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ZusammenfassungUm den Erfolg und die Effektivität von Fortbildungsveranstaltungen zu ermitteln und die Qualität der medizinischen Fortbildung zu verbessern, brauchen Kursanbieter, Dozierende und Instruktoren von praktischen Übungen Zugang zu klar strukturierten und umfangreichen Evaluations- und Assessmentdaten. Die AO führte 2016 ein neues, schlankes und einheitliches Evaluations- und Assessmentsystem ein, das AO Trauma Deutschland seit 2019 benutzt. Die erstellten Berichte haben den Dozierenden ermöglicht, die Fortbildungsveranstaltungen den Bedürfnissen der Teilnehmer anzupassen. Das neue System hat es den verschiedenen Komitees auch ermöglicht, zukünftige Fortbildungsveranstaltungen zu planen und die Qualität der medizinischen Weiterbildung stetig zu verbessern. Insgesamt waren die von AO Trauma Deutschland angebotenen Veranstaltungen erfolgreich und wurden den Bedürfnissen der Teilnehmer/-innen gerecht.

INTRODUCTION: Identifying objective performance metrics for surgical training in orthopedic surgery is imperative for effective training and patient safety. The objective of this study was to determine if an internationally agreed, metric-based objective assessment of video recordings of an unstable pertrochanteric 31A2 intramedullary nailing procedure distinguished between the performance of experienced and novice orthopedic surgeons. MATERIALS AND METHODS: Previously agreed procedure metrics (i.e., 15 phases of the procedure, 75 steps, 88 errors, and 28 sentinel errors) for a closed reduction and standard cephalomedullary nail fixation with a single cephalic element of an unstable pertrochanteric 31A2 fracture. Experienced surgeons trained to assess the performance metrics with an interrater reliability (IRR) > 0.8 assessed 14 videos from 10 novice surgeons (orthopaedic residents/trainees) and 20 videos from 14 experienced surgeons (orthopaedic surgeons) blinded to group and procedure order. RESULTS: The mean IRR of procedure assessments was 0.97. No statistically significant differences were observed between the two groups for Procedure Steps, Errors, Sentinel Errors, and Total Errors. A small number of Experienced surgeons made a similar number of Total Errors as the weakest performing Novices. When the scores of each group were divided at the median Total Error score, large differences were observed between the Experienced surgeons who made the fewest errors and the Novices making the most errors (p < 0.001). Experienced surgeons who made the most errors made significantly more than their Experienced peers (p < 0.003) and the best performing Novices (p < 0.001). Error metrics assessed with Area Under the Curve demonstrated good to excellent Sensitivity and Specificity (0.807-0.907). DISCUSSION: Binary performance metrics previously agreed by an international Delphi meeting discriminated between the objectively assessed video-recorded performance of Experienced and Novice orthopedic surgeons when group scores were sub-divided at the median for Total Errors. Error metrics discriminated best and also demonstrated good to excellent Sensitivity and Specificity. Some very experienced surgeons performed similar to the Novice group surgeons that made most errors. CONCLUSIONS: The procedure metrics used in this study reliably distinguish Novice and Experienced orthopaedic surgeons' performance and will underpin quality-assured novice training.

Small group discussion (SGD) is a well-known educational method to promote active learning. Best practices for running SGDs in face-to-face events are described in the literature; however, little has been reported regarding synchronous online delivery. The aim of this study was to determine learner and instructor preferences for online SGDs in terms of group size and composition and to formulate best practices based on participant and faculty feedback. We designed an 8-module online course for surgeons managing upper extremity trauma. Participants were pre-assigned into 2 types of group: 1 faculty with 5 participants or 2 faculty with 8 participants. We collected feedback from 91 participants and 34 faculty over the 8 weeks in multiple ways. Participants preferred way to run an online SGD is to have 2 faculty with 4–5 participants (80%), rotating to different faculty every week (67%), and interacting with peers from different countries (95%). Pre-course assessment questions and pre-recorded presentations enhanced the online discussions for 82%. From open text comments, we identified that cases/content, faculty, participant engagement, and technical support worked well. The course could be improved by adding more extensive technical and connectivity checks, having a different time scheduling, and integrating more supporting materials.

To examine how to optimise the integration of multiple-choice questions (MCQs) for learning in continuing professional development (CPD) events in surgery, we implemented and evaluated two methods in two subspecialities over multiple years. The same 12 MCQs were administered pre- and post-event in 66 facial trauma courses. Two different sets of 10 MCQs were administered pre- and post-event in 21 small animal fracture courses. We performed standard psychometric tests on responses from participants who completed both the pre- and post-event assessment. The average difficulty index pre-course was 57% with a discrimination index of 0.20 for small animal fractures and 53% with a discrimination index of 0.15 for facial trauma. For the majority of the individual MCQs, the scores were between 30%-70% and the discrimination index was >0.10. The difficulty index post-course increased in both groups (to 75% and 62%). The pre-course MCQs resulted in an average score in the expected range for both formats suggesting they were appropriate for the intended level of difficulty and an appropriate pre-course learning activity. Post-course completion resulted in increased scores with both formats. Both delivery methods worked well in all regions and overall quality depends on applying a solid item development and validation process.

Introduction Although intraoperative imaging is important for assessing the quality of several steps during fracture fixation, most trainees and surgeons have received little formal education on this topic and report they learn "on the job" and "through practice". A planning committee of orthopedic trauma surgeons was established to design a curriculum using "backward planning" to identify patient problems, identify gaps in surgeons' knowledge and skills, and define competencies as a framework for education in order to optimize patient care. Materials and methods The committee defined 8 competencies related to intraoperative imaging, with detailed learning objectives for each one (e.g. select the imaging modality, set up the operating room). An interactive, case-based half-day seminar to deliver these objectives for 2-D and 3-D intraoperative imaging during the fixation of common fractures was designed. The seminar was delivered in several locations worldwide over a 6-year period and evaluation and assessment data were gathered online. A full-day procedures course was added and delivered 6 times to address the skills component of competencies. Results 17 seminars and 6 courses were delivered and attended by an average of 26 and 17 participants respectively (ranges 13–42 and 13–20). Pre-event gap analysis and assessment question scores confirmed needs and motivation to learn in all events. 97% of the 442 seminar participants and 98% of the 100 course participants would recommend the events to colleagues. An average of 88% and 90% respectively learned something new and plan to use it in their practice (range 63%-100%). Commitment to change (CTC) statements showed intended practice improvements related to all competencies. Discussion The large percentages of high impact ratings for all events suggest the content met the needs of many participants. Post-event reduction in gap scores and an increase in the desired level of ability for most competencies suggests the content addressed many gaps. Conclusions Case-based, interactive seminars and courses addressing knowledge, skills, and attitudes to optimize the use of intraoperative imaging during the fixation of common fractures help address unmet educational needs for trainees and complements existing formal training.

Background A critical step in curriculum development is conducting a needs assessment of learners. In spine surgery, the educational needs of trainees, and especially of practicing surgeons, evolve frequently due to changes in practice, technology, etc. To monitor these changes and adapt the educational offerings, organizations delivering continuing medical education (CME) and continuing professional development (CPD) periodically repeat needs assessments. Methods An international needs assessment in the form of a set of 15 online questions was designed and circulated in 2017 and in 2021 to the AO Spine community of members and registered users to gather input in five main areas: educational needs in spine pathologies and techniques, required improvements in practice, preferences for types of educational offerings, and profiling information. Results We received and analyzed 1,204 responses in English during the main reporting period in the 2017 needs assessment from residents, fellows, and practicing surgeons in orthopedics and neurosurgery, and 1,845 in 2021. Spine surgeons wish to improve their knowledge related to all the common pathologies, with some variability among regions and stage of career. Minimally invasive spine surgery (MISS) was the highest-rated need within surgical techniques in all regions (except North America) and all stages of career. Data show a strong preference for face-to-face courses with hands-on training, high demand for mentorship/fellowship/observership, and solid interest in online and blended education. Conclusions The needs assessment process pointed out general trends but also identified varying needs depending on the local situation and stage of career. For this reason, CME/CPD providers must adapt to the local situation to provide educational offerings that meet learner needs.

Some mutations affecting dynamin 2 (DNM2) can cause dominantly inherited Charcot–Marie–Tooth (CMT) neuropathy. Here, we describe the analysis of mice carrying the DNM2 K562E mutation which has been associated with dominant-intermediate CMT type B (CMTDIB). Contrary to our expectations, heterozygous DNM2 K562E mutant mice did not develop definitive signs of an axonal or demyelinating neuropathy. Rather, we found a primary myopathy-like phenotype in these mice. A likely interpretation of these results is that the lack of a neuropathy in this mouse model has allowed the unmasking of a primary myopathy due to the DNM2 K562E mutation which might be overshadowed by the neuropathy in humans. Consequently, we hypothesize that a primary myopathy may also contribute to the disease mechanism in some CMTDIB patients. We propose that these findings should be considered in the evaluation of patients, the determination of the underlying disease processes and the development of tailored potential treatment strategies., Human Molecular Genetics, 29 (8), ISSN:0964-6906, ISSN:1460-2083

Myelination requires extensive plasma membrane rearrangements, implying that molecules controlling membrane dynamics play prominent roles. The large GTPase dynamin 2 (DNM2) is a well-known regulator of membrane remodeling, membrane fission, and vesicular trafficking. Here, we genetically ablated Dnm2 in Schwann cells (SCs) and in oligodendrocytes of mice. Dnm2 deletion in developing SCs resulted in severely impaired axonal sorting and myelination onset. Induced Dnm2 deletion in adult SCs caused a rapidly-developing peripheral neuropathy with abundant demyelination. In both experimental settings, mutant SCs underwent prominent cell death, at least partially due to cytokinesis failure. Strikingly, when Dnm2 was deleted in adult SCs, non-recombined SCs still expressing DNM2 were able to remyelinate fast and efficiently, accompanied by neuropathy remission. These findings reveal a remarkable self-healing capability of peripheral nerves that are affected by SC loss. In the central nervous system, however, we found no major defects upon Dnm2 deletion in oligodendrocytes., eLife, 8, ISSN:2050-084X

Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin., Author summary Myelin is formed by the wrapping of glial cell membranes around axons and is required for the fast conduction of nerve impulses and to support axons. In the peripheral nervous system, myelin is produced by Schwann cells. Peripheral myelin defects cause debilitating diseases, whose molecular pathogeneses are only partially understood. Here, we reveal for the first time how 2 crucial extracellular modulators of myelin formation, neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211), work together in the peripheral nervous system. Although Lm211 was believed to promote myelination, we show that it can also inhibit myelin formation by suppressing the activity of Nrg1III, limiting the activation of its downstream signaling cascade. These results help to explain why certain inherited neuropathies are characterized by hypermyelination and redundant myelin sheaths.

Functionally and spatially distinct PI 3-K pathways act either early to promote myelination downstream of axonal Neuregulin1 or late to inhibit myelination downstream of α6β4 integrin and Sgk1., The PI 3-kinase (PI 3-K) signaling pathway is essential for Schwann cell myelination. Here we have characterized PI 3-K effectors activated during myelination by probing myelinating cultures and developing nerves with an antibody that recognizes phosphorylated substrates for this pathway. We identified a discrete number of phospho-proteins including the S6 ribosomal protein (S6rp), which is down-regulated at the onset of myelination, and N-myc downstream-regulated gene-1 (NDRG1), which is up-regulated strikingly with myelination. We show that type III Neuregulin1 on the axon is the primary activator of S6rp, an effector of mTORC1. In contrast, laminin-2 in the extracellular matrix (ECM), signaling through the α6β4 integrin and Sgk1 (serum and glucocorticoid-induced kinase 1), drives phosphorylation of NDRG1 in the Cajal bands of the abaxonal compartment. Unexpectedly, mice deficient in α6β4 integrin signaling or Sgk1 exhibit hypermyelination during development. These results identify functionally and spatially distinct PI 3-K pathways: an early, pro-myelinating pathway driven by axonal Neuregulin1 and a later-acting, laminin–integrin-dependent pathway that negatively regulates myelination.

Radial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during peripheral nerve development. Radial sorting is impaired in models of human diseases, congenital muscular dystrophy (MDC) 1A, MDC1D and Fukuyama, owing to loss-of-function mutations in the genes coding for laminin α2, Large or fukutin glycosyltransferases, respectively. It is not clear which receptor(s) are activated by laminin 211, or glycosylated by Large and fukutin during sorting. Candidates are αβ1 integrins, because their absence phenocopies laminin and glycosyltransferase deficiency, but the topography of the phenotypes is different and β1 integrins are not substrates for Large and fukutin. By contrast, deletion of the Large and fukutin substrate dystroglycan does not result in radial sorting defects. Here, we show that absence of dystroglycan in a specific genetic background causes sorting defects with topography identical to that of laminin 211 mutants, and recapitulating the MDC1A, MDC1D and Fukuyama phenotypes. By epistasis studies in mice lacking one or both receptors in SCs, we show that only absence of β1 integrins impairs proliferation and survival, and arrests radial sorting at early stages, that β1 integrins and dystroglycan activate different pathways, and that the absence of both molecules is synergistic. Thus, the function of dystroglycan and β1 integrins is not redundant, but is sequential. These data identify dystroglycan as a functional laminin 211 receptor during axonal sorting and the key substrate relevant to the pathogenesis of glycosyltransferase congenital muscular dystrophies.

Background & Aims: Chromosomal aberrations are frequently observed in hepatitis C virus (HCV)- and alcohol-related hepatocellular carcinomas (HCCs). The mechanisms by which chromosomal aberrations occur during hepatocarcinogenesis are still unknown. However, these aberrations are considered to be the result of deregulation of some mitotic proteins, including the alteration of Cyclin B1 and Aurora kinase A expression, and the phosphorylation of gamma-tubulin. Our study aims at investigating changes in expression of the above mentioned proteins and related intracellular pathways, in in vitro and in vivo models of both HCV- and alcohol- dependent HCCs. Methods: In this study, the molecular defects and the mechanisms involved in deregulation of the mitotic machinery were analyzed in human hepatoma cells, expressing HCV proteins treated or not with ethanol, and in liver tissues from control subjects (n = 10) and patients with HCV- (n = 10) or alcohol-related (n = 10) HCCs. Results: Expression of Cyclin B1, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin was analyzed in models reproducing HCV infection and ethanol treatment in HCC cells. Interestingly, HCV and alcohol increased the expression of Cyclin B, Aurora kinase A, and tyrosine- phosphorylated gamma-tubulin also in tissues from patients with HCV- or alcohol-related HCCs. In vitro models suggest that HCV requires the expression of PKR (RNA-activated protein kinase), as well as JNK (c-Jun N-terminal kinase) and p38MAPK (p38 mitogen-activated protein kinase) proteins; while, ethanol bypasses all these pathways. Conclusions: Our results support the idea that HCV and alcohol may promote oncogenesis by acting through the same mitotic proteins, but via different signaling pathways. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Cell–cell interactions promote juxtacrine signals in specific subcellular domains, which are difficult to capture in the complexity of the nervous system. For example, contact between axons and Schwann cells triggers signals required for radial sorting and myelination. Failure in this interaction causes dysmyelination and axonal degeneration. Despite its importance, few molecules at the axo-glial surface are known. To identify novel molecules in axo-glial interactions, we modified the ‘pseudopodia' sub-fractionation system and isolated the projections that glia extend when they receive juxtacrine signals from axons. By proteomics we identified the signalling networks present at the glial-leading edge, and novel proteins, including members of the Prohibitin family. Glial-specific deletion of Prohibitin-2 in mice impairs axo-glial interactions and myelination. We thus validate a novel method to model morphogenesis and juxtacrine signalling, provide insights into the molecular organization of the axo-glial contact, and identify a novel class of molecules in myelination., Neuron–glia interactions are critical in the nervous system, where they result in the extension of glial pseudopodia. Poitelon et al. isolate these protrusions using an in vitro assay, and, by characterising their proteomes, identify Prohibitin-2 as a regulator of myelination.

During development, Schwann cells extend lamellipodia-like processes to segregate large- and small-caliber axons during the process of radial sorting. Radial sorting is a prerequisite for myelination and is arrested in human neuropathies because of laminin deficiency. Experiments in mice using targeted mutagenesis have confirmed that laminins 211, 411, and receptors containing the β1 integrin subunit are required for radial sorting; however, which of the 11 α integrins that can pair with β1 forms the functional receptor is unknown. Here we conditionally deleted all the α subunits that form predominant laminin-binding β1 integrins in Schwann cells and show that only α6β1 and α7β1 integrins are required and that α7β1 compensates for the absence of α6β1 during development. The absence of either α7β1 or α6β1 integrin impairs the ability of Schwann cells to spread and to bind laminin 211 or 411, potentially explaining the failure to extend cytoplasmic processes around axons to sort them. However, double α6/α7 integrin mutants show only a subset of the abnormalities found in mutants lacking all β1 integrins, and a milder phenotype. Double-mutant Schwann cells can properly activate all the major signaling pathways associated with radial sorting and show normal Schwann cell proliferation and survival. Thus, α6β1 and α7β1 are the laminin-binding integrins required for axonal sorting, but other Schwann cell β1 integrins, possibly those that do not bind laminins, may also contribute to radial sorting during peripheral nerve development.

Myogenic differentiation is a highly orchestrated multistep process controlled by extracellular growth factors that modulate largely unknown signals into the cell affecting the muscle-transcription program. P38MAPK-dependent signalling, as well as PI3K/Akt pathway, has a key role in the control of muscle gene expression at different stages during the myogenic process. P38MAPK affects the activities of transcription factors, such as MyoD and myogenin, and contributes, together with PI3K/Akt pathway, to control the early and late steps of myogenic differentiation. The aim of our work was to better define the role of PKR, a dsRNA-activated protein kinase, as potential component in the differentiation program of C2C12 murine myogenic cells and to correlate its activity with p38MAPK and PI3K/Akt myogenic regulatory pathways. Here, we demonstrate that PKR is an essential component of the muscle development machinery and forms a functional complex with p38MAPK and/or Akt, contributing to muscle differentiation of committed myogenic cells in vitro. Inhibition of endogenous PKR activity by a specific (si)RNA and a PKR dominant-negative interferes with the myogenic program of C2C12 cells, causing a delay in activation of myogenic specific genes and inducing the formation of thinner myofibers. In addition, the construction of three PKR mutants allowed us to demonstrate that both N and C-terminal regions of PKR are critical for the interaction with p38MAPK and Akt. The novel discovered complex permits PKR to timely regulate the inhibition/activation of p38MAPK and Akt, controlling in this way the different steps characterizing skeletal muscle differentiation.

SummaryMyelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells (SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation. These biphasic roles of GPR126 are governed by interactions with Laminin-211, which we define as a novel ligand for GPR126 that modulates receptor signaling via a tethered agonist. Our work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development.