596 research outputs found
Cardiovascular effects of hormone therapy for prostate cancer
No full textJason F Lester,1 Malcolm D Mason1,2 1Velindre Hospital, Whitchurch, 2School of Medicine, Cardiff University, Heath Park, Cardiff, UK Abstract: Androgen deprivation therapy (ADT) has been the mainstay of treatment for advanced prostate cancer for decades, and has been shown to control disease and improve symptoms. In addition, for men with high-risk localized or locally advanced prostate cancer, short-course ADT in combination with radiotherapy improves survival. There is evidence that ADT increases cardiovascular risk, particularly in men with preexisting cardiovascular disease. This increased risk may apply even with short-course ADT. In an individual patient, the benefits of ADT should be balanced against the risk, and patients who require ADT should have risk factors for cardiovascular disease optimized. There is some evidence to suggest that more contemporary methods of delivering ADT may reduce cardiovascular risk. Keywords: androgen deprivation therapy, testosterone, cardiovascular risk, hypercoagulability, prostate cancer patients, dihydrotestosterone, androgen recepto
A single centre phase II trial to assess the immunological activity of TroVax® plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma – the SKOPOS trial
No full textVaccines in combination with chemotherapy have been shown to be safe in different tumor types. We investigated the immunological activity of the TroVax® vaccine in combination with pemetrexed-cisplatin chemotherapy in malignant pleural mesothelioma (MPM).In this first line, open-label, single-arm, phase 2 study, patients with locally advanced or metastatic MPM were enrolled. Eligible patients received up to 9 intramuscular injections of TroVax®, starting two weeks before chemotherapy and continuing at regular intervals during and after chemotherapy to 24 weeks. The primary endpoint was the induction of cellular or humoral anti-5T4 immune response (defined as a doubling of either response at any of six follow-up time points), with a target response rate of 64%.Of 27 patients, enrolled between Feb 2013-Dec 2014, 23 (85%) received at least three doses of TroVax® and one cycle of chemotherapy and were included in the per-protocol analysis (PPA). 22/23 patients (95.6%) developed humoral or cellular immune response to 5T4. Thus, the study reached its primary endpoint. Disease control was observed in 87% of patients (partial response: 17.4%, stable disease: 69.6%). The median progression-free survival was 6.8 months and median overall survival 10.9 months. Treatment-related adverse events were comparable to those observed in patients with chemotherapy alone. Translational immunology studies revealed a circulating baseline immune signature that was significantly associated with long-term (>20 months in n = 8/23, 34.8%) survival.In this phase 2 trial, TroVax® with pemetrexed-cisplatin chemotherapy showed robust immune activity, acceptable safety and tolerability to warrant further investigation in a phase 3 setting
The Myth of Urban Unity. Religion and Social Performance in Late Medieval Braunschweig
No full textArlinghaus F-J. The Myth of Urban Unity. Religion and Social Performance in Late Medieval Braunschweig. In: Goodson C, Lester AE, Symes C, eds. Cities, Texts, and Social Networks, 400-1500: Experiences and Perceptions of Medieval Urban Space. Farnham: Ashgate; 2010: 215-232
Investigation of the interaction between corticomuscular coherence, motor precision and perceived difficulty in wrist flexion and extension
No full textIncludes abstract.Includes bibliographical references.Recently, behavioural (motor precision) differences were reported between isometric wrist flexion and extension. Neurophysiological as well as clinical differences have also been reported between these antagonistic movements. Corticomuscular coherence (CMC), i.e. the frequency specific temporal coupling between the electroencephalogram (EEG) and electromyogram (EMG) recorded during isometric force production, reflects the functional connectivity between cortex and muscle. A single muscle (flexor digitorum superficialis) study suggests a positive correlation between 15-35 Hz (beta) CMC and motor precision of the muscle. Yet, no study has simultaneously compared CMC and motor precision between wrist flexion and extension. Task perceived difficulty, which is a perceptual variable, may influence both motor precision and CMC, but has not been studied yet. The main aim of the present study was to investigate the interaction between CMC, motor precision and perceived difficulty in isometric wrist flexion and extension tasks
Characterization and structure in the development of Tudor comedy
No full textThe role of characterization in dramatic structure is assessed by theoretical criteria.
Characters who perform actions necessary for the completion of the narrative sequence are
said to be "bound" to the narrative; those without such obligations are "free". Characters
who maintain a single, constant meaning during the course of a play are said to be "static";
characters who change or develop into new roles are "dynamic". Horatian decorum
demanded that comic characters be static, and the characters of Plautine and Terentian
tradition were almost always bound to narrative intrigue. However, evaluations of six
Tudor comedies show an increasing use of non-classical characterization within the comic
form.
In the early comedies lohan lohan and Roister Doister all characters are bound and
static, yet the impetus to enlarge the role of characterization is evident. The characters of
lohan lohan are expanded from their French source, and Roister Doister includes
extraneous episodes in which Udall displays his braggart hero. Free characters abound in
Misogonus; as well the play brings dynamic characterization into the scope of comedy with
the conversion of its prodigal son.
Free characters offer new possibilities of non-narrative plotting. In comedies of the
1580s favourite traditional characters appear as diversions outside the action, and thematic
arrangements of characters inform the increasingly complex plots. Lyly stresses the
symbolic potential of characters in Endimion, whereas Greene uses dynamic
characterization to heighten the illusion of independent figures in Friar Bacon and Friar
Bungay. Love's Labour's Lost exposes the limitations of comic artifice by pulling the
characters between convention and individualization.
By the end of the sixteenth century free and dynamic characters had become
common, and characterization had established a sizable claim on the design of English
comedy. These developments set the English form apart from its neoclassical counterparts
The political orientations of black students from all-black towns: the cases of boley, oklahoma; grambling, louisiana; and mound bayou, mississippi
No full textThis study examines the political orientations of black high school students living in the all-black towns of Boley, Oklahoma; Grambling, Louisiana; and Mound Bayou, Mississippi. For comparative purposes, the study also examines the political orientations of black students living in one multi-ethnic town (Rural Town). The primary intent of this investigation is to determine to what degree the students from these towns are socialized to accept the American political system. In essence, this research seeks to determine to what extent are the students committed to certain values, norms and traditions generally associated with the American society. This study also examines the students' feelings about black nationalism. It attempts to determine the extent to which the students in the three all-black towns and one multi-ethnic town accept the concept black nationalism. A major concern is to determine if there is a correlation between one's acceptance or rejection of the values associated with the American political system and one's feelings about black nationalism. The data for this research were obtained from a paper and pencil questionnaire administered to one-hundred and seventy-two black town students and forty-two multi-ethnic town students in the Spring and Sumner of 1984. The questionnaire consisted of questions concerning the personal and family background of the students, the American political system, and the students' feelings about black nationalism. Additional information on black nationalism and all-black towns was obtained through library research. Findings of this study show that the vast majority of the students in the all-black towns and the multi-ethnic town displayed more support for the American political system than disaffection for the system. The data indicate that more than thr ee-f our ths of all the students can be classified as moderate conformers to conformers. However, the black town students show more support for the political system than those from Rural Town. Findings concerning the students' feelings about black nationalism show that the students in Rural Town displayed a higher degree of support for black nationalism than those in the three all-black towns. However, the vast majority of all the students can be classified in the moderate nationalist to nationalist categories. Only in the town of Boley do the students show strong support of black national!sm. The results of this research show that there is an association between the degree of political socialization and the degree of black nationalism. However, the data indicate that the relationship between the two variables is a negative one. That is, the findings show that those students who oppose the American political system are more likely to display support for black nationalism
Longitude : a privacy-preserving location sharing protocol for mobile applications
No full textLocation sharing services are becoming increasingly popular. Although many location sharing services allow users to set up privacy policies to control who can access their location, the use made by service providers remains a source of concern. Ideally, location sharing providers and middleware should not be able to access users’ location data without their consent. In this paper, we propose a new location sharing protocol called Longitude that eases privacy concerns by making it possible to share a user’s location data blindly and allowing the user to control who can access her location, when and to what degree of precision. The underlying cryptographic algorithms are designed for GPS-enabled mobile phones. We describe and evaluate our implementation for the Nexus One Android mobile phone
Incremental spoken dialogue processing : architecture and lower-level components
No full textBaumann T. Incremental spoken dialogue processing : architecture and lower-level components. Bielefeld: Bielefeld University; 2013.Diese Arbeit befasst sich mit Sprachdialogsystemen, also Mensch-Maschine-Schnittstellen die (primär) über gesprochene Sprache genutzt werden. Sprachdialogsysteme sind vor allem deshalb attraktiv, weil Sprache eine besonders natürliche und intuitive Interaktionsform darstellt.
Der Nutzen von Sprachdialogsystemen ergibt sich jedoch bisher daraus, dass sie helfen, relativ einfache Aufgaben sinnvoll zu erfüllen – denn tatsächlich ist die Natürlichkeit bisheriger Sprachdialogsysteme stark durch das vereinfachende Verarbeitungsschema der Ping-Pong-Interaktion eingeschränkt: Übliche Dialogsysteme erwarten einen vollständigen und abgeschlossenen Redebeitrag, auf den das System (nach einer gewissen Verarbeitungszeit) mit einem gleichfalls vollständigen, oft ununterbrechbaren Redebeitrag antwortet. Die Redebeiträge von System und Nutzer sind also überlappungsfrei, was nicht den tatsächlichen Gegebenheiten natürlichsprachlicher Interaktion entspricht, die von einem beiderseitigen Geben und Nehmen lebt, und bei der auch der jeweilige Zuhörer hilft, den Redebeitrag des jeweiligen Sprechers durch Mimik, kurze Einwürfe, und dergleichen mitzugestalten.
Schritthaltende Verarbeitung ist ein Konzept, bei der die Verarbeitung bereits während der Eingabephase abläuft und Zwischenergebnisse bereits erzeugt werden bevor die Eingabe abgeschlossen ist. Einem Dialogsystem erlaubt schritthaltende Verarbeitung Reaktionen zu erzeugen die zeitgleich zur noch laufenden Eingabe erfolgen, oder entgegengebrachte Nutzerrückmeldungen in laufende Systemausgaben zu integrieren.
Dadurch erlaubt schritthaltende Verarbeitung eine schnellere Rückkopplung zwischen Nutzer und System, was zu höherer Interaktivität und besserem gegenseitigen Verständnis führen kann. Das Ziel dieser Arbeit ist, den Nutzen schritthaltender Verarbeitung auf die Interaktionsqualität von Sprachdialogsystemen zu untersuchen. Dabei beschränkt sich die detaillierte Analyse auf signalnahe Komponenten (Spracherkennung und -synthese); Module übergeordneter Abstraktionsgrade sind in den Beispielsystemen teilweise weniger ausgefeilt, oder nur simuliert.
Die Leitfrage der Arbeit ist, inwieweit feingliedrig schritthaltende Verarbeitung technisch realisierbar ist und auf natürlichere Weise interagierende Sprachdialogsysteme ermöglicht. Darüber hinaus wird argumentiert, dass Dialog proaktives Handeln verlangt, also nicht rein auf Basis bereits vorliegender Erkenntnis, sondern außerdem auf Grundlage von Schätzungen über die (nähere) Zukunft.
Bei schritthaltender Verarbeitung werden sehr viele Zwischenergebnisse erzeugt und da diese jeweils nur aus einem begrenzten Kontext heraus erzeugt werden, ergibt sich die Erfordernis, sie auch verwerfen zu können; dies erfordert Anpassungen der Systemarchitektur gegenüber bisherigen Systemen.
Kapitel 2 gibt einen Überblick über Fragen der gesprochensprachlichen Interaktion, des Dialogs und Dialogsystemen.
Kapitel 3 vertieft dann die Thematik der schritthaltenden (inkrementellen) Verarbeitung und führt einen Formalismus für die Darstellung von Hypothesen ein, anhand dessen Qualitätsmaße schritthaltender Verarbeitung definiert werden, die ausführlich diskutiert werden.
Kapitel 4 stellt die Architektur des im Rahmen der Arbeit entwickelten Softwaretoolkits für schritthaltende Verarbeitung (engl. incremental processing), InproTK vor und diskutiert Daten- und Verarbeitungsschemata.
Kapitel 5 betrachtet inkrementelle Spracherkennung. Die ‚inkrementelle Qualität’ der Spracherkennung wird intensiv auf mehreren Korpora und für unterschiedliche Varianten in all ihren Aspekten untersucht. Schließlich werden Optimierungsmethoden vorgestellt, welche Qualitätsaspekte gegeneinander abwägen. Der Nutzen inkrementeller Spracherkennung wird beispielhaft in einer Spielanwendung gezeigt.
Kapitel 6 geht den Schritt von möglichst reaktiver zu proaktiver Verarbeitung, welche erlaubt, den Dialogverlauf aktiv zu steuern. Eine Beispielanwendung zeigt, wie durch schritthaltende Verarbeitung die Rückkopplung zwischen Nutzer und System beschleunigt und dadurch Nutzeräußerungen gemeinschaftlich gestaltet werden können. Schließlich wird ein System gezeigt, welches Nutzeräußerungen synchron mitspricht. Dieses System zeigt, dass inkrementelle und proaktive Verarbeitung synchrone Interaktionsfähigkeiten in Echtzeit ermöglichen, indem alle Systemverzögerungen an anderer Stelle durch Prädiktion ausgeglichen werden.
Kapitel 7 betrachtet inkrementelle Sprachsynthese, bei der die Spezifikation der Äußerung noch während der Synthese erweitert oder abgeändert werden kann. Der Nutzen dieser Fähigkeit wird in einer hochdynamischen Umgebung demonstriert, in der Inkrementalität Reaktionen ermöglicht die als deutlich natürlicher im Vergleich zu einem nicht-inkrementellen System eingeschätzt werden. Schließlich wird die Integration inkrementeller Sprachsynthese mit einem Sprachgenerierungsmodul demonstriert, und der Einfluss auf die resultierende Prosodiequalität des Systems bewertet.
Kapitel 8 fasst die Ergebnisse der Arbeit zusammen: feingliedrig schritthaltende Verarbeitung ist technisch möglich und so erfolgreich, dass dadurch für Sprachdialogsysteme vormals unerreichbare Interaktionsmodi ermöglicht werden (u. a. gemeinschaftliche Äußerungsgestaltung, synchrones Sprechen, Berücksichtigung von Änderungen während Systemäußerungen). Schritthaltende Verarbeitung sollte deshalb die Basis für zukünftige Sprachdialogsysteme bilden
Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial
No full textBackground
Impaired double strand DNA repair by homologous repair deficiency (HRD) leads to sensitivity to poly ADP ribose polymerase (PARP) inhibition. Poly-ADP ribose polymerase (PARP) inhibitors target HRD to induce synthetic lethality and are used routinely in the treatment of BRCA1 mutated ovarian cancer in the platinum-sensitive maintenance setting. A subset of non-small cell lung cancers (NSCLCs) harbour impaired DNA double strand break repair. We therefore hypothesised that patients with metastatic non-small cell lung cancer exhibiting partial responses to platinum doublet-based chemotherapy, might enrich for impaired HRD, rendering these tumours more sensitive to inhibition of PARP inhibition by olaparib.
Methods
The Olaparib Maintenance versus Placebo Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer trial (PIN) was a multicentre double-blind placebo controlled randomised phase II screening trial. This study was conducted at 23 investigative hospital sites in the UK. Patients had advanced (stage IIIB/IV) squamous (Sq) or non-squamous (NSq) NSCLC, and had to be chemo-naive, European Cooperative Oncology Group (ECOG) performance status 0-1. Prior immunotherapy with a PD1 or PDL1 inhibitor was allowed. Patients could be registered for PIN prior to (stage 1), or after (stage 2) initiation of induction chemotherapy. If any tumour shrinkage was observed (any shrinkage of RECIST target lesions), following a minimum of 3 cycles of platinum doublet chemotherapy, patients were randomised 1:1 using a centralised online system, to either olaparib (300 mg twice daily by mouth in 21-day cycles) or placebo, which was continued until disease progression, or unacceptable toxicity. Intention to treat (ITT) analyses of the primary endpoint included all randomised participants. Per protocol (PP) safety analysis included all participants who received at least one dose of study drug. Primary endpoint was progression-free survival (PFS), with a one-sided p-value of 0.2 to demonstrate statistical significance. Hazard ratios (HR) for PFS were both unadjusted and adjusted for the randomisation balancing factors (smoking status and histology). The trial was registered with ClinicalTrials.gov (NCT01788332) and EudraCT (2012-003383-51).
Findings
A total of 940 patients were assessed for stage 1 eligibility of whom 263 were registered between Feb 24, 2014 and Nov 7, 2017. 194 patients were excluded prior to stage 2 (no tumour shrinkage or unevaluable) and 70 were randomised; 32 (46%) to Olaparib and 38 (54%) to placebo. 4% (3/70) of patients randomised had a CR and 96% (67/70) had a PR (or other evidence of tumour response/mixed stable) during induction therapy. A total of 36 patients were registered in stage 2 only, i.e., post induction therapy. Intention to treat (ITT) unadjusted analysis showed a PFS hazard ratio (HR) of 0.83 (one-sided 80% CI upper limit 1.03, one-sided unadjusted log rank test p-value=0.23). ITT Cox-adjusted model showed a HR 0.73 (one-sided 80% CI upper limit 0.91, one sided p-value 0.11). Adverse events were reported in 31/32 subjects (97%) in the olaparib arm and 38/38 (100%) in the placebo group. The most commonly reported adverse events in the olaparib group were fatigue (20/31; 65%), nausea (17/31; 55%), anaemia (15/31; 48%) and dyspnea (13/31; 42%). In the placebo group the most common adverse events were fatigue (25/38; 66%), coughing (22/38; 58%), dyspnea (15/38; 39%) and nausea (11/38; 29%). There were no treatment-related deaths.
Interpretation
PFS was longer in the olaparib arm, but this did not reach statistical significance. When the PFS HR was adjusted for smoking status and histology, a significant difference at the one-sided 0.2 level was observed, suggesting that tumour control may be achieved for chemosensitive NSCLC treated with PARP monotherapy. We speculate that this signal may be driven by a molecular subgroup harbouring HRD
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Etching in silicon-dioxide with a controllable sidewall angle
No full textA selective sloped silicon dioxide etching method has been studied using a temperature controlled diode-type reactive ion etch system with CHCl₃, C₂F₆, H₂ and N₂ gases. The SiO₂ was covered by a polyimide mask with vertical sidewalls and window openings from 1.25-4 microns. Control of the sidewall slope in SiO₂ is possible through varying the ratios of CHCl₃ and C₂F₆. High percentages (95-100%) of CHCl₃ resulted in low etch rates of 420 angstroms/min. Large slopes of up to 65 degrees are possible. With C₂F₆ above 5%, larger etch rates close to 2000 angstroms/min. occur and etching becomes vertical with purely anisotropic profiles at 10% C₂F₆. In a simulation study, SiO₂ sidewall slope was found to be controlled by the isotropic deposition rate as well as the anisotropic etch rate. Optical Multichannel Analysis of the discharge showed an increase in silicon dioxide removal when the percentage of C₂F₆ was increased. (Abstract shortened with permission of author.
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