Bridging the gap between computation and clinical biology: validation of cable theory in humans

Introduction: Computerized simulations of cardiac activity have significantly contributed to our understanding of cardiac electrophysiology, but techniques of simulations based on patient-acquired data remain in their infancy. We sought to integrate data acquired from human electrophysiological studies into patient-specific models, and validated this approach by testing whether electrophysiological responses to sequential premature stimuli could be predicted in a quantitatively accurate manner. Methods: Eleven patients with structurally normal hearts underwent electrophysiological studies. Semi-automated analysis was used to reconstruct activation and repolarization dynamics for each electrode. This S(2) extrastimuli data was used to inform individualized models of cardiac conduction, including a novel derivation of conduction velocity restitution. Activation dynamics of multiple premature extrastimuli were then predicted from this model and compared against measured patient data as well as data derived from the ten-Tusscher cell-ionic model. Results: Activation dynamics following a premature S(3) were significantly different from those after an S(2). Patient specific models demonstrated accurate prediction of the S(3) activation wave, (Pearson's R(2) = 0.90, median error 4%). Examination of the modeled conduction dynamics allowed inferences into the spatial dispersion of activation delay. Further validation was performed against data from the ten-Tusscher cell-ionic model, with our model accurately recapitulating predictions of repolarization times (R(2) = 0.99). Conclusions: Simulations based on clinically acquired data can be used to successfully predict complex activation patterns following sequential extrastimuli. Such modeling techniques may be useful as a method of incorporation of clinical data into predictive models

Frameworks for supporting patient and public involvement in research: Systematic review and co-design pilot.

BACKGROUND: Numerous frameworks for supporting, evaluating and reporting patient and public involvement in research exist. The literature is diverse and theoretically heterogeneous. OBJECTIVES: To identify and synthesize published frameworks, consider whether and how these have been used, and apply design principles to improve usability. SEARCH STRATEGY: Keyword search of six databases; hand search of eight journals; ancestry and snowball search; requests to experts. INCLUSION CRITERIA: Published, systematic approaches (frameworks) designed to support, evaluate or report on patient or public involvement in health-related research. DATA EXTRACTION AND SYNTHESIS: Data were extracted on provenance; collaborators and sponsors; theoretical basis; lay input; intended user(s) and use(s); topics covered; examples of use; critiques; and updates. We used the Canadian Centre for Excellence on Partnerships with Patients and Public (CEPPP) evaluation tool and hermeneutic methodology to grade and synthesize the frameworks. In five co-design workshops, we tested evidence-based resources based on the review findings. RESULTS: Our final data set consisted of 65 frameworks, most of which scored highly on the CEPPP tool. They had different provenances, intended purposes, strengths and limitations. We grouped them into five categories: power-focused; priority-setting; study-focused; report-focused; and partnership-focused. Frameworks were used mainly by the groups who developed them. The empirical component of our study generated a structured format and evidence-based facilitator notes for a "build your own framework" co-design workshop. CONCLUSION: The plethora of frameworks combined with evidence of limited transferability suggests that a single, off-the-shelf framework may be less useful than a menu of evidence-based resources which stakeholders can use to co-design their own frameworks

Brexit writings and the war of position over migration, 'race' and class

This timely series of interventions scrutinises the centrality of race and migration to the 2016 Brexit campaign, vote and its aftermath. It brings together five individual pieces, with an accompanying introduction, which interrogate different facets of how race, migration and Brexit interconnect: an examination of the so called 'left behinds' and the fundamental intersections between geography, race and class at the heart of Brexit motivations and contexts; an exploration of arguably parallel and similarly complex developments in the US with the rise of populism and support for Donald Trump; an analysis of the role of whiteness in the experiences of East European nationals in the UK in the face of increased anti-foreigner sentiment and uncertainty about future status; a discussion of intergenerational differences in outlooks on race and immigration and the sidelining of different people and places in Brexit debates; and a studied critique of prevailing tropes about Brexit which create divisive classed and raced categories and seek to oversimplify broader understandings of race, class and migration. Taken together these articles, all arguing for the need to eschew easy answers and superficial narratives, offer important and opportune insights into what Brexit tells us about race and migration in contemporary UK

Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells

The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK

The course of life of patients with childhood atopic dermatitis

Atopic dermatitis mainly covers the period of infancy to adulthood, an important period in the development of an individual. The impairment of quality of life and the psychological wellbeing of children with atopic dermatitis have been well documented but so far no data exist about the impact of atopic dermatitis in childhood on fulfilling age-specific developmental tasks and achieving developmental milestones during this period, referred to as the course of life. The aims of this study were to: (i) assess the course of life and define the disease-related consequences in young adult patients with childhood atopic dermatitis and (ii) determine whether the severity of atopic dermatitis is predictive for the course of life, the disease-related consequences and quality of life later in life. Adult patients who grew up with atopic dermatitis were asked to complete a medical history questionnaire, the Skindex-29, the "course of life" questionnaire and a subjective disease-specific questionnaire. Patients with severe atopic dermatitis in childhood showed a significant delayed social development in their course of life. The results of the disease-specific questionnaire demonstrated remarkable high percentages of psycho-social consequences and physical discomfort caused by atopic dermatitis in childhood. Patients showed a severely negative impact of atopic dermatitis on their current quality of life. This is the first study that applied the "course of life" questionnaire in atopic dermatitis. More insight in the course of life, disease-specific consequences and quality of life of atopic dermatitis is of high importance, especially in case of severe atopic dermatitis. © 2009 The Authors

ImaYDiT - Imagining young disabled people's transitions in a time of major societal change: Research project report

ImaYDiT was funded by DRILL – Disability Research for Independent Living and Learning. This is supported by the Big Lottery Fund. WiltsCIL staff, members of WiltsCIL CoproductionGroup and researchers at UWE came up with the original idea for this project. We wanted to support young disabled people to explore and re-imagine their adult lives and have the best future. This involved taking an ‘assets-based’ approach. This is where we focus on what people can do- rather than what they can’t do – which is a ‘deficit approach’. We also thought that there is not enough research about the whole of young disabled people’s lives. Instead a lot of research only concentrates on transitions through the benefits and service system.Wiltshire Social Services and the Wiltshire Parent Council helped steer the project because, where we could, we also wanted to put young disabled people’s hopes and dreams into action.We want to understand how this group of young disabled people can be supported to become the next generation who are aware of their rights, with ambitions for their futures and able to establish meaningful and independent adult lives

Multi-Proxy Characterisation of the Storegga Tsunami and Its Impact on the Early Holocene Landscapes of the Southern North Sea

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC funded project No. 670518 LOST FRONTIERS, https://europa.eu/european-union/index_en, https://lostfrontiers.teamapp.com/). The project gratefully acknowledges the support of the Estonian Research Council (https://www.etag.ee/en/estonian-research-council/, Grant number: PUTJD829). PGS (https://www.pgs.com/) is acknowledged through provision of data used in this paper under license CA-BRAD-001-2017.Doggerland was a landmass occupying an area currently covered by the North Sea until marine inundation took place during the mid-Holocene, ultimately separating the British landmass from the rest of Europe. The Storegga Event, which triggered a tsunami reflected in sediment deposits in the northern North Sea, northeast coastlines of the British Isles and across the North Atlantic, was a major event during this transgressive phase. The spatial extent of the Storegga tsunami however remains unconfirmed as, to date, no direct evidence for the event has been recovered from the southern North Sea. We present evidence of a tsunami deposit in the southern North Sea at the head of a palaeo-river system that has been identified using seismic survey. The evidence, based on lithostratigraphy, geochemical signatures, macro and microfossils and sedimentary ancient DNA (sedaDNA), supported by optical stimulated luminescence (OSL) and radiocarbon dating, suggests that these deposits were a result of the tsunami. Seismic identification of this stratum and analysis of adjacent cores showed diminished traces of the tsunami which was largely removed by subsequent erosional processes. Our results confirm previous modelling of the impact of the tsunami within this area of the southern North Sea, and also indicate that these effects were temporary, localized, and mitigated by the dense woodland and topography of the area. We conclude that clear physical remnants of the wave in these areas are likely to be restricted to now buried, palaeo-inland basins and incised river valley systems.Publisher PDFPeer reviewe