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Abstract The human brain’s distinctive folding pattern has attracted the attention of researchers from different fields. Neuroscientists have provided insights into the role of four fundamental cell types crucial during embryonic development: radial glial cells, intermediate progenitor cells, outer radial glial cells, and neurons. Understanding the mechanisms by which these cell types influence the number of cortical neurons and the emerging cortical folding pattern necessitates accounting for the mechanical forces that drive the cortical folding process. Our research aims to explore the correlation between biological processes and mechanical forces through computational modeling. We introduce cell-density fields, characterized by a system of advection-diffusion equations, designed to replicate the characteristic behaviors of various cell types in the developing brain. Concurrently, we adopt the theory of finite growth to describe cortex expansion driven by increasing cell density. Our model serves as an adjustable tool for understanding how the behavior of individual cell types reflects normal and abnormal folding patterns. Through comparison with magnetic resonance images of the fetal brain, we explore the correlation between morphological changes and underlying cellular mechanisms. Moreover, our model sheds light on the spatiotemporal relationships among different cell types in the human brain and enables cellular deconvolution of histological sections.

Abstract Muscle synergy analyses are used to enhance our understanding of motor control. Spatially fixed synergy weights coordinate multiple co-active muscles through activation commands, known as activation coefficients. To gain a more comprehensive understanding of motor learning, it is essential to understand how activation coefficients vary during a learning task and at different levels of movement proficiency. Participants walked on a line, a beam, and learned to walk on a tightrope—tasks that represent different levels of proficiency. Muscle synergies were extracted from electromyography signals across all conditions and the number of synergies was determined by the knee-point of the total variance accounted for (tVAF) curve. The results indicated that the tVAF of one synergy decreased with task proficiency, with the tightrope task resulting in the highest tVAF compared to the line and beam tasks. Furthermore, with increasing proficiency and after a learning process, trial-to-trial similarity increased and temporal overlap of synergy activation coefficients decreased. Consequently, we propose that precise adjustment and refinement of synergy activation coefficients play a pivotal role in motor learning.

Abstract A common theory of motor control posits that movement is controlled by muscle synergies. However, the behavior of these synergies during highly complex movements remains largely unexplored. Skateboarding is a hardly researched sport that requires rapid motor control to perform tricks. The objectives of this study were to investigate three key areas: (i) whether motor complexity differs between skateboard tricks, (ii) the inter-participant variability in synergies, and (iii) whether synergies are shared between different tricks. Electromyography data from eight muscles per leg were collected from seven experienced skateboarders performing three different tricks (Ollie, Kickflip, 360°-flip). Synergies were extracted using non-negative matrix factorization. The number of synergies (NoS) was determined using two criteria based on the total variance accounted for (tVAF > 90% and adding an additional synergy does not increase tVAF > 1%). In summary: (i) NoS and tVAF did not significantly differ between tricks, indicating similar motor complexity. (ii) High inter-participant variability exists across participants, potentially caused by the low number of constraints given to perform the tricks. (iii) Shared synergies were observed in every comparison of two tricks. Furthermore, each participant exhibited at least one synergy vector, which corresponds to the fundamental ‘jumping’ task, that was shared through all three tricks.

Abstract The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.

Introduction & Purpose During training and competition, athletes must cope with numerous demands that can influence their performance. These include physiological and mental fatigue, psychological stress, and the ability to adapt quickly to varying situations. Controlling the high number of degrees of freedom with which the musculoskeletal system can produce movements is challenging for the central nervous system CNS (Bernstein, 1967), even without the context of a sporting setting. One common theory in the field of motor control posits the existence of muscle synergies (Turpin et al., 2021). These are constituted of synergy vectors within the spinal cord that comprise the relative weightings of different co-active muscles. Synergy vectors are activated by time-varying activation coefficients, which correspond to the central commands from supraspinal areas. Consequently, the CNS is not required to individually time and scale the activation of each muscle independently; rather, it only regulates the activation of a limited number of synergies (Turpin et al., 2021). This simplification strategy has been extensively studied in a variety of settings, including locomotion (Boccia et al., 2018; McGowan et al., 2010) and reaching movements (Scano et al., 2019). However, muscle synergies were rarely studied in sport-like settings which demands fall beyond daily tasks. In this light, we conducted several studies in order to build a deeper understanding of motor control in movements with high demands. This abstract presents a summary of the main findings of four studies. Specifically, SKATE, examining the complex movements of skateboard tricks; LEARN, demonstrating modifications as participants learned to walk on a tightrope; STRESS, investigating alterations under psychological stress during treadmill walking; and FATIGUE, exploring the fatigue strategies of climbers during overhead hanging tasks. The overarching aim of these studies was to enhance our understanding of motor control and adaptation in movements of a high-demand nature. Methods To study muscle synergies, surface electromyography signals from multiple muscles were recorded, filtered, rectified, amplitude- and time-normalised, and concatenated across captured trials. Subsequently, factorisation algorithms were employed to extract the spatial synergy vectors and time-varying activation coefficients for each participant. The required number of synergies to perform the movement was then determined by the total variance accounted for by a given number of synergies (Turpin et al., 2021). SKATE Seven recreational skateboarders performed three tricks (Ollie, Kickflip, 360°-flip), which involved different rotations of the board in the air. Each participant was required to land the Ollie, Kickflip and 360°-flip successfully six times. Muscle activity of eight muscles per leg was collected and used to extract muscle synergies of each trick during the take-off phase. The degree of similarity between synergy vectors among tricks was quantified by calculating the Pearson correlation coefficient. Synergies were identified as similar if the correlation exceeded a threshold of 0.623 (Kaufmann et al., 2024). LEARN Ten participants were required to walk over a line taped on the floor, a beam, and learn to walk over a tightrope, all within one single data collection session. Muscle activity of thirteen muscles of the right leg was collected for several trials of each walking task and used to extract muscle synergies. The temporal overlap between different synergies within one trial and the trial-to-trial similarity between different trials within one synergy were determined through the Pearson correlation of the activation coefficients (Figure 1A). STRESS Eight participants walked on a treadmill at a self-selected, constant velocity under two conditions in a random order. Once walking during a psychological stress condition, induced by the Paced Auditory Serial Addition Task (Gronwall, 1977), and once without stress. The stress level was measured through the tonic skin conductance, and force insoles were used to determine foot contacts. Muscle activity of four to seven muscles on each leg was collected for all steps and used to extract muscle synergies. The trial-to-trial similarity of the activation coefficients was determined by the Pearson correlation coefficient (Figure 1A). The coefficient of variation among steps was employed to quantify the trial-to-trial similarity of the participants’ stance-phase to gait-cycle ratio as a temporal-spatial gait parameter. FATIGUE Eleven climbers performed sustained isometric finger hangings until failure. Muscle activity of six arm and trunk muscles per limb was recorded throughout the hang and used to extract muscle synergies. Subsequently, similar synergy vectors among participants were clustered. The mean activation from the activation coefficients of synergies within the same cluster was compared between the first and last 20% of the hang in order to identify changes between a non-fatigued and a fatigued stage. Results SKATE Three to six synergies were required among participants and tricks. At least one similar synergy vector was identified for each pair of trick comparisons. Furthermore, one consistent synergy vector was observed in all three tricks. This synergy vector was primarily formed by the quadriceps muscles and was activated during the initial third of the take-off phase, thereby being responsible for the fundamental task of jumping. LEARN Across participants, four to eight synergies were required to complete all walking tasks. Statistical analyses revealed a significantly higher trial-to-trial similarity (p < 0.05) alongside a lower temporal overlap of activation coefficients during walking on a line compared to walking over the beam or the tightrope and during beam walking compared to tightrope walking. Furthermore, trial-to-trial similarity was higher and overlap was lower at the end of the learning process compared to the beginning. STRESS Three to seven synergies were required to walk on the treadmill. During the stress condition, participants exhibited higher stress levels (p < 0.01) and a lower trial-to-trial similarity of the stance-phase to gait-cycle ratio (p < 0.05). No significant differences were found regarding the trial-to-trial similarity of activation coefficients. FATIGUE Participants required two or three synergies to perform the hanging task. Consequently, synergies were identified into two clusters (Figure 1B). The first cluster, which was mainly comprised of forearm muscles, demonstrated no difference in the activation coefficient recruitment between the first and last 20% of the hang. In contrast, the second cluster, which was mainly comprised of more postural muscles such as the trapezius and biceps, exhibited a higher activation during the fatigued stage (p < 0.001). Discussion In light of the findings of the presented studies, three major points warrant discussion. Firstly, similar synergy vectors were present in movements with a high level of complexity, such as skateboard tricks. This result is similar to findings in daily tasks and supports the theory that movements with similar subtasks recruit similar synergy vectors (Boccia et al., 2018; Kaufmann et al., 2024; Scano et al., 2019). We propose that, if fundamental subtasks such as a jump are shared between movements, similar synergies are recruited, even in movements with high technical demands. Secondly, the fine-tuning of time-varying activation coefficients is a key factor for learning and to quickly adapt to changing demands. In particular, the trial-to-trial similarity of activation coefficients increased and temporal overlap decreased with increasing movement proficiency. Additionally, the LEARN study revealed that the amount of activation of different synergies varies in relation to the surface on which the participants walked (Kaufmann et al., 2023). Similarly, the amount of activation of a synergy formed by postural muscles changed throughout fatigue during overhead hangs. Consequently, these findings indicate that activation coefficients adapt to changing demands. This is also evidenced by a simulation study, which demonstrated that solely by scaling the magnitude of activation coefficients, walking was possible with changing mechanical demands, such as weight support, added weight, or added mass (McGowan et al., 2010). Thirdly, it was observed that psychological stress had an effect on temporal-spatial gait parameters, but not on synergies. One possible explanation for this is that even in situations without stress, activation coefficients are recruited flexible across trials. This flexibility is not further increased with the presence of psychological stress. In light of the optimal feedback control theory (Todorov & Jordan, 2002), the flexibility and fine-tuning of the activation coefficients can be elucidated as an update mechanism of the CNS based on permanent feedback, which enables adaptation to task demands and maintains task performance. Conclusion The results of these studies allow us to draw the following conclusions: fundamental subtasks share similar muscle synergies, and fine-tuning as well as flexibility of the temporal activation coefficients is crucial to adapt to varying demands. We demonstrated that sport-like settings can be used to enhance our understanding of human motor control. References Bernstein, N. (1967). The coordination and regulation of movements. Perganmon Press. Boccia, G., Zoppirolli, C., Bortolan, L., Schena, F., & Pellegrini, B. (2018). Shared and task‐specific muscle synergies of Nordic walking and conventional walking. Scandinavian Journal of Medicine & Science in Sports, 28(3), 905-918. https://doi.org/10.1111/sms.12992 Gronwall, D. M. (1977). Paced auditory serial-addition task: A measure of recovery from concussion. Perceptual and Motor Skills, 44(2), 367-373. https://doi.org/10.2466/pms.1977.44.2.367 Kaufmann, P., Koller, W., Wallnöfer, E., Goncalves, B., Baca, A., & Kainz, H. (2023). Trial-to-trial similarity and distinctness of muscle synergy activation coefficients increases during learning and with a higher level of movement proficiency. bioRxiv, 2023.2009.2019.558460. https://doi.org/10.1101/2023.09.19.558460 Kaufmann, P., Zweier, L., Baca, A., & Kainz, H. (2024). Muscle synergies are shared across fundamental subtasks in complex movements of skateboarding. Scientific Reports, 14, Article 12860. https://doi.org/10.1038/s41598-024-63640-5 McGowan, C. P., Neptune, R. R., Clark, D. J., & Kautz, S. A. (2010). Modular control of human walking: Adaptations to altered mechanical demands. Journal of Biomechanics, 43(3), 412-419. https://doi.org/10.1016/j.jbiomech.2009.10.009 Scano, A., Dardari, L., Molteni, F., Giberti, H., Tosatti, L. M., & d’Avella, A. (2019). A comprehensive spatial mapping of muscle synergies in highly variable upper-limb movements of healthy subjects. Frontiers in Physiology, 10, Article 1231. https://doi.org/10.3389/fphys.2019.01231 Todorov, E., & Jordan, M. I. (2002). Optimal feedback control as a theory of motor coordination. Nature Neuroscience, 5, 1226-1235. https://doi.org/10.1038/nn963 Turpin, N. A., Uriac, S., & Dalleau, G. (2021). How to improve the muscle synergy analysis methodology? European Journal of Applied Physiology, 121, 1009-1025. https://doi.org/10.1007/s00421-021-04604-9

Introduction & Purpose Bones adapt its shape and strength in response to mechanical loading. Tissue-level mechanical stresses, i.e., hydrostatic compressive stress and octahedral shear stress, regulate biological events on the cellular and molecular level, and thereby impact tissue histomorphology and changes in bony geometry (Carter & Beaupré, 2007). Mechanobiological multi-scale simulations based on gait analysis data, musculoskeletal (MSK) modelling and finite element (FE) analysis enable to estimate tissue-level bone loads and predict growth patterns (Shefelbine & Carter, 2004). Such simulations have the potential to inform clinical decision-making in patients with pathological bone deformations, e.g. increased femoral anteversion angle (AVA), which are common in children with cerebral palsy (CP). However, the time-consuming process of creating subject-specific models has previously restricted studies to small sample sizes (n = 1-4 participants), thereby limiting the generalizability of findings (Carriero et al., 2011; Yadav et al., 2021). Moreover, the simulations have not been validated directly due to a lack of longitudinal experimental data, which hinders the widespread use and implementation in clinical settings. Over the last years, we focused our research efforts to overcome these hurdles. We developed a workflow to streamline the process to create subject-specific FE model (Koller et al., 2023). In this study we aimed to use this workflow and 1) analyze growth patterns in a comparable large sample of typically developing (TD) children and children with CP and 2) validate the growth predictions, i.e. compare predicted with measured bone growth. Methods Magnetic resonance images (MRI) and three-dimensional motion capture data including marker trajectories and ground reaction forces of 13 TD children (10 ± 2.2 years old, mass: 36.8 ± 9.5 kg) and 12 children with CP (10.4 ± 3.8 years old, mass: 30.1 ± 10.8 kg) were analyzed for this study. All participants walked without walking aids and with a self-selected speed. Details of the data collection are described in previous publications (Kainz et al., 2017; Koller et al., 2023). From 10 TD children we collected the MRI and motion capture data twice with approximately two years between occasions. MRI images were used to create subject-specific MSK models (Veerkamp et al., 2021) based on an OpenSim model (Kaneda et al., 2023), which allows to estimate medial and lateral knee joint contact forces (JCF) as well as the patellofemoral JCF. Each participant’s model and the corresponding gait analysis data were used to calculate joint angles, muscle forces and JCFs using inverse kinematics, static optimization and joint reaction load analyses with OpenSim 4.2, respectively. For each participant, muscle forces and JCF of two representative steps (left and right) were chosen as loading condition for the FE simulations and each side was analyzed separately. Each femur was segmented using 3D Slicer and the geometry was used to calculate the bending of the femoral shaft. Our previously developed tool was used to create subject-specific hexahedral meshes with several layers of elements aligned with the growth plates (Koller et al., 2023). Nine load instances were selected based on the JCF peaks and the valley in-between during the stance phase. JCFs and muscle forces (n = 26) acting on the femur at these timepoints were used as loading conditions for FE analysis. Linear elastic material properties were assigned to the different parts of the femur and FEBio3 was used to calculate principal stresses within the growth plates. The growth rate due to mechanical loading was estimated as the osteogenic index (OI), which was calculated based on the hydrostatic compressive stress and octahedral shear stress for each element within the growth plates (Stevens et al., 1999; Yadav et al., 2021). Positive and negative OI values indicate regions where growth is likely to be promoted or inhibited, respectively. Image comparison methods were employed to identify variability between OIs (Bradski, 2000). The knee flexion angle alters the orientation of knee JCFs in respect to the distal growth plate resulting in different induced stress regimes. Hence, we divided the children with CP in two groups: one with normal knee flexion angles (n = 15 femurs, CPnormal) and one with increased knee flexion (n = 8 femurs, CPhigh_knee_flexion) during the stance phase. For aim 1, we compared the femoral geometry and OI between CP groups and the TD children. For aim 2 (validation), growth predictions were performed for all femurs where data of two occasions was available (n = 20 femurs). Monte-Carlo-analysis (n = 1,320 for each femur) were performed to estimate which mechanobiological model parameters lead to the most realistic simulations. Linear regression analyses were used to identify whether measured development of AVA can be predicted by the mechanobiological multi-scale simulations. Results The bending of the femoral shaft was significantly different between all groups (Figure 1B). The representative reference OI distribution from the TD femurs showed a ring-shape at the proximal growth plate. Within the CP cohort, image comparison revealed higher inter-subject variability (p < 0.001) whereas some participants show ring-shape distribution similar to the TD cohort and others linear-gradient shapes with high values on the lateral side of the growth plate. At the distal growth plate, OI distribution for TD femurs showed highest values in the posterior notch region and on the medial-anterior edge. The OI distribution of the CPnormal group had its peak values in similar areas as the TD group but with additional peaks at the anterior-lateral edge. The OI distribution generated from the CPhigh_knee_flexion group showed a linear gradient from high to low values from anterior to posterior side (Figure 1D). Between data collection sessions, TD children grew 13.5 ± 3.3 cm and gained 8.2 ± 3.2 kg of body mass during the two years. Participants’ AVA changed between -13.1° and 11.8° (mean: -1.3 ± 5.8°) between sessions. Analysis of kinematics, muscle and JCFs did not show differences between those experiencing an increase of AVA to those that showed a decrease. Multi-scale predictions and measurements of AVA development showed significant linear correlation (p < 0.001) with an explanatory power of R2 = 0.5 (Figure 1C). Discussion At the distal growth plate, the OI distribution showed more growth in the anterior compared to the posterior region in the CPhigh_knee_flexion compared to the CPnormal and TD groups. Progressive promoted growth in the anterior compartment over a longer period could lead to higher anterior bending of the femoral shaft. Indeed, our geometrical analysis revealed a more bended femoral shaft in the CPhigh_knee_flexion group compared to other groups. The variability of the OI at the proximal growth plate within the CP cohort was higher compared to the TD group indicating that some CP participants are likely to experience normal growth whereas in others, the proximal femur will develop pathologically. This agrees with clinical observation where some children with CP develop deformities while others don’t. Despite the fact that no significant differences were found in joint kinematics, femoral loading and growth plate orientation between TD children with different growth patterns, multi-scale simulations were sensitive enough to identify differences and predict AVA development with reasonable accuracy. Conclusion Femoral growth is influenced by a complex interplay between gait pattern, femoral morphology and internal loading on a tissue-level. Our results showed that multi-scale simulations are able to discriminate between different growth patterns and predict growth trends in agreement with experimental observations. In order to increase our confidence in the simulations and pave the road to in-silico informed clinical decision-making in the near future, longitudinal simulation studies including a larger sample size and individuals with pathological growth are needed to be conducted. References Bradski, G. (2000). The OpenCV library. Dr. Dobb’s Journal of Software Tools. Carriero, A., Jonkers, I., & Shefelbine, S. J. (2011). Mechanobiological prediction of proximal femoral deformities in children with cerebral palsy. Computer Methods in Biomechanics and Biomedical Engineering, 14(3), 253–262. https://doi.org/10.1080/10255841003682505 Carter, D. R., & Beaupré, G. S. (2007). Skeletal function and form: Mechanobiology of skeletal development, aging, and regeneration. Cambridge University Press. Kainz, H., Hoang, H. X., Stockton, C., Boyd, R. R., Lloyd, D. G., & Carty, C. P. (2017). Accuracy and reliability of marker-based approaches to scale the pelvis, thigh, and shank segments in musculoskeletal models. Journal of Applied Biomechanics, 33(5), 354–360. https://doi.org/10.1123/jab.2016-0282 Kaneda, J. M., Seagers, K. A., Uhlrich, S. D., Kolesar, J. A., Thomas, K. A., & Delp, S. L. (2023). Can static optimization detect changes in peak medial knee contact forces induced by gait modifications? Journal of Biomechanics, 152, Article 111569. https://doi.org/10.1016/j.jbiomech.2023.111569 Koller, W., Gonçalves, B., Baca, A., & Kainz, H. (2023). Intra- and inter-subject variability of femoral growth plate stresses in typically developing children and children with cerebral palsy. Frontiers in Bioengineering and Biotechnology, 11, Article 1140527. https://doi.org/10.3389/fbioe.2023.1140527 Shefelbine, S. J., & Carter, D. R. (2004). Mechanobiological predictions of femoral anteversion in cerebral palsy. Annals of Biomedical Engineering, 32(2), 297–305. https://doi.org/10.1023/B:ABME.0000012750.73170.ba Stevens, S. S., Beaupré, G. S., & Carter, D. R. (1999). Computer model of endochondral growth and ossification in long bones: Biological and mechanobiological influences. Journal of Orthopaedic Research, 17(5), 646–653. https://doi.org/10.1002/jor.1100170505 Veerkamp, K., Kainz, H., Killen, B. A., Jónasdóttir, H., & van der Krogt, M. M. (2021). Torsion Tool: An automated tool for personalising femoral and tibial geometries in OpenSim musculoskeletal models. Journal of Biomechanics, 125, Article 110589. https://doi.org/10.1016/j.jbiomech.2021.110589 Yadav, P., Fernández, M. P., & Gutierrez-Farewik, E. M. (2021). Influence of loading direction due to physical activity on proximal femoral growth tendency. Medical Engineering & Physics, 90, 83-91. https://doi.org/10.1016/j.medengphy.2021.02.008

Abstract Background Our patient presented with acute back pain and dyspnea, without neurological symptoms. The computed tomography (CT) scan showed a circumferent rupture of the ascending aortic intima which was invaginated in the arch and descending aorta. Case presentation A 54-year-old male patient was diagnosed with a Type A aortic dissection. He was immediately transferred to our operation room (OR) from the emergency department of a peripheral hospital. He presented with a circumferential dissection of the ascending aorta originating just distal to the coronary ostia, with the invaginated intimal mass extending through the arch down the descending aorta. In mild hypothermia, the intimal mass was safely extracted and a frozen elephant trunk (FET) procedure was performed. Conclusions Despite the extensive dissection affecting the ascending aorta and aortic arch, resulting in partially occluded supra-aortic vessels by an intimal mass, the patient remained without neurological symptoms in the pre- and post-operative period and remains well one year post surgery.

Abstract Background Healthcare costs are rising worldwide. At the same time, a considerable proportion of care does not benefit or may even be harmful to patients. We aimed to explore attitudes towards low-value care and identify the most important barriers to the de-implementation of low-value care use in primary care in high-income countries. Methods Between May and June 2022, we email surveyed primary care physicians in six high-income countries (Austria, Finland, Greece, Italy, Japan, and Sweden). Physician respondents were eligible if they had worked in primary care during the previous 24 months. The survey included four sections with categorized questions on (1) background information, (2) familiarity with Choosing Wisely recommendations, (3) attitudes towards overdiagnosis and overtreatment, and (4) barriers to de-implementation, as well as a section with open-ended questions on interventions and possible facilitators for de-implementation. We used descriptive statistics to present the results. Results Of the 16,935 primary care physicians, 1,731 answered (response rate 10.2%), 1,505 had worked in primary care practice in the last 24 months and were included in the analysis. Of the respondents, 53% had read Choosing Wisely recommendations. Of the respondents, 52% perceived overdiagnosis and 50% overtreatment as at least a problem to some extent in their own practice. Corresponding figures were 85% and 81% when they were asked regarding their country’s healthcare. Respondents considered patient expectations (85% answered either moderate or major importance), patient’s requests for treatments and tests (83%), fear of medical error (81%), workload/lack of time (81%), and fear of underdiagnosis or undertreatment (79%) as the most important barriers for de-implementation. Attitudes and perceptions of barriers differed significantly between countries. Conclusions More than 80% of primary care physicians consider overtreatment and overdiagnosis as a problem in their country’s healthcare but fewer (around 50%) in their own practice. Lack of time, fear of error, and patient pressures are common barriers to de-implementation in high-income countries and should be acknowledged when planning future healthcare. Due to the wide variety of barriers to de-implementation and differences in their importance in different contexts, understanding local barriers is crucial when planning de-implementation strategies.

Osteosarcomas are the most common primary malignant bone tumors and mostly affect children, adolescents, and young adults. Despite current treatment options such as surgery and polychemotherapy, the survival of patients with metastatic disease remains poor. In recent studies, punicalagin has reduced the cell viability, angiogenesis, and invasion in cell culture trials. The aim of this study was to examine the effects of punicalagin on osteosarcomas in a 3D in vivo tumor model. Human osteosarcoma biopsies and SaOs-2 and MG-63 cells, were grown in a 3D in vivo chorioallantoic membrane (CAM) model. After a cultivation period of up to 72 h, the tumors received daily treatment with punicalagin for 4 days. Weight measurements of the CAM tumors were performed, and laser speckle contrast imaging (LSCI) and a deep learning-based image analysis software (CAM Assay Application v.3.1.0) were used to measure angiogenesis. HE, Ki-67, and Caspase-3 staining was performed after explantation. The osteosarcoma cell lines SaOs-2 and MG-63 and osteosarcoma patient tissue displayed satisfactory growth patterns on the CAM. Treatment with punicalagin decreased tumor weight, proliferation, and tumor-induced angiogenesis, and the tumor tissue showed pro-apoptotic characteristics. These results provide a robust foundation for the implementation of further studies and show that punicalagin offers a promising supplementary treatment option for osteosarcoma patients. The 3D in vivo tumor model represents a beneficial model for the testing of anti-cancer therapies.

BackgroundOsteoarthritis of the hip joint is an increasing functional and health-related problem. The most common surgical treatment is hip replacement to reduce pain and improve function. Rehabilitation after total hip arthroplasty (THA) is not regulated in Austria and mostly depends on the patient’s own initiative and possibilities. Functional deficits, such as valgus thrust of the leg, functional Trendelenburg gait, or Duchenne limp, are characteristic symptoms before and, due to the performance learning effect prior to surgery, also after the operation. Addressing these deficits is possible through neuromuscular-focused exercise therapy. The efficacy of such therapy relies significantly on the quality of performance, the frequency of exercise, and the duration of engagement. Enhancing sustainability is achievable through increased motivation and real-time feedback (RTF) on exercise execution facilitated by digital feedback systems. ObjectiveThis study will be performed to quantify the medium-term effectiveness of digital home exercise feedback systems on functional performance following THA. MethodsA clinical trial with a cluster-randomized, 2-arm, parallel-group design with an 8-week intervention phase and subsequent follow-ups at 3 and 6 months postsurgery will be conducted. Feedback during exercising will be provided through a blended-care program, combining a supervised group exercise program with a self-developed digital feedback system for home exercise. In total, 70 patients will be recruited for baseline. The primary outcome parameters will be the frontal knee range of motion, pelvic obliquity, and lateral trunk lean. Secondary outcomes will be the sum scores of patient-reported outcomes and relevant kinematic, kinetic, and spatiotemporal parameters. ResultsThe trial started in January 2024, and the first results are anticipated to be published by June 2025. RTF-supported home exercise is expected to improve exercise execution quality and therapeutic adherence compared to using paper instructions for excise guidance. ConclusionsThe anticipated findings of this study aim to offer new insights into the effect of a blended-care program incorporating digital RTF on exercise therapy after unilateral THA, in addition to knowledge on the functional status 3 and 6 months postsurgery, for further improvement in the development of rehabilitation guidelines following THA. Trial RegistrationClinicalTrials.gov: NCT06161194; https://clinicaltrials.gov/study/NCT06161194 International Registered Report Identifier (IRRID)PRR1-10.2196/59755

IntroductionThe global health burden of chronic kidney disease (CKD) results from both the disease itself and the numerous health problems associated with it. The aim of this study was to estimate the prevalence of previously undetected CKD in middle-aged patients with risk factors for CKD. Identified patients were included in the Styrian nephrology awareness program “kidney.care 2.0” and data on their demographics, risk factors and kidney function were described.MethodsCross-sectional analysis of baseline data derived from the “kidney.care 2.0” study of 40–65 year old patients with at least one risk factor for CKD (hypertension, diabetes, cardiovascular disease, obesity or family history of end-stage kidney disease). Participants were considered to have previously undetected CKD if their estimated glomular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 and/or albumin creatinine ratio (ACR) ≥ 30 mg/g. We calculated the prevalence of previously undetected CKD and performed multivariate analyses.ResultsA total of 749 participants were included in this analysis. The prevalence of previously undetected CKD in an at-risk population was estimated at 20.1% (95%CI: 17.1–23.6). Multivariable analysis showed age (OR 1.06, 95%CI: 1.02–1.09), diabetes mellitus (OR 1.65, 95%CI: 1.12–2.30) and obesity (OR: 1.55, 95%CI: 1.04–2.30) to be independent predictors of CKD. The majority of patients with previously undetected CKD had category A2-A3 albuminuria (121 out of 150). Most patients with previously undetected eGFR < 60 ml/min/1.73 m2 were in stage G3 (36 out of 39 patients).DiscussionPragmatic, targeted, risk-based screening for CKD in primary care successfully identified a significant number of middle-aged patients with previously undetected CKD and addressed the problem of these patients being overlooked for future optimized care. The intervention may slow progression to kidney failure and prevent related cardiovascular events.

Abstract Excessive loads at lower limb joints can lead to pain and degenerative diseases. Altering joint loads with muscle coordination retraining might help to treat or prevent clinical symptoms in a non-invasive way. Knowing how much muscle coordination retraining can reduce joint loads and which muscles have the biggest impact on joint loads is crucial for personalized gait retraining. We introduced a simulation framework to quantify the potential of muscle coordination retraining to reduce joint loads for an individuum. Furthermore, the proposed framework enables to pinpoint muscles, which alterations have the highest likelihood to reduce joint loads. Simulations were performed based on three-dimensional motion capture data of five healthy adolescents (femoral torsion 10°–29°, tibial torsion 19°–38°) and five patients with idiopathic torsional deformities at the femur and/or tibia (femoral torsion 18°–52°, tibial torsion 3°–50°). For each participant, a musculoskeletal model was modified to match the femoral and tibial geometry obtained from magnetic resonance images. Each participant’s model and the corresponding motion capture data were used as input for a Monte Carlo analysis to investigate how different muscle coordination strategies influence joint loads. OpenSim was used to run 10,000 simulations for each participant. Root-mean-square of muscle forces and peak joint contact forces were compared between simulations. Depending on the participant, altering muscle coordination led to a maximum reduction in hip, knee, patellofemoral and ankle joint loads between 5 and 18%, 4% and 45%, 16% and 36%, and 2% and 6%, respectively. In some but not all participants reducing joint loads at one joint increased joint loads at other joints. The required alteration in muscle forces to achieve a reduction in joint loads showed a large variability between participants. The potential of muscle coordination retraining to reduce joint loads depends on the person’s musculoskeletal geometry and gait pattern and therefore showed a large variability between participants, which highlights the usefulness and importance of the proposed framework to personalize gait retraining.

Microscopy of stained blood smears is still a ubiquitous technique in pathology. It is often used in addition to automated electronic counters or flow cytometers to evaluate leukocytes and their morphologies in a rather simple manner and has low requirements for resources and equipment. However, despite the constant advances in microscopy, computer science, and pathology, it still usually follows the traditional approach of manual assessment by humans. We aimed to extend this technique using AI-based automated cell recognition methods while maintaining its technical simplicity. Using the web platform IKOSA, we developed an AI-based workflow to segment and identify all blood cells in DAPI-Giemsa co-stained blood smears. Thereby, we could automatically detect and classify neutrophils (young and segmented), lymphocytes, eosinophils, and monocytes, in addition to erythrocytes and platelets, in contrast to previously published algorithms, which usually focus on only one type of blood cell. Furthermore, our method delivers quantitative measurements, unattainable by the classical method or formerly published AI techniques, and it provides more sophisticated analyses based on entropy or gray-level co-occurrence matrices (GLCMs), which have the potential to monitor changes in internal cellular structures associated with disease states or responses to treatment. We conclude that AI-based automated blood cell evaluation has the potential to facilitate and improve routine diagnostics by adding quantitative shape and structure parameters to simple leukocyte counts of classical analysis.

Crossover aluminium alloys have recently been introduced as a new class of coarse-grained age-hardenable alloys. Here, we study the evolution of precipitation of the T-phase — [Formula: see text]-phase — in a 5xxx/7xxx crossover alloy with coarse- and ultrafined microstructures. Both alloys were examined using differential scanning calorimetry, X-ray diffraction and in situ transmission electron microscopy. The ultrafine-grained alloy revealed significant different and accelerated precipitation behaviour due to grain boundaries acting as fast diffusion paths. Additionally, the ultrafine-grained alloy revealed high resistance to grain growth upon heating, an effect primarily attributed to inter-granular precipitation synergistically with trans-granular precipitation of T-phase.

This study identified patterns of classroom and family experiences and developmental outcomes for young children in segregated early education. This study is based on data from a high-quality early education program serving young children from low-income households in 19 schools across the U.S. The sample included 1,521 children during the 2016-2017 school year. The analysis examined patterns of association between the racial/ethnic composition of Educare sites and family risk factors, classroom quality, and children's language and social-emotional performance and growth across the academic year. Research Findings: Findings indicated that although classroom quality, measured through traditional tools, did not vary by school racial/ethnic composition, sociodemographic risk factors, children's language and social-emotional outcomes did vary by this variable. Practice or Policy: We discuss our results in relation to promotive and inhibitive processed within and outside early education programs, as well as the continued impact of structural equities and lack of culturally responsive pedagogy on children's learning opportunities and development.

Abstract 3D inkjet printing is a fast, reliable, and non‐contact bottom–up approach to printing small and large models and is one of the fastest additive manufacturing technologies available. These attributes position inkjet printing as a promising tool for the additive manufacturing of biomaterials, for example, tissue engineering scaffolds. However, due to the stringent technical rheological requirements of current inkjet technologies, there is a lack of photopolymer resins suitable for the inkjet printing of biomaterials. Hence, a novel ink engineered for 3D piezoelectric inkjet printing of biomaterials is designed and developed. The novel resin leverages a biodegradable amino acid phosphorodiamidate matrix copolymerized with a dialkyne ether to modulate the viscosity. Copolymerization with commercially available thiols facilitates the photochemical thiol‐yne curing reaction. The ink exhibits optimal viscosity, eliminating the need for solvents, as well as reliable jetting and sufficiently swift curing kinetics. Furthermore, the formulation is successfully demonstrated in an industrial inkjet printhead. Notably, the resulting materials have low cytotoxicity and, hence, have significant promise in advancing the applications of 3D inkjet printing of biological scaffolds.

Colorado’s High Plains stand at anomalously high elevations (~1300–2100 m) for their continental interior setting, but when and why this region became elevated is poorly understood. The Cenozoic history of the High Plains is also likely linked with that of the Rocky Mountains, where the timing and cause(s) of uplift are similarly debated. We present apatite (U-Th)/He (AHe) data for 10 samples from Tertiary intrusives along a ~200 km west-to-east transect across the High Plains of southeastern Colorado to constrain the timing of exhumation and to gain insight into when and why regional elevation gain occurred. Mean sample AHe dates for the ~24–22 Ma East Spanish Peak pluton and associated radial dikes from the westernmost High Plains are 18.8 ± 1.4 to 14.1 ± 1.7 Ma, recording substantial postemplacement erosion. AHe results for the mafic to ultramafic Apishapa Dikes (oldest ~37 Ma, youngest ~14 Ma) located ~20–40 km farther north and east on the High Plains range from 12.0 ± 1.4 to 6.2 ± 1.9 Ma, documenting continued exhumation on the western High Plains during the ~12–5 Ma deposition of the Ogallala Formation farther east and suggesting that the western limit of Ogallala deposition was east of the Apishapa Dikes. In far southeastern Colorado, the Two Buttes lamprophyre was emplaced at 36.8 ± 0.4 Ma and yields a Late Oligocene AHe date of 27.1 ± 4 Ma. Here, the Ogallala Formation unconformably overlies Two Buttes, indicating that the regional ~12 Ma age for the base of the Ogallala is a minimum age for the exposure of the pluton at the surface. The AHe data presented here document that kilometer-scale erosion affected all of the southeastern Colorado High Plains in Oligo-Miocene time. While exhumation can have multiple possible causes, we favor contemporaneous surface uplift capable of elevating the region to modern heights.

Introduction Task-shifting from primary care physicians (PCPs) to nurses is one option to better and more efficiently meet the needs of the population in primary care and to overcome PCP shortages. This protocol outlines an overview of systematic reviews to assess the effects of delegation or substitution by nurses of PCPs’ activities regarding clinical, patient-relevant, professional and health services-related outcomes.Methods and analysis We will conduct a systematic literature search for secondary literature in PubMed/MEDLINE, EMBASE, CINAHL and Cochrane databases. Systematic reviews, meta-analyses and Health Technology Assessments in German and English comprising randomised controlled trials and prospective controlled trials will be considered for inclusion. Search terms will include Medical Subject Headings combined with free text words. At least one-third of abstracts and full-text articles are reviewed by two independent reviewers. Methodological quality will be assessed using the Overview Quality Assessment Questionnaire. We will only consider reviews if they include controlled trials, if the profession that substituted or delegated tasks was a nurse, if the profession of the control was a PCP, if the assessed intervention was the same in the intervention and control group and if the Overview Quality Assessment Questionnaire score is ≥5. The corrected covered area will be calculated to describe the degree of overlap of studies in the reviews included in the study. We will report the overview according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Ethics and dissemination The overview of secondary literature does not require the approval of an Ethics Committee and will be published in a peer-reviewed journal.PROSPERO registration number CRD42020183327.

BackgroundSince the beginning of the pandemic in December 2019, Coronavirus disease 2019 (COVID-19) has been a significant challenge to health care systems throughout the world. The introduction of measures to reduce the incidence of infection had a significant impact on the workplace. Overall, companies played a key and adaptive role in coping with the pandemic.MethodsCross-sectional data from an online-survey of 1,183 employees conducted during the COVID-19 pandemic in spring 2021 in Austria were used in the analyses. The influence of health beliefs (e.g., perceived severity), modifying factors (e.g., age) and time-dependent factors (e.g., corona fatigue) on individual adherence were evaluated. The conception of the questionnaire was based on the health belief model.ResultsThe majority of respondents were female (58.3%), worked in companies with more than 250 employees (56.6%) and had been to an academic secondary school or had a university degree (58.3%). Overall, employees were adherent to most of the measures at their company (>80%), except for wearing FFP-2 masks when they were travelling in a car with coworkers (59.3, 95%CI 51.3–66.7%). Overall adherence was associated with high ratings for the meaningfulness of testing (OR: 2.06 95%CI: 1.00–4.22; p = 0.049), the extent to which social norms govern behavior (OR: 6.61 95%CI: 4.66–9.36; p

Abstract In this study, we propose a novel micromechanical model for the brain white matter, which is described as a heterogeneous material with a complex network of axon fibers embedded in a soft ground matrix. We developed this model in the framework of RVE-based multiscale theories in combination with the finite element method and the embedded element technique for embedding the fibers. Microstructural features such as axon diameter, orientation and tortuosity are incorporated into the model through distributions derived from histological data. The constitutive law of both the fibers and the matrix is described by isotropic one-term Ogden functions. The hyperelastic response of the tissue is derived by homogenizing the microscopic stress fields with multiscale boundary conditions to ensure kinematic compatibility. The macroscale homogenized stress is employed in an inverse parameter identification procedure to determine the hyperelastic constants of axons and ground matrix, based on experiments on human corpus callosum. Our results demonstrate the fundamental effect of axon tortuosity on the mechanical behavior of the brain’s white matter. By combining histological information with the multiscale theory, the proposed framework can substantially contribute to the understanding of mechanotransduction phenomena, shed light on the biomechanics of a healthy brain, and potentially provide insights into neurodegenerative processes.