Academic literature on the topic 'Burton, Robert Earl'

In the wake of Douglas Crimp's passing in July 2019, Johanna Burton reflects on her still-evolving intellectual and personal relationship with this figure so crucial to histories of art, activism, and critical writing. Briefly tracing the various areas of thinking with which Crimp was associated over his decades-long career, Burton argues that the sum of Crimp's trajectory of thought is much greater than any of its formidable parts. Crimp has perhaps been most often associated with the onset of a particular tenet of postmodernism, namely the formation of the “Pictures Generation,” (including artists like Troy Brauntuch, Jack Goldstein, Louise Lawler, Sherrie Levine, Robert Longo, and Cindy Sherman). Yet Crimp, dissatisfied with the limits of this discourse, moved in the early 80s purposefully away from it toward other evolving dialogues: first around the AIDS crisis, and later into film, dance, memoir, and beyond. Ultimately, Crimp's legacy, Burton argues, is defined by his desire to unseat rather than produce or maintain established thinking. He models theoretical paradigms that anticipate their own eventual irrelevance in order to make space for others.

Abstract The Bremer Vulkan AG in Bremen-Vegesack was one of the large companies in Germany for which a high degree of continuity can be demonstrated from the Second World War to the early years of the young Federal Republic of Germany. This applies above all to the shipyard’s management personnel. Under the leadership of its go-getting general manager Robert Kabelac and his fellow board members, Bremer Vulkan became a crucial part of naval armament during the war, especially of submarine construction and thus of the German armaments industry. After the end of the Second World War, this constellation turned out to be by no means a burden for the future development of the company. Kabelac and his colleagues succeeded relatively quickly in having war damage repaired and in again acquiring large orders for the shipyard. This enabled the shipyard to resume its successful performance in the maritime industry during the war. If one compares this success story with the situation of many other prominent companies in the defense industry at the beginning of the 1950s, only a few examples can be found where this was achieved in a similarly impressive manner.

RESUMENEste artículo propone un recorrido a través de la figura del pensador de la Baja Edad Media a la Ilustración. Publicada en 1621, la Anatomía de la melancolía de Robert Burton dibuja la imagen del filósofo nuevo, opuesto a los desvergonzados filosofastros que daban título a la comedia de 1615. Demócrito Júnior supone la confirmación de la nueva figura intelectual que ha dejado atrás al clerc de la Baja Edad Media: el humanista del Renacimiento que, gracias a la rehabilitación llevadaa cabo por Marsilio Ficino del mal de la bilis negra, confiesa con orgullo su carácter melancólico, propio del genio fuera de lo común. Su sucesor, el philosophe del siglo XVIII ya no necesita acudir a la afección atrabiliaria para postularse como el guía que ha de conducir y domesticar al pueblo.PALABRAS CLAVE: melancolía, filosofastros, época moderna, philosophe, pueblo.ABSTRACTThis article proposes a journey through the figure of the thinker from the late Middle Ages to the Enlightenment. Published in 1621, Robert Burton’s Anatomy of Melancholy depicts the image of the new philosopher as opposed to those shameless philosophasters, to which the title of his 1615 comedy refers. Democritus Junior embodies the confirmation of the new intellectual figure that has abandoned the clerc of the late Middle Ages: that Renaissance humanist who, thanks to Marsilio Ficino’s rehabilitation of the malady of the black bile, proudly confesses his melancholiccharacter, typical of extraordinary geniuses. His successor, the 18th century philosophe, no longer needs to resort to bad-tempered humour in order to present himself as the guide destined to direct and domesticate common people.KEY WORDS: melancholy, philosophasters, early modern period, philosophe, common people.BIBLIOGRAFÍAAgamben, G., Stanze. La parola e il fantasma nella cultura occidentale, Torino, Einaudi, 1977.Aristóteles, El hombre de genio y la melancolía: problema XXX, I, Barcelona, Quaderns Crema, 1996, edición bilingüe, prólogo y notas de Jackie Pigeaud, traducción de Cristina Serna.Badinter, É., Les passions intellectuelles, vol. I. Désirs de gloire (1735-1751), Paris, Fayard, 1999 (traducción española: Las pasiones intelectuales, vol. I. Deseos de gloria (1735-1751), Buenos Aires, FCE, 2007D’Alembert, “Réflexions sur l’état présent de la République des lettres pour l’article gens de lettres, écrites en 1760 et par conséquent relatives à cette époque”, en OEuvres et correspondances inédites (éditées par Charles Henry), Genève, Slatkine, 1967.Bartra, R., Cultura y melancolía. Las enfermedades del alma en la España del Siglo de Oro, Barcelona, Anagrama, 2001.Bauman, Z., Legisladores e intérpretes. Sobre la modernidad, la posmodernidad y los intelectuales, Buenos Aires, Universidad Nacional de Quilmes, 1997, traducción de Horacio Pons.Burton, R., Philosophaster, Whitefish, Kessinger Publishing, 1992, ed. Latin-English.Burton, R., Anatomía de la melancolía, Madrid, Asociación Española de Neuropsiquiatría, 1997-2002, 3 vols., prefacio de Jean Starobinski, traducción de Ana Sáez Hidalgo, Raquel Álvarez Peláez y Cristina Corredor.Chartier, R., Espacio público, crítica y desacralización en el siglo XVIII. Los orígenes culturales de la Revolución Francesa, Barcelona, Gedisa, 2003, traducción de Beatriz Lonné.Darnton, R., “La dentadura postiza de George Washington”, en El coloquio de los lectores. Ensayos sobre autores, manuscritos, editores y lectores, México, FCE, 2003, prólogo, selección y traducción de Antonio Saborit, pp. 285-310.Darnton, R., Los best sellers prohibidos en Francia antes de la Revolución, Buenos Aires, FCE, 2008, traducción de Antonio Saborit.Diderot, D., “Éléments de physiologie”, en OEuvres complètes de Diderot revues sur les éditions originales comprenant ce qui a été publié à diverses époques et les manuscrits inédits conservés à la Bibliothèque de l›Ermitage, Paris, Garnier frères, 1875-1877, notices, notes, table analytique, étude sur Diderot et le mouvement philosophique au XVIIIe siècle par Jules Assézat [et Maurice Tourneaux].Dumarsais, C. Ch., Nouvelles libertés de penser, Amsterdam, Piget, 1743.Erasmo de Rotterdam, “Colloquio llamado Combite religioso”, en A. Herrán y M. Santos (eds.), Coloquios familiares: edición de Alonso Ruiz de Virués (siglo XVI), Rubí (Barcelona), Anthropos, 2005.Furetière, A., “Hydre”, en Dictionnaire universel, contenant généralement tous les mots françois tant vieux que modernes, et les termes de toutes les sciences et des arts..., Paris, France-expansion, 1972 –reproduction de l’édition de La Haye et Rotterdam, A. et R. Leers, 1690, 3 tomes dans un volume, non paginé.Garin, E., “El filósofo y el mago”, en E. Garin (ed.), El hombre del Renacimiento, Madrid, Alianza, 1990, traducción de Manuel Rivero Rodríguez.Garnier, J.-J., L’Homme de lettres, Paris, Panckoucke, 1764.Goulemot, J.-M., Adieu les philosophes: que reste-t-il des Lumières?, Paris, Seuil, 2001.Klibansky, R., Panofsky, E. y Saxl, F., Saturno y la melancolía. Estudios de historia de la filosofía de la naturaleza, la religión y el arte, Madrid, Alianza, 1991, versión española de María Luisa Balseiro.Le Goff, J., Los intelectuales en la Edad Media, Barcelona, Gedisa, 1986, traducción de Alberto L. Bixio.Lepenies, W., ¿Qué es un intelectual europeo? Los intelectuales y la política del espíritu en la historia europea, Barcelona, Galaxia Gutenberg/Círculo de Lectores, 2008, traducción de Sergio Pawlosky.Masseau, D., L’invention de l’intellectuel dans l’Europe du XVIIIe siècle, Paris, Presses Universitaires de France, 1994.Mornet, D., Les origines intellectuelles de la Révolution française: 1715-1787, Paris, Armand Colin, 1933 (traducción española: Los orígenes intelectuales de la Revolución Francesa, 1715-1787, Buenos Aires, Paidós, 1969, traducción de Carlos A. Fayard).Radin, P., Primitive Religion. Its Nature and Origin, New York, The Viking Press, 1937.Rivera García, A., “La pintura de la crisis: Albrecht Dürer y la Reforma”, Artificium. Revista iberoamericana de estudios culturales y análisis conceptual, 1 (2010), pp. 100-119.Schiebinger, L., Nature’s body. Gender in the Making of Modern Science, New Brunswick (New Jersey), Rutgers University Press, 2006.Starobinski, J., “Habla Demócrito. La utopía melancólica de Robert Burton”, en R. Burton, Anatomía de la melancolía, vol. I, traducción de Julián Mateo Ballorca, pp. 11-29.Taine, H.- A., Histoire de la littérature anglaise, Paris, L. Hachette, 2e édition revue et augmentée, 1866.Tocqueville, A. de, El Antiguo Régimen y la Revolución, Madrid, Istmo, 2004, edición de Antonio Hermosa Andújar.Van Kley, D. K., The Damiens Affair and the Unraveling of the Ancien Régime, 1750-1770, Princeton, Princeton University Press, 1984.Vernière, P., “Naissance et statut de l’intelligentsia en France”, in Ch. Mervaud et S. Menant (éd.), Le siècle de Voltaire: hommage à René Pomeau, Oxford, Voltaire Foundation, 1987, vol. II, pp. 933-941; É. Walter, “Sur l’intelligentsia des Lumières”, Dix-huitième siècle, 5, 1973, pp. 173-201.Voltaire, Les oeuvres complètes de Voltaire / The Complete Works of Voltaire, Genève/Toronto/Paris, Institut et Musée Voltaire/University of Toronto Press, edited by Theodore Besterman], tome 82, Notebooks (vol. 2), 1968.Weber, M., La ética protestante y el “espíritu” del capitalismo, Madrid, Alianza, 2001, traducción de Joaquín Abellán García.

Background: Studies on the clinical manifestation and course of disease in children suffering from Huntington’s disease (HD) are rare. Case reports of juvenile HD (onset ≤ 20 years) describe heterogeneous motoric and non-motoric symptoms, often accompanied with a delay in diagnosis. We aimed to describe this rare group of patients, especially with regard to socio-medical aspects and individual or common treatment strategies. In addition, we differentiated between juvenile and the recently defined pediatric HD population (onset < 18 years). Methods: Out of 2593 individual HD patients treated within the last 25 years in the Huntington Centre, North Rhine-Westphalia (NRW), 32 subjects were analyzed with an early onset younger than 21 years (1.23%, juvenile) and 18 of them younger than 18 years of age (0.69%, pediatric). Results: Beside a high degree of school problems, irritability or aggressive behavior (62.5% of pediatric and 31.2% of juvenile cases), serious problems concerning the social and family background were reported in 25% of the pediatric cohort. This includes an attempted rape and robbery at the age of 12, as problems caused by the affected children, but also alcohol-dependency in a two-year-old induced by a non-HD affected stepfather. A high degree of suicidal attempts and ideations (31.2% in pediatric and 33.3% in juvenile group) was reported, including drinking of solvents, swallowing razor blades or jumping from the fifth floor with following incomplete paraparesis. Beside dopaminergic drugs for treatment of bradykinesia, benzodiazepines and tetrabenazine for treatment of dystonia, cannabinoids, botulinum toxin injection and deep brain stimulation were used for the improvement of movement disorders, clozapine for the treatment of tremor, and dopa-induced hallucinations and zuclopenthixole for the treatment of severe aggressive behavior. Conclusions: Beside abnormalities in behavior from an early age due to HD pathology, children seem to have higher socio-medical problems related to additional burden caused by early affected parents, instable family backgrounds including drug abuse of a parent or multiple changes of partners. Treatment required individualized strategies in many cases.

BackgroundEffective anti-tumour immunity requires cancer antigen expression, but persistent antigen exposure in chronic viral infections and autoimmunity has a detrimental effect on immune function. This is associated with a decline of early differentiated T cell populations in favour of later differentiated, dysfunctional subsets, resulting in an unfavourable skewing of the immune landscape. It is unknown whether this occurs locally within the antigen rich tumour microenvironment, driving immune failure.Materials and MethodsWe combined tumour infiltrating lymphocyte (TIL) high dimensional flow cytometry, bulk exome and RNA sequencing data from multiregional samples obtained from surgically resected tumours of treatment naive patients with non-small cell lung cancer (NSCLC) amongst the first 100 recruited to the prospective, UK-wide lung TRACERx study. Clonal relationship between T cell populations was determined by T cell receptor (TCR) sequencing. We additionally analysed publically available single T cell RNA sequencing data and bulk RNA sequencing data within TCGA.ResultsT cell differentiation skewing (TDS) occurred amongst TILs in association with tumour mutational burden (TMB). Surprisingly, this was most evident within the CD4 compartment that had a greater abundance of central memory cells expressing the key transcription factor TCF7. Amongst CD4 cells, loss of a PD1-CCR7+ T central memory population was accompanied by gain in abundance of PD1+ populations with exhausted (CD57-ICOShiCTLA4hi) and terminally differentiated effector (CD57+Eomes+) features. TCR sequencing revealed early and dysfunctional differentiated populations to be clonally related and CDR3 clustering analysis showed greater similarity of sequences shared vs. non-shared between subsets, consistent with an antigen driven differentiation process. Similar patterns were observed within the CD8 compartment. Identification of these subsets within single T cell RNA sequencing data revealed shared and distinct functional regulators, suggesting the enhanced effector capability of early compared to dysfunctionally differentiated populations. A validated transcriptional signature of TDS generated using TRACERx samples with paired flow cytometry and RNA sequencing data reflected loss of gene expression downstream of TCF7, and predicted worse survival within TRACERx and multiple TCGA cohorts including lung adenocarcinoma (LUAD).ConclusionsOur finding support a model of neoantigen driven T cell differentiation within the tumour microenvironment that drives the depletion of progenitor-like cells and gain in abundance of dysfunctional subsets, resulting in a loss of immune fitness. Our analysis of transcriptomic data elucidates potential regulatory mechanisms and therapeutic targets within the subsets identified.Disclosure InformationE. Ghorani: None. J. Reading: None. J. Henry: None. M. Robert de Massy: None. R. Rosenthal: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics. F. Consultant/Advisory Board; Modest; Achilles Therapeutics. V. Turati: None. A. Furness: None. A. Ben Aissa: None. S. Kumar Saini: None. S. Ramskov: None. A. Georgiou: None. M. Vila De Mucha: None. I. Uddin: None. T. Ronel: None. R. Salgado: None. T. Lund: None. J. Herrero: None. T. Enver: None. S. Hadrup: None. A. Hackshaw: None. K. Peggs: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics. N. McGranahan,: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics. F. Consultant/Advisory Board; Modest; Achilles Therapeutics. B. Chain: None. C. Swanton: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Pfizer, AstraZeneca, BMS, Roche–Ventana and Boehringer Ingelheim. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; ApoGen Biotechnologies, Epic Bioscience and GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. F. Consultant/Advisory Board; Modest; Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche–Ventana, GRAIL, Medicxi and the Sarah Cannon Research Institute. S. Quezada: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics.

Objectives: Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell- therapy that reprograms autologous T cells to target CD19+ leukemia cells, approved in the US (2017) and in the EU (2018). This study reports the feasibility, safety and efficacy of CTL019 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated in Robert-Debré and Saint-Louis University Hospitals (Assistance Publique-Hôpitaux de Paris/Université de Paris). Methods: Patients (pts) with an apheresis performed between march 1, 2016 and june 15, 2019, included in sponsored-clinical trials or treated within the French compassionate program or with the commercial product, were analyzed. All infused pts received a fludarabine-cyclophosphamide based lymphodepletion before a single infusion of CAR-T cells (2 to 5 x 106 CTL019/kg if less than 50 kg; a fixed dose of 1 to 2.5 x 108 CTL019/kg if > 50 kg) Results: 55 pts were referred from 25 French centers. Forty-one pts with a median number of relapses of 2 (range, 1-5) were infused with CTL019 at a median age of 18.2 y (range, 1-29.2). Eight pts were not infused due to progressive disease (n=4), screen failure (n=3) or fatal septic shock (n=1). Six pts were waiting to be infused at time of analysis. Out of the 41 infused pts, 26 had a prior history of allogeneic SCT (63%), 11 had received blinatumomab (27%). Among the 40 pts evaluable at one month post-infusion, 38 were in CR/CRi (95%) (one progression at day 5 after infusion and one toxic death at D6), 35/38 (92.1%) being clone-specific Ig-TCR MRD negative. After 3 months 21 out of 26 evaluable pts (81%) had a negative MRD. The 5 remaining MRD positive pts did relapse. No pt underwent allogeneic HSCT while in CR after CTL019 infusion. Median event free survival (EFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2-36.3). The 18-month OS probability was 80% (95%CI, 58%-92%). The 18-month EFS probability was 58 % (95%CI, 37%-74%). Ten pts relapsed after a median time of 3.4 months (range, 1.9-10): 3 relapses were CD19+ and 5 CD19- (4 out of these 5 pts had a preexposure to blinatumomab), 2 being of undetermined status. Loss of B-cell aplasia (BCA) occurred in 9 pts after a median time of 3 months (range, 2-12), followed by relapse for 2 pts (one concomitant with loss of BCA and one 7 months later). Three pts received a second infusion of CTL019 for loss of BCA with no further expansion of CAR-T cells. Prior treatment with blinatumomab was a significant predictive factor for relapse (HR=6.082, 95%CI, 1.2-30, p=0.0005) in a univariate analysis. There was a trend toward increased risk of relapse with increased disease burden (≥ 5%) before lymphodepletion regimen (HR=2.4, 95%CI, 0.7-8, p=0.14). Twenty-two pts experienced a CRS (≥ grade 3: n=13, all ≥ 10 y). ICU was required for 14 pts (34%). One 29 year-old pt died of an uncontrollable CRS at day 6. Ten pts received tocilizumab, 4 pts siltuximab and 9 pts corticosteroids. Age ≥ 10 y (p=0.04) and a high disease burden just before lymphodepletion (marrow blasts ≥ 5%) (p=0.01) were associated with a higher risk of CRS ≥ grade 3. Nine neurological events have been reported, being reversible except in 2 cases (one death in combination with grade 5 CRS-cf supra-, one HHV6-related encephalitis with neurological sequelae). Among the 9 pts who presented neurological events, 8 experienced CRS grade ≥ 3 (RR=17.2, 95%CI, 3.22-100.3, p=0.0001). By day 28, unresolved neutropenia grade ≥ 3 was reported for 13 pts. G-CSF treatment was required in 21 pts overall. Thrombocytopenia grade ≥3 was reported for 14 pts. Conclusion: CTL019 confirms its efficacy with a high response rate after infusion and very encouraging early outcomes in a cohort of pts heavily pretreated for refractory or multiply relapsed B-ALL. Persistent remissions with a potential for cure were observed without additional HSCT, relapses occurring within the first year after infusion of CTL019. Accurate assessment of a potentially deleterious effect of Blinatumomab preexposure notable on CD19 negative relapse will need more pts and a longer follow-up. Toxicity profile was tolerable and manageable thanks to collaboration between intensivists, neurologists and hematologists. The identification of severe CRS predictive risk factors (high disease burden just before lymphodepletion and age ≥ 10 y) points towards the reinforcement of toxicity monitoring and treatment anticipation in these cases. Disclosures Boissel: NOVARTIS: Consultancy. Baruchel:NOVARTIS: Consultancy.

Abstract Introduction Treatment of patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with the combination of venetoclax (VEN), an oral, selective Bcl-2 inhibitor, and rituximab yielded an ORR of 84% (Roberts et al. Haematologica 2015). Treatment of such pts with VEN in combination with obinutuzumab (Gazyva®, Gazyvaro™, G), a Type II, glycoengineered anti-CD20 antibody, may yield even better treatment outcomes. We present preliminary efficacy and updated safety data from an ongoing phase 1b study (NCT01685892) evaluating this combination in R/R or treatment-naïve (TN) pts with CLL in alternate treatment schedules. Methods Pts with CLL with an ECOG PS ≤1 and adequate organ function are enrolled in a study with a 3+3 design and cohorts ranging from 100 to 600 mg/day of VEN. Pts are assigned to one of two dosing schedules, starting treatment with either VEN (Schedule A) or G (Schedule B). Both schedules include tumor lysis syndrome (TLS) risk mitigation based on disease burden at screening, which includes a gradual VEN ramp-up to the assigned cohort dose. Six cycles of combination therapy will be given and then pts with R/R disease continue single-agent VEN until disease progression; TN pts will receive single-agent VEN for an additional 6 months. Dose-limiting toxicities (DLTs) are identified during the first 21 days of combination therapy in Schedule A or the first 35 days of combination therapy in Schedule B, and focus on TLS, infusion related reactions, and cytopenias. Based on a safety review of data from this trial, the 600 mg cohort will not be explored. Response is first assessed before Cycle 4 according to 2008 International Workshop on CLL guidelines. Results As of April 20, 2015, 32 pts (26 R/R and 6 TN) have been enrolled. Four R/R pts were unenrolled after a sponsor-initiated clinical hold secondary to TLS events in other VEN studies. Patient characteristics include a median age 62.5 (range, 45-80) years, and 62.5% male pts. TLS risk was assessed in 28 pts following protocol modifications adopted after a Sponsor-initiated clinical hold; 96.4% were at medium or high risk for TLS. The highest VEN dose administered in this study was 400 mg/day (administered to 11 R/R and 6 TN pts). Median time on study was 5.5 (range, 0.1-19.6) mo. for all pts and 2.8 (range, 0.9-2.8) mo. for TN pts. Among pts exposed to VEN, dose interruptions were observed in 17/27 (63%) pts. A summary of AEs is presented in Figure 1. Laboratory TLS was observed in 4/32 (12.5%) pts and all were able to continue study treatment after resolution of electrolyte changes; no cases of clinical TLS occurred. One pt with R/R disease in cohort 1 discontinued study participation following disease progression (the pt completed 6 cycles of combination treatment). A second pt with R/R disease in cohort 1 died secondary to acute respiratory failure; Richter's transformation also was suspected in this pt but not confirmed. Twenty pts with R/R disease and 6 TN pts remain on the study. At least 1 response evaluation has been performed in 17 pts with R/R disease. The overall response rate (ORR) by investigator assessment was 100%; 4/17 (23.5%) pts achieved complete response/complete response with incomplete bone marrow recovery (CR/CRi). Among the 13 (76.5%) pts with PRs after 3 cycles of therapy, 3 have improved to CR/CRi at assessments 28 days after completing C6D1. Full MRD data will be available in the near future but early analyses suggest some patients may achieve MRD negative status by Cycle 4. Conclusion These preliminary data suggest that VEN + G can be safely administered in pts with CLL with no difference in tolerability between R/R and TN subgroups. AEs appear to be manageable and no pt has discontinued study participation secondary to cytopenia, the most frequently observed AE. Data suggests that the TLS prophylaxis measures are effective even in patients with a higher disease burden. An expansion phase is planned using a 400 mg per day dose of VEN in R/R and TN pts following a review of safety data assessing potential differences between dosing schedules. The preliminary efficacy data suggest this regimen may be an important option in patients with CLL; a phase 3 study evaluating VEN+G is ongoing. Disclosures Flinn: Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Brunvand:Celgene: Speakers Bureau; Millenium: Speakers Bureau. Choi:Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Dyer:Roche Pharmaceuticals: Speakers Bureau; ONO Pharmaceuticals: Research Funding; Gilead: Research Funding. Gribben:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria; Roche/Genentech: Honoraria; Pharmacyclics: Honoraria. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding. Jones:Acerta Pharma BV: Research Funding. Li:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Vosganian:Genentech, Inc.: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

This thesis takes as its object of study a certain strand of Early Modern English writing characterised by its cornucopian invention, immethodical structure, and creatively exuberant, often chaotic, means of expression. It takes as its point of departure the Erasmian theory of ‘copia' (rhetorical abundance), expanding upon it freely in order to formulate new and independent notions of copious vernacular writing as it is practised in 16th- and 17th-century contexts. Throughout I argue for the continuity and pervasiveness of the pursuit of linguistic plenitude, in contrast to a prevailing belief that the outpouring of 'words' and 'things' started to dissipate in the transition from one century (16th) to the next (17th). The writers to be discussed are Thomas Nashe, Robert Burton, John Taylor the ‘Water-Poet', and Sir Thomas Urquhart. Each of the genres in which these writers operate–prose-poetry, the essay, the pamphlet, and the universal language–emerge either toward the end of the 16th century or during the course of the 17th century, and so can be said to take copious writing in new and experimental directions not fully accounted for in the current scholarship. My contribution to the literature lies principally in its focus on the emergence of these literary forms in an Early Modern English context, with an emphasis on the role played by copiousness of expression in their stylistic development and how they in turn develop the practice of copia.

Critics have observed that in early Stuart England, the broad, socially significant concept of melancholy was recoded as a specifically medical phenomenon—a disease rather than a fashion. This recoding made melancholy seem less a social attitude than a private ailment. However, I argue that at the Stuart universities, this recoded melancholy became a covert expression of the disillusionment, disappointment, and frustration produced by pressures there—the overcrowding and competition which left many men “disappointed” in preferment, alongside James I’s unprecedented royal involvement in the universities. My argument has implications for Jürgen Habermas’s account of the emergence of the public sphere, which he claims did not occur until the eighteenth-century. I argue that although the university was increasingly subordinated to the crown’s authority, a lingering sense of autonomy persisted there, a residue of the medieval university’s relative autonomy from the crown; politicized by the encroaching Stuart presence, an alienated community at the university formed a kind of public in private from authority within that authority’s midst. The audience for the printed book, a sphere apart from court or university, represented a forum in which the publicity at the universities could be consolidated, especially in seemingly “private” literary forms such as the treatise on melancholy. I argue that Robert Burton’s exaggerated performance of melancholy in The Anatomy of Melancholy, which gains him license to say almost anything, resembles the performed melancholy that the student-prince Hamlet uses to frustrate his uncle’s attempts to surveil him. After tracing melancholy’s evolving literary function through Hamlet, I go on to discuss James’s interventions into the universities. I conclude by considering two printed (and widely circulated) books by university men: the aforementioned The Anatomy of Melancholy by Burton, an Oxford cleric, and The Temple by George Herbert, who left a career as Cambridge’s public orator to become a country parson. I examine how each of these books uses the affective pattern of courtly-scholarly disappointment—transumed by Burton as melancholy, and by Herbert as holy affliction—to develop an empathic form of publicity among its readership which is in tacit opposition to the Stuart court.
Thesis (Ph.D, English) -- Queen's University, 2011-09-27 15:30:01.702

AbstractCompetitive industrial transmission systems must perform most efficiently with reference to complex requirements and conflicting key performance indicators. This design challenge translates into a high-dimensional multi-objective optimization problem that requires complex algorithms and evaluation of computationally expensive simulations to predict physical system behavior and design robustness. Crucial for the design decision-making process is the characterization, ranking, and quantification of relevant sources of uncertainties. However, due to the strict time limits of product development loops, the overall computational burden of uncertainty quantification (UQ) may even drive state-of-the-art parallel computing resources to their limits. Efficient machine learning (ML) tools and techniques emphasizing high-fidelity simulation data-driven training will play a fundamental role in enabling UQ in the early-stage development phase.This investigation surveys UQ methods with a focus on noise, vibration, and harshness (NVH) characteristics of transmission systems. Quasi-static 3D contact dynamic simulations are performed to evaluate the static transmission error (TE) of meshing gear pairs under different loading and boundary conditions. TE indicates NVH excitation and is typically used as an objective function in the early-stage design process. The limited system size allows large-scale design of experiments (DoE) and enables numerical studies of various UQ sampling and modeling techniques where the design parameters are treated as random variables associated with tolerances from manufacturing and assembly processes. The model accuracy of generalized polynomial chaos expansion (gPC) and Gaussian process regression (GPR) is evaluated and compared. The results of the methods are discussed to conclude efficient and scalable solution procedures for robust design optimization.

The implementation of early interventions stands out as an interesting approach to reduce harmful use of alcohol by focusing on the early recognition, diagnosis, and treatment across the full trajectory of alcohol use before more severe consequences occur. This chapter provides a brief overview of the literature on early intervention in harmful use of alcohol in Brazil—the largest middle-income country in Latin America, where alcohol use represents a significant burden. Though the scenario is rather worrisome, advances have been made in the past years: more research has been developed and public policies have been carried out to reduce such a burden. Early interventions focused on young people (underage and college students) should be given primarily, with a particularly growing concern on girls. There is robust evidence that screening and brief interventions (SBIs) can, in the short term, reduce problems related to alcohol use, at lower costs than more intensive treatments worldwide. In Brazil, the barriers for its implementation in primary care services seem to be related to integration and intersectional healthcare settings, and to training of professionals, the latter of which could initially be tackled through distance-learning approaches. Further research is still necessary to develop and evaluate SBI approaches addressing vulnerable populations. Finally, the reduction of harmful alcohol-use related consequences requires the joint effort of civil society, government, and the private sector, with special engagement of public health and research institutes to consolidate evidence-based strategies and measures.

Chapter 4 follows Shakespeare as he explores the lines of affiliation between the Cynic-inspired fantasy of unstoppable critical agency and his period’s romanticized portrait of intellectual melancholy. Drawing support from a range of early modern sources, including Robert Burton’s similar appropriation of Diogenes in his preface to The Anatomy of Melancholy, it shows that Shakespeare has Hamlet lay claim to a specifically Cynic form of thoughtful sadness, one that posits contemplative self-enclosure as public activism’s final frontier. After linking both Hegel’s and Marx’s philosophies of history to the legacy of Hamlet’s Cynic melancholy, the chapter shows how Shakespeare’s ultimate interest in problematizing this stance allows us to turn the tables on Hamlet’s modern philosophical reception: instead of using modern philosophy as a lens for better understanding an early modern Hamlet, we can use an early modern Hamlet as a lens for better understanding the conditions and limits of modern philosophy.

The pharmacovigilance has been evolved as a professional and ethical practice in ensuring the safety of medicines. The Adverse Drug Reactions (ADRs) associated with the use of medicines including Anti-Tuberculous Therapy (ATT) through a robust system of pharmacovigilance helps in promoting the safety of patients at large. The occurrence of ADRs associated with the use of ATT is expected, a large number of medicines are combined and used for prolonged duration. The suspected ADRs associated with first line ATT are well documented. However, the drugs used in second line or multidrug resistant to tuberculosis (TB), namely bedaquiline, reported to cause QT prolongation in electrocardiogram reading as one of the most common ADRs. Therefore, early identification and prevention of ADRs during ATT is essential for promoting the rational use and reduce the burden of anti-microbial resistance, besides achieving better treatment outcomes.

The requirements to reduce engine fuel burn costs and gaseous emissions combine to ensure that gas turbine engine manufacturers continually seek to increase the peak cycle temperatures of new engine designs. Consequently, high-pressure turbine components must be developed that can withstand increasing gas temperatures, resulting in the continuous introduction of new technologies that allow appropriate service life. Accurate gas path measurements are vital for early understanding of the performance of a new design, although the accurate measurement of fluid temperature in a turbine stage is becoming increasingly difficult. The use of active probe-assembly cooling is important to ensure a sufficiently robust measurement system. Cooling issues may also affect the measurement performance because the component to which the temperature instrumentation is attached is cooled (for example, a guide vane). The use of a radial traverse total temperature device in the turbine section of a large civil aero-engine has previously been reported and the results analysed and compared to expectation. One outcome of ongoing work has been a proposal for a new design of turbine traverse probe with improved total temperature measurement accuracy. The new design directly addresses those uncertainties caused by conduction of heat from the thermocouple junction and into the cooled probe support. Extensive conjugate CFD modelling followed by validation tests in a high temperature free-jet rig confirmed the success of the design in reducing the magnitude of the thermal conduction error. The probe is likely to be used in future tests to improve engine performance validation.