Assessment of Technical Competence in Distal Radius Fracture Fixation by a Volar Locking Plate: A Global Delphi Consensus Study.

PURPOSE: Volar locking plate fixation of distal radius fractures is a common orthopedic procedure and should be mastered by graduating orthopedic residents. Surgical education is transitioning from a traditional time-based approach to competency-based medical education. Valid and objective assessment is essential for successful transition. The purpose of this study was to develop a comprehensive, procedure-specific assessment tool to evaluate technical competence in volar locking plate osteosynthesis of a distal radius fracture. METHODS: International orthopedic/trauma experts involved in resident education participated as panelists in a four-round online Delphi process to reach consensus on the content of the assessment tool. Round 1 was an item-generating round, in which the panelists identified potential assessment parameters. In round 2, the panelists rated the importance of each suggested assessment parameter and reached consensus on which to include in the assessment tool. Round 3 yielded specific assessment score intervals for specific bone and fracture models and is not reported in this study. In round 4, the panelists assigned weights to the assessment parameters on a 1-10 scale to determine how each parameter should have an impact on the overall results. RESULTS: Eighty-seven surgeons, representing 42 countries, participated in the study. Round 1 resulted in 45 assessment parameters, grouped into five procedural steps. After round 2, the number of parameters was reduced to 39. After the final round, an additional parameter was removed and weights were assigned to the remaining parameters. CONCLUSIONS: Using a systematic methodology, a preliminary assessment tool to evaluate technical competence in distal radius fracture fixation was developed. A consensus of international experts supports the content validity of the assessment tool. CLINICAL RELEVANCE: This assessment tool represents the first step in the evidence-based assessment essential for competency-based medical education. Before implementation, further studies exploring validity of variations of the assessment tool in different educational contexts are required.

Mice carrying an analogous heterozygous dynamin 2 K562E mutation that causes neuropathy in humans develop predominant characteristics of a primary myopathy.

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.

Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination.

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 α2ß1γ1 (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.

α6ß1 and α7ß1 integrins are required in Schwann cells to sort axons.

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 ß1 integrin subunit are required for radial sorting; however, which of the 11 α integrins that can pair with ß1 forms the functional receptor is unknown. Here we conditionally deleted all the α subunits that form predominant laminin-binding ß1 integrins in Schwann cells and show that only α6ß1 and α7ß1 integrins are required and that α7ß1 compensates for the absence of α6ß1 during development. The absence of either α7ß1 or α6ß1 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 ß1 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, α6ß1 and α7ß1 are the laminin-binding integrins required for axonal sorting, but other Schwann cell ß1 integrins, possibly those that do not bind laminins, may also contribute to radial sorting during peripheral nerve development.

Non-redundant function of dystroglycan and ß1 integrins in radial sorting of axons.

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 αß1 integrins, because their absence phenocopies laminin and glycosyltransferase deficiency, but the topography of the phenotypes is different and ß1 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 ß1 integrins impairs proliferation and survival, and arrests radial sorting at early stages, that ß1 integrins and dystroglycan activate different pathways, and that the absence of both molecules is synergistic. Thus, the function of dystroglycan and ß1 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.

Discrimination, reliability, sensitivity, and specificity of metric-based assessment of an unstable pertrochanteric 31A2 intramedullary nailing procedure performed by experienced and novice surgeons.

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.

Hepatitis C virus and alcohol: same mitotic targets but different signaling pathways.

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.

What are Learner and Instructor Preferences for Group Size and Composition for a Series of Synchronous Online Case Discussions for Upper Extremity Trauma Surgeons?

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.

Experiences from Two Ways of Integrating Pre- and Post-course Multiple-choice Assessment Questions in Educational Events for Surgeons.

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.

Design, delivery, and evaluation of seminars and hands-on courses worldwide on intraoperative imaging in orthopedic trauma.

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.

Schwann cells, but not Oligodendrocytes, Depend Strictly on Dynamin 2 Function.

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.

The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211.

Myelin 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.

Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system.

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 α6ß4 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 α6ß4 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.