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Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

BACKGROUND: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. METHODS: Research-grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rat, a rodent model of retinal degeneration such as retinitis pigmentosa. An investigational new drug (IND)-enabling study with CNS10-NPC was performed in the same rodent model. Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in a large animal model with Yucatan minipigs. RESULTS: Both research-grade hNPC and clinical-grade hNPC can survive and provide functional and morphological protection in a dose-dependent fashion in RCS rats and the optimal cell dose was defined and used in IND-enabling studies. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a good laboratory practice (GLP) toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model with the Yucatan minipig, which has an eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. CONCLUSIONS: These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa.

Abstract Objectives Emergency Medical Communication Centers (EMCC) have a key role in the prehospital chain-of-stroke-survival by recognizing stroke patients and reducing prehospital delay. However, studies on EMCC stroke recognition report both substantial undertriage and overtriage. Since mis-triage at the EMCC challenges the whole chain-of-stroke-survival, by occupying limited resources for non-stroke patients or failing to recognize the true stroke patients, there is a need to achieve a more comprehensive understanding of the dispatchers’ routines and experiences. The aim of this study was to explore factors affecting EMCC dispatcher’s decision-making in stroke calls. Materials and methods A qualitative exploratory study, based on individual semi-structured interviews of 15 medical dispatchers from EMCC Oslo, Norway. Interviews were conducted during August and October 2022 and analyzed using the principles of thematic analysis. Results We identified four themes: [1] Pronounced stroke symptoms are easy to identify [2]. Non-specific neurological symptoms raise suspicion of acute stroke but are difficult to differentiate from other medical conditions [3]. Consistent use of the Criteria Based Dispatch (CBD) protocol may increase EMCC overtriage [4]. Contextual conditions at EMCC can affect dispatchers’ decision-making process and the ability for experiential learning. Conclusions Medical dispatchers at the EMCC perceive vague and non-specific stroke symptoms, such as dizziness, confusion or altered behaviour, challenging to differentiate from symptoms of other less time-critical medical conditions. They also perceive the current CBD protocol in use as less supportive in assessing such symptoms. High workload and strict EMCC response time interval requirements hinder the gathering of essential patient information and the ability to seek guidance in cases of doubt, potentially exacerbating both EMCC undertriage and overtriage. The absence of feedback loops and other strategies for experiential learning in the EMCC hampers the medical dispatcher’s ability to evaluate their own assessments and improve dispatch accuracy.

Abstract Electrons from a laser wakefield accelerator have a limited energy gain due to dephasing and are prone to emittance growth, causing a large divergence. In this paper, we experimentally show that adjusting the plasma density profile can address both issues. Shock-assisted ionisation injection is used to produce 100 MeV quasi-monoenergetic electron bunches in the primary part of the accelerator. Downstream from the accelerator, a second, independently tuneable density region is added, which can be used to either boost the energy of the electron bunches or as a plasma lens for significant divergence reduction. An additional energy gain of 25% and a 40% divergence reduction are obtained. Theoretical models validate the effects.

Abstract 18 Participants were randomized to receive 30 ml/kg bodyweight Ringer’s Lactate at 37° or 15 °C over 30 min. In a second session, participants were crossed over. Over a 120 min period after starting the fluid bolus we measured mean arterial pressure (MAP), cardiac output, systemic vascular resistance, and catecholamine levels. After infusion with cold fluids, the absolute increase in MAP at 45 min was significantly higher at + 6.5 mmHg (95% CI 4.8–8.2) compared with warm fluids (+ 0.6 mmHg, 95% CI, − 1.6 to 2.8; p

Abstract Low Earth Orbit (LEO) has emerged as a unique environment for evaluating altered stem cell properties in microgravity. LEO has become increasingly accessible for research and development due to progress in private spaceflight. Axiom Mission 2 (Ax-2) was launched as the second all-private astronaut mission to the International Space Station (ISS). Frozen human induced pluripotent stem cells (hiPSCs) expressing green fluorescent protein (GFP) under the SOX2 promoter, as well as fibroblasts differentiated from SOX2-GFP hiPSCs, were sent to the ISS. Astronauts then thawed and seeded both cell types into commercially available 96-well plates, which provided surface tension that reduced fluid movement out of individual wells and showed that hiPSCs or hiPSC-derived fibroblasts could survive either in suspension or attached to a Matrigel substrate. Furthermore, both cell types could be transfected with red fluorescent protein (RFP)-expressing plasmid. We demonstrate that hiPSCs and hiPSC-fibroblasts can be thawed in microgravity in off-the-shelf, commercially-available cell culture hardware, can associate into 3D spheroids or grow adherently in Matrigel, and can be transfected with DNA. This lays the groundwork for future biomanufacturing experiments in space.

Abstract Background Team reflexivity and peer feedback in daily clinical work can improve patient safety. However, teams do not always engage in reflection after patient care. A reason could be that team members may lack skills in engaging in team reflection. This study explores the use of interprofessional team-based simulations to encourage and equip teams for reflective conversations in the real-world clinical practice. Methods This was a prospective, explorative study of team members’ perceptions of the use of in situ simulation-based scenarios with critically ill patient cases to train team-based reflections and peer feedback. The study took place in two neurological wards. Prior to the intervention, a 1-day observation in each ward and semi-structured short interviews with physicians and nurses were conducted. Results A total of 94 staff members, 57 nurses, 8 nurse assistants and 29 physicians participated in the in situ simulation scenarios. All team members showed appreciation of the safe learning environment. The authors found that the simulations and the debriefing structure provided an opportunity for training of team reflexivity and feedback. The team members evaluated the simulation-based training very positively, and their initial reaction indicated that they found peer feedback useful for the individual and the team. This approach allowed them to reflect on their own clinical practice. Conclusion The simulation-based training scenarios and the debriefing structure promoted team members’ team reflexivity and peer feedback skills. The method is feasible and could be used in other specialties and situations. The team members’ reactions to feedback were positive, and based on their reflections, there is a potential to increase both individual and team skills as well as improve patient treatment.

Abstract Purpose A breast cancer (BC) diagnosis may negatively affect health-related quality of life (HRQoL). However, there are few comparisons of HRQoL at several time points for women with BC, and particular when subdivided into invasive and in situ tumors. The purpose of this study was to investigate various aspects of HRQoL in women recently diagnosed with invasive BC or ductal carcinoma in situ (in situ) compared to age-matched BC free controls in a population-wide sample recruited through the Cancer Registry of Norway. Methods This cross-sectional study utilized HRQoL data collected in 2020–2022 from a digital survey including 4117 cases (3867 women with invasive BC and 430 with in situ) and 2911 controls. HRQoL was assessed ≥ 21 days after diagnosis, using EORTC QLQ-C30. This includes scores assessing global quality of life (gHRQoL) and HRQoL functions and symptoms. Multivariable regression analyses were used to compare HRQoL between cases and controls and to identify factors associated with gHRQoL and fatigue. Additionally, HRQoL 14 months after diagnosis was analyzed in 1989 of the included cases and in 1212 of the controls. Score differences of ≥ 10 points were considered clinically relevant and thus presented in the results. Results Invasive BC cases had lower gHRQoL, role- and social functioning in addition to more fatigue than controls. In situ cases had lower role—and social functioning than controls. Invasive BC cases scored worse than in situ on all domains, but the differences were not considered clinically relevant. Physical activity was associated with better gHRQoL and less fatigue in invasive BC, in situ and controls. Both invasive BC and in situ cases improved their role- and social functioning scores from diagnosis to 14 months follow-up, however no improvement was seen for fatigue. Conclusion Women with invasive BC and in situ reported lower role- and social functioning scores than controls right after diagnosis with improvements 14 months after diagnosis. Physical activity was associated with better gHRQoL and less fatigue and should, whenever possible, play a key role in the care for BC patients.

Abstract We aimed to identify and characterise behavioural profiles in patients at high risk of SCD, by using deep representation learning of day-to-day behavioural recordings. We present a pipeline that employed unsupervised clustering on low-dimensional representations of behavioural time-series data learned by a convolutional residual variational neural network (ResNet-VAE). Data from the prospective, observational SafeHeart study conducted at two large tertiary university centers in the Netherlands and Denmark were used. Patients received an implantable cardioverter-defibrillator (ICD) between May 2021 and September 2022 and wore wearable devices using accelerometer technology during 180 consecutive days. A total of 272 patients (mean age of 63.1 ± 10.2 years, 81% male) were eligible with a total sampling of 37,478 days of behavioural data (138 ± 47 days per patient). Deep representation learning identified five distinct behavioural profiles: Cluster A (n = 46) had very low physical activity levels and a disturbed sleep pattern. Cluster B (n = 70) had high activity levels, mainly at light-to-moderate intensity. Cluster C (n = 63) exhibited a high-intensity activity profile. Cluster D (n = 51) showed above-average sleep efficiency. Cluster E (n = 42) had frequent waking episodes and poor sleep. Annual risks of malignant ventricular arrhythmias ranged from 30.4% in Cluster A to 9.8% and 9.5% for Clusters D-E, respectively. Compared to low-risk profiles (D-E), Cluster A demonstrated a three-to-four fold increased risk of malignant ventricular arrhythmias adjusted for clinical covariates (adjusted HR 3.63, 95% CI 1.54–8.53, p

Introduction: Several evaluations of lifestyle interventions for childhood obesity exist; however, follow-up beyond 2 years is necessary to validate the effect. The aim of the present study was to investigate long-term weight development following children participating in one of two pragmatic family-centered lifestyle interventions treating childhood obesity. Methods: This real-life observational study included Danish children 4–17 years of age classified as having obesity. Data from 2010 to 2020, from two community-based family-centered lifestyle interventions (designated hereafter as the Aarhus- and the Randers-intervention) were merged with national registers and routine health check-ups, including height and weight. Adjusted mixed effect models were used to model changes in body mass index (BMI) z score. We performed exploratory analyses of the development in BMI z-score within stratified subgroups of children treated in the interventions before investigating potential effect modifications induced by sex, age, family structure, socioeconomic, or immigration status. Results: With a median follow-up of 2.8 years (interquartile range: 1.3; 4.8), 703 children participated in an intervention (445 the Aarhus-intervention; 258 the Randers-intervention) and 2,337 children were not invited to participate (no-intervention). Children in both interventions experienced a comparable reduction in BMI z-scores during the first 6 months compared to the no-intervention group (Aarhus-intervention: −0.12 SD/year and Randers-intervention: −0.25 SD/year). Only children in the Randers-intervention reduced their BMI z-score throughout follow-up (Aarhus-intervention vs. no-intervention: 0.01 SD/year; confidence interval [CI]: −0.01; 0.04; Randers-intervention vs. no-intervention: −0.05 SD/year; CI: −0.08; −0.02). In subgroup comparisons, combining the two interventions, family income below the median (−0.05 SD/year, CI: −0.02; −0.09), immigrant background (0.04 SD/year, CI: 0.00; 0.07), or receiving intervention less than 1 year (0.04 SD/year, CI: 0.00; 0.08) were associated with a yearly increase in BMI z score. In addition, effect modification analyses did not observe any interaction by sex, age, family structure, socioeconomic, or immigration. Conclusions: Although the more dynamic intervention with longer duration obtained and sustained a minor reduction in BMI z score, the clinical impact may only be modest and still not effective enough to induce a long-term beneficial development in BMI in children with obesity.

In the present study, we present a cross-country comparison of the status and condition of sustainable development (SD) in the Nordic physical education (PE) curricula. The aim of the study was to increase knowledge of how SD perspectives are represented and conceptualised in the Nordic PE curricula. An expert-driven research approach was used where representatives from Denmark, Finland, Iceland, Norway, and Sweden provided country overviews and completed surveys to elaborate on the status, pre-conditions, prospect/future, and research initiatives in relation to SD in PE. The study shows that SD perspectives seldom are explicitly mentioned in the Nordic PE curricula, and that little is known regarding how PE teachers understand SD in relation to PE goals and content in their countries. Suggestions on specific SD goals to focus on in Nordic PE, as well as suggestions on future research are provided and discussed in the paper.

During COVID-19, distance learning has given students around the world unforeseen challenges, including the way their learning is being assessed. Assessment for learning (AfL) can contribute to the development of students' strategies to meet unknown challenges as lifelong learners. The purpose of AfL is to inform learning, and it can play a significant role in achieving lifelong learning strategies, such as self-regulation, effectiveness and independent learning. This article presents qualitative findings from a study examining students' perceptions (24 students) of teaching and assessment practices in upper secondary school in Norway in the spring of 2020. The findings show that students valued individual teacher feedback to support learning. The students experienced flexibility in teaching practices, and moreover, they were trusted to do the work they were told. However, regarding assessments, they felt it was unfair and that student involvement in assessment was lacking. There was little variation in the assignments, which were mostly individual, written assignments. An important message is that they missed collaborating with other students and that many of them were left alone with their schoolwork.

This study explores school leaders' and teachers' experiences of leadership in assessment during the Covid-19 lockdowns. A total of 148 school leaders and 582 teachers participated in a survey, and 15 school leaders from four schools also participated in focus group interviews. In Norway, the pandemic led to closed schools for long periods, from spring 2020 to spring 2022. Moreover, all final exams were cancelled, and all final gradings were made by individual teachers. In a disruptive and chaotic situation, it was up to school leaders at each school to ensure that teachers' assessment practices used to decide students' final grades were valid and reliable. The extraordinary circumstances that the pandemic created in schools also created a need for leadership functions beyond the ordinary. It seems that the disruptive situation during the Covid-19 school lockdowns led to a re-distribution of school leadership tasks connected to assessment, which in turn motivated more development and innovation, even stronger collaboration, and a more focused ability to solve problems related to assessment challenges in school. This study also revealed a need for more teacher support and assessment capability within school leadership to ensure fairness, validity and reliability in final assessment.

AIMS/HYPOTHESIS: Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression. METHODS: Human LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The groups were not statistically different in age. DNA was extracted from LEC for methylation analysis using Illumina Infinium 850K MethylationEPIC BeadChip and protein was extracted for Wnt phospho array analysis. Wound healing was studied using a scratch assay in LEC or 1-heptanol wounds in organ-cultured corneas. Organ-cultured corneas and LEC were transfected with WNT5A siRNA, miR-203a mimic or miR-203a inhibitor or were treated with recombinant Wnt-5a (200 ng/ml), DNA methylation inhibitor zebularine (1-20 µmol/l) or biodegradable nanobioconjugates (NBCs) based on polymalic acid scaffold containing antisense oligonucleotide (AON) to miR-203a or a control scrambled AON (15-20 µmol/l). RESULTS: There was significant differential DNA methylation between diabetic and non-diabetic LEC. WNT5A promoter was hypermethylated in diabetic LEC accompanied with markedly decreased Wnt-5a protein. Treatment of diabetic LEC and organ-cultured corneas with exogenous Wnt-5a accelerated wound healing by 1.4-fold (p