Continuity of Local Time: An applied perspective

Continuity of local time for Brownian motion ranks among the most notable mathematical results in the theory of stochastic processes. This article addresses its implications from the point of view of applications. In particular an extension of previous results on an explicit role of continuity of (natural) local time is obtained for applications to recent classes of problems in physics, biology and finance involving discontinuities in a dispersion coefficient. The main theorem and its corollary provide physical principles that relate macro scale continuity of deterministic quantities to micro scale continuity of the (stochastic) local time.Comment: To appear in: "The fascination of Probability, Statistics and Their Applications. In honour of Ole E. Barndorff-Nielsen on his 80th birthday

Visual parameter optimisation for biomedical image processing

Background: Biomedical image processing methods require users to optimise input parameters to ensure high quality output. This presents two challenges. First, it is difficult to optimise multiple input parameters for multiple input images. Second, it is difficult to achieve an understanding of underlying algorithms, in particular, relationships between input and output. Results: We present a visualisation method that transforms users’ ability to understand algorithm behaviour by integrating input and output, and by supporting exploration of their relationships. We discuss its application to a colour deconvolution technique for stained histology images and show how it enabled a domain expert to identify suitable parameter values for the deconvolution of two types of images, and metrics to quantify deconvolution performance. It also enabled a breakthrough in understanding by invalidating an underlying assumption about the algorithm. Conclusions: The visualisation method presented here provides analysis capability for multiple inputs and outputs in biomedical image processing that is not supported by previous analysis software. The analysis supported by our method is not feasible with conventional trial-and-error approaches

Efficiency of primary saliva secretion: an analysis of parameter dependence in dynamic single-cell and acinus models, with application to aquaporin knockout studies

Secretion from the salivary glands is driven by osmosis following the establishment of osmotic gradients between the lumen, the cell and the interstitium by active ion transport. We consider a dynamic model of osmotically driven primary saliva secretion and use singular perturbation approaches and scaling assumptions to reduce the model. Our analysis shows that isosmotic secretion is the most efficient secretion regime and that this holds for single isolated cells and for multiple cells assembled into an acinus. For typical parameter variations, we rule out any significant synergistic effect on total water secretion of an acinar arrangement of cells about a single shared lumen. Conditions for the attainment of isosmotic secretion are considered, and we derive an expression for how the concentration gradient between the interstitium and the lumen scales with water- and chloride-transport parameters. Aquaporin knockout studies are interpreted in the context of our analysis and further investigated using simulations of transport efficiency with different membrane water permeabilities. We conclude that recent claims that aquaporin knockout studies can be interpreted as evidence against a simple osmotic mechanism are not supported by our work. Many of the results that we obtain are independent of specific transporter details, and our analysis can be easily extended to apply to models that use other proposed ionic mechanisms of saliva secretion

Tracing North Atlantic volcanism and seaway connectivity across the Paleocene–Eocene Thermal Maximum (PETM)

Abstract. There is a temporal correlation between the peak activity of the North Atlantic Igneous Province (NAIP) and the Paleocene–Eocene Thermal Maximum (PETM), suggesting that the NAIP may have initiated and/or prolonged this extreme warming event. However, corroborating a causal relationship is hampered by a scarcity of expanded sedimentary records that contain both climatic and volcanic proxies. One locality hosting such a record is the island of Fur in Denmark, where an expanded pre- to post-PETM succession containing hundreds of NAIP ash layers is exceptionally well preserved. We compiled a range of environmental proxies, including mercury (Hg) anomalies, paleotemperature proxies, and lithium (Li) and osmium (Os) isotopes, to trace NAIP activity, hydrological changes, weathering, and seawater connectivity across this interval. Volcanic proxies suggest that NAIP activity was elevated before the PETM and appears to have peaked during the body of the δ13C excursion but decreased considerably during the PETM recovery. This suggests that the acme in NAIP activity, dominated by flood basalt volcanism and thermogenic degassing from contact metamorphism, was likely confined to just ∼ 200 kyr (ca. 56.0–55.8 Ma). The hundreds of thick (> 1 cm) basaltic ashes in the post-PETM strata likely represent a change from effusive to explosive activity, rather than an increase in NAIP activity. Detrital δ7Li values and clay abundances suggest that volcanic ash production increased the basaltic reactive surface area, likely enhancing silicate weathering and atmospheric carbon sequestration in the early Eocene. Signals in lipid biomarkers and Os isotopes, traditionally used to trace paleotemperature and weathering changes, are used here to track seaway connectivity. These proxies indicate that the North Sea was rapidly cut off from the North Atlantic in under 12 kyr during the PETM recovery due to NAIP thermal uplift. Our findings reinforce the hypothesis that the emplacement of the NAIP had a profound and complex impact on Paleocene–Eocene climate, both directly through volcanic and thermogenic degassing and indirectly by driving regional uplift and changing seaway connectivity

Roadmap on multiscale materials modeling

Modeling and simulation is transforming modern materials science, becoming an important tool for the discovery of new materials and material phenomena, for gaining insight into the processes that govern materials behavior, and, increasingly, for quantitative predictions that can be used as part of a design tool in full partnership with experimental synthesis and characterization. Modeling and simulation is the essential bridge from good science to good engineering, spanning from fundamental understanding of materials behavior to deliberate design of new materials technologies leveraging new properties and processes. This Roadmap presents a broad overview of the extensive impact computational modeling has had in materials science in the past few decades, and offers focused perspectives on where the path forward lies as this rapidly expanding field evolves to meet the challenges of the next few decades. The Roadmap offers perspectives on advances within disciplines as diverse as phase field methods to model mesoscale behavior and molecular dynamics methods to deduce the fundamental atomic-scale dynamical processes governing materials response, to the challenges involved in the interdisciplinary research that tackles complex materials problems where the governing phenomena span different scales of materials behavior requiring multiscale approaches. The shift from understanding fundamental materials behavior to development of quantitative approaches to explain and predict experimental observations requires advances in the methods and practice in simulations for reproducibility and reliability, and interacting with a computational ecosystem that integrates new theory development, innovative applications, and an increasingly integrated software and computational infrastructure that takes advantage of the increasingly powerful computational methods and computing hardware

What Facilitates Return to Work? Patients Experiences 3 Years After Occupational Rehabilitation

Objective We have limited knowledge about the specific elements in an occupational rehabilitation programme that facilitate the process leading to return to work (RTW) as perceived by the patients. The aim of the study was to explore individual experiences regarding contributing factors to a successful RTW, 3 years after a resident occupational rehabilitation programme. Methods The study is based on interviews of 20 individuals who attended an occupational rehabilitation programme 3 years earlier. Ten informants had returned to work (RTW) and ten were receiving disability pension (DP). Data were analysed by systematic text condensation inspired by Giorgi’s phenomenological analysis. Results The core categories describing a successful RTW process included positive encounters, increased self-understanding and support from the surroundings. While the informants on DP emphasized being seen, heard and taken seriously by the professionals, the RTW group highlighted being challenged to increase self-understanding that promoted new acting in every-day life. Being challenged on self-understanding implied increased awareness of own identity, values and resources. Support from the surroundings included support from peer participants, employer and social welfare system. Conclusion Successful RTW processes seem to comprise positive encounters, opportunities for increased self-understanding and support from significant others. An explicit focus on topics like identity, own values and resources might improve the outcome of the rehabilitation process

Resolving the genetic heterogeneity of prelingual hearing loss within one family: Performance comparison and application of two targeted next generation sequencing approaches.

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Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study

Background: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. Methods: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40). Findings: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. Interpretation: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes. Funding: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development

Influence of Efforts of Employer and Employee on Return-to-Work Process and Outcomes

Background Research on disability and RTW outcome has led to significant advances in understanding these outcomes, however, limited studies focus on measuring the RTW process. After a prolonged period of sickness absence, the assessment of the RTW process by investigating RTW Effort Sufficiency (RTW-ES) is essential. However, little is known about factors influencing RTW-ES. Also, the correspondence in factors determining RTW-ES and RTW is unknown. The purpose of this study was to investigate 1) the strength and relevance of factors related to RTW-ES and RTW (no/partial RTW), and 2) the comparability of factors associated with RTW-ES and with RTW. Methods During 4 months, all assessments of RTW-ES and RTW (no/partial RTW) among employees applying for disability benefits after 2 years of sickness absence, performed by labor experts at 3 Dutch Social Insurance Institute locations, were investigated by means of a questionnaire. Results Questionnaires concerning 415 cases were available. Using multiple logistic regression analysis, the only factor related to RTW-ES is a good employer-employee relationship. Factors related to RTW (no/partial RTW) were found to be high education, no previous periods of complete disability and a good employer-employee relationship. Conclusions Different factors are relevant to RTW-ES and RTW, but the employer-employee relationship is relevant for both. Considering the importance of the assessment of RTW-ES after a prolonged period of sickness absence among employees who are not fully disabled, this knowledge is essential for the assessment of RTW-ES and the RTW process itself

Working Together May Be Better: Activation of Reward Centers during a Cooperative Maze Task

Humans use theory of mind when predicting the thoughts and feelings and actions of others. There is accumulating evidence that cooperation with a computerized game correlates with a unique pattern of brain activation. To investigate the neural correlates of cooperation in real-time we conducted an fMRI hyperscanning study. We hypothesized that real-time cooperation to complete a maze task, using a blind-driving paradigm, would activate substrates implicated in theory of mind. We also hypothesized that cooperation would activate neural reward centers more than when participants completed the maze themselves. Of interest and in support of our hypothesis we found left caudate and putamen activation when participants worked together to complete the maze. This suggests that cooperation during task completion is inherently rewarding. This finding represents one of the first discoveries of a proximate neural mechanism for group based interactions in real-time, which indirectly supports the social brain hypothesis