Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention

Breast cancer screening has led to a dramatic increase in the detection of pre-invasive breast lesions. While mastectomy is almost guaranteed to treat the disease, more conservative approaches could be as effective if patients can be stratified based on risk of co-existing or recurrent invasive disease.Here we use a range of biomarkers to interrogate and classify purely non-invasive lesions (PNL) and those with co-existing invasive breast cancer (CEIN). Apart from Ductal Carcinoma In Situ (DCIS), relative homogeneity is observed. DCIS contained a greater spread of molecular subtypes. Interestingly, high expression of p-mTOR was observed in all PNL with lower expression in DCIS and invasive carcinoma while the opposite expression pattern was observed for TOP2A.Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively. Furthermore, HER2 expression showed the best concordance between DCIS and its invasive counterpart.We propose that these biomarkers can be used to improve the management of patients with pre-invasive breast lesions following further validation and clinical trials. p53 and Ki67 could be used to stratify patients into low and high-risk groups for co-existing disease. Knowledge of expression of more actionable targets such as HER2 or TOP2A can be used to design chemoprevention or neo-adjuvant strategies. Increased knowledge of the molecular profile of pre-invasive lesions can only serve to enhance our understanding of the disease and, in the era of personalised medicine, bring us closer to improving breast cancer care.

An Evaluation of the Dual Diagnosis (substance use and mental health )Strategy in the South Eastern Trust Workers and Service Users Perceptions of Dual Diagnosis Issues

In the UK it is estimated that over 33% of psychiatric patients with enduring mental illness have a substance misuse problem, whilst over 50 % of clients currently accessing drug and alcohol services have a mental health problem. Between 2003 and 2013 in Northern Ireland, there were 741 recorded suicides by patients who were in contact with mental health services. Of this number, 68% (n=501) had a history of either alcohol or drug misuse or both, resulting in an average of 46 patient suicides per year associated with dual diagnosis (University of Manchester 2015).
The current evaluation examined staff attitudes towards working with dual diagnosis (co-existing difficulties) issues, staff confidence in working with clients with dual diagnosis, workers’ perceptions of the South Eastern dual diagnosis strategy and service user perspectives of dual diagnosis service provision.
The purpose of the evaluation was to provide evidence regarding the following in accordance with the current dual diagnosis strategy;
Staff understanding of the concept of dual diagnosis,
Staff attitudes towards working with dual diagnosis,
Staff confidence in working with individuals, who present with dual diagnosis,
Service users’ perspectives of SE Trust provision for dual diagnosis.
Staff views on the South Eastern Trust Dual Diagnosis Strategy.

The influence of multimorbidity on hospital, intensive care, and emergency department use at the end of life for patients with chronic conditions

Thesis (Master's)--University of Washington, 2016-03

Microcystin-LR detection in water by the Fabry–Pérot interferometer using an optical fibre coated with a sol–gel imprinted sensing membrane

Cyanobacteria deteriorate the water quality and are responsible for emerging outbreaks and epidemics causing harmful diseases in Humans and animals because of their toxins. Microcystin-LR (MCT) is one of the most relevant cyanotoxin, being the most widely studied hepatotoxin. For safety purposes, the World Health Organization recommends a maximum value of 1 μg L−1 of MCT in drinking water. Therefore, there is a great demand for remote and real-time sensing techniques to detect and quantify MCT. In this work a Fabry–Pérot sensing probe based on an optical fibre tip coated with a MCT selective thin film is presented. The membranes were developed by imprinting MCT in a sol–gel matrix that was applied over the tip of the fibre by dip coating. The imprinting effect was obtained by curing the sol–gel membrane, prepared with (3-aminopropyl) trimethoxysilane (APTMS), diphenyl-dimethoxysilane (DPDMS), tetraethoxysilane (TEOS), in the presence of MCT. The imprinting effect was tested by preparing a similar membrane without template. In general, the fibre Fabry–Pérot with a Molecular Imprinted Polymer (MIP) sensor showed low thermal effect, thus avoiding the need of temperature control in field applications. It presented a linear response to MCT concentration within 0.3–1.4 μg L−1 with a sensitivity of −12.4 ± 0.7 nm L μg−1. The corresponding Non-Imprinted Polymer (NIP) displayed linear behaviour for the same MCT concentration range, but with much less sensitivity, of −5.9 ± 0.2 nm L μg−1. The method shows excellent selectivity for MCT against other species co-existing with the analyte in environmental waters. It was successfully applied to the determination of MCT in contaminated samples. The main advantages of the proposed optical sensor include high sensitivity and specificity, low-cost, robustness, easy preparation and preservation.

The structural effects of divalent cations and insulin on phospholipid model membranes /

It is well accepted that structural studies with model membranes are of considerable value in understanding the structure of biological membranes. Many studies with models of pure phospholipids have been done; but the effects of divalent cations and protein on these models would make these studies more applicable to intact membrane. The present study, performed with above view, is a structural analysis of divalent io~cardio1ipin complexes using the technique of x-ray diffraction. Cardiolipin, precipitated from dilute solution by divalent ionscalcium, magnesium and barium, contains little water and the structure formed is similar to the structure of pure cardiolipin with low water content. The calcium-cardiolipin complex forms a pure hexagonal type II phase that exists from 40 to 400 C. The molar ratio of calcium and cardiolipin in the complex is 1 : 1. Cardiolipin, precipitated with magnesium and barium forms two co-existing phases, lamellar and hexagonal, the relative quantity of the two phases being dependent on temperature. The hexagonal phase type II consisting of water filled channels formed by adding calcium to cardiolipin may have a remarkable permeability property in intact membrane. Pure cardiolipin and insulin at pH 3.0 and 4.0 precipitate but form no organised structure. Lecithin/cardiolipin and insulin precipitated at pH 3.0 give a pure lamellar phase. As the lecithin/cardiolipin molar ratio changes from 93/7 to SO/50, (a) the repeat distance of the lamellar changes from 72.8 X to 68.2 A; (b) the amount of protein bound increases in such a way that cardiolipin/insulin molar ratio in the complex reaches a maximum constant value at lecithin/cardiolipin molar ratio 70/30. A structural model based on these data shows that the molecular arrangement of lipid and protein is a lipid bilayer coated with protein molecules. The lipid-protein interaction is chiefly electrostatic and little, if any, hydrophobic bonding occurs in this particular system. So, the proposed model is essentially the same as Davson-Daniellifs model of biological membrane.

Relationship Building with Aboriginal Elders in the Publicly Funded Secondary School Classroom: A Study of Ethical Space from an Aboriginal Persepective

This is a current story of ethical space in education that is often neglected in the design of educational experiences for Aboriginal students. This story is told through an Aboriginal lens rooted in the structured Two Row Wampum Belt relational agreement between Aboriginal peoples and Settlers. Through ethnographic narrative based on an extensive literature review, individual in-depth interviews, and a personal journal, this study documents the processes of acceptance, silence, complications, and then rejection to position Aboriginal Elders as inclusive bodies of knowledge in publicly funded secondary school classrooms. Aboriginal Elders are valued as Knowledge Holders, as Aboriginal teachers, guides, and mentors. Yet, the complexities of colonial rights, politics, and policies continue to intrude deeply into the lives of Aboriginal peoples to cause silence, confusion, and struggle rather than an evolution of new knowledge amongst two co-existing solitudes under the original terms of the Two Row Wampum Belt. The study was delayed and then came to an end when the school boards and local schools scrutinized its operating policies and unresolved funding issues. This study demonstrated that despite the Two Row Wampum Belt agreement that promised a co- existent relationship between Aboriginal peoples and Settlers, the strategy of inviting Aboriginal Elders to work alongside teachers in the classroom was viewed as being in conflict with the Settler’s institutional/educational objectivities, and, as such, was denied to Aboriginal students.

Portrait du journalisme à la pige à l’heure de la convergence

Cette recherche explore le journalisme indépendant dans le contexte contemporain de convergences socio-techno-médiatiques. Je questionne ici l’existence d’un lien entre les pratiques de pige et de convergence en journalisme et son apport dans le développement de l’univers journalistique. Il s’agit d’une étude exploratoire et empirique, consacrée aux expériences des journalistes indépendants et développée autour des concepts de tactique, résistance, liberté et gouvernance. J’ai constitué ainsi un cadre théorique à partir de l’articulation théorique de Michel Foucault relative au pouvoir. Je défends l’idée selon laquelle la pige et la convergence en journalisme sont chacun des mouvements libres qui coexistent et qui, ensemble, constituent une force motrice pour le dispositif de pouvoir que le journalisme représente dans un système démocratique avancé. La liberté de mouvement des journalistes indépendants leur permet de mener plus loin le journalisme dans le contexte actuel de convergences et d’augmenter l’horizon d’applicabilité de ce domaine de la communication de masse.

La poétique du roman historique de Eveline Hasler

À l'aide des tout derniers modèles narratologiques développés entre autres par Ansgar Nünning, nous nous penchons sur l'oeuvre d'Eveline Hasler, une voix phare de la littérature alémanique contemporaine. À partir d’un corpus de six romans, nous examinons de façon systématique sa poétique du roman historique au regard 1) des techniques narratives, 2) de la marginalité de ses personnages en société, 3) de la conception de l’Histoire, 4) de l'image critique qu'elle présente de la Suisse. Il en ressort un portrait très nuancé de l'oeuvre de Hasler, puisqu’elle allie un récit principalement réaliste, plutôt traditionnel, mais aussi inspiré du langage cinématographique, à des passages métahistoriographiques postmodernes, où une narratrice assimilable à l’auteure fait part au « je » de ses réflexions sur l'Histoire. Même si ces brefs passages relativement rares rappellent sans contredit la posture de l’historien, ils s’inscrivent toutefois dans la fiction, laquelle actualise le passé dans la perspective historique d’un lecteur contemporain. De fait, l’œuvre de Hasler se présente comme un jeu habile avec la liberté poétique et le souci de véracité historique, ce à quoi concourt l’imbrication de documents originaux en italique dans le roman. Par ailleurs, la question de la marginalité en société joue un rôle prépondérant chez Hasler, car tous ses personnages principaux sont autant de marginaux, de Außenseiter. Cette problématique montre entre autres les limites de l’Aufklärung, étant donné que ses tenants, les adversaires des marginaux, se targuent le plus souvent d’être motivés par la pensée éclairante pour mieux la pervertir. Il en résulte la mise à l’écart des individus dérangeants — la prétendue sorcière, le géant et les femmes qui remettent en cause l’organisation patriarcale. Or, certains marginaux de Hasler parviennent à s’arracher un espace de liberté dans la marge, au prix de leurs racines helvétiques. Ainsi, ces marginaux peinent à s’inscrire dans l’Histoire dite officielle, ce que Hasler tente de rectifier en leur redonnant une voix. Sur le plan individuel, la plupart d’entre eux expérimentent une évolution circulaire, puisqu’ils ne parviennent pas à sortir de la marge (sauf peut-être Henry Dunant). Cette impression de tourner en rond s’oppose à une conception de l’Histoire humaine qui se déroule en continuum, puisque les exclusions d’hier préfigurent celles d’aujourd’hui. Au-delà de cette mesure humaine du temps, l’horizon temporel de la nature s’inscrit pour sa part dans la permanence. Ainsi, Hasler développe une conception historique qui varie selon des points de vue coexistants. Cet amalgame est le plus souvent marqué par un certain pessimisme, comme le dénote la vie d’Emily Kempin associée au mythe d’Icare. Finalement, tous les acteurs historiques de Hasler appartiennent au contexte helvétique et en présentent une image assez rétrograde, laquelle se dévoile non seulement à travers la fictionnalisation des lieux, mais aussi par des références à trois symboles nationaux : les Alpes, le réduit helvétique et la légende de Guillaume Tell. Hasler fait le procès de ces mythes, associés à la liberté et à la sauvegarde de ce « peuple de bergers », en montrant que la Suisse n’apporte pas de solution originale aux défis de l’Occident.

A retrospective study of cholinesterase inhibitors for Alzheimer's disease : the effect of cerebrovascular disease on patient outcomes and the impact of biases on the results.

Introduction: La démence peut être causée par la maladie d’Alzheimer (MA), la maladie cérébrovasculaire (MCEREV), ou une combinaison des deux. Lorsque la maladie cérébrovasculaire est associée à la démence, les chances de survie sont considérées réduites. Il reste à démontrer si le traitement avec des inhibiteurs de la cholinestérase (ChEIs), qui améliore les symptômes cognitifs et la fonction globale chez les patients atteints de la MA, agit aussi sur les formes vasculaires de démence. Objectifs: La présente étude a été conçue pour déterminer si la coexistence d’une MCEREV était associée avec les chances de survie ou la durée de la période jusqu’au placement en hebergement chez les patients atteints de la MA et traités avec des ChEIs. Des études montrant de moins bons résultats chez les patients souffrant de MCEREV que chez ceux n’en souffrant pas pourrait militer contre l’utilisation des ChEIs chez les patients atteints à la fois de la MA et la MCEREV. L'objectif d'une seconde analyse était d'évaluer pour la première fois chez les patients atteints de la MA l'impact potentiel du biais de « temps-immortel » (et de suivi) sur ces résultats (mort ou placement en hebergement). Méthodes: Une étude de cohorte rétrospective a été conduite en utilisant les bases de données de la Régie de l’Assurance Maladie du Québec (RAMQ) pour examiner la durée de la période jusqu’au placement en hebergement ou jusqu’au v décès des patients atteints de la MA, âgés de 66 ans et plus, avec ou sans MCEREV, et traités avec des ChEIs entre le 1er Juillet 2000 et le 30 Juin 2003. Puisque les ChEIs sont uniquement indiquées pour la MA au Canada, chaque prescription de ChEIs a été considérée comme un diagnostic de la MA. La MCEREV concomitante a été identifié sur la base d'un diagnostic à vie d’un accident vasculaire cérébral (AVC) ou d’une endartériectomie, ou d’un diagnostic d'un accident ischémique transitoire au cours des six mois précédant la date d’entrée. Des analyses séparées ont été conduites pour les patients utilisant les ChEIs de façon persistante et pour ceux ayant interrompu la thérapie. Sept modèles de régression à risque proportionnel de Cox qui ont varié par rapport à la définition de la date d’entrée (début du suivi) et à la durée du suivi ont été utilisés pour évaluer l'impact du biais de temps-immortel. Résultats: 4,428 patients ont répondu aux critères d’inclusion pour la MA avec MCEREV; le groupe de patients souffrant seulement de la MA comptait 13,512 individus. Pour le critère d’évaluation composite considérant la durée de la période jusqu’au placement en hebergement ou jusqu’au décès, les taux de survie à 1,000 jours étaient plus faibles parmi les patients atteints de la MA avec MCEREV que parmi ceux atteints seulement de la MA (p<0.01), mais les différences absolues étaient très faibles (84% vs. 86% pour l’utilisation continue de ChEIs ; 77% vs. 78% pour la thérapie avec ChEIs interrompue). Pour les critères d’évaluation secondaires, la période jusqu’au décès était plus courte chez les patients avec la MCEREV que sans la MCEREV, mais la période jusqu’au vi placement en hebergement n’était pas différente entre les deux groupes. Dans l'analyse primaire (non-biaisée), aucune association a été trouvée entre le type de ChEI et la mort ou le placement en maison d'hébergement. Cependant, après l'introduction du biais de temps-immortel, on a observé un fort effet différentiel. Limitations: Les résultats peuvent avoir été affectés par le biais de sélection (classification impropre), par les différences entre les groupes en termes de consommation de tabac et d’indice de masse corporelle (ces informations n’étaient pas disponibles dans les bases de données de la RAMQ) et de durée de la thérapie avec les ChEIs. Conclusions: Les associations entre la coexistence d’une MCEREV et la durée de la période jusqu’au placement en hebergement ou au décès apparaissent peu pertinentes cliniquement parmi les patients atteints de la MA traités avec des ChEIs. L’absence de différence entre les patients atteints de la MA souffrant ou non de la MCEREV suggère que la coexistence d’une MCEREV ne devrait pas être une raison de refuser aux patients atteints de la MA l’accès au traitement avec des ChEIs. Le calcul des « personne-temps » non exposés dans l'analyse élimine les estimations biaisées de l'efficacité des médicaments.

Self-Assembly of Stimuli-Responsive Water-Soluble [60]Fullerene End-Capped Ampholytic Block Copolymer

Well-defined, water-soluble, pH and temperature stimuli-responsive [60]fullerene (C₆₀) containing ampholytic block copolymer of poly((methacrylic acid)-block-(2-(dimethylamino)ethyl methacrylate))-block–C₆₀ (P(MAA-b-DMAEMA)-b-C₆₀) was synthesized by the atom transfer radical polymerization (ATRP) technique. The self-assembly behaviour of the C₆₀ containing polyampholyte in aqueous solution was characterized by dynamic light scattering (DLS), and transmission electron microscopy. This amphiphilic mono-C₆₀ end-capped block copolymer shows enhanced solubility in aqueous medium at room and elevated temperatures and at low and high pH but phase-separates at intermediate pH of between 5.4 and 8.8. The self assembly of the copolymer is different from that of P(MAA-b-DMAEMA). Examination of the association behavior using DLS revealed the co-existence of unimers and aggregates at low pH at all temperatures studied, with the association being driven by the balance of hydrophobic and electrostatic interactions. Unimers and aggregates of different microstructures are also observed at high pH and at temperatures below the lower critical solution temperature (LCST) of PDMAEMA. At high pH and at temperatures above the LCST of PDMAEMA, the formation of micelles and aggregates co-existing in solution is driven by the combination of hydrophobic, electrostatic, and charge-transfer interactions.

What does a transdiagnostic approach have to offer the treatment of anxiety disorders?

Purpose: The purpose of this paper is to review the rationale for 'transdiagnostic' approaches to the understanding and treatment of anxiety disorders. Methods: Databases searches and examination of the reference lists of relevant studies were used to identify papers of relevance. Results: There is increasing recognition that diagnosis-specific interventions for single anxiety-disorders are of less value than might appear since a large proportion of patients have more than one co-existing anxiety disorder and the treatment of one anxiety disorder does not necessarily lead to the resolution of others. As transdiagnostic approaches have the potential to address multiple co-existing anxiety disorders they are potentially more clinically relevant than single anxiety disorder interventions. They may also have advantages in ease of dissemination and in treating anxiety disorder not otherwise specified. Conclusions: The merits of the various transdiagnostic cognitive-behavioral approaches that have been proposed are reviewed. Such approaches have potential benefits, particularly in striking the balance between completely idiosyncratic formulations and diagnosis-driven treatments of anxiety disorders. However, caution is needed to ensure that transdiagnostic theories and treatments benefit from progress made by research on diagnosis-specific treatments, and further empirical work is needed to identify the shared maintaining processes that need to be targeted in the treatment of anxiety disorders.

'Eden Cinema' by Marguerite Duras

Duras’s theatre work has been profoundly neglected by UK theatre academics and practitioners, and Eden Cinema has almost no performance history in Britain. My project asked three interconnected research questions: how developing the performance contributes to understanding Duras’s theatre and specifically Eden Cinema’s problems of performability; how multimedia performance emphasising mediated sound and the live body reconfigures memory, autobiography, storytelling, gender and racial identity; how to locate a performance style appropriate for Durasian narratives of displacement and death which reflect the discontinuous and mutable form of Duras’s ‘texte/film/théâtre’. Drawing on my research interests in gender, post-colonial hybridity and performed deconstruction, I focused my staging decisions on the discontinuities and ambivalences of the text. I addressed performability by avoiding the temptation to resolve the strange ellipses in the text and instead evoked the text’s imperfect and fragmented memories, and its uncertain spatial and temporal locations, by means of a fluid theatrical form. The mise-en-scène represented imagined and remembered spaces simultaneously, and co-existing historical moments. The performance style counterpointed live and mediated action and audio-visual forms. A complex through-composed soundscape, comprising voice-over, sound and music, became a key means for evoking overlapping temporalities, interconnected narratives and fragmented memories that were dispersed across the performance. The disempowerment of the mother figure and the silent indigenous servant in the text was demonstrated through their spatial centrality but physical stillness. The servant’s colonial subaltern identity was paralleled and linked with the mother’s disenfranchisement through their proxemic relationships. I elicited a performance style which evoked ‘characters’, whose being was deferred across different regimes of reality and who ‘haunted’ the stage rather than inhabited it. I developed the project further in the additional written outcomes and presentations, and the subsequent performance of Savannah Bay where problems of performability intensify until embodiment is almost erased except via voice.

Contribution of the geriatrician to the management of cancer in older patients

With an increasingly aged population, many patients will present with cancer in their 80s and 90s. Although some may be very fit, frail individuals will require the input of geriatricians to aid in the assessment of co-existing morbidity, in an attempt to assess those most likely to benefit from active treatment of their cancer, and those in whom the ‘giants of geriatric medicine’ require special consideration before undergoing definitive cancer therapy. The role of the geriatrician in assessment and management of such patients, together with communication and end of life care, may be more important in ensuring a good quality of life, than the cancer therapy itself. Whilst numbers of geriatricians will not be adequate to care for all elderly patients with cancer, a variety of assessment scales will help target financial and manpower resources to those most at risk.

”Jag tror på något” : Konstruktioner av tro och tilltro

”I believe in something”: Constructions of Beliefs in Sweden Research results are dependent on how social phenomena are conceptualized. In the present article, consequences are discussed of the standardized conceptualization of religiosity as ”church-oriented”. In its place, a multifaceted approach to the phenomenon of religious belief is suggested. This approach was used for an analysis on how eleven Swedish women and men with different religious and spiritual as well as non-religious and atheist affiliation talk about beliefs. The results suggest that beliefs were meaningful because they related to specific perceptions of a Zeitgeist. It was hereafter underlined that belief in ”something” or other brief descriptions of the sacred placed the sacred outside of the individual. Finally, while subjective authority is valued for choosing to believe, this subjectivity seems in part to be dependent on collective dimensions of recognition. The value of choosing beliefs can be conceptualized as a meaningful yet analytically distinct aspect of belief co-existing with descriptions of the sacred. Thus, it is concluded that a multifaceted approach to religious belief may develop our understanding of religion and religiosity in contemporary society

Spectrum of carcinoembryonic antigen immunoreactivity from isolated ductal hyperplasias to atypical hyperplasias associated with infiltrating ductal breast cancer

Aims - To study the immunohistochemical expression of carcinoembryonic antigen (CEA) in ductal hyperplasia of the breast and to investigate its putative relation with atypia and co-existing infiltrating ductal carcinoma.Methods - Paraffin wax embedded tissue from 37 cases of isolated ductal hyperplasia (five with atypia and 32 without atypia) and 25 cases of ductal hyperplasia associated infiltrating ductal carcinoma (IDC) (seven with atypia and 18 without atypia) was stained with a monoclonal anti-CEA antibody using a standard avidin biotin immunoperoxidase method.Results - CEA immunoreactivity was observed in eight (12.8%) ductal hyperplasia cases. The percentage of CEA positivity in ductal hyperplasia cases with atypia (33.3%) was substantially higher than that observed in cases of ductal hyperplasia without atypia (8.0%). Six cases of ductal hyperplasia associated IDC reacted with CEA; in these six cases the neoplastic cells of the co-existing carcinoma were also CEA positive. The percentage of CEA immunoreactivity in ductal hyperplasia associated IDC was higher than that observed in isolated ductal hyperplasia (24.0 v 5.4%). The percentage of CEA immunoreactivity in atypical ductal hyperplasia associated IDC was similar to that observed in IDC alone (42.9 v 40.0%).Conclusions-The presence of CEA immunoreactivity has been confirmed in benign proliferative breast lesions. The prevalence of such immunoreactivity increases from 3.1% in isolated, nonatypical ductal hyperplasia to 42.9% in atypical ductal hyperplasia associated IDC. This finding and the similarity of the frequency of CEA positivity in atypical ductal hyperplasia associated IDC and in IDC alone suggests that there is a pathogenetic link between ductal hyperplasia and some types of breast cancer.