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Arschang Valipour,1 Pallav L Shah,2 Felix J Herth,3 Christophe Pison,4 Christian Schumann,5 Ralf-Harto Hübner,6 Peter I Bonta,7 Romain Kessler,8 Wolfgang Gesierich,9 Kaid Darwiche,10 Bernd Lamprecht,11 Thierry Perez,12 Dirk Skowasch,13 Gaetan Deslee,14 Armelle Marceau,15 Frank C Sciurba,16 Reinoud Gosens,17 Jorine E Hartman,18 Francesca Conway,2 Marina Duller,1 Martin Mayse,19 Holly S Norman,19 Dirk-Jan Slebos18 On behalf of the AIRFLOW-2 Trial Study Group1Department of Respiratory and Critical Care Medicine, Karl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Krankenhaus Nord-Klinik Floridsdorf, Vienna, Austria; 2Royal Brompton & Harefield NHS Trust, Chelsea & Westminster Hospital and Imperial College, London, UK; 3Thoraxklinik, Department of Pneumology and Critical Care Medicine and Translational Lung Research Center Heidelberg (TLRCH), University of Heidelberg, Heidelberg, Germany; 4CHU Grenoble Alpes, Service Hospitalier Universitaire Pneumologie Physiologie; Université Grenoble Alpes, Grenoble, France; 5Clinic of Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care, Klinikverbund Allgaeu, Kempten and Immenstadt, Germany; 6Charité Universitätsmedizin Berlin, Medizinische Klinik m. Schw. Infektiologie und Pneumologie, Campus Virchow, Berlin, Germany; 7Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 8Service de Pneumologie, Nouvel Hôpital Civil, Université de Strasbourg, Strasbourg, France; 9Asklepios-Fachkliniken Munich-Gauting, Comprehensive Pneumology Center Munich, Gauting, Germany; 10Department of Pulmonary Medicine, Section of Interventional Pneumology, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 11Department of Pulmonary Medicine, Kepler Universitatsklinikum GmbH, Linz, Austria; 12CHU de Lille – Hôpital Calmette, Lille, France; 13Department of Internal Medicine II - Cardiology/Pneumology, University of Bonn, Bonn, Germany; 14CHU de Reims, Hôpital Maison Blanche, Service de Pneumologie, Reims, France; 15Service de Pneumologie, Hôpital Universitaire Bichat, Paris, France; 16University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 17Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; 18Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 19Nuvaira, Inc., Minneapolis, MN, USACorrespondence: Dirk-Jan SlebosDepartment of Pulmonary Diseases/Interventional Bronchoscopy AA11, University Medical Center Groningen, PO Box 30001, Groningen, the NetherlandsTel +31 503612357Fax +31503619320Email d.j.slebos@umcg.nlPurpose: COPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, targeted lung denervation (TLD), which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study assessed the durability of safety and efficacy of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD two years post randomization.Patients and Methods: TLD was performed in COPD patients (FEV1 30– 60% predicted, CAT≥ 10 or mMRC≥ 2) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system (Nuvaira, Inc., USA). Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed.Results: Eighty-two subjects (FEV1 41.6± 7.4% predicted, 50.0% male, age 63.7± 6.8 yrs, 24% with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p=0.04, HR=0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p=0.18, HR=0.71). No significant changes in lung function or SGRQ-C were found 2 years post randomization between groups.Conclusion: In a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe AECOPD over 2 years. Further, lung function and quality of life remained stable following TLD.Clinical Trial Registration: NCT02058459.Keywords: COPD exacerbation, targeted lung denervation, bronchoscopy, COPD

Wolfgang Schuette,1 Claus-Peter Schneider,2,3 Walburga Engel-Riedel,4 Christian Schumann,5,6 Martin Kohlhaeufl,7 Monika Heidi Ursel Serke,8 Gert Hoeffken,9 Cornelius Kortsik,10 Martin Reck11 1Department of Internal Medicine II, Hospital Martha-Maria Halle-Doelau, Halle, 2Department of Pneumonology, Central Hospital, Bad Berka, 3Department of Internal Medicine, DRK Manniske Hospital, Bad Frankenhausen, 4Cologne Clinics, Merheim Lung Hospital, Cologne, 5Pneumonology, Department of Internal Medicine II, University Hospital Ulm, 6Clinic for Pneumology, Thoracic Oncology, Sleep, and Respiratory Critical Care, Kempten-Oberallgäu, 7Center of Pneumonology and Chest Surgery, Hospital Schillerhoehe, Gerlingen, 8Pneumonology, Lung Clinics, Hemer, 9Center of Pneumonology, Chest and Vascular Surgery, Specialty Hospital Coswig, Coswig, 10Department of Pneumonology, Catholic Hospital, Mainz, 11Department of Thoracic Oncology, Lung Clinic, Grosshansdorf, Germany Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC).Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS).Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0–1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03–1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195–2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS.Conclusion: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0–1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy. Keywords: bevacizumab, pemetrexed, carboplatin, NSCLC, elderly patients

Angel T Brown,1 Jason Hitchcock,2 Christopher Schumann,2 J Michael Wells,1,3,4 Mark T Dransfield,1,3,4 Surya P Bhatt1,3 1Division of Pulmonary, Allergy, and Critical Care Medicine, 2Department of Cardiopulmonary Rehabilitation, 3UAB Lung Health Center, University of Alabama at Birmingham, 4Veterans Affairs Medical Center, Birmingham, AL, USA Background: Despite known benefits, a significant proportion of patients with COPD do not complete pulmonary rehabilitation (PR). Little is known regarding which factors promote successful completion of PR. Methods: We analyzed data from a prospectively maintained database of subjects with COPD who attended a PR program at the University of Alabama at Birmingham, from 1996 to 2013. Subjects were categorized as either completers or non-completers, based on successful completion of at least 8 weeks of PR. Demographics and comorbidities were recorded. Short Form 36 Health Survey, Beck Depression Inventory-II, and San Diego Shortness of Breath Questionnaire were administered to all participants at baseline and on completion of PR to assess participants’ perception of their health status, severity of depression, and dyspnea with performance of activities of daily living. Univariate and multivariable analyses were performed to identify predictors of successful completion of PR. Results: Four hundred and forty subjects were included, of whom 229 completed PR. Forty-one percent were female, and 17% were African American. Compared with non-completers, completers had greater Short Form 36 Health Survey pain score, lower forced expiratory volume in the first second, and lower Beck Depression Inventory score, and included a lower percentage of current smokers. On multivariate analysis, cigarette smoking at enrollment was associated with lower likelihood of completion of PR (adjusted odds ratio 0.38, 95% confidence interval 0.16–0.90; P=0.02).Conclusion: Cigarette smoking was the sole independent predictor of PR dropout, and smoking cessation may warrant greater emphasis prior to enrollment. Keywords: pulmonary rehabilitation, COPD, completion

Olena Taratula,1 Mehulkumar Patel,2 Canan Schumann,1 Michael A Naleway,1 Addison J Pang,1 Huixin He,2 Oleh Taratula1 1Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA; 2Department of Chemistry, Rutgers University-Newark, Newark, NJ, USA Abstract: We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chemically modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a molecular design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with luteinizing hormone-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-infrared (NIR) irradiation of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-production by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%–95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy. Keywords: graphene nanosheets, phthalocyanine, photothermal therapy, photodynamic therapy, theranostic

Background: Emergency hormonal contraceptives (EHC) are contraceptives used to prevent unintended pregnancy following unprotected sexual intercourse (USI) or contraceptive failure. The EHCs available without a prescription include medicines containing levonorgestrel (LNG) in more than 80 countries and, recently, based on an EU-switch ellaOne®, which contains ulipristal acetate (UPA). EHCs work by stopping or delaying ovulation. Those containing LNG can be used up to 72 hours after USI or contraceptive failure, while UPA can be used up to 120 hours. In the context of the UPA implementation process, Germany switched LNG to non-prescription status as well. Objectives: To develop recommendations, a protocol, and a continuing education program for pharmacists to assure quality when giving advice and dispensing EHCs in community pharmacies without a medical prescription. Methods: The recommendations were developed by an iterative process of drafting, recognizing, and discussing comments and proposals for amendments as well a seeking agreement with a number of stakeholders such as the Federal Ministry of Health (BMG), Federal Institute for Drugs and Medical Devices (BfArM), Federal Chamber of Physicians (BÄK), Drug Commission of German Physicians (AkdÄ), professional organizations/associations of gynaecologists, pharmaceutical OTC-industry as well as government-controlled, private, and church-based organizations and centres providing advice on sex education and family planning. Results: The recommendations were eventually endorsed by the BMG in consultation with the BfArM. Conclusions: The recommendations were made public, published in the professional journal and used in an uncounted number of continuing education programs based on the curriculum and provided by the State Chambers of Pharmacists.

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Premixed flames exhibit different asymptotic regimes of interaction between heat release and turbulence depending on their respective length scales. At high Karlovitz number, the dilatation caused by heat release does not have any relevant effect on turbulent kinetic energy with respect to non-reacting flow, while at low Karlovitz number, the mean shear is a sink of turbulent kinetic energy, and counter-gradient transport is observed. This latter phenomenon is not well captured by closure models commonly used in Large Eddy Simulations that are based on gradient diffusion. The massive amount of data available from Direct Numerical Simulation (DNS) opens the possibility to develop data-driven models able to represent physical mechanisms and non-linear features present in both these regimes. In this work, the databases are formed by DNSs of two planar hydrogen/air flames at different Karlovitz numbers corresponding to the two asymptotic regimes. In this context, the Generative Adversarial Network (GAN) gives the possibility to successfully recognize and reconstruct both gradient and counter-gradient phenomena if trained with databases where both regimes are included. Two GAN models were first trained each for a specific Karlovitz number and tested using the same dataset in order to verify the capability of the models to learn the features of a single asymptotic regime and assess its accuracy. In both cases, the GAN models were able to reconstruct the Reynolds stress subfilter scales accurately. Later, the GAN was trained with a mixture of both datasets to create a model containing physical knowledge of both combustion regimes. This model was able to reconstruct the subfilter scales for both cases capturing the interaction between heat release and turbulence closely to the DNS as shown from the turbulent kinetic budget and barycentric maps. [ABSTRACT FROM AUTHOR]