacts (3.91 vs 0.97, P=0.001) scores, but not in Activity score (3.57 vs 1.75, P=0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (P<0.001; 95% confidence interval: 17.6–23.9). Compared w

Background Debate continues as to whether acute bronchodilator responsiveness (BDR) predicts long-term outcomes in COPD. Furthermore, there is no consensus on a threshold for BDR. Methods At baseline and during the 4-year Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT®) trial, patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg. Patients were split according to three BDR thresholds: ≥12% + ≥200 mL above baseline (criterion A), ≥15% above baseline (criterion B); and ≥10% absolute increase in percent predicted FEV1 values (criterion C). Several outcomes (pre-dose spirometry, exacerbations, St. George's Respiratory Questionnaire [SGRQ] total score) were assessed according to presence or absence of BDR in the treatment groups. Results 5783 of 5993 randomized patients had evaluable pre- and post-bronchodilator spirometry at baseline. Mean age (SD) was 64 (8) years, with 75% men, mean post-bronchodilator FEV1 1.33 ± 0.44 L (47.6 ± 12.7% predicted) and 30% current smokers. At baseline, 52%, 66%, and 39% of patients had acute BDR using criterion A, B, and C, respectively. The presence of BDR was variable at follow-up visits. Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used. Conclusions A large proportion of COPD patients demonstrate significant acute BDR. BDR in these patients is variable over time and differs according to the criterion used. BDR status at baseline does not predict long-term response to tiotropium. Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD.

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In c

Introduction: Long-acting β2-agonists [LABAs] and long-acting muscarinic antagonists [LAMAs]) are primary therapies for chronic obstructive pulmonary disease (COPD). Despite improvements in lung function and patient-reported outcomes (PROs) with these therapies, there is room to optimize outcomes further. Combined use of LABAs and LAMAs is recommended when symptoms are not improved with a single agent, and LABA/LAMA fixed-dose combinations (FDCs) are at the forefront of drug development in COPD. Areas covered: This review focusses on the three LABA/LAMA FDCs (indacaterol/glycopyrrolate1 [IND/GLY] 27.5/15.6 µg twice daily, umeclidinium/vilanterol [UMEC/VI] 62.5/25 µg once daily and tiotropium/olodaterol [Tio/Olo] 5/5 µg once daily approved in the US. Phase III clinical trials have shown benefits in lung function, dyspnea and health status with FDCs of IND/GLY, UMEC/VI and Tio/Olo versus placebo and monotherapies. Expert commentary: Data from recent studies of three LABA/LAMA combinations, reviewed here, indicate that dual bronchodilation may be beneficial above and beyond both the monotherapies and LABA/ICS combinations, in providing improvements in lung function and PROs for patients with COPD, which may encourage a shift away from the use of ICS in COPD management, in particular for non-exacerbating patients.

RationaleChronic bronchitis is, by definition, a chronic condition, but the development and remission of this condition in cigarette smokers with or without chronic obstructive pulmonary disease (COPD) are poorly understood. Also, it is unclear how the persistence or new development of chronic bronchitis affects symptoms and outcomes.ObjectivesTo ascertain the relationship between smoking status and the presence or absence of chronic bronchitis and the subsequent effects on symptoms and outcomes.MethodsWe analyzed 1,775 current or ex-smokers with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 0-IV COPD in phase 2 of the Genetic Epidemiology of COPD (COPDGene) Study, which included subjects after 5 years of follow-up from phase 1. We asked subjects at enrollment and at 5 years of follow-up about symptoms consistent with chronic bronchitis. We divided subjects into four groups: persistent chronic bronchitis- (negative at phase 1/negative at phase 2), resolved chronic bronchitis (positive/negative), new chronic bronchitis (negative/positive), and persistent chronic bronchitis+ (positive/positive). We analyzed respiratory symptoms, health-related quality of life, lung function, exacerbation frequency, and 6-minute walk distance.Measurements and main resultsCompared with the persistent chronic bronchitis- group, members of the persistent chronic bronchitis+ group were more likely to have continued smoking (53.4%). Subjects with new chronic bronchitis were more likely to have resumed (6.6%) or continued smoking (45.6%), whereas subjects with resolved chronic bronchitis were more likely to have quit smoking (23.5%). Compared with the persistent chronic bronchitis- group, the other groups had a shorter 6-minute walk distance, worse lung function, greater exacerbation frequency, and worse respiratory symptoms. Modified Medical Research Council dyspnea and St. George's Respiratory Questionnaire scores worsened between phase 1 and phase 2 in subjects with

The diagnosis of language proficiency for grouping limited English-speaking dents in bilingual education programs has been a problem for three reasons: consistent identification of language proficiency skills for functioning in a and/or bilingual classroom; b) non-specification of appropriate norm-referenced criterion-referenced tests for assessing receptive and expressive English; and availability of criteria for grouping bilingual students. To address these problems, English as a Second Language Assessment Battery (ESLAB), a criterion-measure, was constructed and validated with secondary students. Item analysis based on logical and empirical knowledge included revision rearrangement of items. The data findings were: a) percentile (p) values 89.9% for the Aural Comprehension Test, 1.7% to 64.4% for the Structural Test, and 0.6% to 69.5% for the IRI; and b) the point biserial (RPB) values .67 for the Aural Comprehension Test, -.01 to .47 for the Structural Competency and 0.0 to .70 for the IRI. Reliability involved the computation of internal consistency. The Hoyt estimate of reliability for the Aural Comprehension Test was .81, for the Structural Competency Test .37, and for the IRI .83 and .79 for the total. Cronbach's alpha values were .74 for the IRI and .21 for the total test statistics. The SEm for the three tests was 4.25. Four types of validity were established: a) face validity based on examiner's and examinee's judgements, b) content validity determined by language and reading experts analyzing test items in terms of the specified objectives, c) predictive validity using Kendall's tau (Nie et al., 1975) to correlate each test level results (Beginner I, Begin- ner II, Intermediate I, Intermediate II, and Advanced) with the four Teacher Estimates (T.E.) and ESL report card grades, and d) concurrent validity used only for the IRI. This study examined the Receptive Area (listening and reading) through the Comprehension Test, the Structural Competency Test, and