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While research in the learning sciences has spurred advancements in educational technology, the implementation of those learning resources in natural learning contexts advances teaching and learning. In this paper, two faculty members at the University of Central Florida used courseware generated with artificial intelligence as the primary learning resource for their students. The selection and enhancement of this courseware is contextualized for each course. Instructor implementation practices over multiple semesters are described and related to resulting student engagement and exam scores. Finally, benefits of the adaptive courseware are discussed not only for student outcomes, but the qualitative changes faculty identified and the impact that iterative changes in teaching practice had on instructors as well as students.

Abstract Classifying gait patterns into homogeneous groups could enhance communication among healthcare providers, clinical decision making and clinical trial designs in boys with Duchenne muscular dystrophy (DMD). Sutherland’s classification has been developed 40 years ago. Ever since, the state-of-the-art medical care has improved and boys with DMD are now longer ambulatory. Therefore, the gait classification requires an update. The overall aim was to develop an up-to-date, valid DMD gait classification. A total of 137 three-dimensional gait analysis sessions were collected in 30 boys with DMD, aged 4.6–17 years. Three classes were distinguished, which only partly aligned with increasing severity of gait deviations. Apart from the mildly affected pattern, two more severely affected gait patterns were found, namely the tiptoeing pattern and the flexion pattern with distinct anterior pelvic tilt and posterior trunk leaning, which showed most severe deviations at the ankle or at the proximal segments/joints, respectively. The agreement between Sutherland’s and the current classification was low, suggesting that gait pathology with the current state-of-the-art medical care has changed. However, overlap between classes, especially between the two more affected classes, highlights the complexity of the continuous gait changes. Therefore, caution is required when classifying individual boys with DMD into classes.

Pancreatic ductal adenocarcinoma (PDAC) is reported to be amongst the cancers with the lowest survival rate at 5 years. In the present study we aimed to validate a targeted next-generation sequencing (tNGS) panel to use in clinical routine, investigating genes important for PDAC diagnostic, prognostic and potential theragnostic aspect. In this NGS panel we also designed target regions to inquire about loss of heterozygosity (LOH) of chromosome 18 that has been described to be possibly linked to a worse disease progression. Copy number alteration has also been explored for a subset of genes. The last two methods are not commonly used for routine diagnostic with tNGS panels and we investigated their possible contribution to better characterize PDAC. A series of 140 formalin-fixed paraffin-embedded (FFPE) PDAC samples from 140 patients was characterized using this panel. Ninety-two % of patients showed alterations in at least one of the investigated genes (most frequent KRAS, TP53, SMAD4, CDKN2A and RNF43). Regarding LOH evaluation, we were able to detect chr18 LOH starting at 20% cell tumor percentage. The presence of LOH on chr18 is associated with a worse disease- and metastasis-free survival, in uni- and multivariate analyses. The present study validates the use of a tNGS panel for PDAC characterization, also evaluating chr18 LOH status for prognostic stratification.

Abstract Background Besides motor impairments, up to 90% of the children and adolescents with unilateral cerebral palsy (uCP) present with somatosensory impairments in the upper limb. As somatosensory information is of utmost importance for coordinated movements and motor learning, somatosensory impairments can further compromise the effective use of the impaired upper limb in daily life activities. Yet, intervention approaches specifically designated to target these somatosensory impairments are insufficiently investigated in children and adolescents with uCP. Therefore, the aim of this randomized controlled trial (RCT) is to compare the effectiveness of somatosensory discrimination therapy and dose-matched motor therapy to improve sensorimotor upper limb function in children and adolescents with uCP, who experience somatosensory impairments in the upper limb. We will further explore potential behavioral and neurological predictors of therapy response. Methods A parallel group, evaluator-blinded, phase-II, single-center RCT will be conducted for which 50 children and adolescents with uCP, aged 7 to 15 years, will be recruited. Participants will be randomized to receive 3 weekly sessions of 45 minutes of either somatosensory discrimination therapy or upper limb motor therapy for a period of 8 weeks. Stratification will be performed based on age, manual ability, and severity of tactile impairment at baseline. Sensorimotor upper limb function will be evaluated at baseline, immediately after the intervention and after 6 months follow-up. The primary outcome measure will be bimanual performance as measured with the Assisting Hand Assessment. Secondary outcomes include a comprehensive test battery to objectify somatosensory function and measures of bimanual coordination, unimanual motor function, and goal attainment. Brain imaging will be performed at baseline to investigate structural brain lesion characteristics and structural connectivity of the white matter tracts. Discussion This protocol describes the design of an RCT comparing the effectiveness of somatosensory discrimination therapy and dose-matched motor therapy to improve sensorimotor upper limb function in children and adolescents with uCP. The results of this study may aid in the selection of the most effective upper limb therapy, specifically for children and adolescents with tactile impairments. Trial registration ClinicalTrials.gov (NCT06006065). Registered on August 8, 2023.

PurposeIn children with cerebral palsy, flexion deformities of the knee can be treated with a distal femoral extension osteotomy combined with either patellar tendon advancement or patellar tendon shortening. The purpose of this study was to establish a consensus through expert orthopedic opinion, using a modified Delphi process to describe the surgical indications for distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening. A literature review was also conducted to summarize the recent literature on distal femoral extension osteotomy and patellar tendon shortening/patellar tendon advancement.MethodA group of 16 pediatric orthopedic surgeons, with more than 10 years of experience in the surgical management of children with cerebral palsy, was established. The group used a 5-level Likert-type scale to record agreement or disagreement with statements regarding distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening. Consensus for the surgical indications for distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening was achieved through a modified Delphi process. The literature review, summarized studies of clinical outcomes of distal femoral extension osteotomy/patellar tendon shortening/patellar tendon advancement, published between 2008 and 2022.ResultsThere was a high level of agreement with consensus for 31 out of 44 (70%) statements on distal femoral extension osteotomy. Agreement was lower for patellar tendon advancement/patellar tendon shortening with consensus reached for 8 of 21 (38%) of statements. The literature review included 25 studies which revealed variation in operative technique for distal femoral extension osteotomy, patellar tendon advancement, and patellar tendon shortening. Distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening were generally effective in correcting knee flexion deformities and extensor lag, but there was marked variation in outcomes and complication rates.ConclusionThe results from this study will provide guidelines for surgeons who care for children with cerebral palsy and point to unresolved questions for further research.Level of evidencelevel V.

Abstract Thin‐films patterned with complex motifs are of fundamental interest because of their advanced optical, mechanical and electronic properties, but fabrication of these materials remains challenging. Self‐organization strategies, such as immersion controlled reaction‐diffusion patterning, have shown great potential for production of patterned thin‐films. However, the autonomous nature of such processes limits controllable pattern customizability and complexity. Here, it is demonstrated that photography inspired manipulation processes can overcome this limitation to create highly‐complex tapestries of micropatterned films (MPF's). Inspired by classical photographic processes, MPF's are developed, bleached, exposed, fixed, and contoured into user‐defined shapes and photographic toning reactions are used to convert the chemical composition MPF's, while preserving the original stripe patterns. By applying principles of composite photography, highly complex tapestries composed of multiple MPF layers are designed, where each layer can be individually manipulated into a specific shape and composition. By overcoming fundamental limitations, this synergistic approach broadens the design possibilities of reaction‐diffusion processes, furthering the potential of self‐organization strategies for the development of complex materials.

Balance impairments are common in cerebral palsy. When balance is perturbed by backward support surface translations, children with cerebral palsy have increased co-activation of the plantar flexors and tibialis anterior muscle as compared to typically developing children. However, it is unclear whether increased muscle co-activation is a compensation strategy to improve balance control or is a consequence of reduced reciprocal inhibition. During translational perturbations, increased joint stiffness due to co-activation might aid balance control by resisting movement of the body with respect to the feet. In contrast, during rotational perturbations, increased joint stiffness will hinder balance control as it couples body to platform rotation. Therefore, we expect increased muscle co-activation in response to rotational perturbations if co-activation is caused by reduced reciprocal inhibition but not if it is merely a compensation strategy. We perturbed standing balance by combined backward translational and toe-up rotational perturbations in 20 children with cerebral palsy and 20 typically developing children. Perturbations induced forward followed by backward movement of the center of mass. We evaluated reactive muscle activity and the relation between center of mass movement and reactive muscle activity using a linear feedback model based on center of mass kinematics. In typically developing children, perturbations induced plantar flexor balance correcting muscle activity followed by tibialis anterior balance correcting muscle activity, which was driven by center of mass movement. In children with cerebral palsy, the switch from plantar flexor to tibialis anterior activity was less pronounced than in typically developing children due to increased muscle co-activation of the plantar flexors and tibialis anterior throughout the response. Our results thus suggest that a reduction in reciprocal inhibition causes muscle co-activation in reactive standing balance in children with cerebral palsy.

Joint hyper-resistance is a common symptom in neurological disorders. It has both neural and non-neural origins, but it has been challenging to distinguish different origins based on clinical tests alone. Combining instrumented tests with parameter identification based on a neuromechanical model may allow us to dissociate the different origins of joint hyper-resistance in individual patients. However, this requires that the model captures the underlying mechanisms. Here, we propose a neuromechanical model that, in contrast to previously proposed models, accounts for muscle short-range stiffness (SRS) and its interaction with muscle tone and reflex activity. We collected knee angle trajectories during the pendulum test in 15 children with cerebral palsy (CP) and 5 typically developing children. We did the test in two conditions – hold and pre-movement – that have been shown to alter knee movement. We modeled the lower leg as an inverted pendulum actuated by two antagonistic Hill-type muscles extended with SRS. Reflex activity was modeled as delayed, linear feedback from muscle force. We estimated neural and non-neural parameters by optimizing the fit between simulated and measured knee angle trajectories during the hold condition. The model could fit a wide range of knee angle trajectories in the hold condition. The model with personalized parameters predicted the effect of pre-movement demonstrating that the model captured the underlying mechanism and subject-specific deficits. Our model may help with the identification of neural and non-neural origins of joint hyper-resistance and thereby opens perspectives for improved diagnosis and treatment selection in children with spastic CP, but such applications require further studies to establish the method’s reliability.

A low-cost, tri-axial 50 Hz magnetic field monitoring sensor was designed, calibrated and verified. The sensor was designed using off-the-shelf components and commercially available coils. It can measure 50 Hz magnetic fields originating from high-voltage power lines from 0.08 µT to 364 µT, divided into two measurement ranges. The sensor was calibrated both on-board and in-lab. The on-board calibration takes the circuit attenuation, noise and parasitic components into account. In the in-lab calibration, the output of the developed sensor is compared to the benchmark, a narrowband EHP-50. The sensor was then verified in situ under high-voltage power lines at two independent measurement locations. The measured field values during this validation were between 0.10 µT and 13.43 µT, which is in agreement with other reported measurement values under high-voltage power lines in literature. The results were compared to the benchmark, for which average deviations of 6.2% and 1.4% were found, at the two independent measurement locations. Furthermore, fields up to 113.3 µT were measured in a power distribution sub-station to ensure that both measurement ranges were verified. Our network, four active sensors in the field, had high uptimes of 96%, 82%, 81% and, 95% during a minimum 3-month interval. In total, over 6 million samples were gathered with field values that ranged from 0.08 µT to 45.48 µT. This suggests that the proposed solution can be used for this monitoring, although more extensive long-term testing with more sensors is required to confirm the uptime under multiple circumstances.

Introduction: Histological data on muscle fiber size and proportion in (very) young typically developing (TD) children is not well documented and data on capillarization and satellite cell content are also lacking.Aims: This study investigated the microscopic properties of the medial gastrocnemius muscle in growing TD children, grouped according to age and gender to provide normal reference values in healthy children.Methods: Microbiopsies of the medial gastrocnemius (MG) muscle were collected in 46 TD boys and girls aged 2–10 years subdivided into 4 age groups (2–4, 4–6, 6–8 and 8–10 years). Sections were immunostained to assess fiber type cross-sectional area (fCSA) and proportion, the number of satellite cells (SC), capillary to fiber ratio (C/F), capillary density for type I and II fiber (CFD), capillary domain, capillary-to-fiber perimeter exchange index (CFPE) and heterogeneity index. fCSA was normalized to fibula length2 and the coefficient of variation (CV) was calculated to reflect fCSA intrasubject variability.Results: Absolute fCSA of all fibers increased with age (r = 0.72, p < 0.001) but more in boys (+112%, p < 0.05) than in girls (+48%, p > 0.05) Normalized fCSA, CV and fiber proportion did not differ between age groups and gender. C/F was strongly correlated with age in boys (r = 0.83, p < 0.001), and to a lesser extent in girls (r = 0.37, p = 0.115), while other capillary parameters as well as the number of SC remained stable with increasing age in boys and girls.Discussion: This study provides reference values of histological measures in MG according to age in normally growing boys and girls. These data may be used as a reference to determine disease impact and efficacy of therapeutic approach on the muscle.

PurposeThe purpose of this study was to establish consensus for the assessment of foot alignment and function in ambulatory children with cerebral palsy, using expert surgeon's opinion through a modified Delphi technique.MethodsThe panel used a five-level Likert-type scale to record agreement or disagreement with 33 statements regarding the assessment of foot alignment and function. Consensus was defined as at least 80% of responses being in the highest or lowest of two of the five Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest two ratings. There was no agreement if neither threshold was reached.ResultsConsensus was achieved for 25 (76%) statements, general agreement for 4 (12%) statements, and lack of consensus for 4 (12%) of the statements. There was consensus that the functional anatomy of the foot is best understood by dividing the foot into three segments and two columns. Consensus was achieved concerning descriptors of foot segmental alignment for both static and dynamic assessment. There was consensus that radiographs of the foot should be weight-bearing. There was general agreement that foot deformity in children with cerebral palsy can be classified into three levels based on soft tissue imbalance and skeletal malalignment.ConclusionThe practices identified in this study can be used to establish best care guidelines, and the format used will be a template for future Delphi technique studies on clinical decision-making for the management of specific foot segmental malalignment patterns commonly seen in children with cerebral palsy.Level of evidenceV.

PurposeThere is marked variation in indications and techniques for hamstring surgery in children with cerebral palsy. There is particular uncertainty regarding the indications for hamstring transfer compared to traditional hamstring lengthening. The purpose of this study was for an international panel of experts to use the Delphi method to establish consensus indications for hamstring surgery in ambulatory children with cerebral palsy.MethodsThe panel used a five-level Likert-type scale to record agreement or disagreement with statements regarding hamstring surgery, including surgical indications and techniques, post-operative care, and outcome measures. Consensus was defined as at least 80% of responses being in the highest or lowest two of the five Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest two ratings. There was no agreement if neither of these thresholds was reached.ResultsThe panel reached consensus or general agreement for 38 (84%) of 45 statements regarding hamstring surgery. The panel noted the importance of assessing pelvic tilt during gait when considering hamstring surgery, and also that lateral hamstring lengthening is rarely needed, particularly at the index surgery. They noted that repeat hamstring lengthening often has poor outcomes. The panel was divided regarding hamstring transfer surgery, with only half performing such surgery.ConclusionThe results of this study can help pediatric orthopedic surgeons optimize decision-making in their choice and practice of hamstring surgery for ambulatory children with cerebral palsy. This has the potential to reduce practice variation and significantly improve outcomes for ambulatory children with cerebral palsy.Level of evidencelevel V.

PurposeThe purpose of this study was to develop consensus for the surgical indications of anterior distal femur hemiepiphysiodesis in children with cerebral palsy using expert surgeon opinion through a modified Delphi technique.MethodsThe panel used a 5-level Likert-type scale to record agreement or disagreement with 27 statements regarding anterior distal femur hemiepiphysiodesis. Consensus was defined as at least 80% of responses being in the highest or lowest 2 of the Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest 2 ratings.ResultsFor anterior distal femur hemiepiphysiodesis, 27 statements were surveyed: consensus or general agreement among the panelists was achieved for 22 of 27 statements (22/27, 82%) and 5 statements had no agreement (5/27, 18%). There was general consensus that anterior distal femur hemiepiphysiodesis is indicated for ambulatory children with cerebral palsy, with at least 2 years growth remaining, and smaller (

Abstract Background The opening of pannexin1 channels is considered as a key event in inflammation. Pannexin1 channel-mediated release of adenosine triphosphate triggers inflammasome signaling and activation of immune cells. By doing so, pannexin1 channels play an important role in several inflammatory diseases. Although pannexin1 channel inhibition could represent a novel clinical strategy for treatment of inflammatory disorders, therapeutic pannexin1 channel targeting is impeded by the lack of specific, potent and/or in vivo-applicable inhibitors. The goal of this study is to generate nanobody-based inhibitors of pannexin1 channels. Results Pannexin1-targeting nanobodies were developed as potential new pannexin1 channel inhibitors. We identified 3 cross-reactive nanobodies that showed affinity for both murine and human pannexin1 proteins. Flow cytometry experiments revealed binding capacities in the nanomolar range. Moreover, the pannexin1-targeting nanobodies were found to block pannexin1 channel-mediated release of adenosine triphosphate. The pannexin1-targeting nanobodies were also demonstrated to display anti-inflammatory effects in vitro through reduction of interleukin 1 beta amounts. This anti-inflammatory outcome was reproduced in vivo using a human-relevant mouse model of acute liver disease relying on acetaminophen overdosing. More specifically, the pannexin1-targeting nanobodies lowered serum levels of inflammatory cytokines and diminished liver damage. These effects were linked with alteration of the expression of several NLRP3 inflammasome components. Conclusions This study introduced for the first time specific, potent and in vivo-applicable nanobody-based inhibitors of pannexin1 channels. As demonstrated for the case of liver disease, the pannexin1-targeting nanobodies hold great promise as anti-inflammatory agents, yet this should be further tested for extrahepatic inflammatory disorders. Moreover, the pannexin1-targeting nanobodies represent novel tools for fundamental research regarding the role of pannexin1 channels in pathological and physiological processes. Graphical Abstract

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.

The use of integrated heaters is widespread in silicon photonics for waveguide temperature control. The dynamical behavior of the heaters is important for determining their usefulness for certain applications. There exists ambiguity in the literature when it comes to reporting the thermo-optic time constants of Si photonic devices. Many studies report devices with different heating and cooling times without providing an explanation to this phenomenon. In this paper, a comprehensive theoretical framework is developed for interpreting experimental results. This framework is developed for interferometric devices (Mach–Zehnder-based) and resonant devices (rings). With this framework, the impact of measurement conditions on the obtained thermo-optic time constant can be simulated, and we provide an explanation to the observed difference between heating and cooling time constants. We also provide guidelines on how to disentangle optical non-linearities from the pure thermal response, which should be useful in for future reporting of thermo-optic time constants.