Merkel cell polyomavirus-specific CD8 T cells in Merkel cell carcinoma: T cell receptor diversity & novel immune therapies

Thesis (Ph.D.)--University of Washington, 2016-06

Are diagnosis specific outcome indicators based on administrative data useful in assessing quality of hospital care?

Background: Hospital performance reports based on administrative data should distinguish differences in quality of care between hospitals from case mix related variation and random error effects. A study was undertaken to determine which of 12 diagnosis-outcome indicators measured across all hospitals in one state had significant risk adjusted systematic ( or special cause) variation (SV) suggesting differences in quality of care. For those that did, we determined whether SV persists within hospital peer groups, whether indicator results correlate at the individual hospital level, and how many adverse outcomes would be avoided if all hospitals achieved indicator values equal to the best performing 20% of hospitals. Methods: All patients admitted during a 12 month period to 180 acute care hospitals in Queensland, Australia with heart failure (n = 5745), acute myocardial infarction ( AMI) ( n = 3427), or stroke ( n = 2955) were entered into the study. Outcomes comprised in-hospital deaths, long hospital stays, and 30 day readmissions. Regression models produced standardised, risk adjusted diagnosis specific outcome event ratios for each hospital. Systematic and random variation in ratio distributions for each indicator were then apportioned using hierarchical statistical models. Results: Only five of 12 (42%) diagnosis-outcome indicators showed significant SV across all hospitals ( long stays and same diagnosis readmissions for heart failure; in-hospital deaths and same diagnosis readmissions for AMI; and in-hospital deaths for stroke). Significant SV was only seen for two indicators within hospital peer groups ( same diagnosis readmissions for heart failure in tertiary hospitals and inhospital mortality for AMI in community hospitals). Only two pairs of indicators showed significant correlation. If all hospitals emulated the best performers, at least 20% of AMI and stroke deaths, heart failure long stays, and heart failure and AMI readmissions could be avoided. Conclusions: Diagnosis-outcome indicators based on administrative data require validation as markers of significant risk adjusted SV. Validated indicators allow quantification of realisable outcome benefits if all hospitals achieved best performer levels. The overall level of quality of care within single institutions cannot be inferred from the results of one or a few indicators.

Why does dissimilarity matter? Exploring self-categorization, self-enhancement, and uncertainty reduction

Although relational demographers have based their arguments on self-categorization theory, they have paid little attention to the underlying processes associated with this theory. The authors examined whether demographic dissimilarity affects individuals' identification with groups by affecting the group's prototype valence and clarity and the individual's perceptions of self-prototypicality. The data showed that the proportion of women and non-Australians in 34 work groups negatively influenced prototype valence, prototype clarity, and self-prototypicality for all members of the group. These results provide support for the continued use of self-categorization theory by relational demographers.

Personality disorders in the community: Results from the Australian National Survey of Mental Health and Well-Being Part III - Relationships between specific type of personality disorder, Axis 1 mental disorders and physical conditions with disability and health consultations

Background The aims of this study were threefold. First, to ascertain whether personality disorder (PD) was a significant predictor of disability (as measured in a variety of ways) over and above that contributed by Axis I mental disorders and physical conditions. Second, whether the number of PD diagnoses given to an individual resulted in increasing severity of disability, and third, whether PD was a significant predictor of health and mental health consultations with GPs, psychiatrists, and psychologists, respectively, over the last 12 months. Method Data were obtained from the National Survey of Mental Health and Wellbeing, conducted between May and August 1997. A stratified random sample of households was generated, from which all those aged 18 and over were considered potential interviewees. There were 10 641 respondents to the survey, and this represented a response rate of 78%. Each interviewee was asked questions indexing specific ICD-10 PD criteria. Results Five measures of disability were examined. It was found that PD was a significant predictor of disability once Axis I and physical conditions were taken into account for four of the five disability measures. For three of the dichotomously-scored disability measures, odds ratios ranged from 1.88 to 6.32 for PD, whilst for the dimensionally-scored Mental Summary Subscale of the SF-12, a beta weight of -0.17 was recorded for PD. As regards number of PDs having a quasi-linear relationship to disability, there was some indication of this on the SF-12 Mental Summary Subscale and the two role functioning measures, and less so on the other two measures. As regards mental consultations, PD was a predictor of visits to GPs, psychiatrists and psychologists, over and above Axis I disorders and physical conditions. Conclusion The study reports findings from a nationwide survey conducted within Australia and as such the data are less influenced by the selection and setting bias inherent in other germane studies. However, it does support previous findings that PD is a significant predictor of disability and mental health consultations independent of Axis I disorders and physical conditions.

Estimates of sex- and age-class-specific survival probabilities for a southern Great Barrier Reef green sea turtle population

Sex- and age-class-specific survival probabilities of a southern Great Barrier Reef green sea turtle population were estimated using a capture - mark - recapture (CMR) study and a Cormack - Jolly - Seber (CJS) modelling approach. The CMR history profiles for 954 individual turtles tagged over a 9-year period ( 1984 - 1992) were classified into three age classes ( adult, subadult, juvenile) based on somatic growth and reproductive traits. Reduced-parameter CJS models, accounting for constant survival and time-specific recapture, fitted best for all age classes. There were no significant sex-specific differences in either survival or recapture probabilities for any age class. Mean annual adult survival was estimated at 0.9482 (95% CI: 0.92 - 0.98) and was significantly higher than survival for either subadults or juveniles. Mean annual subadult survival was 0.8474 ( 95% CI: 0.79 - 0.91), which was not significantly different from mean annual juvenile survival estimated at 0.8804 ( 95% CI: 0.84 - 0.93). The time-specific adult recapture probabilities were a function of sampling effort but this was not the case for either juveniles or subadults. The sampling effort effect was accounted for explicitly in the estimation of adult survival and recapture probabilities. These are the first comprehensive sex- and age-class-specific survival and recapture probability estimates for a green sea turtle population derived from a long-term CMR program.

Identification and analysis of venom gland-specific genes from the coastal taipan (Oxyuranus scutellatus) and related species

Australian terrestrial elapid snakes contain amongst the most potently toxic venoms known. However, despite the well-documented clinical effects of snake bite, little research has focussed on individual venom components at the molecular level. To further characterise the components of Australian elapid venoms, a complementary (cDNA) microarray was produced from the venom gland of the coastal taipan (Oxyuranus scutellatus) and subsequently screened for venom gland-specific transcripts. A number of putative toxin genes were identified, including neurotoxins, phospholipases, a pseudechetoxin-like gene, a venom natriuretic peptide and a nerve growth factor together with other genes involved in cellular maintenance. Venom gland-specific components also included a calglandulin-like protein implicated in the secretion of toxins from the gland into the venom. These toxin transcripts were subsequently identified in seven other related snake species, producing a detailed comparative analysis at the cDNA and protein levels. This study represents the most detailed description to date of the cloning and characterisation of different genes associated with envenomation from Australian snakes.

Are you sure? the role of uncertainty in career

Although uncertainty is a fundamental human experience, professionals in the career field have largely overlooked the role that it plays in people's careers. The changed nature of careers has resulted in people experiencing increased uncertainty in their career that is beyond the uncertainty experienced in their job. The author explores the role of uncertainty in people's experience of their careers and examines the implications for career counseling theory and practice. A review of the career theory and career counseling literature indicates that although contemporary approaches have been offered to respond to the changed nature of career, none of the approaches have identified uncertainty as a core part of individuals' experience of their career. The broader literature on uncertainty is then reviewed at the societal, organizational, and individual levels.

Individual calibration for estimating free-living walking speed using the MTI monitor

Purpose: This study was conducted to devise a new individual calibration method to enhance MTI accelerometer estimation of free-living level walking speed. Method: Five female and five male middle-aged adults walked 400 m at 3.5, 4.5, and 5.5 km(.)h(-1), and 800 in at 6.5 km(.)h(-1) on an outdoor track, following a continuous protocol. Lap speed was controlled by a global positioning system (GPS) monitor. MTI counts-to-speed calibration equations were derived for each trial, for each subject for four such trials with each of four MTI, for each subject for the average MTI. and for the pooled data. Standard errors of the estimate (SEE) with and without individual calibration were compared. To assess accuracy of prediction of free-living walking speed, subjects also completed a self-paced, brisk 3-km walk wearing one of the four MTI, and differences between actual and predicted walking speed with and without individual calibration were examined. Results: Correlations between MTI counts and walking speed were 0.90 without individual calibration, 0.98 with individual calibration for the average MTI. and 0.99 with individual calibration for a specific MTI. The SEE (mean +/- SD) was 0.58 +/- 0.30 km(.)h(-1) without individual calibration, 0.19 +/- 0.09 km h(-1) with individual calibration for the average MTI monitor, and 0.16 +/- 0.08 km(.)h(-1) with individual calibration for a specific MTI monitor. The difference between actual and predicted walking speed on the brisk 3-km walk was 0.06 +/- 0.25 km(.)h(-1) using individual calibration and 0.28 +/- 0.63 km(.)h(-1) without individual calibration (for specific accelerometers). Conclusion: MTI accuracy in predicting walking speed without individual calibration might be sufficient for population-based studies but not for intervention trials. This individual calibration method will substantially increase precision of walking speed predicted from MTI counts.

Individual or population approaches to the promotion of physical activity... is that the question?

A recent editorial raised several issues about the role of exercise physiologists in the fight against physical inactivity in Australia. This opinion piece argues that we must strive to work together in multidisciplinary groups to improve our understanding of the mechanisms which link PA and health and the ways to persuade people to become more active. Prescription of specific exercise programs supported by exercise physiologists is one strategy for helping to activate Australians, but it is unlikely that that this atone will have a significant impact on population health. If we are to activate the 10,000,000 Australians who are currently insufficiently active for health benefit, we will need the combined efforts of governments, NGOs, teachers, planners, marketing experts, veterinarians, and ALL our health professionals, to combine forces to activate Australia. (c) 2006 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

UMA ANÁLISE DOS CÂNTICOS ENTOADOS PELA COMUNIDADE CARISMA E SUAS INFLUÊNCIAS, NO INDIVIDUAL E NO COLETIVO, DIANTE DA TRANSFORMAÇÃO SOCIAL

A curiosidade do que acontece com os cânticos entoados pela comunidade carisma e a maneira com que toca as pessoas, no âmbito individual e no coletivo foi o que gerou essa pesquisa. A associação do significado das letras dos cânticos relacionado à transformação social que acontece dentro do trabalho e missão social urbana da Comunidade Carisma acabou sendo o foco desse trabalho. Sabe-se que a música tem um poder imenso de atuar na área emocional e nas experiências do ser humano, atuando tanto no individual, quanto no coletivo da pessoa. Então, até que ponto, música não é uma alienação, mas sim um instrumento de despertar individual e coletivamente - para a transformação e a aplicabilidade de todo este envolvimento social que a Comunidade Carisma vive? Dentro do que é a base teológica da comunidade, a ordem do culto e toda a sua liturgia, foi feito um levantamento de toda estrutura da mesma. E como se processa o louvor e o significado das letras dos cânticos compostos por membros deste ministério, com a ação que começa no individual, reporta-se ao coletivo e que gera transformação social dentro e fora da comunidade.(AU)

A specific and rapid neural signature for parental instinct

Darwin originally pointed out that there is something about infants which prompts adults to respond to and care for them, in order to increase individual fitness, i.e. reproductive success, via increased survivorship of one's own offspring. Lorenz proposed that it is the specific structure of the infant face that serves to elicit these parental responses, but the biological basis for this remains elusive. Here, we investigated whether adults show specific brain responses to unfamiliar infant faces compared to adult faces, where the infant and adult faces had been carefully matched across the two groups for emotional valence and arousal, as well as size and luminosity. The faces also matched closely in terms of attractiveness. Using magnetoencephalography (MEG) in adults, we found that highly specific brain activity occurred within a seventh of a second in response to unfamiliar infant faces but not to adult faces. This activity occurred in the medial orbitofrontal cortex (mOFC), an area implicated in reward behaviour, suggesting for the first time a neural basis for this vital evolutionary process. We found a peak in activity first in mOFC and then in the right fusiform face area (FFA). In mOFC the first significant peak (p<0.001) in differences in power between infant and adult faces was found at around 130 ms in the 10-15 Hz band. These early differences were not found in the FFA. In contrast, differences in power were found later, at around 165 ms, in a different band (20-25 Hz) in the right FFA, suggesting a feedback effect from mOFC. These findings provide evidence in humans of a potential brain basis for the "innate releasing mechanisms" described by Lorenz for affection and nurturing of young infants. This has potentially important clinical applications in relation to postnatal depression, and could provide opportunities for early identification of families at risk.

Tailoring treatment to the individual in type 2 diabetes practical guidance from the Global Partnership for Effective Diabetes Management

Good glycaemic control continues to be the most effective therapeutic manoeuvre to reduce the risk of development and/or progression of microvascular disease, and therefore remains the cornerstone of diabetes management despite recent scepticism about tight glucose control strategies. The impact on macrovascular complications is still a matter of debate, and so glycaemic control strategies should be placed in the context of multifactorial intervention to address all cardiovascular risk factors. Approaches to achieve glycaemic targets should always ensure patient safety, and results from recent landmark outcome studies support the need for appropriate individualisation of glycaemic targets and of the means to achieve these targets, with the ultimate aim to optimise outcomes and minimise adverse events, such as hypoglycaemia and marked weight gain. The primary goal of the Global Partnership for Effective Diabetes Management is the provision of practical guidance to improve patient outcomes and, in this article, we aim to support healthcare professionals in appropriately tailoring type 2 diabetes treatment to the individual. Patient groups requiring special consideration are identified, including newly diagnosed individuals with type 2 diabetes but no complications, individuals with a history of inadequate glycaemic control, those with a history of cardiovascular disease, children and individuals at risk of hypoglycaemia. Practical guidance specific to each group is provided.

Web based expert elicitation of uncertainties in environmental model inputs

When constructing and using environmental models, it is typical that many of the inputs to the models will not be known perfectly. In some cases, it will be possible to make observations, or occasionally physics-based uncertainty propagation, to ascertain the uncertainty on these inputs. However, such observations are often either not available or even possible, and another approach to characterising the uncertainty on the inputs must be sought. Even when observations are available, if the analysis is being carried out within a Bayesian framework then prior distributions will have to be specified. One option for gathering or at least estimating this information is to employ expert elicitation. Expert elicitation is well studied within statistics and psychology and involves the assessment of the beliefs of a group of experts about an uncertain quantity, (for example an input / parameter within a model), typically in terms of obtaining a probability distribution. One of the challenges in expert elicitation is to minimise the biases that might enter into the judgements made by the individual experts, and then to come to a consensus decision within the group of experts. Effort is made in the elicitation exercise to prevent biases clouding the judgements through well-devised questioning schemes. It is also important that, when reaching a consensus, the experts are exposed to the knowledge of the others in the group. Within the FP7 UncertWeb project (http://www.uncertweb.org/), there is a requirement to build a Webbased tool for expert elicitation. In this paper, we discuss some of the issues of building a Web-based elicitation system - both the technological aspects and the statistical and scientific issues. In particular, we demonstrate two tools: a Web-based system for the elicitation of continuous random variables and a system designed to elicit uncertainty about categorical random variables in the setting of landcover classification uncertainty. The first of these examples is a generic tool developed to elicit uncertainty about univariate continuous random variables. It is designed to be used within an application context and extends the existing SHELF method, adding a web interface and access to metadata. The tool is developed so that it can be readily integrated with environmental models exposed as web services. The second example was developed for the TREES-3 initiative which monitors tropical landcover change through ground-truthing at confluence points. It allows experts to validate the accuracy of automated landcover classifications using site-specific imagery and local knowledge. Experts may provide uncertainty information at various levels: from a general rating of their confidence in a site validation to a numerical ranking of the possible landcover types within a segment. A key challenge in the web based setting is the design of the user interface and the method of interacting between the problem owner and the problem experts. We show the workflow of the elicitation tool, and show how we can represent the final elicited distributions and confusion matrices using UncertML, ready for integration into uncertainty enabled workflows.We also show how the metadata associated with the elicitation exercise is captured and can be referenced from the elicited result, providing crucial lineage information and thus traceability in the decision making process.

The individual and society in the GDR under Honecker : orthodoxy, dissidence and internal debate.

The thesis offers a comparative interdisciplinary approach to the examination of the intellectual debates about the relationship between individual and society in the GDR under Honecker. It shows that there was not only a continuum of debate between the academic disciplines, but also from the radical critics of the GDR leadership such as Robert Havemann, Rudolf Bahro and Stefan Heym through the social scientists, literary critics and legal theorists working in the academic institutions to theorists close to the GDR leadership. It also shows that the official line and policy of the ruling party itself on the question of the individual and society was not static over the period, but changed in response to internal and external pressures. Over the period 1971 - 1989 greater emphasis was placed by many intellectuals on the individual, his needs and interests. It was increasingly recognised that conflicts could exist between the individual and society in GDR socialism. Whereas the radical critics argued that these conflicts were due to features of GDR society, such as the hierarchical system of labour functions and bureaucracy, and extrapolated from this a general conflict between the political leadership and population, orthodox critics argued that conflicts existed between a specific individual and society and were largely due to external and historical factors. The internal critics also pointed to the social phenomena which were detrimental to the individual's development in the GDR, but they put forward less radical solutions. With the exception of a few radical young writers, all theorists studied in this thesis gave precedence to social interests over individual interests and so did not advocate a return to `individualistic' positions. The continuity of sometimes quite controversial discussions in the GDR academic journals and the flexibility of the official line and policy suggests that it is inappropriate to refer to GDR society under Honecker simply as totalitarian, although it did have some totalitarian features. What the thesis demonstrates is the existence of `Teiloffentlichkeiten' in which critical discussion is conducted even as the official, orthodox line is given out for public consumption in the high-circulation media.

Individual differences in the sensory perception of fats

Excessive consumption of dietary fat is acknowledged to be a widespread problem linked to a range of medical conditions. Despite this, little is known about the specific sensory appeal held by fats and no previous published research exists concerning human perception of non-textural taste qualities in fats. This research aimed to address whether a taste component can be found in sensory perception of pure fats. It also examined whether individual differences existed in human taste responses to fat, using both aggregated data analysis methods and multidimensional scaling. Results indicated that individuals were able to detect both the primary taste qualities of sweet, salty, sour and bitter in pure processed oils and reliably ascribe their own individually-generated taste labels, suggested that a taste component may be present in human responses to fat. Individual variation appeared to exist, both in the perception of given taste qualities and in perceived intensity and preferences. A number of factors were examined in relation to such individual differences in taste perception, including age, gender, genetic sensitivity to 6-n-propylthiouracil, body mass, dietary preferences and intake, dieting behaviours and restraint. Results revealed that, to varying extents, gender, age, sensitivity to 6-n-propylthiouracil, dietary preferences, habitual dietary intake and restraint all appeared to be related to individual variation in taste responses to fat. However, in general, these differences appeared to exist in the form of differing preferences and levels of intensity with which taste qualities detected in fat were perceived, as opposed to the perception of specific taste qualities being associated with given traits or states. Equally, each of these factors appeared to exert only a limited influence upon variation in sensory responses and thus the potential for using taste responses to fats as a marker for issues such as over-consumption, obesity or eating disorder is at present limited.