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Rebekka Wlassits,1 Mathias Müller,2 Karl H Fenzl,1 Thomas Lamprecht,3 Ludwig Erlacher3 1Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Austria; 2Department für Biomedizinische Wissenschaften, Institut für Tierzucht und Genetik, Veterinärmedizinische Universität Wien, Vienna, Austria; 3Ludwig Erlacher, Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, AustriaCorrespondence: Rebekka Wlassits, Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Kundratstraße 3, 1100 Wien, Austria, Tel +43 1 60910 72238, Email rebekka.wlassits@gesundheitsverbund.atAbstract: Rheumatoid arthritis (RA) is a systemic, chronic, immune-mediated inflammatory condition. Treatments options encompass conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors (TNFis) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) including Janus Kinase inhibitors (JAKinibs). Orally administered JAKinibs have demonstrated comparable or, in specific cases, superior efficacy compared to bDMARDs in inflammatory conditions. However, the escalating clinical utilization has been accompanied by the emergence of serious adverse effects, including major adverse cardiac events (MACE), malignancies and venous thrombotic episodes (VTE), leading to regulatory restrictions imposed by health authorities in both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).Keywords: rheumatoid arthritis, treatment, safety restrictions, major adverse cardiac events, malignancies, venous thrombotic episodes

Andreas Horner,1 Horst Olschewski,2 Sylvia Hartl,3 Arschang Valipour,4 Georg-Christian Funk,5 Michael Studnicka,6 Monika Merkle,7 Bernhard Kaiser,1 Eva Maria Wallner,8 Stephan Brecht,8 Bernd Lamprecht1 1Johannes Kepler University Linz, Kepler University Hospital, Department of Pulmonology, Linz, Austria; 2Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, and Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 3Department of Respiratory and Critical Care Medicine, Klinik Penzing and Sigmund Freud University, Medical School, Vienna, Austria; 4Karl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria; 5Department of Internal and Respiratory Medicine, Klinik Ottakring, Vienna, Austria; 6Department of Pulmonary Medicine, Paracelsus Medical University, Salzburg, Austria; 7Specialist Office for Pulmonology Dr. Merkle, Vienna, Austria; 8A. Menarini Pharma GmbH, Vienna, AustriaCorrespondence: Andreas Horner, Johannes Kepler University Linz, Kepler University Hospital, Department of Pulmonology, Altenberger Strasse, 69, 4040 Linz and Krankenhausstrasse 9, 4020 Linz, Austria, Email Andreas.Horner@kepleruniklinikum.atBackground: Symptoms of depression, pain and limitations in physical activity may affect quality of life in COPD patients independent from their respiratory burden. We aimed to analyze the associations of these factors in outpatients with COPD in Austria in a stable phase of disease.Methods: We conducted a national, cross-sectional study among patients with COPD. For depression, the Patient Health Questionnaire-9 (PHQ-9) and for respiratory symptoms the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) were used along with 10-point scales for physical activity and pain.Results: After exclusion of 211 patients due to non-obstructive spirometry or missing data, 630 patients (62.5% men; mean age 66.8 ± 8.6 (SD) years; mean FEV1%pred. 54.3 ± 16.5 (SD)) were analyzed. Of these, 47% reported one or more exacerbations in the previous year, 10.4% with hospitalization. A negative depression score was found in 54% and a score suggesting severe depression (PHQ-9 score ≥ 15) in 4.7%. In a multivariate linear regression model, self-reported pain, dyspnea, and number of exacerbations were predictors for higher PHQ-9-scores. A negative pain score was found in 43.8%, and a score suggesting severe pain in 2.9% (8– 10 points of 10-point scale). Patients reporting severe pain were more often female, had more exacerbations, and reported more respiratory and depressive symptoms, a lower quality of life, and less physical activity. About 46% of patients rated their physical activity as severely impaired. These patients were significantly older, had more exacerbations, concomitant heart disease, a higher pain and depression score, and a lower quality of life (SGRQ-C – total score and all subscores).Conclusions: In Austria, nearly half of stable COPD outpatients reported symptoms of depression, which were associated with lower levels of self-reported physical activity, more pain, and respiratory symptoms. The associations were particularly strong for depression with SGRQ-C.Keywords: chronic obstructive pulmonary disease, depression, PHQ-9, pain, quality of life, St. George’s Respiratory Questionnaire, physical activity

The article presents selected issues within the field of space syntax, its theoretical assumptions, and application possibilities, taking into account, especially, works in the field of social and economic geography, and spatial management. The article attempts to present Polish works in the field of space syntax as related to the wider spectrum of its global applications. In Poland, the theory and research tools of space syntax are rarely used. It appears that there are two factors that influence the current marginalisation of space syntax. The first one is the relative complexity of the research procedure, which requires knowledge of specialist computer software. The second arises directly from the fact that, in reality, only occasional use of space syntax tools has been attempted within the Polish arena. This determines the actual lack of a native space syntax community that would support subsequent researchers who are ready to conduct such studies.

David Lang,1,2 Wolfgang Haslinger,2 Kaveh Akbari,2,3 Mario Scala,2,3 Benedikt Hergan,2,3 Christian Asel,2,3 Andreas Horner,1,2 Romana Wass,1,2 Elmar Brehm,1,2 Bernhard Kaiser,1 Bernd Lamprecht1,2 1Johannes Kepler University Hospital, Department of Pulmonology, Linz, Austria; 2Johannes Kepler University, Medical Faculty, Linz, Austria; 3Johannes Kepler University Hospital, Central Radiology Institute, Linz, AustriaCorrespondence: David LangKepler University Hospital, Department of Pulmonology, MedCampus III, Krankenhausstraße 9, Linz 4020, AustriaTel +43 5 7680 83 73797Email david.lang@kepleruniklinikum.atObjective: To evaluate serum tumor markers (STM) as predictive biomarkers in advanced non-small cell lung cancer (NSCLC) treated with chemo-immunotherapy.Methods: Patients having received platinum-based chemo-(CHT) and PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) combination therapy were retrospectively followed. Carcinoembryonic antigen (CEA), carbohydrate antigen 19– 9 (CA19-9), cytokeratin-19 fragments (CYFRA 21– 1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis. The marker with the highest relative elevation was defined “leading STM”, its change was assessed between CHT-ICI as well as mono-ICI maintenance initiation and the respective subsequent restaging. Corresponding computed tomography evaluations were analyzed using response evaluation criteria in solid tumors (RECIST). For CHT-ICI combination and subsequent mono-ICI-maintenance therapy, leading STM and RECIST response were evaluated regarding progression-free (PFS) and overall survival (OS) in Kaplan–Meier analyses.Results: Among 80 CHT-ICI patients (41% women, mean age 63 years), median PFS was 5 months (M;4,9), median OS was 15M (10,/). PFS was significantly (p=0.042) longer, when the leading STM had decreased at first restaging under CHT-ICI combination therapy (9M (5,12; n=41) vs 5M (3,6; n=16)). In the 54 (67.5%) patients who received subsequent mono-ICI maintenance therapy, STM decrease was similarly associated with significantly (p< 0.001) longer PFS (16M (7,/; n=16) vs 3.5M (2,6; n=22)). Patients with radiologically stable or progressive disease and concomitant leading STM decrease had similar PFS in the CHT-ICI combination phase (4M (3,7; n=16) vs 4.5M (2,6; n=14)), but longer PFS in the mono-ICI maintenance setting (13M (7,16; n=10) vs 3M (2,4; n=17)). Median OS was not reached in most subgroups.Conclusion: Leading STM dynamics provide predictive biomarker information additional to radiological response evaluation patients receiving CHT-ICI combination therapy, especially in the mono-ICI maintenance setting.Keywords: carcinoembryonic antigen, platinum doublet chemotherapy, pembrolizumab, CYFRA 21-1, RECIST, nivolumab

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

Andreas Horner,1– 3 Otto C Burghuber,4 Sylvia Hartl,5 Michael Studnicka,6 Monika Merkle,7 Horst Olschewski,8 Bernhard Kaiser,1 Eva Maria Wallner,9 Bernd Lamprecht1,2 1Department of Pulmonology, Kepler University Hospital, Linz, Austria; 2Faculty of Medicine, Johannes Kepler University, Linz, Austria; 3Institute of General, Family and Preventive Medicine, Paracelsus Medical University, Salzburg, Austria; 4First Department of Respiratory and Critical Care Medicine, and Ludwig Boltzmann Institute of COPD and Respiratory Epidemiology, Otto Wagner Hospital and Sigmund Freud University, Medical School, Vienna, Austria; 5Second Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital and Sigmund Freud University, Medical School, Vienna, Austria; 6Department of Pulmonary Medicine, Paracelsus Medical University, Salzburg, Austria; 7Specialist Office for Pulmonology Dr. Merkle, Vienna, Austria; 8Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, and Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 9A. Menarini Pharma GmbH, Vienna, AustriaCorrespondence: Andreas HornerKepler University Hospital, Department of Pulmonology, Krankenhausstrasse 9, Linz A4021, AustriaTel +43 (0) 5 7680 83 – 6911Fax +43 (0) 5 7680 83 – 6915Email andreas.horner@kepleruniklinikum.atBackground: COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients.Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician’s diagnosis of COPD and age ≥ 40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded.Results: Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV1/FVC < 0.7) and 77 were excluded due to missing data. Finally, 850 patients (62.8% men; mean age 66.2 ± 0.3 (SE) years; mean FEV1%pred. 51.5 ± 0.6 (SE)) were analyzed. Last year, 55.4% reported at least one exacerbation, and 12.7% were hospitalized for COPD exacerbation. Mean SGRQ-C total score was 43.1 ± 0.83 (SE) and mean component scores for symptoms, activity and impacts were 55.6, 55.4 and 30.5, respectively. Half of the patients (50.3%) reported not being able to do any sports and 78.7% stated that their respiratory symptoms did not allow them doing anything they would like to do. In patients with less severe COPD (FEV1pred ≥ 50% and non-frequent exacerbations), global health status was overrated, ie, estimated as better by the physician than by the patient, while it was underrated in more severe COPD.Conclusion: In Austria, the burden of disease in COPD outpatients tends to be underestimated in patients with milder airway obstruction and less exacerbations and overestimated in patients with more severe airway obstruction and frequent exacerbations. Our finding suggests that validated assessment of global health status might decrease these differences of perception.Keywords: chronic obstructive pulmonary disease, limitations, quality of life, St. Georges Respiratory Questionnaire

Formulating localisation strategies is crucial to ensuring the development of local suppliers, which in turn results in job creation, increased export earnings, and local and national economic growth. The aim of this article is to present a generic decision support system (DSS) to guide localisation decision-making. Multi-criteria decision analysis (MCDA) is used to develop the model, which is then applied to a biometric identity management system (BIMS) case study that places the study within the context of the tool, die and mould-making (TDM) industry of South Africa.

The Tygerberg Children's Choir (TCC) is rooted in South Africa's Afrikaner culture. Its transition to a multicultural children's choir, within a drastically changed political dispensation, furnished a rich subject for a historiographic choir identity investigation. From its establishment in 1972 until 2019, Hendrik D. Loock was the conductor. Since then the choir has continued under Karina Erasmus. The TCC is one of the oldest existing mixed-gender regional children's choirs in the country, directed by the longest serving conductor of such a choir. The choir's identity and Loock's forty-seven-year directorship are interwoven, his work perceived as a significant cultural contribution. With his late wife Theresa (TCC accompanist, choral trainer, and arranger of choir music for thirty-two years), Loock confirmed a uniquely familial leadership profile amongst children's choirs. This qualitative biographic report about the life and contribution of Loock and the TCC merges thematically analysed data from the TCC's archival collection, non-participant observations, face-to-face interviews, and contextual information.

Marina V Ivanova1, Constanze Lamprecht1, M Jimena Loureiro1, J Torin Huzil1,2, Marianna Foldvari11School of Pharmacy, 2Faculty of Applied Mathematics, University of Waterloo, Waterloo, ON, CanadaBackground: Carbon nanotubes (CNTs) are novel materials with considerable potential in many areas related to nanomedicine. However, a major limitation in the development of CNT-based therapeutic nanomaterials is a lack of reliable and reproducible data describing their chemical and structural composition. Knowledge of properties including purity, structural quality, dispersion state, and concentration are essential before CNTs see widespread use in in vitro and in vivo experiments. In this work, we describe the characterization of several commercially available and two in-house-produced CNT samples and discuss the physicochemical profiles that will support their use in nanomedicine.Methods: Eighteen single-walled and multi-walled CNT raw materials were characterized using established analytical techniques. Solid CNT powders were analyzed for purity and structural quality using thermogravimetric analysis and Raman spectroscopy. Extinction coefficients for each CNT sample were determined by ultraviolet-visible near infrared absorption spectroscopy. Standard curves for each CNT sample were generated in the 0–5 µg/mL concentration range for dispersions prepared in 1,2-dichlorobenzene.Results: Raman spectroscopy and thermogravimetric analysis results demonstrated that CNT purity and overall quality differed substantially between samples and manufacturer sources, and were not always in agreement with purity levels claimed by suppliers. Absorbance values for individual dispersions were found to have significant variation between individual single-walled CNTs and multi-walled CNTs and sources supplying the same type of CNT. Significant differences (P < 0.01) in extinction coefficients were observed between and within single-walled CNTs (24.9–53.1 mL•cm-1•mg-1) and multi-walled CNTs (49.0–68.3 mL•cm-1•mg-1). The results described here suggest a considerable role for impurities and structural inhomogeneities within individual CNT preparations and the resulting spectroscopic properties of their dispersions.Conclusion: Raw CNT materials require thorough analytical workup before they can be used as nanoexcipients. This applies especially to the determination of CNT purity, structure, and concentration. The results presented here clearly demonstrate that extinction coefficients must be determined for individual CNT preparations prior to their use.Keywords: carbon nanotubes, pharmaceutical characterization, Raman spectroscopy, thermogravimetric analysis, ultraviolet-visible near infrared spectroscopy