Background: Demonstrating competency before independent practice is increasingly important in surgery. This study tests the hypothesis that a high-fidelity cleft lip simulator can be used to discriminate performance between training levels, demonstrating its utility for assessing procedural competence. Methods: During this prospective cohort study, participants performed a unilateral cleft lip repair on a high-fidelity simulator. Videos were blindly rated using the Objective Structured Assessment of Technical Skills (OSATS) and the Unilateral Cleft Lip Repair Competency Assessment Tool (UCLR). Digital measurement of symmetry was estimated. Influence of training level and cumulative prior experience on each score was estimated using Pearson r. Results: Participants (n = 26) ranged from postgraduate year 3 to craniofacial fellow. Training level correlated best with UCLR (R = 0.4842, P = 0.0122*) and more weakly with OSATS (R = 0.3645, P = 0.0671), whereas cumulative prior experience only weakly correlated with UCLR (R = 0.3450, P = 0.0843) and not with OSATS (R = 0.1609, P = 0.4323). UCLR subscores indicated marking the repair had little correlation with training level (R = 0.2802, P = 0.1656), whereas performance and result did (R = 0.5152, P = 0.0071*, R = 0.4226, P = 0.0315*, respectively). Correlation between symmetry measures and training level was weak.Conclusions: High-fidelity simulation paired with an appropriate procedure-specific assessment tool has the construct validity to evaluate performance for cleft lip repair. Simply being able to mark a cleft lip repair is not an accurate independent assessment method nor is symmetry of the final result.

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Summary:B.Y. was born full term after a large vertex encephalocele was diagnosed prenatally. The unique challenge to repairing B.Y.’s encephalocele was a microcephalic skull and large proportion of likely functional extracranial brain tissue, which would need to be preserved. At Boston Children’s Hospital, a simulation-based collaborative presurgical planning and rehearsal process, using both digital and 3D printed models, enabled successful technical completion and outcome of an otherwise inoperable case.

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Mutations within the epidermal growth factor receptor (EGFR/erbB1/Her1) are often associated with carcinogenesis. Specific mutations common in non-small cell lung cancer (NSCLC), including EGFR-L858R and EGFR-DL747-P753, lead to ligand-independent phosphorylation, however the molecular mechanism by which these mutations in the EGFR kinase domain confer constitutive activity remain unknown. Here, using multiple sub-diffractionlimit imaging modalities, we reveal the altered behavior of NSCLCassociated EGFR mutants within the plasma membrane_including altered receptor dimerization, dynamics, and structure_which collectively dysregulate receptor activity. Using multi-color single particle tracking (SPT) and Hidden Markov Model analysis, EGFR mutants are shown to form stable dimers in the absence of ligand and exhibit a slower mobility that is consistent with receptor signaling. These results were confirmed using two-color, single-molecule super-resolution microscopy (dSTORM) to visualize the spatial distribution of receptors. Receptor clustering was quantified by localization-based crosscorrelation analysis to show ligand-induced aggregation of EGFR as well as ligand-independent aggregation of EGFR mutants. Since the receptor ectodomain is known to play a critical role in dimerization, live cell FRET measurements between the EGFR N-terminus and the plasma membrane was used to quantify changes in ectodomain structure. We found that unliganded EGFR mutants are more readily found in the extended conformation, similar to the ligand bound wild type receptor. Therefore, mutation within the kinase domain biases the structural equilibrium of the extracellular domain toward a dimercompetent state. Collectively, these data support a model where oncogenic signaling from NSCLC-associated EGFR mutants is a result of productive dimerization between non-ligand bound receptors. Furthermore, because these mutations are found in the kinase domain, this work introduces the concept that oncogenic EGFR signaling may be controlled in part by a form of ''inside-out'' signaling.