Journal articles on the topic 'Edith Rothe'

Resumen En el presente artículo (i) se desarrolla una crítica al discurso histórico-filosófico de Kant para explicitar sus condiciones de posibilidad, desde lo cual se erige un modelo hermenéutico que (ii) hace inteligible la historia filosofante de la filosofía presente en Los progresos de la metafísica desde los tiempos de Leibniz y Wolff, mostrando cómo las condiciones operan allí y constituyen una determinada narrativa que da cuenta de las perspectivas desde las cuales se ofrece la historia; después (iii) se realiza la interpretación de la historia desde el modelo con el fin de señalar su sostenibilidad; al final, (iv) se vincula la historia filosófica con la propia filosofía trascendental de Kant, legitimando con ello al modelo y señalando cómo el horizonte del proyecto crítico es esa misma historia. Palabras clave Metafísica: Historia; Razón; Teleología; Discurso. Referencias Allison, Henry E., Kant’s Transcendental Idealism. An Interpretation and Defense, USA: Yale University Press, 2004. Allison, H. E., Editor’s Introduction, a What real progress has metaphysics made in Germany since the time of Leibniz and Wolff?, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison, Peter Heath, Cambridge University Press, USA, 2002. Allison, Henry E., “General Introduction”, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison y Peter Heath, USA: Cambridge University Press, 2002. Beiser, Frederick C., “Moral Faith and the Highest Good”, en The Cambridge Companion to Kant and Modern Philosophy, edit. Paul Guyer, USA: Cambridge University Press, 2006. Caimi, Mario, “La metafísica de Kant”, en Kant, Immanuel, Los Progresos de la metafísica desde los tiempos de Leibniz y Wolff, trad. Mario Caimi, México: Fondo de Cultura Económica, UNAM, UAM, 2011. Duque, Félix, “Estudio Introductorio”, en Kant, Immanuel, Los progresos de la metafísica, trad. Félix Duque, Madrid: Tecnos, 1987. Ferrarin, Alberto, The Powers of Reason. Kant and the Idea of Cosmic Philosophy, USA: University of Chicago Press, 2015. Grondin, Jean, Introduction to Metaphysics. From Parmenides to Levinas, trad. Lukas Soderstorm, USA: Columbia University Press, 2012. Guyer, Paul, “The Unity of Nature and Freedom”, en Guyer, Paul, Kant’s System of Nature and Freedom, USA: Oxford University Press, 2005. Heidegger, Martin, Kant y el problema de la metafísica, trad. Gred Ibscher Roth, México: Fondo de Cultura Económica, 1996. Kant, El conflicto de las facultades, trad. Roberto Rodríguez Aramayo, en Immanuel Kant, Kant III, España: Gredos, 2014. Kant, Immanuel, Idea para una historia universal en clave cosmopolita, trad. Roberto Rodríguez Aramayo, en Immanuel Kant, Kant III, España: Gredos, 2014. Kant, Immanuel, Crítica de la razón pura, trad. Mario Caimi, México: FCE, UNAM, UAM, 2011. Kant, Immanuel, Los progresos de la metafísica, trad. Mario Caimi, México: Fondo de Cultura Económica, UNAM, UAM, 2011. Kant, Immanuel, Conjectural beginning of human history, trad. Allen W. Wood, en Immanuel Kant, Anthropology, History and Education, edit. Gunter Zoller, Robert B. Louden, USA: Cambridge University Press, 2007. Kant, Immanuel, On the use of teleological principles in philosophy, trad. Gunter Zoeller, en Kant, Immanuel, Anthropology, History and Education, edit. Gunter Zoller, Robert B. Louden, USA: Cambridge University Press, 2007. Kant, Immanuel, On a recently prominent tone of superiority in philosophy, trad. Peter Heath, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison, Peter Heath, USA: Cambridge University Press, 2002. Kant, Immanuel, Proclamation of the imminent conclusion of a treaty of perpetual peace in philosophy, trad. Peter Heath, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison, Peter Heath, USA: Cambridge University Press, 2002. Kerszberg, Pierre, Critique and Totality, USA State University of New York Press, USA, 1997. Kuhen, Manfred, “Kant’s Critical Philosophy and its Reception –the first five yearse (1781-1786)”, en The Cambridge Companion to Kant and Modern Philosophy, edit. Paul Guyer, USA: Cambridge University Press, 2006. Leibniz, Gottfried, El método verdadero, trad. J. Echeverría, en Leibniz, Leibniz, España: Gredos 2014. Longuenesse, Béatrice, Kant and the Capacity to Judge. Sensibility and Discursivity in the Transcendental Analytic of the Critique of Pure Reason, trad. Charles T. Wolfe, USA: Princeton University Press, 1998. Lyotard, Jean-Francois, Enthusiasm. The Kantian Critique of History, trad. Georges Van Den Abbeele, USA: Standford University Press, 2009. Martínez Marzoa, Felipe, Historia de la filosofía antigua, Madrid: Akal, 1995. Martínez Marzoa, Felipe, Releer a Kant, España: Anthropos, 1989. Platón, Fedón, trad. Carlos García Gual, en Platón, Platón I, España: Gredos, 2014. Platón, Menón, trad. Francisco José Olivieri, en Platón, Platón I, España: Gredos, 2014. Sevilla, Sergio, “Kant: Razón histórica y razón trascendental”, en Kant después de Kant, edit. Javier Muguerza, Roberto Rodríguez Aramayo, Madrid: Tecnos, 1989. Spinoza, Baruch, Ética demostrada según el orden geométrico, trad. Oscar Cohan, México: Fondo de Cultura Económica, 2015. Tugendhat, Ernst, Introducción a la filosofía analítica, trad. José Navarro Pérez, España: Gedisa, 2003. Vieinard-Baron, Jean-Louis, Platón et l’idealisme allemande (1770-1830), Paris: Beauchesne, 1979. Vilar, Gerard, “El concepto del Bien Supremo en Kant”, en Kant después de Kant, edit. Javier Muguerza, Roberto Rodríguez Aramayo, Madrid: Tecnos, 1989. Zammito, John, The Genesis of Kant’s Critique of Judgment, USA: The University of Chicago Press, 1992.

Background:Rheumatoid arthritis (RA) has bene associated with atherosclerosis and cardiovascular (CV) disease. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) is suitable to detect synovial and vascular inflammation. Tofacitinib has been used to effectively treat RA.Objectives:We wished to assess the effects of tofacitinib treatment on synovitis and vascular inflammation simultaneously by 18FDG-PET/CT.Methods:Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib and evaluated at baseline and after 6 and 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (aCCP) levels. All patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in order to determine vascular and synovial inflammation in five aortic segments and five articular regions, respectively. In the joints, mean (SUVmean) and maximum standard uptake values (SUVmax), while in the aorta, mean (TBRmean) and maximum target-to-background ratios (TBRmax) were determined. Carotid intima-media thickness (IMT), arterial stiffness (PWV) and endothelial dysfunction (FMD) were determined by ultrasound.Results:One-year tofacitinib treatment significantly attenuated vascular and synovial inflammation as visualized by PET/CT. Articular SUVmean (p=0.010), SUVmax (p=0.001), as well as aorta TBRmax (p<0.001) significantly decreased over time. Synovial inflammation as determined by PET/CT variably and positively associated with aCCP, RF, CRP, ApoB, lipoprotein A (LpA), IMT and PWV. Vascular inflammation (TBRmax) inversely correlated with HAQ and positively with ESR, ApoA, and PWV. Uni- and multivariable analyses suggested that articular SUV values were independently associated with CRP, ApoB, LpA, IMT and PWV, while aortic TBRmax was determined by HAQ and PWV.Conclusion:18F-PET/CT is suitable to simultaneously assess synovial and vascular inflammation in RA. One-year tofacitinib treatment dampened inflammation. PET/CT changes were associated with markers of systemic inflammation, atherogenic lipids, carotid atherosclerosis and arterial stiffness.References:[1]Gotthardt M, Bleeker-Rovers CP, Boerman OC, Oyen WJ. Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. J Nucl Med. 2010;51(12):1937-49.[2]Bucerius J, Hyafil F, Verberne HJ, Slart RH, Lindner O, Sciagra R, et al. Position paper of the Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) on PET imaging of atherosclerosis. Eur J Nucl Med Mol Imaging. 2016;43(4):780-92.Acknowledgements:This research was supported by the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program’ (Z.S.); by the European Union grant GINOP-2.3.2-15-2016-00015 (G.P., G.T. and Z.S.) and by the Pfizer Investigator Initiated Research Grant no. WI188341 (Z.S.).Disclosure of Interests:Attila Hamar: None declared, Zsolt Hascsi: None declared, Anita Pusztai: None declared, Monika Czókolyová: None declared, Edit Végh: None declared, Zsófia Pethö: None declared, Katalin Gulyás: None declared, Boglárka Soós: None declared, György Kerekes: None declared, Éva Szekanecz: None declared, Katalin Hodosi: None declared, Sándor Szántó Speakers bureau: Abbvie, MSD, Novartis, Consultant of: Abbvie, MSD, Novartis, Gabriella Szücs Speakers bureau: Boehringer, Actelion, Roche, Consultant of: Boehringer, Actelion, Roche, Tamas Seres: None declared, Zoltán Szekanecz Speakers bureau: Abbvie, Pfizer, Roche, Novartis, Lilly, Sager, Janssen, Consultant of: Pfizer, Abbvie, Roche, Novartis, Grant/research support from: Pfizer, Szilvia Szamosi Speakers bureau: Roche

Background:Rheumatoid arthritis (RA) has been associated with increased cardiovascular (CV) risk and metabolic changes.Objectives:We wished to determine how the Janus kinase (JAK) inhibitor tofacitinib influences vascular pathophysiology and metabolites of the arginine and methionine-homocysteine pathways.Methods:Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib and evaluated at baseline and after 6 and 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (aCCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels.Results:Twenty-six patients completed the study. Tofacitinib treatment maintained FMD and PWV. Ten mg bid tofacitinib significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. Tofacitinib transiently increased L-citrulline and L-NMMA and decreased homocysteine levels after 12 months. Based on L-citrulline, L-ornithine, ADMA and SDMA levels, L-arginine remained highly available for endothelial NO production. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with aCCP. Regarding vascular pathophysiology, only PWV and methionine correlated with each other after 12 months.Conclusion:Tofacitinib suppressed systemic inflammation in RA yielding stabilization of vascular function. It may exert CV protective effects in RA, at least in part, by shifting L-arginine metabolism to high arginine availability and decreasing homocysteine levels.Acknowledgements:This research was supported by the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program ’(Z.S.); by the European Union grant GINOP-2.3.2-15-2016-00015 (Z.S.) and by the WI188341 investigator-initiated research (IIR) grant obtained from Pfizer US (Z.S.).Disclosure of Interests:Boglárka Soós: None declared, Attila Hamar: None declared, Anita Pusztai: None declared, Monika Czókolyová: None declared, Edit Végh: None declared, Szilvia Szamosi Speakers bureau: Roche, Zsófia Pethö: None declared, Katalin Gulyás: None declared, György Kerekes: None declared, Éva Szekanecz: None declared, Sándor Szántó Speakers bureau: Abbvie, MSD, Novartis, Consultant of: Abbvie, Novartis, Gabriella Szücs Speakers bureau: Actelion, Roche, Sager, Boehringer, Consultant of: Boehringer, Actelion, Sager, Uwe Christians: None declared, Jelena Klawitter: None declared, Tamas Seres: None declared, Zoltán Szekanecz Speakers bureau: Pfizer, Abbvie, Roche, Lilly, Novartis, Boehringer, Consultant of: Pfizer, Abbvie, Novartis, Grant/research support from: Pfizer

Emerging data indicate that germline mutations in transcription factors involved in hematopoiesis can lead to a cascade of downstream molecular alterations that modify the function of megakaryocytes (MK) and platelets. Our group and others have found that mutations in ETV6 lead to mild thrombocytopenia with a bleeding diathesis, red cell macrocytosis, and predisposition to lymphoblastic leukemia. The mechanisms responsible for thrombocytopenia and propensity for bleeding in patients with ETV6 mutations are unknown. We described families with missense mutations in the central domain (p.Pro214Leu) and the ETS DNA binding domain (p.Arg418Gly) of ETV6 that result in aberrant cellular localization of ETV6, decreased transcriptional repression, and impaired MK maturation. Deep sequencing of the platelet transcriptome revealed significant differences in mRNA expression levels between patients with the ETV6 p.Pro214Leu mutation and non-affected family members, indicating that ETV6 is critically involved in defining the molecular phenotype and function of platelets. We hypothesize that normal regulation and function of ETV6 is essential for the transcriptional machinery that controls megakaryocyte differentiation and formation of platelets that function normally under homeostatic conditions. We have successfully generated a CRISPR-Cas9 model to edit the genome of ETV6-expressing iPSC derived megakaryocyte cell line (imMKCL) to characterize the role of wild-type ETV6 in megakaryocyte development and elucidate the molecular mechanism driving mutant ETV6 mislocalization, transcriptional dysregulation, and subsequent dysmegakaryopoiesis and thrombocytopenia. In this imMKCL model, we have genetically engineered the cells to express wild-type, P214L, and the DNA binding domain mutations R418G and R369Q ETV6 fused to HALOtag, a reporter protein that can react with ligands carrying a variety of functionalities, including fluorescent labels, affinity handles, and attachment to solid phase, making this novel reporter conducive to immunofluorescence imaging, biochemical pulldown, and ChIPSeq. This system allows us to express wild type and mutant forms of ETV6 in appropriate allele ratios in imMKCL cells and various hematopoietic-relevant cell lines. Using this approach, we detected nuclear localization of wild-type ETV6 and altered cytoplasmic localization of both P214L and R418G ETV6 mutants. We have also demonstrated dimerization between both wild-type and mutant ETV6 in this cell model. Importantly, we have used HALOtag protein immunoprecipitation to demonstrate ETV6 binding to FLI1, another ETS family member and key transcriptional regulator of megakaryocyte development, suggesting that ETV6 and FLI1 cooperate to regulate megakaryopoiesis under homeostatic conditions. Altogether, these data suggest that mutant ETV6 functions as a dominant negative, sequestering wild type ETV6 in the cytoplasm, de-regulating key transcriptional targets for homeostatic megakaryocyte development. Ongoing studies will define the full repertoire of protein interactions and transcriptional targets of wild-type and mutant ETV6. Discoveries from this novel tool will further advance our understanding of normal megakaryocyte and platelet biology, and will provide potential therapeutic targets for disorders of platelet number and function to optimize the clinical approach to these patients. Disclosures Callaghan: Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau.

Background:Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with osteoporosis. There have been very few data on the use of peripheral quantitative computed tomography (QCT) in anti-TNF-treated patients.Objectives:We wished to assess volumetric bone mineral density (BMD) by forearm QCT in conjunction with dual-energy X-ray absorptiometry (DXA) and bone biomarkers in RA and AS.Methods:Forty RA and AS patients treated with etanercept (ETN) or certolizumab pegol (CZP) were included in a 12-month follow-up study. Peripheral QCT and DXA BMD were determined. Bone biomarkers, such as PTH, osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin, DKK-1 and cathepsin K (CATHK) were assessed by ELISA.Results:There was no further bone loss during anti-TNF treatment. Volumetric and areal BMD showed significant correlations with each other (p<0.05). Total QCT BMD after 12 months was inversely determined by disease activity at baseline in the full cohort (p=0.030). Cortical BMD was negatively determined by baseline disease activity (p=0.005) and CATHK (p=0.025). In RA, VITD-0 determined QTRABBMD-12 (p=0.005). In the full cohort, the one-year change in QTRABBMD was related to TNF inhibition together with higher VITD-0 (p=0.031). Therapy and lower CATHK determined QCORTBMD changes (p=0.006). In RA, treatment together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment together with RANKL-0 (p<0.05) determined QCT BMD changes.Conclusion:QCT confirmed that biologics may attenuate bone loss. Disease activity, CATHK, RANKL and VITD may predict the effects of anti-TNF treatment on volumetric BMD changes. There may be differences between RA and AS in this respect.Acknowledgements:This research was supported by Hungarian National Scientific Research Fund (OTKA) grant No. K 105073 (H.P.B. and Z.S.); by the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program ’(Z.S.); by the European Union grant GINOP-2.3.2-15-2016-00050 (Z.S.); and by the Pfizer Investigator Initiated Research Grants no. WS1695414 and WS1695450 (Z.S.).Disclosure of Interests:Balázs Juhász: None declared, Katalin Gulyás: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Anita Pusztai: None declared, Agnes Szentpetery: None declared, Zsófia Pethö: None declared, Nóra Bodnár: None declared, Attila Hamar: None declared, Levente Bodoki: None declared, Harjit Pal Bhattoa: None declared, Éva Szekanecz: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Szilvia Szamosi Speakers bureau: Roche, Csaba Horváth: None declared, Sándor Szántó Speakers bureau: Abbvie, MSD, Novartis, Consultant of: Abbvie, Novartis, Gabriella Szücs Speakers bureau: Roche, Boehringer, Actelion, Sager, Consultant of: Actelion, Boehringer, Hennie Raterman: None declared, WIllem Lems Speakers bureau: Pfizer, Amgen, Lilly, UCB, Galapagos, Consultant of: Pfizer, Amgen, Lilly, UCB, Galapagos, Oliver FitzGerald Speakers bureau: AbbVie, Janssen, Pfizer, Consultant of: BMS, Celgene, Eli Lilly, Janssen, Pfizer, Grant/research support from: AbbVie, BMS, Eli Lilly, Novartis, Pfizer, Zoltán Szekanecz Speakers bureau: Pfizer, Roche, Abbvie, Novartis, Lilly, Sanofi, Consultant of: Pfizer, Abbvie, Novartis, Grant/research support from: Pfizer, UCB.

e14074 Background: Accurate and comprehensive interpretation of genomic variants has become a bottleneck in clinical sequencing applications due to the accelerated implementation of precision oncology and the rapid growth of relevant biomedical findings. We therefore are motivated to build Ephesus, a framework enabling curation of clinical evidence for biomarkers in somatic cancers. Currently Ephesus is the primary content source for Roche NAVIFY Mutation Profiler (NMP). Methods: Ephesus’ data model ensures adherence to best practice in clinical genomic content curation. Variant classification followed the AMP guidelines for somatic variant interpretation. Approvals and recommendations from regulatory agencies and organizations (FDA, NCCN, etc.) are applied on a regional basis. The data model is mapped to a set of PostgreSQL relational tables. Strategies such as data normalization according to standard ontologies, a submit-review-approval workflow with change logs, and biologically relevant datatype constraints are adopted to enforce data integrity. Ephesus is deployed as a web application, of which the UI allows users to conduct edits, filtering, sorting and bulk operations on entities by attributes. To maximize curation efficiency, a number of inference rules are applied before the content is ingested into NMP. Results: Currently Ephesus is developed to guide data collection, browsing and summarizing related to these primary entities: Biomarkers, Evidence items, Genes, Variants, Variant groups, and Drugs. The content exported on 2020/01/27 contains > 170K biomarker profiles (including combinations), in the context of 13 major cancer types. To evaluate the clinical reporting value of the curated knowledge, more than 60k real clinical cancer patient samples from the AACR GENIE project were queried against Ephesus. We compared the results to the latest content from several major knowledgebases. We see that the performance of Ephesus/NMP excels the others. Conclusions: We have developed Ephesus, a practical content curation framework which provides a highly structured and user-friendly environment for clinically relevant somatic biomarkers. The framework improved the productivity and quality of the manual curation, met clinical interpretation scope and complexity, and assures data integrity and auditability. [Table: see text]

Background:Pneumococcal vaccination is recommended in patients with RA who are receiving conventional synthetic/biologic DMARDs.1 Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor engineered to have a greater selectivity for JAK1 versus JAK2, JAK3, and tyrosine kinase 2, and is approved for the treatment of RA.Objectives:The aim of this analysis was to assess the impact of long-term treatment with UPA + background MTX on immunologic responses to Prevnar 13® (Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]; PCV13) in patients with RA enrolled in the ongoing Phase 2 open-label extension study BALANCE-EXTEND.Methods:Patients from BALANCE-EXTEND receiving PCV13 vaccination were required to be on UPA 15 mg once daily (QD) or 30 mg QD and background MTX for ≥4 weeks prior to, and after, PCV13 vaccination; MTX was not interrupted prior to vaccination. Vaccination antibody titers were collected pre-vaccination (Week 0) and post-vaccination (Weeks 4 and 12). The primary variable was the proportion of patients with satisfactory humoral response to PCV13 (≥2-fold increase in antibody concentration from pre-vaccination [Week 0] in ≥6/12 pneumococcal antigens [1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F]) at 4 weeks post-vaccination.Results:Of 111 patients (UPA 15 mg, n=87; UPA 30 mg, n=24), 86% were female, most (98%) were white, and mean (standard deviation) age was 58.4 (12.0) years. Prior to vaccination, patients had a median (range) duration of RA of 9.3 (3.4–35.0) years and had been receiving UPA for a median (range) of 3.9 (3.0–4.9) years. All but 3 patients were taking concomitant MTX, and 44.1% were taking a CS (median daily dose, 5.0 mg). All 111 patients received PCV13, none discontinued UPA during the first 4 weeks, and blood samples were available from 83/23 and 79/22 patients in the UPA 15/30 mg groups at Weeks 4 and 12, respectively. At 4 weeks, satisfactory humoral response to PCV13 occurred in 67.5% (95% confidence interval [CI]: 57.4–77.5) and 56.5% (95% CI: 36.3–76.8) of patients receiving UPA 15 and 30 mg, respectively. At 12 weeks, satisfactory humoral response to PCV13 occurred in 64.6% (95% CI: 54.0–75.1) and 54.5% (95% CI: 33.7–75.4) of patients receiving UPA 15 and 30 mg, respectively (Figure 1). There was no clear difference in response between patients receiving and not receiving concomitant CS. Within 30 days post-vaccination, 2 adverse events (AEs) were considered as possibly related to UPA (1 case of diverticulitis, UPA 15 mg; 1 case of anemia, UPA 30 mg) and no serious AEs were reported (Table 1). Two patients experienced pyrexia and 1 subject each experienced vaccination-site pain and headache within 1 day post-vaccination (all in UPA 15 mg group).Table 1.Safety through 30 days post-PVC13 vaccination in UPA-treated patientsEvent, n (%)UPA 15 mg QD (n=87)UPA 30 mg QD (n=24)Any AE15 (17.2)3 (12.5)Serious AE00AE leading to discontinuation of study drug00AE with reasonable possibility of being related to UPAa1 (1.1)b1 (4.2)cDeath00aAs assessed by the investigator. bDiverticulitis. cAnemia.AE, adverse event; PVC13, Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]; QD, once daily; UPA, upadacitinib.Conclusion:Satisfactory humoral response to PCV13 at 4 weeks occurred in ~two-thirds of patients with RA receiving long-term treatment with UPA 15 mg QD + background MTX. This is broadly consistent with pneumococcal vaccine humoral responses observed in patients with RA treated with other JAK inhibitors, biologics, or placebo.2–4References:[1]Singh JA, et al. Arthritis Care Res 2016;68:1–25.[2]Winthrop KL, et al. Arthritis Res Ther 2019;21:102.[3]Bingham CO, et al. Ann Rheum Dis 2015;74:818–22.[4]Winthrop KL, et al. Ann Rheum Dis 2016;75:687–95.Acknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing assistance was provided by Frances Smith, PhD, of 2 the Nth, which was funded by AbbVie.Disclosure of Interests:Kevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, and UCB., Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, and UCB., Juan Ignacio Vargas Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, and UCB, Edit Drescher: None declared, CONRADO GARCIA GARCIA: None declared, Alan Friedman Shareholder of: AbbVie, Employee of: AbbVie, Jeffrey Enejosa Shareholder of: AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, Justin Klaff Shareholder of: AbbVie, Employee of: AbbVie, Alan Kivitz Shareholder of: Amgen, Novartis, Gilead, GlaxoSmithKline, Pfizer Inc., and Sanofi, Speakers bureau: AbbVie, Celgene, Eli Lilly, Flexion, Genzyme, Horizon, Merck, Novartis, UCB, Pfizer Inc., Regeneron, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Genzyme, Gilead, Janssen, Pfizer Inc., Regeneron, Sanofi, SUN Pharma Advanced Research, and UCB

Background:Depression is present in up to half of patients with Rheumatoid Arthritis (RA). The association between this mood disorder and disease activity scores, including DAS28, SDAI and CDAI, has previously been described by various authors.Objectives:The aim of our study was assessed the effect of depression on the components of different disease activity scores.Methods:We performed a cross-sectional study of consecutive adults with RA, according to ACR/EULAR 2010 criteria. Sociodemographic data, comorbidities and current treatment were recorded. Disease activity was evaluated using DAS28-ESR, DAS28-CRP, SDAI and CDAI. Depression was assessed using PHQ-9 questionnaire. The PHQ-9 values were categorized in 4 groups as follows: 5 to 9, 10 to 14, 15 to 19, 20 or greater, represents mild, moderate, moderate/severe, and severe depression, respectively. A cutoff value of 10 or greater was set to define major depression. Statistical analysis: Student´s T, ANOVA and Chi2 tests. Multiple logistic regression.Results:Two hundred fifty eight patients were included, with a median (m) disease duration of 9 years (IQR 3.6-16.7). The m PHQ-9 score was 6 (IQR 2-12.3) and the prevalence of major depression was 33.7%. Patients with major depression had more tender and swollen joint count (TJC and SJC) (mean 4.9±4.3 vs 2.3±3.7, p<0.0001 and 2.9±3.3 vs 1.7±3.4, p=0.009), more pain (VAS [cm] mean 5.6±2.7 vs 3.3±2.6, p<0.0001), higher patient and physician global assessment (PGA and PhGA) (VAS [cm] mean 5.4±2.9 vs 3.1±2.5, p<0.0001 and 4.4±2.7 vs 2.4±2.4, p<0.0001) and CRP (mean 1.7±3.3 vs 0.7±1.1 mg/dl, p=0.01). ESR values were higher in the group with major depression, but the difference did not reach significance. Disease activity was higher in the depression group by all scores: DAS28-ESR (mean 4.3±1.4 vs 3.3±1.3, p<0.0001), DAS28-CRP (mean 3.9±1.4 vs 2.8±1.7, p<0.0001), SDAI (mean 19.2±12.7 vs 10.3±10.1, p<0.0001) and CDAI (mean 17.6±10.9 vs 9.6±9.9, p<0.0001). While 41 (15.9%) patients had high disease activity according to DAS28-ESR, only 34 (13.2%) had SDAI>26.In the multivariate analysis, evaluating the association of major depression with the different components of DAS28-ESR, DAS28-CRP, SDAI and CDAI, we observed that the presence of this mood disorder remained significantly associated with higher PGA in all the scores. In addition, a significant association was seen with higher TJC in both DAS28 scores.Conclusion:Patients with major depression had higher disease activity. It´s presence has a significantly association with the subjective items of the disease activity scores, particularly PGA. CRP value was the only objective component associated with depression.Disclosure of Interests:Carolina Ayelen Isnardi Speakers bureau: Bristol Myers Squibb, Janssen, Grant/research support from: Pfizer, Emilce Edith Schneeberger Speakers bureau: Abbvie, Amgen, Bristol Myers Squibb, Janssen, Eli Lilly, Boehringer Ingelheim, Pfizer, Genzyme, Grant/research support from: Pfizer, Dafne Capelusnik Speakers bureau: Bristol Myers Squibb, Grant/research support from: Pfizer, Marcela Bazzarelli: None declared, Laura Barloco: None declared, Eliana Soledad Blanco: None declared, Alejandro Benitez Speakers bureau: Abbvie, Novartis, Amgen, Federico Benavidez: None declared, SANTIAGO SCARAFIA: None declared, María Alicia Lazaro Speakers bureau: Abbvie, Rodolfo Perez Alamino Speakers bureau: Pfizer, Abbvie, Amgen, Bristol-Myers-Squibb, Lilly, Janssen, Novartis, Federico Colombres: None declared, María Paula Kohan: None declared, Julia Sosa: None declared, Luciana Gonzalez Lucero: None declared, Ana Lucía Barbaglia: None declared, Hernan Maldonado Ficco Speakers bureau: Pfizer, Abbvie, Jansen, Novartis, Bago, Bristol, Eli Lilly., Consultant of: Pfizer, Abbvie, Novartis, Jansen, Bago, Eli Lilly., Gustavo Citera Speakers bureau: Abbvie, Bristol-Myers-Squibb, Lilly, Jansen, Gema, Pfizer, Roche, Grant/research support from: Pfizer

Background:Cardiovascular (CV) disease and osteoporosis (OP) have become increasing challenges in the ageing population, even more in patients with inflammatory rheumatic diseases, such as rheumatoid arthritis (RA) and spondyloarthropathies. Both RA and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss, accelerated atherosclerosis, increased CV morbidity and mortality.Objectives:Bone and vascular biomarkers and parameters along with the effect of one-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS.Methods:Fifty-three patients including 36 RA patients treated with etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were assessed by ELISA. Bone density was assessed by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and pulse-wave velocity (PWV) were assessed by ultrasound. The effects of vascular markers on bone and bone effects on vasculature undergone statistical analysis.Results:Serum levels of vascular endothelial growth factor (VEGF), PDGF-BB, angiopoietin 2 (Ang2) and cathepsin K (CathK) decreased, procollagen type 1 N-propeptide (P1NP) and sclerostin (SOST) levels increased, soluble receptor activator nuclear kappa B ligand (sRANKL) and osteoprotegerin (OPG) levels showed no differences. When bone and vascular markers were correlated with each other, at baseline, OPG correlated with Ang2 and adiponectin. SOST correlated positively with ccIMT. DXA L2-4 BMD, DXA L1 BMD and DXA femoral neck (FN) BMD correlated with FMD and CRP. QCT trabecular BMD correlated with ccIMT and PON1. According to the univariate analysis, FMD correlated with OPG, ccIMT correlated with SOST and QCT trabecular BMD. Ang1, Ang2 and PDGF-BB showed correlation with Dickkopf-1 (DKK1). Ang2 also correlated with OPG. As suggested by the multivariate analysis, OPG determined FMD; DKK1 was an independent predictor of Ang1, Ang2 and PDGF-BB. OPG was a predictor of Ang2.Conclusion:In our study of anti-TNF treated RA and AS patients, vascular and bone parameters showed numerous correlations. The therapy was clinically effective, it halted further bone loss over 1 year and reduced the production of angiogenic markers.Acknowledgments:This research was supported by an investigator-initiated research grant from Pfizer.Disclosure of Interests:Monika Czókolyová: None declared, Katalin Gulyás: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Zsófia Pethö: None declared, Szilvia Szamosi: None declared, Attila Hamar: None declared, Anita Pusztai: None declared, Emese Balogh: None declared, Nóra Bodnár: None declared, Levente Bodoki: None declared, Agnes Szentpetery: None declared, Harjit Pal Bhattoa: None declared, György Kerekes: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Sándor Szántó: None declared, Gabriella Szücs: None declared, Hennie Raterman Grant/research support from: UCB, Consultant of: Abbvie, Amgen, Bristol-Myers Sqibb, Cellgene and Sanofi Genzyme, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen

Background:Oral JAK inhibitor, tofacitinib appeared as a new therapeutic option, beside biological therapies, which has already proven its safety and effectivity in RA, but we lack of knowledge how it affects density of bone structures and bone turnover markers.Objectives:The aim of this study was to assess the effects of one-year tofacitinib therapy on bone metabolism in patients with RA.Methods:Altogether 30 RA patients with active disease were recruited and treated with tofacitinib in this 12-months follow-up study. Mean age of patients were 52.8±10.0 years, duration of rheumatoid arthritis were 7.7±5.0 years. Half of the patients haven’t received biological treatment prior tofacitinib therapy, other half of the patients switched to tofacitinib therapy after completing washout. 15 patients received 2x5mg and 15 patients received 2x10mg tofacitinib daily for 12 months. On both arms 2-2 patients have discontinued treatment and excluded from the study. Assessments were performed at baseline, month 6 and 12. Levels of CRP and IgM rheumatoid factor (RF) antibodies were measured by quantitaive nephelometry and levels of anti-CCP, sclerostin, osteocalcin (OC), P1NP were assesed by ELISA. Bone density was assesed by DXA (dual-energy X-ray absorptiometry, Lunar) and pQCT imaging techniques. Levels of DKK-1, OPG, RANKL were measured by multiplex microbead immunoassay (BioLegend LEGENDplex). In addition, disease activity (DAS28), age and disease duration were also measured. Correlations were determined by Spearman’s analysis. Univariate and multiple regression analysis using the stepwise method was applied to investigate independent associations between DXA measurements (dependent variables) and laboratory parameters (independent variables).Results:Tofacitinib significantly reduced DAS28 (p<0.001) and HAQ values (p=0.001), also level of CRP (p<0.001) and We (p=0.014). With respect to bone biomarkers we have experienced significant increase in levels of OC (p=0.013), OPG (p=0.006), sclerostin (p=0.026) and vitamin-D (p=0.017) at month 6, also in levels of OPG and vitamin-D (p=0.004, p=0.003) at month 12. We have found decrease in levels of CTX at month 6 (p=0.009) and 12 (p=0.003). When we examined the groups separately, we’ve found significant increase in levels of P1NP (p=0.027, p=0.005), OPG (p=0.005, p=0.002) and vitamin-D (p=0.001, p=0.004) at month 6 and 12, also in OC at month 6 (p=0.027) in Group A (2x5mg). In Group B (2x10mg) we’ve experienced a significant decrease in levels of phosphate and CTX at month 6 and 12 (p=0.012, p=0.021, and p=0.005, p=0.007).Conclusion:One year tofacitinib treatment effectively stabilized bone density in patients with rheumatoid arthritis, and led to the increase of bone turnover markers, which is beneficial for ossification in long term.Acknowledgments:This research was supported by an investigator-initiated research grant from Pfizer.Disclosure of Interests:Attila Hamar: None declared, Anita Pusztai: None declared, Edit Végh: None declared, Ágnes Horváth: None declared, Szilvia Szamosi: None declared, Zsófia Pethö: None declared, Sándor Szántó: None declared, Gabriella Szücs: None declared, Harjit Pal Bhattoa: None declared, Gábor Tajti: None declared, György Panyi: None declared, Katalin Hodosi: None declared, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen

Background:Systemic sclerosis (SSc) is a multisystem autoimmune disease of complex etiopathogeny, heterogeneous in its phenotypic expression and with a limited prognosis (1). The loss of muscle mass is a serious consequence of many chronic diseases and also is observed in SSc (2). This body composition alterations results in weakness, limitations and physical disability (3). SARC-F simple questionnaire, validated, is a key diagnostic feature for the fast assessment of geriatric syndromes associated with skeletal muscle wasting. However, there is no data about the SARC-F in SSc.Objectives:To assess the association between the SARC-F questionnaire with clinical features in patients with systemic sclerosis (SSc).Methods:Ninety-four patients diagnosed with systemic sclerosis were recruited and evaluated. Sarcopenia was assessed by the SARC-F questionnaire. Clinical features as disease duration time, comorbidities, body mass index (BMI), functional capacity by the Health Assessment Questionnaire (HAQ), inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatine phosphokinase (CPK), hemoglobin, creatinin and albumin) were medical record. Frequency analysis, descriptive analysis and Pearson’s correlation were performed. Statistical significance was considered as p<0,05.Results:Of the 94 patients analyzed, most were women (87/94;92.6%) with mean age of 60.5±10.3 years, median disease duration time of 11.2 (7.5-18.9) and median number of comorbidities was 1.00 (1.00-2.00). The mean of BMI was 25.9±4.7 Kg/m2. Twenty-one of the patients were classified as active or passive smokers, thirty-five said they were former smokers and thirty-eight never smoked. Sixty-nine (80, 2%) out of the ninety-four patients in the study had at least one type of comorbidity (mean 1, 44±1, 04). Eighty-three patients (88.3%) showed a SARC-F score without signs suggestive of sarcopenia (0-5) and eleven patients (11.7%) showed suggestive to sarcopenia (6-10). In HAQ, fifty-seven (60.6%) patients had mild incapacity, thirty-five (37.2%) had moderate incapacity, and two patients (2.2%) had severe incapacity. Higher SARC-F scores were associated with greater number of comorbidities (r=0.2; p=0.027), higher physical disability by HAQ (r= 0.5;p=0.000) and lower albumin levels (r= -0.3; p= 0.048). On other hand, SARC-F was not associated with time of diagnosis, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatine Phosphokinase (CPK), hemoglobin, hematocrit and creatinine.Conclusion:SARC-F scores were associated with comorbidities, physical disability and lower albumin levels in systemic sclerosis patients. Considering that comorbidities, physical disability and the albumin deficit enhances the patient’s muscle loss, SARC-F appears to be a good tool to screen sarcopenia risk factors in systemic sclerosis patients. Longitudinal studies are necessary to validate the SARC-F questionnaire in this population.References:[1]Hochberg MC et al. Sixth edit. (Elsevier, ed.). Philadelphia; 2015;[2]Sakuma K et al. Pflügers Arch - Eur J Physiol. 2017;469(5-6):573-591.[3]Caimmi C, et al. Clin Rheumatol. 2018;37(4):987-997.Acknowledgments:We thank the Coordination for the Improvement of Higher Level Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES) institution, the Foundation for Research Support of the Rio Grande do Sul State (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul—FAPERGS), the Research and Events Incentive Fund (Fundo de Incentivo à Pesquisa e Eventos—FIPE) of HCPA and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq).Disclosure of Interests:Leonardo Santos: None declared, Rafaela Cavalheiro do Espírito Santo: None declared, Vanessa Hax: None declared, Rafael Mendonça da Silva Chakr: None declared, Ricardo Xavier Consultant of: AbbVie, Pfizer, Novartis, Janssen, Eli Lilly, Roche

Background: BCL11A is a key transcription factor that suppresses the production of fetal hemoglobin (HbF) in red blood cells (RBCs), leading to the production of adult Hb (HbA). In diseases with hemoglobin production defects such as b-thalassemia, or in sickle cell disease (SCD), HbF upregulation could ameliorate anemia and reduce transfusion requirements, such as in β-thalassemia, or reduce clinical complications, including vaso-occlusive crises (VOCs), in SCD. To induce potentially curative levels of HbF in erythrocytes, we used the ex vivo CRISPR-Cas9-based gene-editing platform to edit the erythroid enhancer region of BCL11A in hematopoietic stem and progenitor cells (HSPCs), producing CTX001. Aims: CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) are multi-center, first-in-human studies of CTX001 for transfusion-dependent b-thalassemia (TDT) and SCD, respectively. Here, we present available safety and efficacy results from all patients with at least 3 months of follow-up from both studies as of July 2020. Methods: Patients (aged 18 to 35 years) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/year or ≥10 units/year in the previous 2 years, and those with severe SCD, defined as ≥2 VOCs/year requiring medical care in the previous 2 years, were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF (filgrastim) and plerixafor (for TDT) or plerixafor alone (SCD). The erythroid enhancer region of BCL11A was edited in CD34+ cells using a specific CRISPR guide RNA and Cas9 nuclease. Prior to CTX001 infusion on Day +1, patients received myeloablation with 4 days of busulfan. Patients were monitored for stem cell engraftment and hematopoietic recovery, adverse events, total Hb and HbF production, hemolysis, F-cells, pRBC transfusion requirements (TDT), and VOCs (SCD) during follow-up. Results: Data are presented for patients with TDT (N=5; RBC transfusion history range: 23.5 to 61 units/year; CTX001 post-infusion follow-up through Months 15, 6, 4, 4, and 3, respectively) and with SCD (N=2; 7 VOCs/year and 7.5 VOCs/year, respectively, annualized over 2 years prior to consent; CTX001 post-infusion follow-up through Months 12 and 3, respectively). In the patients with TDT, median neutrophil engraftment occurred on Day +32 (range: +27 to +36); median platelet engraftment occurred on Day +37 (range: +34 to +52). In the patients with SCD, neutrophil engraftment occurred on Day +30 and Day +22 and platelet engraftment occurred on Day +30 and Day +33, respectively. All patients demonstrated increases in total Hb and HbF over time (Figure). Patients with TDT ceased receiving pRBC transfusions soon after CTX001 infusion, with the last pRBC transfusion occurring between 0.9 and 1.9 months after CTX001 infusion. The first patient with TDT who received CTX001 has remained transfusion-free for over 15 months. Patients with SCD have had no VOCs since CTX001 infusion. The first SCD patient who received CTX001 has remained free of VOCs for over 1 year. In all 7 patients, the safety profile after CTX001 infusion was generally consistent with busulfan myeloablation. Four serious adverse events (SAEs) related or possibly related to CTX001 were reported in 1 patient with TDT: headache, haemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome. All 4 of these SAEs occurred in the context of HLH and were either resolved or clinically improving at the time of this analysis. No other CTX001-related SAEs were reported in the other patients with TDT or in any patients with SCD. Conclusions: These data demonstrate that CTX001, a first-in-human, CRISPR-Cas9-modified autologous HSPC product, has resulted in increases in HbF and total Hb in the first 7 patients infused. All patients infused with CTX001 demonstrated hematopoietic engraftment with a post-infusion safety profile generally consistent with myeloablation. All 5 patients with TDT have been transfusion-free since ~2 months after CTX001 infusion and the 2 patients with severe SCD have had no VOCs during follow-up after CTX001 infusion. These early data demonstrate that CTX001 is a potential functional cure for the treatment of TDT and SCD. Data will be updated for the presentation. Data from these ongoing studies were submitted on behalf of the CLIMB THAL-111 and CLIMB SCD-121 Investigators. Figure Disclosures Frangoul: Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bobruff:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cappellini:BMS: Honoraria; CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fernandez:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Grupp:Juno/BMS: Other; Cellectis: Other; TCR2: Other: SAB; Servier: Research Funding; Janssen/JnJ: Consultancy; CBMG: Consultancy; Humanigen: Consultancy; GlaxoSmithKline: Consultancy; Roche: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Allogene: Other; Kite/Gilead: Research Funding; Novartis: Consultancy, Other: SSC, Research Funding; Adaptimmune: Other: SAB; Jazz: Other: SSC. Handgretinger:Amgen: Honoraria. Ho:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Imren:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Kattamis:Agios: Consultancy; Vertex: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Genesis Pharma SA: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apopharma/Chiesi: Honoraria, Speakers Bureau. Lekstrom-Himes:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Locatelli:Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Lu:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. de Montalembert:Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulcahey:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Shanbhag:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Sheth:Agios: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; La Jolla: Research Funding; Acceleron: Consultancy; Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding; DisperSol Technologies: Research Funding; Terumo: Research Funding; Vertex Pharmaceuticals/CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Soni:CRISPR Therapeutics: Current Employment, Current equity holder in private company. Steinberg:Vertex Pharmaceuticals/CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Imara: Membership on an entity's Board of Directors or advisory committees. Weinstein:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wu:Bayer: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Background:In the SELECT-PsA 1 and 2 clinical trials, upadacitinib (UPA) demonstrated efficacy and safety in patients (pts) with active psoriatic arthritis (PsA).1,2 PsA is associated with varying degrees of psoriatic symptoms; however, the impact of skin severity on treatment outcomes is not well understood.Objectives:This post-hoc analysis assessed the effects of baseline skin severity on UPA efficacy.Methods:SELECT-PsA 1 and SELECT-PsA 2 enrolled pts with PsA and prior inadequate response (IR) or intolerance to ≥1 non-biologic disease-modifying antirheumatic drug (DMARD)1 or ≥1 biologic DMARD2, respectively. In both trials, pts received once daily UPA 15 mg or UPA 30 mg or placebo (switched at Wk 24 to either UPA 15 mg or 30 mg); SELECT-PsA 1 also included the active comparator adalimumab (ADA). Only continuous UPA 15 mg and ADA are presented here. In this analysis, pts were divided into subgroups based on the extent of psoriasis at baseline (body surface area [BSA] of ≥3%-<10% or BSA ≥10%); efficacy endpoints were analyzed at Wk 56. Results for binary endpoints are based on non-responder imputation; continuous endpoints are based on mixed model repeated measures analysis with as-observed data.Results:In the UPA 15 mg and ADA groups, respectively, 32% (138/429) and 31% (132/429) of pts had a BSA ≥3-<10% at baseline in SELECT-PsA 1; 18% (76/429) in each treatment group had a BSA ≥10%. In SELECT-PsA 2, 38% (80/211) had a BSA ≥3-<10% and 24% (50/211) had a BSA ≥10% at baseline in the UPA 15 mg group. Across pt populations (non-biologic DMARD-IR and biologic DMARD-IR), generally consistent results were observed between patients in both skin severity subgroups (Figure 1). In non-biologic DMARD-IR pts, a numerically greater proportion of UPA 15 mg pts with lower skin involvement compared with higher skin involvement achieved PASI100 and PASI≤1, two more stringent skin endpoints. The achievement of MDA was generally consistent across skin severity subgroups; when pts were required to achieve the skin component of MDA, results were numerically better in the ≥3-<10% skin severity group (Table 1). In non-biologic DMARD-IR pts, results were similar between UPA 15 mg and ADA.Conclusion:UPA is a viable treatment option for pts with active PsA regardless of the extent of psoriasis at baseline. Although these results are of interest and hypothesis-generating, they should be interpreted with caution due to low sample size.References:[1]McInnes IB et al. Ann Rheum Dis, 2020; 79:12[2]Mease PJ et al. Ann Rheum Dis, 2020; doi: 10.1136/annrheumdis-2020-218870Table 1.Additional Efficacy Outcomes at Week 56 Stratified by Severity of Skin Involvement at BaselineSELECT-PsA 1n/N (%) [95% CI]UPA 15 mgADAsIGA 0/1 w/at least 2 point improvement from BLa ≥3%-<10%71/128 (55.5) [46.9, 64.1]53/124 (42.7) [34.0, 51.4] ≥10%29/76 (38.2) [27.2, 49.1]33/77 (42.9) [31.8, 53.9]MDA + skinb ≥3%-<10%58/138 (42.0) [33.8, 50.3]56/132 (42.4) [34.0, 50.9] ≥10%19/76 (25.0) [15.3, 34.7]28/79 (35.4) [24.9, 46.0]SELECT-PsA 2n/N (%) [95% CI]UPA 15 mgsIGA 0/1 w/at least 2 point improvement from BLa ≥3%-<10%24/71 (33.8) [22.8, 44.8] ≥10%18/50 (36.0) [22.7, 49.3] MDA + skinb ≥3%-<10%22/80 (27.5) [17.7, 37.3] ≥10%9/50 (18.0) [7.4, 28.6]a defined as achieving an sIGA score of 0 or 1 and at least a 2 point improvement from BL, evaluated in pts with BL sIGA ≥2.b defined as achieving 5 of the 7 criteria, with PASI ≤1 or BSA-psoriasis ≤3 as a required component.ADA, adalimumab; BL, baseline; CI, confidence interval; MDA, minimal disease activity; sIGA, Static Investigator Global Assessment of psoriasis; UPA, upadacitinibAcknowledgements:AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial. AbbVie, Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. Medical writing support was provided by Ramona Vladea, PhD and Jamie Urbanik, PharmD both of AbbVie Inc.Disclosure of Interests:Joseph F. Merola Consultant of: Merck, Bristol-Myers Squibb, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and Leo Pharma, Pascal Richette Consultant of: AbbVie, Biogen, Janssen, BMS, Roche, Pfizer, Amgen, Sanofi-Aventis, UCB, Lilly, Novartis, and Celgene, Ennio Lubrano Speakers bureau: AbbVie, Celgene, Janssen, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Celgene, Janssen, MSD, Novartis, and Pfizer, Grant/research support from: AbbVie, Celgene, Janssen, MSD, Novartis, and Pfizer, Edit Drescher: None declared, Lilian Soto: None declared, Charles Lovan Shareholder of: AbbVie, Employee of: AbbVie, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Ralph Lippe Shareholder of: AbbVie, Employee of: AbbVie, Michael Lane Shareholder of: AbbVie, Employee of: AbbVie, Mitsumasa Kishimoto Consultant of: AbbVie, Amgen-Astellas BioPharma, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Celgene, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, Teijin Pharma, and UCB Pharma.

This article discusses the relationship between the intensification of teachers’ labour and health of professors. The data obtained are based on research that had for object the work of post-graduation programs professors in a public university. The qualitative research, theoretically and methodologically grounded by historical-dialectical materialism, used interviews as the main instrument of data collection. For that, were interviewed 11 professors from two post-graduation programs of the Federal University of Goiás (UFG), in the period from 2010 to 2012, namely PPGEO and PPGEcoEvol, the programs that achieved concept six in the CAPES evaluation. The present research is justified by the observation of the profound transformations that occurred not only in higher education, but also in Brazilian post-graduation, especially after the State Reform of the 1990s. The new requirements have improved over time and have culminated in the increase of the evaluation demands made by the agencies of promotion of research, which unfold in intensification of labour. The report of professors interviewed showed a series of physical and psychological symptoms in all professors, either due to lack of rest, work overload or difficulty in handling the demands of academic and administrative work linked to post-graduation studies.ResumoO presente artigo discute a relação entre intensificação do trabalho docente e a saúde de professores. Os dados obtidos baseiam-se em pesquisa que teve como objeto de estudo o trabalho docente de uma universidade pública vinculado a programas de pós-graduação. A pesquisa de caráter qualitativo foi fundamentada teórica e metodologicamente pelo materialismo histórico-dialético e utilizou como principal instrumento de coleta de dados a entrevista. Para tanto foram entrevistados 11 professores vinculados aos dois programas de pós-graduação mais bem avaliados da Universidade Federal de Goiás (UFG), no período de 2010 a 2012 pela Capes. Estes dois programas, a saber, PPGEO e PPGEcoEvol obtiveram o conceito seis na avaliação mencionada. A presente pesquisa justifica-se pela observação das profundas transformações ocorridas não apenas no ensino superior, mas também na pós-graduação brasileira, principalmente em momento posterior à Reforma do Estado da década de 1990. As novas exigências têm se aprimorado ao longo do tempo e têm culminado no aumento das cobranças avaliativas feitas pelas agências de fomento à pesquisa, as quais se desdobram em intensificação do trabalho. O relato dos docentes entrevistados sinalizou para uma série de sintomas físicos e psicológicos na totalidade dos professores, seja pela falta de descanso, pela sobrecarga de trabalho ou pela dificuldade em manejar as exigências do trabalho acadêmico e administrativo vinculado à pós-graduação.Keywords: Teachers’ labour, Health of professors, Intensification of labour.Palavras-chave: Trabalho docente, Saúde docente, Intensificação do trabalho. ReferencesANTUNES, Caio; SILVA, Hugo Leonardo Fonseca da; FREITAS, Joana Alice Ribeiro de; MORAES, Livia de Cássia Godoi. Trabalho, o mundo sob ataque: crise estrutural do capital, medidas contratendenciais e a atual situação da classe trabalhadora. In: LOURENÇO, Edivânia Ângela de Souza; NAVARRO, Vera Lucia (Orgs.). O avesso do trabalho IV. São Paulo: Outras expressões, 2017, pp. 429-445.ANTUNES, Ricardo. Os sentidos do trabalho: ensaios de afirmação negação. São Paulo: Boitempo, 2009.ANTUNES, Ricardo. O privilégio da servidão. São Paulo: Boitempo, 2018.BOSI, Antônio de Pádua. A precarização do trabalho docente nas instituições de ensino superior do Brasil nesses últimos 25 anos. Educação e Sociedade, 28(101), pp. 1503-1523, 2007. Disponível em: http://www.scielo.br/pdf/es/v28n101/a1228101. Acesso em 20 de agosto de 2012.CARVALHO, Diana Carvalho de. Trabalho docente na pós-graduação: impasses que se colocam para os programas e o professor universitário no contexto atual das políticas de avaliação. In: MANCEBO, Deise; SILVA JUNIOR, João dos Reis da; OLIVEIRA, João Ferreira (Orgs.). Reformas e políticas: educação superior e pós-graduação no Brasil. Campinas: Alínea, 2008, pp. 223-235.CHAVES, Vera Lucia Jacob; MENDES, Odete da Cruz. REUNI: o contrato de gestão na reforma da educação superior pública. Cadernos ANPAE, 8, 1-14, 2009. Disponível em: http://www.anpae.org.br/congressos_antigos/simposio2009/352.pdf. Acesso em: 18 de janeiro de 2017.CHESNAIS, François. A Mundialização do Capital. São Paulo: Xamã, 1996.CAPES - Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (2013a). Ficha de Avaliação do Programa (Biodiversidade). Brasília. Disponível em: http://avaliacaotrienal2013.capes.gov.br/resultados/fichas-de-avaliacao. Acesso em 18 de janeiro de 2017.CAPES - Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (2013b). Ficha de Avaliação do Programa (Geografia). Brasília. Disponível em: http://avaliacaotrienal2013.capes.gov.br/resultados/fichas-de-avaliacao. Acesso em: 18 de janeiro de 2017.CRUZ, Roberto Moraes. Trabalho docente, modo degradado de funcionamento institucional e patologias do trabalho. In: SOUZA, M. de; MARTINS, F.; ARAÚJO; J. N. G. de (Orgs.). Dimensões da violência: conhecimento, subjetividade e sofrimento psíquico. São Paulo: Casa do Psicólogo, 2011, pp. 207-222.DAL ROSSO, Sadi. Mais trabalho! A intensificação do labor na sociedade contemporânea. São Paulo: Boitempo, 2008.DAÚD, Cristina dos Santos Dias. Dimensionamento da alocação de vagas de técnicos administrativos nas universidades públicas federais. 2015. Dissertação (Mestrado em Administração), Faculdade de Administração, Universidade Federal de Lavras. Lavras, 2015.DRUCK, Graça. Trabalho, precarização e resistências: novos e velhos desafios? Cadernos CRH, 24(1), 37-57, 2011. Disponível em: http://www.scielo.br/pdf/ccrh/v24nspe1/a04v24nspe1. Acesso em 10 de setembro de 2016.FARIA, José Henrique de. Gestão participativa: relações de poder e de trabalho nas organizações. São Paulo: Atlas, 2009.FREITAS, Joana Alice Ribeiro de. Violência no trabalho docente em uma universidade pública: da demanda inicial sobre assédio moral ao problema real da precarização do trabalho. 2013. Dissertação (Mestrado em Organizações e Desenvolvimento), Faculdade de Economia e Administração, Curitiba, 2013.GOMES, Alfredo Marcelo. As reformas e políticas da educação superior no Brasil. In: MANCEBO, Deise; SILVA JUNIOR, João dos Reis da; OLIVEIRA, João Ferreira (Orgs.). Reformas e políticas: educação superior e pós-graduação no Brasil. Campinas: Alínea, 2008, pp. 23-51.LACAZ, Francisco Antonio de Castro. O campo da saúde do trabalhador: resgatando conhecimentos e práticas sobre as relações trabalho-saúde. Cadernos de Saúde Pública, 23(4), 2007. Disponível em: http://www.scielo.br/pdf/csp/v23n4/02.pdf. Acesso em: 16 de janeiro, 2016.LAURELL, Asa Cristina. A saúde-doença como processo social. Revista Latinoamericana de salud, (2). pp. 7-25, 1982. Disponível em: https://fopspr.files.wordpress.com/2009/01/saudedoenca.pdf. Acesso em: 09 de janeiro de 2017.LIMA, Maria de Fátima Evangelista Mendonça; LIMA-FILHO, Dario de Oliveira. Condições de trabalho e saúde do/a professor/a universitário/o. Ciências & Cognição, 14(3), 62-82, 2009. Disponível em: http://www.cienciasecognicao.org/pdf/v14_3/m253.pdf. Acesso em 12 de setembro de 2017.LIMA, Antônio Bosco de; MARQUES, Mara Rúbia Alves; SILVA, Sarita Medina; SILVA, Maria Vieira; PALAFOX, Gabriel Humberto Muñoz. Reforma e qualidade da educação no Brasil. In: LOMBARDI, José Claudinei; LUCENA, Carlos; PREVITALI, Fabiane Santana (Orgs.). Mundialização do trabalho, transição histórica e reformismo educacional. Campinas: Librum, 2014, pp. 208-232.MACIEL, Rosana. Mendes; PREVITALI, Fabiane Santana. A reestruturação produtiva e seus impactos no trabalho docente. In: PREVITALI, Fabiane Santana (Org.). Trabalho, educação e reestruturação produtiva. São Paulo: Xamã, 2012, pp.109-126.MANCEBO, Deise. A educação superior no Brasil: expansão e tendências (1995-2014). In: SILVA JUNIOR, João dos Reis da; ROTHEN, José Carlos; SOUSA, José Vieira de; AZEVEDO, Mário Luiz Neves. (Orgs.). Política de educação superior brasileira: apontamentos e perspectivas. Belo Horizonte: Fino Traço, 2017, pp. 101-120.MARX, Karl. Os manuscritos econômico-filosóficos de 1844. São Paulo: Boitempo, 2004.MARX, Karl. Grundrisse: manuscritos econômicos de 1857-1858: esboços da crítica da economia política. São Paulo: Boitempo, 2011.MARX, Karl. O Capital. (Livro 1). São Paulo: Boitempo, 2013.MÉSZÁROS, Istvan. Para além do capital. São Paulo: Boitempo, 2002.MÉSZÁROS, Istvan. A crise estrutural do capital. São Paulo: Boitempo, 2008.NAVARRO, Vera L.; ALESSI, Neiry Primo; LIMA, Maria da Glória. A violência no trabalho e a saúde do trabalhador no contexto da reestruturação produtiva no Brasil. SILVA, José Fernando da; LIMA, Ricardo Barbosa de; DAL ROSSO, Sadi (Orgs.). Violência e trabalho no Brasil. Goiânia: Editora da UFG, 2001, pp. 229-246.PINA, José Augusto; STOTZ, Eduardo Navarro. Intensificação do trabalho e saúde do trabalhador: uma abordagem teórica. Revista Brasileira de Saúde Ocupacional 39(130), 150-160, 2014. Disponível em: http://www.scielo.br/pdf/rbso/v39n130/0303-7657-rbso-39-130-150.pdf. Acesso em 09 de janeiro de 2018.SELIGMANN-SILVA, Edith. Trabalho e desgaste mental: o direito de ser dono de si mesmo. São Paulo: Editora Cortez, 2011.SGUISSARDI, Valdemar; SILVA JUNIOR, João dos Reis da. Trabalho intensificado nas federais: pós-graduação e produtivismo acadêmico. São Paulo: Xamã, 2009.SILVA JUNIOR, João dos Reis da. The new brazilian university: a busca por resultados comercializáveis: para quem? Bauru: Canal 6, 2017.SILVA JUNIOR, João dos Reis da; SGUISSARDI, Valdemar. Novas faces da educação superior no Brasil: reforma do Estado e mudança na produção. São Paulo: Cortez. Bragança Paulista: EDUSF, 2001.

Las sociedades difusas. La construcción/deconstrucción sociocultural de fronteras y márgenes es una publicación colectiva editada por Juan A. Roche Cárcel en la que se aborda la indeterminación de márgenes y fronteras que se vive en tiempos actuales en las más diversas áreas de la vida social desde un amplio abanico de perspectivas y discursos generados por un conjunto de excelentes investigadores en el ámbito de las ciencias sociales.

In September of 2012, the American novelist Philip Roth published an open letter to Wikipedia in The New Yorker. “I am Philip Roth,” it began, and proceeded to explain how the editors of Wikipedia had gotten the inspiration for his novel The Human Stain wrong. Though the article had in fact only mentioned a theory about his sources, Roth was adamant that it did not belong anywhere in a discussion of his novel. He wanted the idea removed entirely. This, it turns out, was a profound misunderstanding of the editorial practices of Wikipedia, and the theory that Roth would prefer we forget remains in the article to this day. His letter in The New Yorker, of course, is duly cited. How well should librarians understand the editorial process behind Wikipedia’s articles? In this workshop, we will take a practical approach to the problem and have a look at what goes on behind the scenes, even edit some pages if we feel so inclined. The workshop will be led by Thomas Basbøll, a philosopher and writing consultant who has spent a few years working as a volunteer editor at Wikipedia and even has even been banned from editing certain pages for a time. The overall goal of the workshop is to demystify one of the most accessed sources of knowledge in the world and help librarians decide how to best help people like Philip Roth, and his readers, make sense of its “authority”. Thomas Basbøll is the resident writing consultant at the Copenhagen Business School Library. He holds an MA in philosophy from the University of Copenhagen, and a PhD from the Copenhagen Business School. He works closely with students, teachers and researchers in their attempts to master “the craft of research” and is an avid blogger (blog.cbs.dk/inframethodology/).

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Historians of Modern Architecture have cultivated the image of the architect as a temperamental genius, unconcerned by issues of politeness or pragmatics—a reading reinforced in cultural representations of Modern Architects, such as Howard Roark, the protagonist in Ayn Rand’s 1943 novel The Fountainhead (a character widely believed to be based on the architect Frank Lloyd Wright). The perception of the Modern Architect as an artistic hero or genius has also influenced the reception of their work. Despite their indisputable place within the architectural canon, many important works of Modern Architecture were contested on pragmatic grounds, such as cost, brief and particularly concerning issues of suitability and effectiveness in relation to climate and weather. A number of famed cases resulted in legal action between clients and architects, and in many more examples historians have critically framed these accounts to highlight alternate issues and agendas. “Complaints about the weather,” in relation to architecture, inevitably raise issues regarding a work’s “success,” particularly in view of the tensions between artistry and functionality inherent in the discipline of architecture. While in more recent decades these ideas have been framed around ideas of sustainability—particularly in relation to contemporary buildings—more traditionally they have been engaged through discussions of an architect’s ethical responsibility to deliver a habitable building that meets the client’s needs. This paper suggests these complaints often raise a broader range of issues and are used to highlight tensions inherent in the discipline. In the history of Modern Architecture, these complaints are often framed through gender studies, ethics and, more recently, artistic asceticism. Accounts of complaints and disputes are often invoked in the social construction (or deconstruction) of artistic genius – whether in a positive or negative light. Through its discussion of a number of famed examples, this paper will discuss the framing of climate in relation to the figure of the Modern Architect and the reception of the architectural “masterpiece.” Dear Monsieur Le Corbusier … In June 1930 Mme Savoye, the patron of the famed Villa Savoye on the outskirts of Paris, wrote to her architect, Le Corbusier, stating: “it is still raining in our garage” (Sbriglio 144)—a persistent theme in their correspondence. This letter followed another sent in March after discovering leaks in the garage and several bedrooms following a visit during inclement weather. While sent prior to the building’s completion, she also noted that rainfall on the bathroom skylight “makes a terrible noise […] which prevents us from sleeping in bad weather” (Sbriglio 142). Claiming to have warned Le Corbusier about the concern, the contractor refused to accept responsibility, prompting some rather fiery correspondence between the two. This problem, compounded by issues with the heating system, resulted in the house feeling, as Sbriglio notes, “cold and damp” and subject to “substantial heat loss due to the large glazing”—a cause for particular concern given the health problems of the clients’ only child, Roger Savoye, that saw him spend time in a French Sanatorium (Sbriglio 145). While the cause of Roger’s illness is not clear, at least one writer (albeit with a noticeable lack of footnotes or supporting evidence) has linked this directly to the villa (de Botton 65). Mme Savoye’s complaints about dampness, humidity, condensation and leaking in her home persisted in subsequent years, prompting Benton to summarise in 1987, “every autumn […] there were cries of distress from the Savoye family with the first rains” (Villas 204). These also extended to discussion of the heating system, which while proving insufficient was also causing flooding (Benton, "Villa" 93). In 1935 Savoye again wrote to Le Corbusier, wearily stating: It is raining in the hall, it’s raining on the ramp and the wall of the garage is absolutely soaked [….] it’s still raining in my bathroom, which floods in bad weather, as the water comes in through the skylight. The gardener’s walls are also wet through. (Sbriglio 146-7) Savoye’s understandable vexation with waterproofing problems in her home continued to escalate. With a mixture of gratitude and frustration, a letter sent two years later stated: “After innumerable demands you have finally accepted that this house which you built in 1929 in uninhabitable…. Please render it inhabitable immediately. I sincerely hope that I will not have to take recourse to legal action” (Sbriglio 147). Paradoxically, Le Corbusier was interested in the potential of architecture and urban planning to facilitate health and well-being, as well as the effects that climate may play in this. Early twentieth century medical thought advocated heliotherary (therapeutic exposure to sunlight) for a diverse range of medical conditions, ranging from rickets to tuberculosis. Similarly the health benefits of climate, such as the dryness of mountain air, had been recognised for much longer, and had led to burgeoning industries associated with health, travel and climate. The dangers of damp environments had also long been medically recognised. Le Corbusier’s awareness of the health benefits of sunshine led to the inclusion of a solarium in the villa that afforded both framed and unframed views of the surrounding countryside, such as those that were advocated in the seventeenth century as an antidote to melancholy (Burton 65-66). Both Benton and Sbriglio present Mme Savoye’s complaints as part of their comprehensive histories of an important and influential work of Modern Architecture. Each reproduce excerpts from archival letters that are not widely translated or accessible, and Benton’s 1984 essay is the source other authors generally cite in discussing these matters. In contrast, for example, Murphy’s 2002 account of the villa’s conversion from “house” to “historical monument” cites the same letters (via Benton) as part of a broader argument that highlights the “undomestic” or “unhomely” nature of the work by cataloguing such accounts of the client’s experience of discomfort while residing in the space – thus revisiting a number of common criticisms of Modern Architecture. Le Corbusier’s reputation for designing buildings that responded poorly to climate is often referenced in popular accounts of his work. For example, a 1935 article published in Time states: Though the great expanses of glass that he favors may occasionally turn his rooms into hothouses, his flat roofs may leak and his plans may be wasteful of space, it was Architect Le Corbusier who in 1923 put the entire philosophy of modern architecture into a single sentence: “A house is a machine to live in.” Reference to these issues are usually made rather minimally in academic accounts of his work, and few would agree with this article’s assertion that Le Corbusier’s influence as a phrasemaker would rival the impact of his architecture. In contrast, such issues, in relation to other architects, are often invoked more rhetorically as part of a variety of historical agendas, particularly in constructing feminist histories of architecture. While Corbusier and his work have often been the source of intellectual contention from feminist scholars—for example in regard to authorial disputes and fractious relationships with the likes of Eileen Gray or Charlotte Perriand – discussion of the functional failures in the Villa Savoye are rarely addressed from this perspective. Rather, feminist scholars have focussed their attention on a number of other projects, most notably the case of the Farnsworth House, another canonical work of Modernism. Dear Herr Mies van der Rohe … Mies van der Rohe’s Farnsworth House, completed in 1951 in Plano Illinois, was commissioned as a country weekend residence by an unmarried female doctor, a brief credited with freeing the architect from many of the usual pragmatic requirements of a permanent city residence. In response Mies designed a rectilinear steel and glass pavilion, which hovered (to avoid the flood levels) above the landscape, sheltered by maple trees, in close proximity to the Fox River. The refined architectural detail, elegant formal properties, and poetic relationship with the surrounding landscape – whether in its autumnal splendour or covered in a thick blanket of snow – captivated architects seeing it become, like the Villa Savoye, one of the most revered architectural works of the twentieth century. Prior to construction a model was exhibited in the Museum of Modern Art in New York and, upon completion the building became a pilgrimage site for architects and admirers. The exhibition of the design later fuelled debate about whether Dr Farnsworth constituted a patron or a client (Friedman 134); a distinction generating very different expectations for the responsibilities of the architect, particularly regarding the production of a habitable home that met the client’s brief versus producing a design of architectural merit. The house was intended as a frame for viewing and contemplating nature, thus seeing nature and climate aligned with the transcendental qualities of the design. Following a visit during construction, Farnsworth described the building’s relationship to the elements, writing: “the two horizontal planes of the unfinished building, floating over the meadows, were unearthly beautiful under a sun which glowed like a wild rose” (5). Similarly, in 1951, Arthur Drexler described the building as “a quantity of air caught between a floor and a roof” (Vandenberg 6). Seven years later the architect himself asserted that nature “gained a more profound significance” when viewed from within the house (Friedman 139). While the transparency of the house was “forgiven” by its isolated location and the lack of visibility from neighbouring properties, the issues a glass and steel box might pose for the thermal comfort of its occupant are not difficult to imagine. Following the house’s completion, Farnsworth fitted windows with insect screens and blinds (although Mies intended for curtains to be installed) that clumsily undermined the refined and minimalistic architectural details. Controversy surrounding the house was, in part, the result of its bold new architectural language. However, it was also due to the architect-client relationship, which turned acrimonious in a very public manner. A dispute between Mies and Farnsworth regarding unpaid fees was fought both in the courtroom and the media, becoming a forum for broader debate as various journals (for example, House Beautiful), publicly took sides. The professional female client versus the male architect and the framing of their dispute by historians and the media has seen this project become a seminal case-study in feminist architectural histories, such as Friedman’s Women and the Making of the Modern House of 1998. Beyond the conflict and speculation about the individuals involved, at the core of these discussions were the inadequacies of the project in relation to comfort and climate. For example, Farnsworth describes in her journal finding the house awash with several inches of water, leading to a court session being convened on the rooftop in order to properly ascertain the defects (14). Written retrospectively, after their relationship soured, Farnsworth’s journal delights in recounting any errors or misjudgements made by Mies during construction. For example, she described testing the fireplace to find “the house was sealed so hermetically that the attempt of a flame to go up the chimney caused an interior negative pressure” (2). Further, her growing disenchantment was reflected in bleak descriptions aligning the building with the weather. Describing her first night camping in her home, she wrote: “the expanses of the glass walls and the sills were covered with ice. The silent meadows outside white with old and hardened snow reflected the bleak [light] bulb within, as if the glass house itself were an unshaded bulb of uncalculated watts lighting the winter plains” (9). In an April 1953 article in House Beautiful, Elizabeth Gordon publicly sided with Farnsworth as part of a broader campaign against the International Style. She condemned the home, and its ‘type’ as “unlivable”, writing: “You burn up in the summer and freeze in the winter, because nothing must interfere with the ‘pure’ form of their rectangles” (250). Gordon included the lack of “overhanging roofs to shade you from the sun” among a catalogue of “human qualities” she believed architects sacrificed for the expression of composition—a list that also included possessions, children, pets and adequate kitchen facilities (250). In 1998 excerpts from this article were reproduced by Friedman, in her seminal work of feminist architectural history, and were central in her discussion of the way that debates surrounding this house were framed through notions of gender. Responding to this conflict, and its media coverage, in 1960 Peter Blake wrote: All great houses by great architects tend to be somewhat impractical; many of Corbu’s and Wright’s house clients find that they are living in too expensive and too inefficient buildings. Yet many of these clients would never exchange their houses for the most workable piece of mediocrity. (88) Far from complaining about the weather, the writings of its second owner, Peter Palumbo, poetically meditate the building’s relationship to the seasons and the elements. In his foreword to a 2003 monograph, he wrote: life inside the house is very much a balance with nature, and an extension of nature. A change in the season or an alteration of the landscape creates a marked change in the mood inside the house. With an electric storm of Wagnerian proportions illuminating the night sky and shaking the foundations of the house to their very core, it is possible to remain quite dry! When, with the melting snows of spring, the Fox River becomes a roaring torrent that bursts its banks, the house assumes a character of a house-boat, the water level sometimes rising perilously close to the front door. On such occasions, the approach to the house is by canoe, which is tied to the steps of the upper terrace. (Vandenberg 5) Palumbo purchased the house from Farnsworth and commissioned Mies’s grandson to restore it to its original condition, removing the blinds and insect screens, and installing an air-conditioning system. The critical positioning of Palumbo has been quite different from that of Farnsworth. His restoration and writings on the project have in some ways seen him positioned as the “real” architectural patron. Furthermore, his willingness to tolerate some discomfort in his inhabitation has seen him in some ways prefigure the type of resident that will be next be discussed in reference to recent owners of Wright properties. Dear Mr Wright … Accounts of weatherproofing problems in buildings designed by Frank Lloyd Wright have become the basis of mythology in the architectural discipline. For example, in 1936 Herbert Johnson and J. Vernon Steinle visited Wright’s Richard Lloyd Jones house in Oklahoma. As Jonathan Lipman wrote, “Steinle’s most prominent recollection of the house was that there were scores of tubs and canning jars in the house catching water leaking through the roof” (45). While Lipman notes the irony that both the house and office Wright designed for Johnson would suffer the same problem, it is the anecdotal accounts of the former that have perhaps attracted the most interest. An oft-recounted story tells of Johnson telephoning Wright, during a dinner party, with regard to water dripping from the ceiling into his guest-of-honour’s soup; the complaint was reportedly rebuffed unsympathetically by Wright who suggested the lady should move her chair (Farr 272). Wright himself addressed his reputation for designing buildings that leaked in his Autobiography. In reference to La Miniatura in Pasadena, of 1923, he contextualised difficulties with the local climate, which he suggested was prone to causing leaks, writing: “The sun bakes the roof for eleven months, two weeks and five days, shrinking it to a shrivel. Then giving the roof no warning whatever to get back to normal if it could, the clouds burst. Unsuspecting roof surfaces are deluged by a three inch downpour.” He continued, stating: I knew all this. And I know there are more leaking roofs in Southern California than in all the rest of the world put together. I knew that the citizens come to look upon water thus in a singularly ungrateful mood. I knew that water is all that enables them to have their being there, but let any of it through on them from above, unexpectedly, in their houses and they go mad. It is a kind of phobia. I knew all this and I have taken seriously precautions in the details of this little house to avoid such scenes as a result of negligible roofs. This is the truth. (250) Wright was quick to attribute blame—directed squarely at the builder. Never one for quiet diplomacy, he complained that the “builder had lied to [him] about the flashing under and within the coping walls” (250) and he was ignorant of the incident because the client had not informed him of the leak. He suggested the client’s silence was undoubtedly due to her “not wishing to hurt [his] feelings”. Although given earlier statements it might be speculated that she did not wish to be accused of pandering to a phobia of leaks. Wright was dismissive of the client’s inconvenience, suggesting she would be able to continue as normal until the next rains the following year and claiming he “fixed the house” once he “found out about it” (250). Implicit in this justification was the idea that it was not unreasonable to expect the client to bear a few days of “discomfort” each year in tolerance of the local climate. In true Wright style, discussions of these problems in his autobiography were self-constructive concessions. While Wright refused to take responsibility for climate-related issues in La Minatura, he was more forthcoming in appreciating the triumphs of his Imperial Hotel in Japan—one of the only buildings in the vicinity to survive the 1923 earthquake. In a chapter of his autobiography titled “Building against Doomsday (Why the Great Earthquake did not destroy the Imperial Hotel),” Wright reproduced a telegram sent by Okura Impeho stating: “Hotel stands undamaged as monument of your genius hundreds of homeless provided perfectly maintained service. Congratulations” (222). Far from unconcerned by nature or climate, Wright’s works celebrated and often went to great effort to accommodate the poetic qualities of these. In reference to his own home, Taliesin, Wright wrote: I wanted a home where icicles by invitation might beautify the eaves. So there were no gutters. And when the snow piled deep on the roofs […] icicles came to hang staccato from the eaves. Prismatic crystal pendants sometimes six feet long, glittered between the landscape and the eyes inside. Taliesin in winter was a frosted palace roofed and walled with snow, hung with iridescent fringes. (173) This description was, in part, included as a demonstration of his “superior” understanding and appreciation of nature and its poetic possibilities; an understanding not always mirrored by his clients. Discussing the Lloyd Lewis House in Libertyville, Illinois of 1939, Wright described his endeavours to keep the house comfortable (and avoid flooding) in Spring, Autumn and Summer months which, he conceded, left the house more vulnerable to winter conditions. Utilising an underfloor heating system, which he argued created a more healthful natural climate rather than an “artificial condition,” he conceded this may feel inadequate upon first entering the space (495). Following the client’s complaints that this system and the fireplace were insufficient, particularly in comparison with the temperature levels he was accustomed to in his workplace (at The Daily News), Wright playfully wrote: I thought of various ways of keeping the writer warm, I thought of wiring him to an electric pad inside his vest, allowing lots of lead wire so he could get around. But he waved the idea aside with contempt. […] Then I suggested we appeal to Secretary Knox to turn down the heat at the daily news […] so he could become acclimated. (497) Due to the client’s disinclination to bear this discomfort or use any such alternate schemes, Wright reluctantly refit the house with double-glazing (at the clients expense). In such cases, discussion of leaks or thermal discomfort were not always negative, but were cited rhetorically implying that perfunctory building techniques were not yet advanced enough to meet the architect’s expectations, or that their creative abilities were suppressed by conservative or difficult clients. Thus discussions of building failures have often been invoked in the social construction of the “architect-genius.” Interestingly accounts of the permeability of Wright’s buildings are more often included in biographical rather that architectural writings. In recent years, these accounts of weatherproofing problems have transformed from accusing letters or statements implying failure to a “badge of honour” among occupants who endure discomfort for the sake of art. This changing perspective is usually more pronounced in second generation owners, like Peter Palumbo (who has also owned Corbusier and Wright designed homes), who are either more aware of the potential problems in owning such a house or are more tolerant given an understanding of the historical worth of these projects. This is nowhere more evident than in a profile published in the real estate section of the New York Times. Rather than concealing these issues to preserve the resale value of the property, weatherproofing problems are presented as an endearing quirk. The new owners of Wright’s Prefab No. 1 of 1959, on Staten Island declared they initially did not have enough pots to place under the fifty separate leaks in their home, but in December 2005 proudly boasted they were ‘down to only one leak’ (Bernstein, "Living"). Similarly, in 2003 the resident of a Long Island Wright-designed property, optimistically claimed that while his children often complained their bedrooms were uncomfortably cold, this encouraged the family to spend more time in the warmer communal spaces (Bernstein, "In a House"). This client, more than simply optimistic, (perhaps unwittingly) implies an awareness of the importance of “the hearth” in Wright’s architecture. In such cases complaints about the weather are re-framed. The leaking roof is no longer representative of gender or power relationships between the client and the uncompromising artistic genius. Rather, it actually empowers the inhabitant who rises above their circumstances for the sake of art, invoking a kind of artistic asceticism. While “enlightened” clients of famed architects may be willing to suffer the effects of climate in the interiors of their homes, their neighbours are less tolerant as suggested in a more recent example. Complaints about the alteration of the micro-climate surrounding Frank Gehry’s Walt Disney Concert Hall in Los Angeles prompted the sandblasting of part of the exterior cladding to reduce glare. In 2004, USA Today reported that reflections from the stainless steel cladding were responsible for raising the temperature in neighbouring buildings by more than 9° Celsius, forcing neighbours to close their blinds and operate their air-conditioners. There were also fears that the glare might inadvertently cause traffic problems. Further, one report found that average ground temperatures adjacent to the building peaked at approximately 58° Celsius (Schiler and Valmont). Unlike the Modernist examples, this more recent project has not yet been framed in aid of a critical agenda, and has seemingly been reported simply for being “newsworthy.” Benign Conversation Discussion of the suitability of Modern Architecture in relation to climate has proven a perennial topic of conversation, invoked in the course of recurring debates and criticisms. The fascination with accounts of climate-related problems—particularly in discussing the work of the great Modernist Architects like Le Corbusier, Mies van der Rohe and Frank Lloyd Wright—is in part due to a certain Schadenfreude in debunking the esteem and authority of a canonical figure. This is particularly the case with one, such as Wright, who was characterised by significant self-confidence and an acerbic wit often applied at the expense of others. Yet these accounts have been invoked as much in the construction of the figure of the architect as a creative genius as they have been in the deconstruction of this figure—as well as the historical construction of the client and the historians involved. In view of the growing awareness of the threats and realities of climate change, complaints about the weather are destined to adopt a new significance and be invoked in support of a different range of agendas. While it may be somewhat anachronistic to interpret the designs of Frank Lloyd Wright or Mies van der Rohe in terms of current discussions about sustainability in architecture, these topics are often broached when restoring, renovating or adapting the designs of such architects for new or contemporary usage. In contrast, the climatic problems caused by Gehry’s concert hall are destined to be framed according to a different set of values—such as the relationship of his work to the time, or perhaps in relation to contemporary technology. While discussion of the weather is, in the conversational arts, credited as benign topic, this is rarely the case in architectural history. References Benton, Tim. The Villas of Le Corbusier 1920-1930. New Haven: Yale UP, 1987. ———. “Villa Savoye and the Architects’ Practice (1984).” Le Corbusier: The Garland Essays. Ed. H. Allen Brooks. New York: Garland, 1987. 83-105. Bernstein, Fred A. “In a House That Wright Built.” New York Times 21 Sept. 2003. 3 Aug. 2009 < http://www.nytimes.com/2003/09/21/nyregion/in-a-house-that-wright-built.html >. ———. “Living with Frank Lloyd Wright.” New York Times 18 Dec. 2005. 30 July 2009 < http://www.nytimes.com/2005/12/18/realestate/18habi.html >. Blake, Peter. Mies van der Rohe: Architecture and Structure. Harmondsworth: Penguin, 1963 (1960). Burton, Robert. The Anatomy of Melancholy, vol. II. Eds. Nicolas K. Kiessling, Thomas C. Faulkner and Rhonda L. Blair. Oxford: Clarendon, 1995 (1610). Campbell, Margaret. “What Tuberculosis Did for Modernism: The Influence of a Curative Environment on Modernist Design and Architecture.” Medical History 49 (2005): 463–488. “Corbusierismus”. Art. Time 4 Nov. 1935. 18 Aug. 2009 < http://www.time.com/time/magazine/article/0,9171,755279,00.html >. De Botton, Alain. The Architecture of Happiness. London: Penguin, 2006. Farnsworth, Edith. ‘Chapter 13’, Memoirs. Unpublished journals in three notebooks, Farnsworth Collection, Newberry Library, Chicago, unpaginated (17pp). 29 Jan. 2009 < http://www.farnsworthhouse.org/pdf/edith_journal.pdf >. Farr, Finis. Frank Lloyd Wright: A Biography. New York: Charles Scribner’s Sons, 1961. Friedman, Alice T. Women and the Making of the Modern House: A Social and Architectural History. New York: Harry N. Abrams, 1998. Gordon, Elizabeth. “The Threat to the Next America.” House Beautiful 95.4 (1953): 126-30, 250-51. Excerpts reproduced in Friedman. Women and the Making of the Modern House. 140-141. Hardarson, Ævar. “All Good Architecture Leaks—Witticism or Word of Wisdom?” Proceedings of the CIB Joint Symposium 13-16 June 2005, Helsinki < http://www.metamorfose.ntnu.no/Artikler/Hardarson_all_good_architecture_leaks.pdf >. Huck, Peter. “Gehry’s Hall Feels Heat.” The Age 1 March 2004. 22 Aug. 2009 < http://www.theage.com.au/articles/2004/02 /27/1077676955090.html >. Lipman, Jonathan. Frank Lloyd Wright and the Johnson Wax Buildings. Introduction by Kenneth Frampton. London: Architectural Press, 1984. Murphy, Kevin D. “The Villa Savoye and the Modernist Historic Monument.” Journal of the Society of Architectural Historians 61.1 (2002): 68-89. “New L.A. 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