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Abstract Introduction Emergency care of critically ill patients in the trauma room is an integral part of interdisciplinary work in hospitals. Live threatening injuries require swift diagnosis, prioritization, and treatment; thus, different medical specialties need to work together closely for optimal patient care. Training is essential to facilitate smooth performance. This study presents a training tool for familiarization with trauma room algorithms in immersive virtual reality (VR), and a first qualitative assessment. Materials and methods An interdisciplinary team conceptualized two scenarios and filmed these in the trauma room of the University Medical Center Mainz, Germany in 3D-360°. This video content was used to create an immersive VR experience. Participants of the Department of Anesthesiology were included in the study, questionnaires were obtained and eye movement was recorded. Results 31 volunteers participated in the study, of which 10 (32,2%) had completed specialist training in anesthesiology. Participants reported a high rate of immersion (immersion(mean) = 6 out of 7) and low Visually Induced Motion Sickness (VIMS(mean) = 1,74 out of 20). Participants agreed that VR is a useful tool for medical education (mean = 1,26; 1 very useful, 7 not useful at all). Residents felt significantly more secure in the matter after training (p

BackgroundWorking in an operating room (OR) is physically and mentally challenging: the operation itself demands the surgeon's full attention, while time and cost efficiency constraints, daily planning, and emergency care interfere with the procedure. Thus, multitasking becomes an integral surgical competence. This study aims to examine the effect of disruptions during surgery in a highly immersive virtual reality (IVR) operation environment combined with a virtual reality (VR) laparoscopy simulator. ObjectiveThis study aims to identify distractions in the OR and their importance in the clinical setting. MethodsAn IVR environment was created using a high-resolution, stereoscopic 360° video of the OR. Different distractions were identified, classified as auditory, visual, or audio-visual, and recorded accordingly. The surrounding was combined with a VR laparoscopic simulator. Participants—medical students and surgical residents—received proficiency-based training in basic laparoscopic skills and were blinded to the aim of the experiment. Following a cross-over design, each participant received a unique order of virtual distraction factors while performing tasks on the laparoscopic simulator. During the experiment, subjective passing of time, stress, heart rate, and visually induced motion sickness are recorded. After the experiment, validated questionnaires for usability, immersion, and stress were completed, as well as subjective evaluation of the distractions. The questionnaires used included the system usability scale, Self-Assessment Manikin score, National Aeronautics and Space Administration Task Load Index, and the immersion rating scale as described by Nichols. Performance in the laparoscopic tasks in relation to distractions will be evaluated by the Wilcoxon test and ANOVA for continuous variables. Subgroup analyses in regard to age, gender, and expertise (medical students vs surgical residents) are planned. ResultsThe described trial started in August 2022 and is ongoing. By July 2024, a total of 30 medical students and 9 surgeons have completed the study. ConclusionsWe present a study protocol aiming to identify the impact of different disruptions in OR during laparoscopic training in IVR. Hence, it may lead to an improved awareness of distractions and facilitate accommodations toward an improved work environment. Prior research leads to the hypothesis that the performance of a more experienced surgeon is less impacted by distractions than the performance of inexperienced surgeons and medical students. Furthermore, we investigate which type of distraction has the largest impact on performance. With this knowledge, specific multitasking training can be devised, which may be particularly useful in medical education, for which VR might play a leading role. Additionally, workplace surroundings in the OR can be optimized with this knowledge. Trial RegistrationGerman Registry for Clinical Trials DRKS00030033; https://drks.de/search/en/trial/DRKS00030033 International Registered Report Identifier (IRRID)DERR1-10.2196/59014

Abstract Stress exposure impairs brain structure and function, resulting in cognitive deficits and increased risk for psychiatric disorders such as depression, schizophrenia, anxiety and post-traumatic stress disorder. In particular, stress exposure affects function and structure of hippocampal CA1 leading to impairments in episodic memory. Here, we applied longitudinal deep-brain optical imaging to investigate the link between changes in activity patterns and structural plasticity of dorsal CA1 pyramidal neurons and hippocampal-dependent learning and memory in mice exposed to stress. We found that several days of repeated stress led to a substantial increase in neuronal activity followed by disruption of the temporal structure of this activity and spatial coding. We then tracked dynamics of structural excitatory connectivity as a potential underlying cause of the changes in activity induced by repeated stress. We thus discovered that exposure to repeated stress leads to an immediate decrease in spinogenesis followed by decrease in spine stability. By comparison, acute stress led to stabilization of the spines born in temporal proximity to the stressful event. Importantly, the temporal relationship between changes in activity levels, structural connectivity and activity patterns, suggests that loss of structural connectivity mediates the transition between increased activity and impairment of temporal organization and spatial information content in dorsal CA1 upon repeated stress exposure.

Abstract Li‐ion solid‐state batteries have the potential for high energy densities and improved safety. Oxidic all solid‐state batteries require co‐sintering of the Li‐ion conductive solid electrolyte, the active electrode material, and an electronic conductive additive to give a composite electrode. A first step for the realization of this complex system is the study of the sintering behavior of the active material itself as a single‐phase component and to investigate the electrochemical activity as well as the electronic properties after heat treatment. In this study monolithic NCM622 cathodes with a thickness of about 90 μm were sintered at temperatures up to 900°C by using a low‐melting glass as sintering additive. For these ceramic cathodes sintered at T = 800°C, an electronic conductivity of 3.0 × 10–3 S cm–1 and six orders of magnitude lower Li‐ion conductivity of about 10–9 S cm–1 were determined by DC conductivity measurement. To investigate the electrochemical performance of the sintered cathode material, the porous microstructure was infiltrated with liquid electrolyte and a charging capacity of 140 mAh g–1 (92% of the theoretical capacity) was measured with C/50 cycling rate. In comparison, the electrochemical performance without infiltration of a Li‐ion conductive liquid was tested with polyethylene oxide as polymeric separator. With these measurements the ability of the sintered cathode to charge/discharge as well as to provide sufficient high electronic conductivity has been demonstrated.

Subpopulations of neurons display increased activity during memory encoding and manipulating the activity of these neurons can induce artificial formation or erasure of memories. Thus, these neurons are thought to be cellular engrams. Moreover, correlated activity between pre- and postsynaptic engram neurons is thought to lead to strengthening of their synaptic connections, thus increasing the probability of neural activity patterns occurring during encoding to reoccur at recall. Therefore, synapses between engram neurons can also be considered as a substrate of memory, or a synaptic engram. One can label synaptic engrams by targeting two complementary, non-fluorescent, synapse-targeted GFP fragments separately to the pre- and postsynaptic compartment of engram neurons; the two GFP fragments reconstitute a fluorescent GFP at the synaptic cleft between the engram neurons, thereby highlighting synaptic engrams. In this work we explored a transsynaptic GFP reconstitution system (mGRASP) to label synaptic engrams between hippocampal CA1 and CA3 engram neurons identified by different Immediate-Early Genes: cFos and Arc. We characterized the expression of the cellular and synaptic labels of the mGRASP system upon exposure to a novel environment or learning of a hippocampal-dependent memory task. We found that mGRASP under the control of transgenic ArcCreERT2 labeled synaptic engrams more efficiently than when controlled by viral cFostTA, possibly due to differences in the genetic systems rather than the specific IEG promoters.

Introduction: To objectively assess the quality of laparoscopic camera navigation (LCN), the structured assessment of LCN skills (SALAS) score was developed and validated for laparoscopic cholecystectomy. The aim of this pre-clinical study was to investigate the influence of LCN on surgical performance during virtual cholecystectomy (vCHE) using this score. Methods: A total of 84 medical students were included in this prospective study. Individual characteristics were assessed with questionnaires. Participants completed a structured 2-day training course on a validated virtual reality laparoscopic simulator. At the end of the course, all students took over LCN during vCHE, all performed by the same surgeon. The numbers of errors regarding centering, horizon adjustment and instrument visualisation as well as manual and verbal corrections by the surgeon were recorded to calculate the SALAS score (range 5–25) to investigate the influence of LCN on surgical performance. The study population was divided by the recorded SALAS score into low and medium performers (Group A; 1st–3rd quartile; n = 60) and high performers (Group B, 4th quartile, n = 21). Results: The SALAS score of the camera assistant correlates positively with the surgeon's overall performance in vCHE (P < 0.001), and the surgeon's virtual laparoscopic performance was significantly better in Group B (P < 0.001). Moreover, a significantly shorter operation time during vCHE was shown for Group B (Median (IQR); Group A: 508 s [429 s; 601 s]; Group B: 422 s [365 s; 493 s]; P = 0.001). Frequent gaming and a higher self-confidence to assist during a basic laparoscopic procedure were associated with a higher SALAS score (P = 0.013). Conclusion: In this pre-clinical setting, the surgeon's virtual performance is significantly influenced by the LCN quality. LCN by high performers resulted in a shorter operation time and a lower error rate.

The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.

The development of regenerative therapies for central nervous system diseases can likely benefit from an understanding of the peripheral nervous system repair process, particularly in identifying potential gene pathways involved in human nerve repair. This study employed RNA sequencing (RNA-seq) technology to analyze the whole transcriptome profile of the human peripheral nerve in response to an injury. The distal sural nerve was exposed, completely transected, and a 1 to 2 cm section of nerve fascicles was collected for RNA-seq from six participants with Parkinson’s disease, ranging in age between 53 and 70 yr. Two weeks after the initial injury, another section of the nerve fascicles of the distal and pre-degenerated stump of the nerve was dissected and processed for RNA-seq studies. An initial analysis between the pre-lesion status and the postinjury gene expression revealed 3,641 genes that were significantly differentially expressed. In addition, the results support a clear transdifferentiation process that occurred by the end of the 2-wk postinjury. Gene ontology (GO) and hierarchical clustering were used to identify the major signaling pathways affected by the injury. In contrast to previous nonclinical studies, important changes were observed in molecular pathways related to antiapoptotic signaling, neurotrophic factor processes, cell motility, and immune cell chemotactic signaling. The results of our current study provide new insights regarding the essential interactions of different molecular pathways that drive neuronal repair and axonal regeneration in humans.

Despite the regenerative capabilities of peripheral nerves, severe injuries or neuronal trauma of critical size impose immense hurdles for proper restoration of neuro-muscular circuitry. Autologous nerve grafts improve re-establishment of connectivity, but also comprise substantial donor site morbidity. We developed a rat model which allows the testing of different cell applications, i.e., mesenchymal stem cells, to improve nerve regeneration in vivo. To mimic inaccurate alignment of autologous nerve grafts with the injured nerve, a 20 mm portion of the sciatic nerve was excised, and sutured back in place in reversed direction. To validate the feasibility of our novel model, a fibrin gel conduit containing autologous undifferentiated adipose-derived stem cells was applied around the coaptation sites and compared to autologous nerve grafts. After evaluating sciatic nerve function for 16 weeks postoperatively, animals were sacrificed, and gastrocnemius muscle weight was determined along with morphological parameters (g-ratio, axon density & diameter) of regenerating axons. Interestingly, the addition of undifferentiated adipose-derived stem cells resulted in a significantly improved re-myelination, axon ingrowth and functional outcome, when compared to animals without a cell seeded conduit. The presented model thus displays several intriguing features: it imitates a certain mismatch in size, distribution and orientation of axons within the nerve coaptation site. The fibrin conduit itself allows for an easy application of cells and, as a true critical-size defect model, any observed improvement relates directly to the performed intervention. Since fibrin and adipose-derived stem cells have been approved for human applications, the technique can theoretically be performed on humans. Thus, we suggest that the model is a powerful tool to investigate cell mediated assistance of peripheral nerve regeneration.

Here we report a novel microelectrode array recording approach to measure tonic (resting) and phasic release of dopamine (DA) in DA-rich areas such as the rat striatum and nucleus accumbens. The resulting method is tested in intact central nervous system (CNS) and in animals with extensive loss of the DA pathway using the neurotoxin, 6-hydroxyDA (6-OHDA). The self-referencing amperometric recording method employs Nafion-coated with and without m-phenylenediamine recording sites that through real-time subtraction allow for simultaneous measures of tonic DA levels and transient changes due to depolarization and amphetamine-induced release. The recording method achieves low-level measures of both tonic and phasic DA with decreased recording drift allowing for enhanced sensitivity normally not achieved with electrochemical sensors in vivo.

Engrailed-1 (En1) is expressed in the ventral ectoderm of the developing limb where it plays an instructive role in the dorsal-ventral patterning of the forelimb. Besides its well-described role as a transcription factor in regulating gene expression through its DNA-binding domain, En1 may also be secreted to form an extracellular gradient, and directly impact on the formation of the retinotectal map. We show here that absence of En1 causes mispatterning of the forelimb and thus defects in the dorsal-ventral pathfinding choice of motor axons in vivo. In addition, En1 but not En2 also has a direct and specific repulsive effect on motor axons of the lateral aspect of the lateral motor column (LMC) but not on medial LMC projections. Moreover, an ectopic dorsal source of En1 pushes lateral LMC axons to the ventral limb in vivo. Thus, En1 controls the establishment of limb innervation through two distinct molecular mechanisms.

Abstract This resource is a curriculum designed to disseminate and evaluate the skills that a senior medical student is expected to know prior to starting their pediatric residency. This curriculum, typically done during the month-long sub-internship, consists of three parts. Prior to their sub-internship, students watch an online video on how to care transition a patient. During the first week of their sub-internship, students participated in three 1-hour interactive workshops teaching organization skills, presentation skills, and professionalism/communication skills. During the last week of their sub-internship, students underwent five objective structured clinical exams (OSCEs), the latter two of which used simulation. Feedback was given at the end of the OSCEs. This resource includes the care transition tool our institution uses, two videos that demonstrate to the learner the improper way and the proper way to use the care transition tool, the materials need for the three workshops, and five OSCE station instructions and resources. This curriculum was studied over the course of 2 years. Pre- and postcurriculum confidence surveys based on the skills taught showed that learners increased their confidence in each of the curriculums areas. In addition, final evaluations were given to the learners asking them to assess the effectiveness of each component in increasing their knowledge in each of the six ACGME competencies. Each component was viewed as favorable in all six of the ACGME competencies.

Ductal adenocarcinoma of the pancreas is a lethal disease. Surgical extirpation only offers the slim chance for long-term survival in localized disease. We report on a 73 year old female patient who initially underwent successful resection of pancreatic adenocarcinoma in May 2005. She was treated with adjuvant chemotherapy with gemcitabine. In October 2010 the patient noticed increasing dyspnea with haemoptysis. She was soon referred to our center. After the diagnosis of pulmonary adenocarcinoma with widespread metastasis, she was treated with systemic chemotherapy. For a period of next three years, she was treated with different chemotherapy regimens due to repeated episodes of tumor progression. To the best of our knowledge after reviewing the literature, this case represents an unusually clinical course with metachronous pulmonary adenocarcinoma arising after treatment of a primary pancreatic cancer after a long latency period.

Prefrontal cortical activity in the primate brain emerging from minicolumnar microcircuits plays a critical role in cognitive processes dealing with executive control of behavior. However, the specific operations of columnar laminar processing in prefrontal cortex are not completely understood. Here we show via implementation of unique microanatomical recording and stimulating arrays, that minicolumns in prefrontal cortex are involved in the executive control of behavior in rhesus macaque nonhuman primates performing a delayed match-to-sample (DMS) task. Prefrontal cortical (PFC) neurons demonstrate functional interactions between pairs of putative pyramidal cells within specified cortical layers via anatomically oriented minicolumns. Results reveal target-specific, spatially tuned firing between inter-laminar (layer 2/3 and layer 5) pairs of neurons participating in the gating of information during the decision making phase of the task with differential correlations between activity in layer 2/3 and layer 5 in the integration of spatial vs. object-specific information for correct task performance. Such inter-laminar processing was exploited by the interfacing of an online model which delivered stimulation to layer 5 locations in a pattern associated with successful performance thereby closing the columnar loop externally in a manner that mimicked normal processing in the same task. These unique technologies demonstrate that PFC neurons encode and process information via minicolumns which provides a closed loop form of executive function, hence disruption of such inter-laminar processing could form the bases for cognitive dysfunction in primate brain.

During development, fibroblast growth factors (FGF) are essential for early patterning events along the anterior-posterior axis, conferring positional identity to spinal motor neurons by activation of different Hox codes. In the periphery, signaling through one of four fibroblast growth factor receptors supports the development of the skeleton, as well as induction and maintenance of extremities. In previous studies, FGF receptor 2 (FGFR2) was found to interact with axon bound molecules involved in axon fasciculation and extension, thus rendering this receptor an interesting candidate for the promotion of proper peripheral innervation. However, while the involvement of FGFR2 in limb bud induction has been extensively studied, its role during axon elongation and formation of distinct nervous projections has not been addressed so far. We show here that motor neurons in the spinal cord express FGFR2 and other family members during the establishment of motor connections to the forelimb and axial musculature. Employing a conditional genetic approach to selectively ablate FGFR2 from motor neurons we found that the patterning of motor columns and the expression patterns of other FGF receptors and Sema3A in the motor columns of mutant embryos are not altered. In the absence of FGFR2 signaling, pathfinding of motor axons is intact, and also fasciculation, distal advancement of motor nerves and gross morphology and positioning of axonal projections are not altered. Our findings therefore show that FGFR2 is not required cell-autonomously in motor neurons during the formation of initial motor projections towards limb and axial musculature.

The neuromuscular junctions are the specialized synapses whereby spinal motor neurons control the contraction of skeletal muscles. The formation of the neuromuscular junctions is controlled by a complex interplay of multiple mechanisms coordinately activated in motor nerve terminals and in their target myotubes. However, the transcriptional regulators that control in motor neurons the genetic programs involved in neuromuscular junction development remain unknown. Here, we provide evidence that the Onecut transcription factor HNF-6 regulates in motor neurons the formation of the neuromuscular junctions. Indeed, adult Hnf6 mutant mice exhibit hindlimb muscle weakness and abnormal locomotion. This results from defects of hindlimb neuromuscular junctions characterized by an abnormal morphology and defective localization of the synaptic vesicle protein synaptophysin at the motor nerve terminals. These defects are consequences of altered and delayed formation of the neuromuscular junctions in newborn mutant animals. Furthermore, we show that the expression level of numerous regulators of neuromuscular junction formation, namely agrin, neuregulin-2 and TGF-ß receptor II, is downregulated in the spinal motor neurons of Hnf6 mutant newborn animals. Finally, altered formation of neuromuscular junction-like structures in a co-culture model of wildtype myotubes with mutant embryonic spinal cord slices is rescued by recombinant agrin and neuregulin, indicating that depletion in these factors contributes to defective neuromuscular junction development in the absence of HNF-6. Thus, HNF-6 controls in spinal motor neurons a genetic program that coordinates the formation of hindlimb neuromuscular junctions.

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with C57BL/6. Using an enzyme-based MEA (microelectrode array) that is selective for measuring glutamate in vivo , we measured depolarization-induced glutamate release. Within a discrete layer of the striatum, glutamate release was significantly increased in Balb/c Tg mice compared with wt (wild-type) littermates. Furthermore, Balb/c mice released approx. 50–60% of the amount of glutamate compared with C57BL/6 mice. This is similar to the lower levels of endogenous GLUD1 protein in Balb/c compared with C57BL/6 mice. The development of these Glud1 -overexpressing mice may allow for the exploration of key molecular events produced by chronic exposure of neurons to moderate, transient increases in glutamate release, a process hypothesized to occur in neurodegenerative disorders.

The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.

Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed.Here we present the neurobiological actions of dopamine neuron stimulating peptide-11 (DNSP-11), an 11-mer peptide from the proGDNF domain. In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced cell death, significantly decreasing TUNEL-positive cells and levels of caspase-3 activity. In vivo, a single injection of DNSP-11 into the normal adult rat substantia nigra is taken up rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of PD. Unlike GDNF, DNSP-11 was found to block staurosporine- and gramicidin-induced cytotoxicity in nutrient-deprived dopaminergic B65 cells, and its neuroprotective effects included preventing the release of cytochrome c from mitochondria.Collectively, these data support that DNSP-11 exhibits potent neurotrophic actions analogous to GDNF, making it a viable candidate for a PD therapeutic. However, it likely signals through pathways that do not directly involve the GFRalpha1 receptor.