Rationally Designed Magnetic Nanoparticles for Cochlear Drug Delivery: Synthesis, Characterization, and In Vitro Biocompatibility in a Murine Model.

Hypothesis: Magnetic nanoparticles (MNPs) for cochlear drug delivery can be precisely engineered for biocompatibility in the cochlea. Background: MNPs are promising drug delivery vehicles that can enhance the penetration of both small and macromolecular therapeutics into the cochlea. However, concerns exist regarding the application of oxidative, metal-based nanomaterials to delicate sensory tissues of the inner ear. Translational development of MNPs for cochlear drug deliver requires specifically tuned nanoparticles that are not cytotoxic to inner ear tissues. We describe the synthesis and characterization of precisely tuned MNP vehicles, and their in vitro biocompatibility in murine organ of Corti organotypic cultures. Methods: MNPs were synthesized via 2-phase ligand transfer process with precise control of nanoparticle size. Core and hydrodynamic sizes of nanoparticles were characterized using electron microscopy and dynamic light scattering, respectively. In vitro biocompatibility was assayed via mouse organ of Corti organotypic cultures with and without an external magnetic field gradient. Imaging was performed using immunohistochemical labeling and confocal microscopy. Outer hair cell, inner hair cell, and spiral ganglion neurites were individually quantified. Results: Monocore PEG-MNPs of 45 and 148 nm (mean hydrodynamic diameter) were synthesized. Organ of Corti cultures demonstrated preserved outer hair cell, inner hair cell, and neurite counts across 2 MNP sizes and doses, and irrespective of external magnetic field gradient. Conclusion: MNPs can be custom-synthesized with precise coating, size, and charge properties specific for cochlear drug delivery while also demonstrating biocompatibility in vitro.

Preoperative Briefings and Postoperative Debriefings to Increase Resident Operative Autonomy and Performance.

OBJECTIVE: To implement the use of standardized preoperative briefings and postoperative debriefings for surgical cases involving residents in an effort to improve resident autonomy and skill acquisition. DESIGN: Prospective longitudinal study. SETTING: Johns Hopkins Department of Otolaryngology-Head and Neck Surgery. PARTICIPANTS: Resident and attending physicians. RESULTS: Joint Huddles for Improving Resident Education (JHFIRE) tool was created and successfully implemented by 19 residents and 17 faculty members. Over the course of three data collection periods spanning an academic year, overall scores improved though not statistically significantly in the metrics of Zwisch autonomy, Resident Performance, and Objective Structured Assessment of Technical Skills (OSATS) scores. Female residents were scored significantly higher by attendings than their male counterparts in the assessment of baseline Resident Performance. CONCLUSIONS: (1) JHFIRE tool implemented a standardized preoperative briefing and postoperative debriefing to improve communication and resident skill acquisition; (2) The tool was accepted and utilized throughout an academic year; (3) Zwisch, Resident Performance, and OSATS scores improved though not significantly.

The Role of Preoperative Briefing and Postoperative Debriefing in Surgical Education.

OBJECTIVE: To study the impact of a new preoperative briefing and postoperative debriefing tool on the perceived quality of surgical education and to assess attitudes of residents and attendings regarding this tool. DESIGN: Surrounding introduction and use of the tool (JHFIRE: Joint Huddles for Improving Resident Education), perceived quality of surgical education was assessed with pre- and postintervention System for Evaluation of Teaching Qualities (SETQ) surveys. Additionally, a postintervention Likert survey regarding the JHFIRE tool itself was completed by residents and faculty. SETTING: Johns Hopkins University Department of Otolaryngology-Head and Neck Surgery, a tertiary care academic institution. PARTICIPANTS: All residents and attendings who used the tool were invited to participate. 40 participants (13 residents, 27 attendings) completed the preintervention SETQ. 11 participants (3 residents, 7 attendings, 1 unspecified) completed the postintervention SETQ. For postintervention qualitative assessment of the tool itself, 12 participants (3 residents, 7 attendings, 2 unspecified) provided feedback. RESULTS: The tool was well-received with large subjective benefit in improving resident surgical education. A total of 88% thought that the time spent on the debriefings was "just right" and 91% planned to make the debriefings a regular part of operative performance assessments. Despite this overwhelmingly positive feedback, there was no overall difference in pre- and postintervention SETQ scores for climate of surgical education in the Department (4.25 ± 0.55 vs. 4.10 ± 0.88, p = 0.63). CONCLUSIONS: Introduction of 4 item preoperative briefing and 4 item postoperative debriefing checklists was welcomed by both residents and faculty for its ability to shape surgical education in the operating room into a guided discovery model of hands-on education. Overall SETQ scores did not change, but most participants found value in the tool and plan to continue its use.

Structural insights of SmKDAC8 inhibitors: Targeting Schistosoma epigenetics through a combined structure-based 3D QSAR, in vitro and synthesis strategy.

A predictive structure-based 3D QSAR (COMBINEr 2.0) model of the Schistosoma mansoni lysine deacetylase 8 enzyme (SmKDAC8) was developed, validated and used to perform virtual screening (VS) of the NCI Diversity Set V database (1593 compounds). Three external datasets (with congeneric structures to those experimentally resolved in complexes by X-ray and previously reported as SmKDAC8 inhibitors) were employed to compose and validate the most predictive model. Two series characterized by 104 benzodiazepine derivatives (BZDs) and 60 simplified largazole analogs (SLAs), recently reported by our group as human KDAC inhibitors, were tested for their inhibition potency against SmKDAC8 to probe the predictive capability of the quantitative models against compounds with diverse structures. The SmKDAC8 biochemical results confirmed: (1) the benzodiazepine moiety as a valuable scaffold to further investigate when pursuing SmKDAC8 inhibition; (2) the predictive capability of the COMBINEr 2.0 model towards non-congeneric series of compounds, highlighting the most influencing ligand-protein interactions and refining the structure-activity relationships. From the VS investigations, the first 40 top-ranked compounds were obtained and biologically tested for their inhibition potency against SmKDAC8 and hKDACs 1, 3, 6 and 8. Among them, a non-hydroxamic acid benzothiadiazine dioxide derivative (code NSC163639), showed interesting activity and selectivity against SmKDAC8. To further elucidate the structure-activity relationships of NSC163639, two analogs (herein reported as compounds 3 and 4) were synthesized and biologically evaluated. Results suggest the benzothiadiazine dioxide moiety as a promising scaffold to be used in a next step to derive selective SmKDAC8 inhibitors.

Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.

A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.