Impact of an Interactive On-line Tool on Therapeutic Decision-Making for Patients with Advanced Non-Small-Cell Lung Cancer

Background:Treatment guidelines provide recommendations but cannot account for the wide variability in patient-tumor characteristics in individual patients. We developed an on-line interactive decision tool to provide expert recommendations for specific patient scenarios in the first-line and maintenance settings for advanced non–small-cell lung cancer. We sought to determine how providing expert feedback would influence clinical decision-making.Method:Five lung cancer experts selected treatment for 96 different patient cases based on patient and/or tumor-specific features. These data were used to develop an on-line decision tool. Participant physicians entered variables for their patient scenario with treatment choices, and then received expert treatment recommendations for that scenario. To determine the impact on decision-making, users were asked whether the expert feedback impacted their original plan.Results:A total of 442 individual physicians, of which 88% were from outside the United States, entered 653 cases, with report on impact in 389 cases. Expert feedback affected treatment choice in 73% of cases (23% changed and 50% confirmed decisions). For cases with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion, all experts selected targeted therapy whereas 51% and 58% of participants did not. Greater variability was seen between experts and participants for cases involving EGFR or ALK wild-type tumors. Participants were 2.5-fold more likely to change to expert recommended therapy for ALK fusions than for EGFR mutations (p = 0.017).Conclusion:This online tool for treatment decision-making resulted in a positive influence on clinician's decisions. This approach offers opportunities for improving quality of care and meets an educational need in application of new therapeutic paradigms

Modelling Cognitive Decline in the Hypertension in the Very Elderly Trial [HYVET] and Proposed Risk Tables for Population Use

Although, on average, cognition declines with age, cognition in older adults is a dynamic process. Hypertension is associated with greater decline in cognition with age, but whether treatment of hypertension affects this is uncertain. Here, we modelled dynamics of cognition in relation to the treatment of hypertension, to see if treatment effects might better be discerned by a model that included baseline measures of cognition and consequent mortalityThis is a secondary analysis of the Hypertension in the Very Elderly Trial (HYVET), a double blind, placebo controlled trial of indapamide, with or without perindopril, in people aged 80+ years at enrollment. Cognitive states were defined in relation to errors on the Mini-Mental State Examination, with more errors signifying worse cognition. Change in cognitive state was evaluated using a dynamic model of cognitive transition. In the model, the probabilities of transitions between cognitive states is represented by a Poisson distribution, with the Poisson mean dependent on the baseline cognitive state. The dynamic model of cognitive transition was good (R(2) = 0.74) both for those on placebo and (0.86) for those on active treatment. The probability of maintaining cognitive function, based on baseline function, was slightly higher in the actively treated group (e.g., for those with the fewest baseline errors, the chance of staying in that state was 63% for those on treatment, compared with 60% for those on placebo). Outcomes at two and four years could be predicted based on the initial state and treatment.A dynamic model of cognition that allows all outcomes (cognitive worsening, stability improvement or death) to be categorized simultaneously detected small but consistent differences between treatment and control groups (in favour of treatment) amongst very elderly people treated for hypertension. The model showed good fit, and suggests that most change in cognition in very elderly people is small, and depends on their baseline state and on treatment. Additional work is needed to understand whether this modelling approach is well suited to the valuation of small effects, especially in the face of mortality differences between treatment groups.ClinicalTrials.gov NCT0012281

The Communist Party and the New Party

This is an Author's Accepted Manuscript of an article published in Contemporary British History, vol. 23(4), 2009, pp.477-491 copyright Taylor & Francis, available online at: http://www.tandfonline.com/doi/full/10.1080/13619460903198101The New Party was never at the centre of the concerns of the Communist Party of Great Britain (CPGB). However, the CPGB had to take a line on the new organisation when it was formed, and tried to use it to smear Labour and Independent Labour Party politicians as enemies of the working class. As the 1931 political crisis unfolded, the New Party became increasingly an irrelevance at the side of the much more tangible threat of the National government, although communists did campaign against Mosley in late 1931. Ultimately, the New Party was significant for the communists because it seemed to offer some vindication of the 'class against class' line; because it suggested that the CPGB was not always wrong in its analysis; because it led to increased attention to the party's youth movement; and because it led to the leading left-wing polemicist of the 1930s, John Strachey, working with the CPGB for almost a decade

Transgressing the moral economy: Wheelerism and management of the nationalised coal industry in Scotland

This article illuminates the links between managerial style and political economy in post-1945 Britain, and explores the origins of the 1984–1985 miners' strike, by examining in longer historical context the abrasive attitudes and policies of Albert Wheeler, Scottish Area Director of the National Coal Board (NCB). Wheeler built on an earlier emphasis on production and economic criteria, and his micro-management reflected pre-existing centralising tendencies in the industries. But he was innovative in one crucial aspect, transgressing the moral economy of the Scottish coalfield, which emphasised the value of economic security and changes by joint industrial agreement

Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis

Objective High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data. Methods To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data. Results Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age. Conclusion Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals. Clinical trials registration The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.The corresponding author is funded by the Australian National Health and Medical Research Council, National Institute for Dementia Research, and Dementia Centre for Research Collaboration (NHMRC NNIDR DCRC)

The limitations of hibonite as a single-mineral oxybarometer for early solar system processes

The relationships between the composition of hibonite with the general formula CaAl12-2x-yMgxTi4 +xTi3 +yO19, the oxidation state of Ti (Ti3 +/ΣTi, where ΣTi = Ti3 + + Ti4 +), and oxygen fugacity (fO2) were investigated experimentally. It was found that hibonite can be synthesised with a range of Ti3 +/ΣTi values at constant fO2 and with a constant Ti3 +/ΣTi value for a range of fO2s. It was also found that if hibonite with the formula CaAl12-yTi3 +yO19 (Ti3 +/ΣTi = 1) is equilibrated with a melt of CAI composition at fO2s below the iron-wüstite buffer then the resulting hibonite contained Mg, with Mg per formula unit (pfu) ~ 0.8 Ti pfu, and Ti3 +/ΣTi ~ 0.2, irrespective of the fO2. These results suggest that the availability of Mg, rather than fO2, is the key factor that determines Ti3 +/ΣTi of hibonite. The structures of synthetic samples of hibonite with the general formula CaAl12-2xMgxTi4 +xO19, where 0 ≤ X < 1, were determined by Rietveld refinement of X-ray powder diffraction data. The predominant site occupied by Ti4 + was found to change from M2 to M4 with increasing Ti content. The range of Ti concentrations over which the site occupancy changed corresponds to that observed in meteoritic hibonite. This change in the Ti4 + site produces changes in the Ti K-edge XANES spectra, particularly in the intensity of the pre-edge feature, for constant Ti3 +/ΣTi. The observed dependence of the pre-edge on the Ti4 + site was reproduced by ab initio simulations of the XANES spectra. The XANES spectra of natural hibonite with variable Ti content from the Murchison carbonaceous chondrite closely match the spectra of the synthetic samples with similar Ti contents. These differences in the spectra of meteoritic hibonite could be misinterpreted as being due to changes in Ti3 +/ΣTi, but are instead due to differences in ΣTi, which relate to the petrogenetic history. Crystal chemistry exerts a first order control on the Ti site occupancy and Ti3 +/ΣTi value of hibonite. As a result, no simple relationship between Ti3 +/ΣTi and fO2 should be expected. It is unlikely that hibonite will be useful as an oxybarometer for solar processes without Ti3 +/ΣTi standards that are compositionally matched to the unknown

Urban interventionism as a challenge to aesthetic order::Towards an aesthetic criminology

This article is concerned with ideas of urban order and considers the scope for playing with people’s expectations of order. In particular, drawing on criminological, philosophical and urban studies literatures, the article explores the notion of aesthetic order. The power to dictate aesthetic order is highlighted. The example of urban interventionism is used to consider those that challenge an approved aesthetic order. Here the article draws on cultural criminology and visual criminology, with illustrations coming from research in Toronto, Canada. Influenced by Alison Young’s (2014a) conceptualisation of ‘cities within the city’, the article considers how different people using the same space have different or overlapping ways of understanding aesthetic order. Of relevance to criminology, it is contended that people or things that contravene an approved aesthetic order may face banishment and criminalisation. It is concluded that respect for such difference is required. An aesthetic criminology is suggested

First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade \u3e 1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (\u3e 9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks

Livro didático público paranaense "lingua portuguesa e literatura" : o professor-autor e o gênero discursivo

Orientadora: Profa. Dra. Iara Bemquerer CostaAutor não autorizou a divulgação do arquivo digitalTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Humanas, Letras e Artes, Programa de Pós-Graduação em Letras. Defesa: Curitiba, 23/04/2012Bibliografia: fls. 163-178Área de concentração :Resumo: Esta pesquisa descritivo-explicativa tem como objetivo averiguar a relacao dialogica entre o Livro Didatico Publico Paranaense \Lingua Portuguesa e Literatura. (LDP-PR) e os livros representantes do genero discursivo Livro Didatico de Lingua Portuguesa (LD-LP). A partir de uma perspectiva socio-historico-discursiva e empregando fontes bibliografica e documental, desenvolvemos esta pesquisa em duas etapas. Na primeira, procuramos efetuar uma reflexao teorica sobre os Generos Discursivos (BAKHTIN) e sobre como a abordagem sociointeracionista se apropria desta concepcao bakhtiniana e discute a questao da didatizacao dos generos (SCHNEUWLY e DOLZ). Na segunda, aplicamos estes pressupostos ao LDP-PR com o intuito de averiguar o encaminhamento didatico dado aos textos de generos discursivos empregados neste material didatico. A partir desta averiguacao do conteudo tematico do LDP-PR, realizada pelo trabalho com as praticas de leitura, escrita e oralidade, buscamos sustentacao para a analise deste LD como um exemplar do genero LD-LP. Nossos resultados mostram que o LDP-PR inova na escolha do conteudo tematico, mas mantem o estilo (marcado pelo emprego de discursos injuntivos, explicativos e expositivos) e a construcao composicional (de textualidade multimodal) tipicos do genero LD-LP. Creditamos a autoria multipla (constituida por professores da rede escolar), marcada pela experiencia reduzida e a merce da Secretaria de Estado da Educacao do Parana (SEED-PR) este apego ao genero consolidado.Abstract: This descriptive-explanatory research aims to investigate the dialogic relationship between the Parana‘s Public Textbook "Portuguese and Literature" (LDP-PR) and the representative books of the discursive genre of Portuguese Textbook (LP-LD). From a socio-historic-discursive perspective and by the use of bibliographical and documentary sources, we developed this research in two stages. In the first one, we carried out a theoretical reflection about the Discursive Genres (BAKHTIN) and how the social interactionist approach appropriates this Bakhtinian concept and discusses the issue of making genre educational (SCHNEUWLY and DOLZ). In the second one, we applied these assumptions to the LDP-PR with the intent of investigating the educational directions given to the texts of discursive genres employed in such a teaching materials. From this investigation of the LDP-PR‘s thematic contents, performed through the work with reading, writing and speaking skills practices, we sought support for the analysis of this LD as an exemplar of the LD-LP genre. Our results reveal that the LDP-PR innovates the choice of the thematic content but retains the style (marked by the use of injunctive, explanatory and expository discourses) and compositional construction (multimodal textuality) that is typical of the LD-LP genre. We attribute to the multiple authorship (made up of teachers from the public educational system), marked by limited experience and at the mercy of the Parana‘s State Department of Education (SEED-PR), this attachment to the consolidated genre

Behavioural Risk Factors in Mid-Life Associated with Successful Ageing, Disability, Dementia and Frailty in Later Life: A Rapid Systematic Review.

BACKGROUND: Smoking, alcohol consumption, poor diet and low levels of physical activity significantly contribute to the burden of illness in developed countries. Whilst the links between specific and multiple risk behaviours and individual chronic conditions are well documented, the impact of these behaviours in mid-life across a range of later life outcomes has yet to be comprehensively assessed. This review aimed to provide an overview of behavioural risk factors in mid-life that are associated with successful ageing and the primary prevention or delay of disability, dementia, frailty and non-communicable chronic conditions. METHODS: A literature search was conducted to identify cohort studies published in English since 2000 up to Dec 2014. Multivariate analyses and a minimum follow-up of five years were required for inclusion. Two reviewers screened titles, abstracts and papers independently. Studies were assessed for quality. Evidence was synthesised by mid-life behavioural risk for a range of late life outcomes. FINDINGS: This search located 10,338 individual references, of which 164 are included in this review. Follow-up data ranged from five years to 36 years. Outcomes include dementia, frailty, disability and cardiovascular disease. There is consistent evidence of beneficial associations between mid-life physical activity, healthy ageing and disease outcomes. Across all populations studied there is consistent evidence that mid-life smoking has a detrimental effect on health. Evidence specific to alcohol consumption was mixed. Limited, but supportive, evidence was available relating specifically to mid-life diet, leisure and social activities or health inequalities. CONCLUSIONS: There is consistent evidence of associations between mid-life behaviours and a range of late life outcomes. The promotion of physical activity, healthy diet and smoking cessation in all mid-life populations should be encouraged for successful ageing and the prevention of disability and chronic disease.This work was funded by the National Institute for Health and Care Excellence (NICE), invitation to tender reference DDER 42013, and supported by the National Institute for Health Research School for Public Health Research. The scope of the work was defined by NICE and the protocol was agreed with NICE prior to the start of work. The funders had no role in data analysis, preparation of the manuscript or decision to publish.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014440