Effect of intracerebroventricular administration of alglucosidase alfa in two mouse models of Lafora disease: Relevance for clinical practice.

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy with onset during early adolescence. The disease is caused by mutations in EPM2A, encoding laforin, or EPM2B, encoding malin. Both proteins have functions that affect glycogen metabolism, including glycogen dephosphorylation by laforin and ubiquitination of enzymes involved in glycogen metabolism by malin. Lack of function of laforin or malin results in the accumulation of polyglucosan that forms Lafora bodies in the central nervous system and other tissues. Enzyme replacement therapy through intravenous administration of alglucosidase alfa (Myozyme®) has shown beneficial effects removing polyglucosan aggregates in Pompe disease. We evaluated the effectiveness of intracerebroventricular administration of alglucosidase alfa in the Epm2a-/- knock-out and Epm2aR240X knock-in mouse models of Lafora disease. Seven days after a single intracerebroventricular injection of alglucosidase alfa in 12-month-old Epm2a-/- and Epm2aR240X mice, the number of Lafora bodies was not reduced. Additionally, a prolonged infusion of alglucosidase alfa for 2 or 4 weeks in 6- and 9-month-old Epm2a-/- mice did not result in a reduction in the number of LBs or the amount of glycogen in the brain. These findings hold particular significance in guiding a rational approach to the utilization of novel therapies in Lafora disease.

Epm2aR240X knock-in mice present earlier cognitive decline and more epileptic activity than Epm2a-/- mice.

Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a-/- and Epm2b-/- mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2aR240X knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2aR240X mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2aR240X knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a-/- knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision.

Early Treatment with Metformin Improves Neurological Outcomes in Lafora Disease.

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.

Gene replacement therapy for Lafora disease in the Epm2a -/- mouse model.

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. Common symptoms include seizures, dementia, and a progressive neurological decline leading to death within 5-15 years from onset. The disease results from mutations transmitted with autosomal recessive inheritance in the EPM2A gene, encoding laforin, a dual-specificity phosphatase, or the EPM2B gene, encoding malin, an E3-ubiquitin ligase. Laforin has glucan phosphatase activity, is an adapter of enzymes involved in glycogen metabolism, is involved in endoplasmic reticulum-stress and protein clearance, and acts as a tumor suppressor protein. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein can lead to alterations in this complex, leading to the formation of Lafora bodies that contain abnormal, insoluble, and hyperphosphorylated forms of glycogen called polyglucosans. We used the Epm2a -/- knock-out mouse model of Lafora disease to apply a gene replacement therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment by means of neuropathological studies, behavioral tests, video-electroencephalography recording, and proteomic/phosphoproteomic analysis. Gene therapy with recombinant adeno-associated virus containing the EPM2A gene ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Improvements were observed for up to nine months following a single intracerebroventricular injection. In conclusion, gene replacement therapy with human EPM2A gene in the Epm2a -/- knock-out mice shows promise as a potential treatment for Lafora disease.

Digital Competencies for Nurses: Tools for Responding to Spiritual Care Needs.

Users show a growing interest in expanding the implementation of digital tools as a support of technical and management issues in healthcare. This medical care has focused on telemedicine but does not include the recognition of needs as an important part of patient-centred healthcare. Nurses interact with patients at critical times in their life journeys, including birth and death, which are historical events linked with religious beliefs. Furthermore, large migration flows have led to multicultural societies in which religion and spirituality are experienced in distinct ways by different people. Finally, most healthcare professionals lack the proper skills to handle the spiritual needs of their patients, especially for core and digital competences. This article shows the results of qualitative research applying as a research tool an open-ended questionnaire, which allows detecting the educational needs for nurses' interventions aimed at providing spiritual support to their patients using digital tools. The results obtained reveal that nurses need education and training on fundamental spiritual concepts and digital competencies to meet the multiple demands of their patients' spiritual needs. Finally, we present an open digital educational proposal for the development of competencies for nurses and other health professionals to provide spiritual care with the support of digital tools.

Influence of motivation and academic performance in the use of Augmented Reality in education. A systematic review.

The recent technologies rise today as a tool of significant importance today, especially in the educational context. In this sense, Augmented Reality (AR) is a technology that is achieving a greater presence in educational centers in the last decade. However, Augmented Reality has not been explored in depth at the Secondary Education stage. Due to this, it is essential to analyze and concentrate the scientific research developed around this educational technology at that stage. Therefore, the aim of this research is to describe the influence that Augmented Reality shows on the motivation and academic performance of students in the Secondary Education stage. In relation to the methodology, a systematic review of the literature has been conducted using the Kitchenham protocol, where several factors have been analyzed, such as subjects, activities, and electronic implementation devices, together with the effects on motivation and student's academic performance. The Scopus and Web of Science (WoS) databases have been used to search for scientific papers, with a total of 344 investigations being analyzed between 2012 and 2022. The methodological stages considered were the formulation of research questions, the choice of data sources, search strategies, inclusion and exclusion criteria and quality assessment, and finally, data extraction and synthesis. The results obtained have shown that the use of AR in the classroom provides higher levels of motivation, reflected by factors such as attention, relevance, confidence, and satisfaction, and reflects better results in the tests carried out on the experimental groups compared to the control groups, which means an improvement in the academic performance of students. These results supply a fundamental theoretical basis, where the different teachers should be supported for the incorporation of AR in the classroom, since how this educational technology has been shown offers great opportunities. Likewise, the development of research in areas not so addressed can further clarify the generality of AR based on its influence on learning. In addition, the fields of natural sciences and logical-mathematical have been the most addressed, managing to implement their contents through object modeling. In short, this research highlights the importance of incorporating Augmented Reality into all areas and educational stages, since it is a significant improvement in the teaching and learning process.

Catch the Open! A Gamified Interactive Immersion Into Open Educational Practices for Higher Education Educators.

Open Education (OE) opens up learning opportunities to, potentially, every person in the world. Additionally, it allows teachers, researchers, and practitioners to find, share, reuse, and improve existing resources under a dependable legal framework. Aiming to spread and foster the introduction of open policies in Higher Education (HE) institutions, the gamified interactive learning experience Catch the Open! was developed. Catch the Open! targets HE educators who wish to learn, or who wish to deepen their existing knowledge, about OE and Open Educational Practices (OEP). Within the gamified learning experience, the user becomes an educator, Alex, the game character, who receives a task from the Rector: to investigate how to best include OE and OEP in teaching and learning practice within the institution. Alex proceeds to explore and gather information in a web-based 2D virtual HE institution where students, colleagues, and guest researchers will help her to develop a comprehensive understanding of OE and the practical application of OEP. The educational content within Catch the Open! is underpinned by an OE competences framework for HE educators, developed in a previous phase of the Erasmus+ OpenGame project. In this paper, the design process to link pedagogical and technological approaches, which results in the Catch the Open! gamified web-based interactive application, is presented as well as the application itself. Moreover, two phases of piloting with 153 HE educators from six different HE institutions are presented. The obtained findings showed that the gamified environment helped in learning about OE. On the other hand, learners also suggested several improvement aspects of the gamified environment, such as the length of finishing a learning mission while playing.

Developing Teaching Practice in Computational Thinking in Palestine.

Sporadic efforts have been made to introduce computational thinking methods into K-12 education in Palestine, but these have been held back by the challenging educational environment. However, a recent in-service training initiative, funded and organized by the Ministry or Education of Palestine, constitutes a significant effort to embed computational thinking in K-12 practice. The middle school teachers who participated in the training course were invited to participate in the present study, and 38 did so. A qualitative approach involving both interviews with teachers and classroom observations was used in data collection. All the teachers agreed to be observed in their classrooms, while 20 of the 38 also agreed to participate in the interviews. The findings showed that teachers of a range of topics, including social sciences and languages, employed computational thinking skills in teaching their students, but they were confronted by a number of challenges, including technical infrastructure and support, and a lack of time to prepare CT classes and space in the curriculum to deliver them. The results indicate that the most appropriate action to support teachers' delivery of CT would be to provide peer exchanges and expert coaching in the integration of CT in the curriculum.

Providing Spiritual Care to In-Hospital Patients During COVID-19: A Preliminary European Fact-Finding Study.

Historically, there has be a close relationship between the nursing services and spiritual care provision to patients, arising due to the evolvement of many hospitals and nursing programmes from faith-based institutions and religious order nursing. With increasing secularism, these relationships are less entwined. Nonetheless, as nurses typically encounter patients at critical life events, such as receiving bad news or dying, nurses frequently understand the need and requirement for both spiritual support and religious for patients and families during these times. Yet there are uncertainties, and nurses can feel ill-equipped to deal with patients' spiritual needs. Little education or preparation is provided to these nurses, and they often report a lack of confidence within this area. The development of this confidence and the required competencies is important, especially so with increasingly multicultural societies with diverse spiritual and religious needs. In this manuscript, we discuss initial field work carried out in preparation for the development of an Erasmus Plus educational intervention, entitled from Cure to Care Digital Education and Spiritual Assistance in Healthcare. Referring specifically to post-COVID spirituality needs, this development will support nurses to respond to patients' spiritual needs in the hospital setting, using digital means. This preliminary study revealed that while nurses are actively supporting patients' spiritual needs, their education and training are limited, non-standardised and heterogeneous. Additionally, most spiritual support occurs within the context of a Judeo-Christian framework that may not be suitable for diverse faith and non-faith populations. Educational preparation for nurses to provide spiritual care is therefore urgently required.

Are we there yet? A systematic literature review of Open Educational Resources in Africa: A combined content and bibliometric analysis.

Although several studies have been conducted to summarize the progress of open educational resources (OER) in specific regions, only a limited number of studies summarize OER in Africa. Therefore, this paper presents a systematic literature review to explore trends, themes, and patterns in this emerging area of study, using content and bibliometric analysis. Findings indicated three major strands of OER research in Africa: (1) OER adoption is only limited to specific African countries, calling for more research and collaboration between African countries in this field to ensure educational equity; (2) most of the OER initiatives in Africa have focused on the creation process and neglected other important perspectives, such as dissemination and open educational practices (OEP) using OER; and (3) on top of the typical challenges for OER adoption (e.g., infrastructure), other personal challenges were identified within the African context, including culture, language, and personality. The findings of this study suggest that more initiatives and cross-collaborations with African and non-African countries in the field of OER are needed to facilitate OER adoption in the region. Additionally, it is suggested that researchers and practitioners should consider individual differences, such as language, personality and culture, when promoting and designing OER for different African countries. Finally, the findings can promote social justice by providing insights and future research paths that different stakeholders (e.g., policy makers, educators, practitioners, etc.) should focus on to promote OER in Africa.

Connection between sleeping patterns and cognitive deterioration in women with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) causes symptoms such as dementia, memory loss, disorientation, and even aggressiveness, and is more common in women than in men. AD may also manifest itself in changes in sleep patterns. However, the relationship between AD (in all stages) and bedtime behavior has not been thoroughly investigated. METHODS: In a prospective, cross-sectional survey, we evaluated 74 women categorized in two different stages of cognitive decline associated with AD (mild and severe) along with 37 women with no cognitive decline who served as controls. We obtained demographic and medical information such as age, health status, and medication, as well as psychiatrically confirmed staging of AD. We also collected actigraphy data for several nights in a row with a medical grade wristband using a 3-axis accelerometer and solid-state on-board memory. These data served as parameters for a clustering machine learning (ML) algorithm. RESULTS: The ML process was able to unsupervisedly identify 85% of the participants according to their pre-assigned degree of dementia. When the clustering was carried out in a binary fashion (i.e., only taking into account healthy members vs. severely affected AD patients), it was possible to correctly classify 91% of the cases. CONCLUSIONS: This study revealed a strong connection between the severity of the intellectual decline and the features distilled from actigraphically derived sleep parameters.

A Systematic Review of Systematic Reviews on Blended Learning: Trends, Gaps and Future Directions.

Blended Learning (BL) is one of the most used methods in education to promote active learning and enhance students' learning outcomes. Although BL has existed for over a decade, there are still several challenges associated with it. For instance, the teachers' and students' individual differences, such as their behaviors and attitudes, might impact their adoption of BL. These challenges are further exacerbated by the COVID-19 pandemic, as schools and universities had to combine both online and offline courses to keep up with health regulations. This study conducts a systematic review of systematic reviews on BL, based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, to identify BL trends, gaps and future directions. The obtained findings highlight that BL was mostly investigated in higher education and targeted students in the first place. Additionally, most of the BL research is coming from developed countries, calling for cross-collaborations to facilitate BL adoption in developing countries in particular. Furthermore, a lack of ICT skills and infrastructure are the most encountered challenges by teachers, students and institutions. The findings of this study can create a roadmap to facilitate the adoption of BL. The findings of this study could facilitate the design and adoption of BL which is one of the possible solutions to face major health challenges, such as the COVID-19 pandemic.

Game-Based Learning for Learners With Disabilities-What Is Next? A Systematic Literature Review From the Activity Theory Perspective.

The design, implementation, and outcome of game-based learning for learners with disabilities have not been sufficiently examined systematically. Particularly, learner-based and contextual factors, as well as the essential roles played by various stakeholders, have not been addressed when game-based learning applications are used in special education. Therefore, a systematic literature review using the Activity Theory (AT) was conducted to analyse studies about game-based learning for learners with disabilities. Content analysis of 96 studies reported relevant information with respect to each activity component-(a) subject (learners with disabilities), (b) technology (game-based learning applications), (c) object (target skills or behaviours), (d) rules (implementation procedure and performance measures), (e) community (learners with disabilities, special education professionals, and parents), (f) division of labour (among learners, professionals, and parents) and (g) outcome (performance of target skills or behaviours). Furthermore, this study identified existing gaps from the reviewed studies, including occasional lack of parental engagement, difficulty of standardising performance measures due to the heterogeneity of learner profiles and contradictions (e.g., opposing views among experts on the role of educational games in social interactions). Finally, recommendations were made under each activity component. The study concluded that both general and domain-specific guidelines should be created for each disability category proposed in this review to assist practitioners who wish to use game-based learning with learners with disabilities.

Structural and Functional Brain Abnormalities in Mouse Models of Lafora Disease.

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a-/- mice revealed abnormal glucose uptake, although no alterations in Epm2b-/- mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.

Digital Transformation in Higher Education Institutions: A Systematic Literature Review.

Higher education institutions (HEIs) have been permeated by the technological advancement that the Industrial Revolution 4.0 brings with it, and forces institutions to deal with a digital transformation in all dimensions. Applying the approaches of digital transformation to the HEI domain is an emerging field that has aroused interest during the recent past, as they allow us to describe the complex relationships between actors in a technologically supported education domain. The objective of this paper is to summarize the distinctive characteristics of the digital transformation (DT) implementation process that have taken place in HEIs. The Kitchenham protocol was conducted by authors to answer the research questions and selection criteria to retrieve the eligible papers. Nineteen papers (1980-2019) were identified in the literature as relevant and consequently analyzed in detail. The main findings show that it is indeed an emerging field, none of the found DT in HEI proposals have been developed in a holistic dimension. This situation calls for further research efforts on how HEIs can understand DT and face the current requirements that the fourth industrial revolution forced.

Analysis of stress's effects on cardiac dynamics: A case study on undergraduate students.

CONTEXT: Early detection of cardiovascular disease could make a difference in terms of treatment success. For that reason, it is important to test the reliability of tools used to deliver diagnoses and to measure the impact of external factors such as stressful situations on alterations in the data collected. Students are an interesting cohort for investigating the effects of stressful situations, as they have a variable number of stress-causing situations in their daily activity over a short period of time. BASIC PROCEDURE: This investigation used 50 students, each of whom underwent two 21 -h tests involving the measurement of heart rate in beats per minute while they were carrying out their normal daily activities with their own tools. In this case study, we measured the impact of stressful situations with a tool for the self-diagnosis of cardiovascular diseases, using data from students on holiday and during their final exams. We asked the students to select two days on which to use the device and perform the test. The requirements for the days were given to them as follows: for the first test, the students were required to select a day off when their main activity was rest; for the second test, the students were required to select a day in their final exams week that they expected to be the hardest day with the most stressful situations. This paper describes a case study in which we measured the impact of stressful situations with the students' own tools for the self-diagnosis of cardiovascular diseases, using data from students on holiday and during their final exams week. These two datasets, as well as the results of the diagnosis, were compared. MAIN FINDINGS: The analysis of the data showed that if the students were healthy, some cardiovascular conditions could change, and some tendencies could be found in the data, unrelated to stress. The addition of stressful situations does not have a direct impact on the diagnosis. Thus, we can assume that analysing the data with this methodology and technology will give us an accurate result independent of a person's activities during the test. CONCLUSIONS: In this sense, and taking into account that the diagnosis was the same in both cases for all the students, we can say that stressful situations don't modify cardiac dynamics, and the diagnosis is useful in all situations. For that reason, the tool is reliable enough to estimate the cardiovascular health of a patient while he or she performs various daily activities by taking advantage of smartphones, commercial heart rate sensors, and IoT platforms.

Advanced Sensors Technology in Education.

The topic presented will show how different kinds of sensors can help to improve our skills in learning environments. When we open the mind and let it take the control to be creative, we can think how a martial art would be improved with registered sensors, or how a person may dance with machines to improve their technique, or how you may improve your soccer kick for a penalties round. The use of sensors seems easy to imagine in these examples, but their use is not limited to these types of learning environments. Using depth cameras to detect patterns in oral presentations, or improving the assessment of agility through low cost-sensors with multimodal learning analytics, or using computing devices as sensors to measure their impact on primary and secondary students' performances are the focus of this study as well. We hope readers will find original ideas that allow them to improve and advance in their own researches.

Intelligent Framework for Learning Physics with Aikido (Martial Art) and Registered Sensors.

Physics is considered a tough academic subject by learners. To leverage engagement in the learning of this STEM area, teachers try to come up with creative ideas about the design of their classroom lessons. Sports-related activities can foster intuitive knowledge about physics (gravity, speed, acceleration, etc.). In this context, martial arts also provide a novel way of visualizing these ideas when performing the predefined motions needed to master the associated techniques. The recent availability of cheap monitoring hardware (accelerometers, cameras, etc.) allows an easy tracking of the aforementioned movements, which in the case of aikido, usually involve genuine circular motions. In this paper, we begin by reporting a user study among high-school students showing that the physics concept of moment of inertia can be understood by watching live exhibitions of specific aikido techniques. Based on these findings, we later present Phy + Aik, a tool for educators that enables the production of innovative visual educational material consisting of high-quality videos (and live demonstrations) synchronized/tagged with the inertial data collected by sensors and visual tracking devices. We think that a similar approach, where sensors are automatically registered within an intelligent framework, can be explored to teach other difficult-to-learn STEM concepts.

Tau-Induced Pathology in Epilepsy and Dementia: Notions from Patients and Animal Models.

Patients with dementia present epilepsy more frequently than the general population. Seizures are more common in patients with Alzheimer's disease (AD), dementia with Lewy bodies (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) than in other dementias. Missense mutations in the microtubule associated protein tau (MAPT) gene have been found to cause familial FTD and PSP, while the P301S mutation in MAPT has been associated with early-onset fast progressive dementia and the presence of seizures. Brains of patients with AD, LBD, FTD and PSP show hyperphosphorylated tau aggregates, amyloid-ß plaques and neuropil threads. Increasing evidence suggests the existence of overlapping mechanisms related to the generation of network hyperexcitability and cognitive decline. Neuronal overexpression of tau with various mutations found in FTD with parkinsonism-linked to chromosome 17 (FTDP-17) in mice produces epileptic activity. On the other hand, the use of certain antiepileptic drugs in animal models with AD prevents cognitive impairment. Further efforts should be made to search for plausible common targets for both conditions. Moreover, attempts should also be made to evaluate the use of drugs targeting tau and amyloid-ß as suitable pharmacological interventions in epileptic disorders. The diagnosis of dementia and epilepsy in early stages of those diseases may be helpful for the initiation of treatments that could prevent the generation of epileptic activity and cognitive deterioration.