From the introduction: "There are two variants of fronto-temporal dementia: a behavioral variant (behavioral FTD, bvFTD, Neary et al. (1998)), which causes changes in behavior and personality but leaves syntax, phonology and semantics relatively intact, and a variant that causes impairments in the language processing system (Primary Progessive Aphasia, PPA (Gorno-Tempini et al., 2004). PPA can be subdivided into subtypes fluent (fluent but empty speech, comprehension of word meaning is affected / `semantic dementia') and non-fluent (agrammatism, hesitant or labored speech, word finding problems). Some identify logopenic aphasia as a FTD-variant: fluent aphasia with anomia but intact object recognition and underlying word meaning."
MULTIFILE
Background:Physical activity can prolong the ability of older adults to live independently. Home-based exercises can help achieve the recommended physical activity levels. A blended intervention was developed to support older adults in performing home-based exercises. A tablet and a personal coach were provided to facilitate the self-regulation of exercise behavior.Objective:In line with the Medical Research Council framework, this study aimed to carry out process evaluation of a blended intervention. The objectives were (1) to assess the long-term usability of the tablet adopted in the blended intervention and (2) to explore how the tablet, in conjunction with a personal coach, supported older adults in performing home-based exercises.Methods:The process evaluation was conducted with a mixed-methods approach. At baseline, older adults participating in the blended intervention were asked to fill out a questionnaire about their general experience with information and communication technology (ICT) devices and rate their own skill level. After 6 months, participants filled out the Usefulness, Satisfaction, and Ease of use (USE) questionnaire to assess the usefulness, satisfaction, and ease of use of the tablet. With a random selection of participants, in-depth interviews were held to explore how the tablet and coach supported the self-regulation. The interviews were double coded and analyzed with the directed content analysis method.Results:At baseline, 29% (65/224) of participants who started the intervention (mean age 72 years) filled out the ICT survey and 36% (37/103) of participants who used the tablet for 6 months (mean age 71 years) filled out the USE questionnaire. Furthermore, with 17% (18/103) of participants (mean age 73 years), follow-up interviews were held. The results of the baseline questionnaire showed that the large majority of participants already had experience with a tablet, used it regularly, and reported being skillful in operating ICT devices. After 6 months of use, the participants rated the usefulness, satisfaction, and ease of use of the tablet on average as 3.8, 4.2, and 4.1, respectively, on a 5-point scale. The analysis of the interviews showed that the participants felt that the tablet supported action planning, behavior execution, and self-monitoring. On the other hand, especially during the first few months, the personal coach added value during the goal setting, behavior execution, and evaluation phases of self-regulation.Conclusions:The results of the process evaluation showed that older adults who participated in the study were positive about the blended intervention that was designed to support them in performing home-based exercises. Participants reported that the tablet helped them to perform the exercises better, more frequently, and safely. It supported them in various phases of self-regulation. The availability of a personal coach was nevertheless crucial. To support physical activity in older adults, a blended approach is promising.
A Magnet-related program has been recently adopted in the Netherlands. Support for staff nurses from nurse middle managers (NMMs) is a key component of such a program. A Bourdieusian ethnographic organizational case study in four hospitals in the Netherlands and the United States (Magnet, Magnet-related and non-Magnet) was conducted to explore NMMs’ supporting role behavior. Bourdieus concepts of habitus, dispositions, field and capital guided the analysis. Eight dispositions constitute NMMs habitus. A caring, clinical and scientific disposition enhance NMMs’ capital in particular organizations-as-fields. Further research is necessary to link Magnet (related) program characteristics to various configurations of dispositions of NMMs habitus.
Huntington’s disease (HD) and various spinocerebellar ataxias (SCA) are autosomal dominantly inherited neurodegenerative disorders caused by a CAG repeat expansion in the disease-related gene1. The impact of HD and SCA on families and individuals is enormous and far reaching, as patients typically display first symptoms during midlife. HD is characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. SCAs are mainly characterized by ataxia but also other symptoms including cognitive deficits, similarly affecting quality of life and leading to disability. These problems worsen as the disease progresses and affected individuals are no longer able to work, drive, or care for themselves. It places an enormous burden on their family and caregivers, and patients will require intensive nursing home care when disease progresses, and lifespan is reduced. Although the clinical and pathological phenotypes are distinct for each CAG repeat expansion disorder, it is thought that similar molecular mechanisms underlie the effect of expanded CAG repeats in different genes. The predicted Age of Onset (AO) for both HD, SCA1 and SCA3 (and 5 other CAG-repeat diseases) is based on the polyQ expansion, but the CAG/polyQ determines the AO only for 50% (see figure below). A large variety on AO is observed, especially for the most common range between 40 and 50 repeats11,12. Large differences in onset, especially in the range 40-50 CAGs not only imply that current individual predictions for AO are imprecise (affecting important life decisions that patients need to make and also hampering assessment of potential onset-delaying intervention) but also do offer optimism that (patient-related) factors exist that can delay the onset of disease.To address both items, we need to generate a better model, based on patient-derived cells that generates parameters that not only mirror the CAG-repeat length dependency of these diseases, but that also better predicts inter-patient variations in disease susceptibility and effectiveness of interventions. Hereto, we will use a staggered project design as explained in 5.1, in which we first will determine which cellular and molecular determinants (referred to as landscapes) in isogenic iPSC models are associated with increased CAG repeat lengths using deep-learning algorithms (DLA) (WP1). Hereto, we will use a well characterized control cell line in which we modify the CAG repeat length in the endogenous ataxin-1, Ataxin-3 and Huntingtin gene from wildtype Q repeats to intermediate to adult onset and juvenile polyQ repeats. We will next expand the model with cells from the 3 (SCA1, SCA3, and HD) existing and new cohorts of early-onset, adult-onset and late-onset/intermediate repeat patients for which, besides accurate AO information, also clinical parameters (MRI scans, liquor markers etc) will be (made) available. This will be used for validation and to fine-tune the molecular landscapes (again using DLA) towards the best prediction of individual patient related clinical markers and AO (WP3). The same models and (most relevant) landscapes will also be used for evaluations of novel mutant protein lowering strategies as will emerge from WP4.This overall development process of landscape prediction is an iterative process that involves (a) data processing (WP5) (b) unsupervised data exploration and dimensionality reduction to find patterns in data and create “labels” for similarity and (c) development of data supervised Deep Learning (DL) models for landscape prediction based on the labels from previous step. Each iteration starts with data that is generated and deployed according to FAIR principles, and the developed deep learning system will be instrumental to connect these WPs. Insights in algorithm sensitivity from the predictive models will form the basis for discussion with field experts on the distinction and phenotypic consequences. While full development of accurate diagnostics might go beyond the timespan of the 5 year project, ideally our final landscapes can be used for new genetic counselling: when somebody is positive for the gene, can we use his/her cells, feed it into the generated cell-based model and better predict the AO and severity? While this will answer questions from clinicians and patient communities, it will also generate new ones, which is why we will study the ethical implications of such improved diagnostics in advance (WP6).
‘Dieren in de dijk’ aims to address the issue of animal burrows in earthen levees, which compromise the integrity of flood protection systems in low-lying areas. Earthen levees attract animals that dig tunnels and cause damages, yet there is limited scientific knowledge on the extent of the problem and effective approaches to mitigate the risk. Recent experimental research has demonstrated the severe impact of animal burrows on levee safety, raising concerns among levee management authorities. The consortium's ambition is to provide levee managers with validated action perspectives for managing animal burrows, transitioning from a reactive to a proactive risk-based management approach. The objectives of the project include improving failure probability estimation in levee sections with animal burrows and enhancing risk mitigation capacity. This involves understanding animal behavior and failure processes, reviewing existing and testing new deterrence, detection, and monitoring approaches, and offering action perspectives for levee managers. Results will be integrated into an open-access wiki-platform for guidance of professionals and in education of the next generation. The project's methodology involves focus groups to review the state-of-the-art and set the scene for subsequent steps, fact-finding fieldwork to develop and evaluate risk reduction measures, modeling failure processes, and processing diverse quantitative and qualitative data. Progress workshops and collaboration with stakeholders will ensure relevant and supported solutions. By addressing the knowledge gaps and providing practical guidance, the project aims to enable levee managers to effectively manage animal burrows in levees, both during routine maintenance and high-water emergencies. With the increasing frequency of high river discharges and storm surges due to climate change, early detection and repair of animal burrows become even more crucial. The project's outcomes will contribute to a long-term vision of proactive risk-based management for levees, safeguarding the Netherlands and Belgium against flood risks.
CRISPR/Cas genome engineering unleashed a scientific revolution, but entails socio-ethical dilemmas as genetic changes might affect evolution and objections exist against genetically modified organisms. CRISPR-mediated epigenetic editing offers an alternative to reprogram gene functioning long-term, without changing the genetic sequence. Although preclinical studies indicate effective gene expression modulation, long-term effects are unpredictable. This limited understanding of epigenetics and transcription dynamics hampers straightforward applications and prevents full exploitation of epigenetic editing in biotechnological and health/medical applications.Epi-Guide-Edit will analyse existing and newly-generated screening data to predict long-term responsiveness to epigenetic editing (cancer cells, plant protoplasts). Robust rules to achieve long-term epigenetic reprogramming will be distilled based on i) responsiveness to various epigenetic effector domains targeting selected genes, ii) (epi)genetic/chromatin composition before/after editing, and iii) transcription dynamics. Sustained reprogramming will be examined in complex systems (2/3D fibroblast/immune/cancer co-cultures; tomato plants), providing insights for improving tumor/immune responses, skin care or crop breeding. The iterative optimisations of Epi-Guide-Edit rules to non-genetically reprogram eventually any gene of interest will enable exploitation of gene regulation in diverse biological models addressing major societal challenges.The optimally balanced consortium of (applied) universities, ethical and industrial experts facilitates timely socioeconomic impact. Specifically, the developed knowledge/tools will be shared with a wide-spectrum of students/teachers ensuring training of next-generation professionals. Epi-Guide-Edit will thus result in widely applicable effective epigenetic editing tools, whilst training next-generation scientists, and guiding public acceptance.
