Generalized Additive Modeling For Multivariate Distributions

In this thesis, we develop tools to study the influence of predictors on multivariate distributions. We tackle the issue of conditional dependence modeling using generalized additive models, a natural extension of linear and generalized linear models allowing for smooth functions of the covariates. Compared to existing methods, the framework that we develop has two main advantages. First, it is completely flexible, in the sense that the dependence structure can vary with an arbitrary set of covariates in a parametric, nonparametric or semiparametric way. Second, it is both quick and numerically stable, which means that it is suitable for exploratory data analysis and stepwise model building. Starting from the bivariate case, we extend our framework to pair-copula constructions, and open new possibilities for further applied and methodological work. Our regression-like theory of the dependence, being built on conditional copulas and generalized additive models, is at the same time theoretically sound and practically useful

A Counterexample Regarding Labelled Well-Quasi-Ordering

Korpelainen, Lozin, and Razgon conjectured that a hereditary property of graphs which is well-quasi-ordered by the induced subgraph order and defined by only finitely many minimal forbidden induced subgraphs is labelled well-quasi-ordered, a notion stronger than that of n-well-quasi-order introduced by Pouzet in the 1970s. We present a counterexample to this conjecture. In fact, we exhibit a hereditary property of graphs which is well-quasi-ordered by the induced subgraph order and defined by finitely many minimal forbidden induced subgraphs yet is not 2-well-quasi-ordered. This counterexample is based on the widdershins spiral, which has received some study in the area of permutation patterns

Functional Analyses of the Three Simian Hemorrhagic Fever Virus Nonstructural Protein 1 Papain-Like Proteases

The N-terminal region of simian hemorrhagic fever virus (SHFV) nonstructural polyprotein 1a is predicted to encode three papain-like proteases (PLP1α, PLP1β, and PLP1γ). Catalytic residues and cleavage sites for each of the SHFV PLP1s were predicted by alignment of the SHFV PLP1 region sequences with each other as well as with those of other arteriviruses, and the predicted catalytic residues were shown to be proximal by homology modeling of the SHFV nsp1s on porcine respiratory and reproductive syndrome virus (PRRSV) nsp1 crystal structures. The functionality of the predicted catalytic Cys residues and cleavage sites was tested by analysis of the autoproteolytic products generated in in vitro transcription/translation reactions done with wild-type or mutant SHFV nsp1 constructs. Cleavage sites were also analyzed by mass spectroscopy analysis of selected immunoprecipitated cleavage products. The data showed that each of the three SHFV PLP1s is an active protease. Cys63 was identified as the catalytic Cys of SHFV PLP1α and is adjacent to an Ala instead of the canonical Tyr observed in other arterivirus PLP1s. SHFV PLP1γ is able to cleave at both downstream and upstream nsp1 junction sites. Although intermediate precursor polyproteins as well as alternative products generated by each of the SHFV PLP1s cleaving at sites within the N-terminal region of nsp1β were produced in the in vitro reactions, Western blotting of SHFV-infected, MA104 cell lysates with SHFV nsp1 protein-specific antibodies detected only the three mature nsp1 proteins

Forces Sauces and Eggs for Soldiers: food, nostalgia, and the rehabilitation of the British military

This article identifies, and considers the political implications of, the association of the contemporary British military and British soldiers with nostalgia. This aspect of the discursive project of rehabilitating the British military post-Iraq has not hitherto been theorized. The article analyses a set of exemplifying texts, four military charity food brands (Eggs for Soldiers, Forces Sauces, Red Lion Foods, and Rare Tea Company Battle of Britain Tea) to ask how nostalgic rehabilitation of the British military unfolds at the intersections of militarization, commemoration, and post-2008 “conscience capitalism”. I outline how military charity food brands are a form of “conscience capitalism” through which the perpetuation of militarized logics are produced as a notionally apolitical social “cause”, rendered intelligible within the terms of existing commoditized discourses of post-2008 vintage nostalgia. I then ask what understandings of British soldiers and the British military are constituted within the discourse of nostalgic rehabilitation, and secondly what forms of commemoration are entailed. I argue that a nostalgic generalization of soldiers and the military nullifies the potential unruliness of individual soldiers and obscures the specifics of recent, controversial, wars. Secondly nostalgic civil–military engagement entails a commemorative logic in which forms of quasi-military service are brought into the most banal spaces of everyday civilian life

Patterns of democracy: Coalition governance and majoritarian modification in the United Kingdom, 2010–2015

The UK is often regarded as the archetype of Westminster democracy and as the empirical antithesis of the power-sharing coalitions of Western Europe. Yet, in recent years a different account has emerged that focuses on the subtler institutional dynamics which limit the executive. It is to this body of scholarship that this article responds, locating the recent chapter of coalition government within the wider context of the UK’s democratic evolution. To do so, the article draws Lijphart’s two-dimensional typology of democracies, developing a refined framework that enables systematic comparison over time. The article demonstrates that between over the course of the 2010-15 Parliament, the UK underwent another period of majoritarian modification, driven by factors including the long-term influence of the constitutional forces unleashed under Labour and the short-term impact of coalition management. The article makes several important contributions, salient in the UK and beyond. Theoretically, it offers a critical rejoinder to debates regarding the relationship between institutional design and democratic performance. Methodologically, it demonstrates that the tools of large-scale comparison can be effectively scaled-down to facilitate withincase analysis. Empirically, it provides a series of conclusions regarding the tenability of the UK’s extant democratic architecture under the weight of pressures to which it continues to be subject

Parkinson’s-adapted cognitive stimulation therapy: a pilot randomized controlled clinical trial

© The Author(s), 2019. Cognitive stimulation therapy (CST) is widely used with people with dementia, but there is no evidence of its efficacy in mild cognitive impairment or dementia in Parkinson’s disease (PD-MCI; PDD) or dementia with Lewy bodies (DLB). We aimed to explore the impact of ‘CST-PD’, which is home-based, individualized CST adapted for this population. In a single-blind, randomized controlled exploratory pilot trial (RCT), we randomized 76 participant–dyads [PD-MCI (n = 15), PDD (n = 40), DLB (n = 21) and their care partners] to CST-PD or treatment as usual (TAU). CST-PD involves home-based cognitively stimulating and engaging activities delivered by a trained care partner. Exploratory outcomes at 12 weeks included cognition (Addenbrooke’s Cognitive Evaluation; ACE-III), neuropsychiatric symptoms and function. In care partners, we assessed burden, stress and general health status. Relationship quality and quality of life were assessed in both dyad members. At 12 weeks, the ACE-III showed a nonstatistically significant improvement in the CST-PD group compared with the TAU group, although neuropsychiatric symptoms increased significantly in the former. In contrast, care partners’ quality of life (d = 0.16) and relationship quality (‘satisfaction’, d = 0.01; ‘positive interaction’, d = 0.55) improved significantly in the CST-PD group, and care burden (d = 0.16) and stress (d = 0.05) were significantly lower. Qualitative findings in the CST-PD recipients revealed positive ‘in the moment’ responses to the intervention, supporting the quantitative results. In conclusion, care-partner-delivered CST-PD may improve a range of care-partner outcomes that are important in supporting home-based care. A full-scale follow-up RCT to evaluate clinical and cost effectiveness is warranted

Governing Uncertainty in a Secular Age: Rationalities of Violence, Theodicy and Torture

This article explores the problem of governing uncertainty in a secular age by focusing on the theological notion of ‘theodicy’ as the underlying rationale for the use of torture in the so-called ‘war on terror’. With God’s departure from the world, the problem of uncertainty acquires new salience as human beings can no longer explain tragic events as part of a transcendent order and must find immanent causes for the ‘evils’ that surround them. Taking a cue from Max Weber, I discuss how the problem of theodicy – how to reconcile the existence of God with the presence of evil in the world – does not disappear in the secular age but is mobilized through a Foucauldian biopolitical logic. Secular theodicy governs uncertainty through the production of economies of knowledge that rationalize processes of criminalization and securitization of entire groups and justify the use of violence. This process is particularly striking when analysing the use of torture in the so-called ‘war on terror’. Through a comparison with medieval practices and focusing on the cases of Guantanamo and Abu Ghraib, the article shows how secular torture is the product of a biopolitical theodicy aimed at governing uncertainty through the construction of the tortured as immanent evils who threaten our ‘good life’ and ‘deserve’ their treatment. Secular theodicy turns torture into an extreme form of governmentality of uncertainty in which the disciplining of conduct becomes the construction of subjectivities based on essentialist, stereotypical and racist – and for these very reasons, reassuring – economies of knowledge

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development

Background: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. Methods: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. Results: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related ‘keratinization’ methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. Conclusions: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment