Dualities and dilemmas: contending with uncertainty in large-scale safety-critical projects

© 2016, Informa UK Limited, trading as Taylor & Francis Group. Uncertainty is a fact of project life. Most decisions that are made on a safety-critical project involve uncertainty, the consequences of which may be highly significant to the safe and timely delivery of the project. Based on interviews with project management practitioners on nine large-scale civil nuclear and aerospace projects, we explore how uncertainty emerges, and how project management practitioners identify, analyse and act on it. We make three important contributions. First, we present three approaches – structural, behavioural and relational – that individuals and organizations can adopt when contending with project uncertainty. Secondly, we characterize nine dualities at play in the management of project uncertainty and thirdly, we identify key differences between how civil nuclear and aerospace project managers confront project uncertainty, which have important implications for how projects might be organized in both these industry sectors. Drawing attention to the structural, behavioural and relational approaches to project uncertainty and the tensions that manifest themselves in each approach should enable the project management community to make progress in environments of high uncertainty where situations are often complex, rapidly changing and confusing, and yet where, for reasons of safety, failure is not an option

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Vitiligo puzzle: the pieces fall in place

A review. Over the years, the role of biochem., immunol., genetic, and other biol. aspects in the pathogenesis of vitiligo has been studied. So far, no convincing model describing the interplay of these contributing factors has been formulated. Based on existing research, we propose that vitiligo has a multi-factorial etiol., characterized by multiple steps, but always involving an increase of external or internal phenol/catechol concn., serving as a preferred surrogate substrate of tyrosinase, competing with its physiol. substrate tyrosine. The conversion of these substrates into reactive quinones is reinforced by a disturbed redox balance (increasing hydrogen peroxide). Such reactive quinones can be covalently bound to the catalytic center of tyrosinase (haptenation). This could give rise to a new antigen, carried by Langerhans cells to the regional lymph node, stimulating the proliferation of cytotoxic T cells. However, the activation of such cytotoxic cells is only a first step in skin melanocyte killing, which also depends on a shift in the balance between immune defense and tolerance, e.g. resulting from a decrease in properly functioning T-regulatory cells. With this new model, based on a synthesis of several of the existing theories, in mind, the external and internal factors involved in the etiopathogenesis of vitiligo are reviewed, against the background of reported clin. data, exptl. studies and existing and potential new therapies. A similar complex mechanism may also lead to some other autoimmune diseases