Computationally Designed Molecules Modulate ALS-Related Amyloidogenic TDP-43307-319 Aggregation.

Abnormal cytosolic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is observed in multiple diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease. Previous studies have shown that TDP-43307-319 located at the C-terminal of TDP-43 can form higher-order oligomers and fibrils. Of particular interest are the hexamers that adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we use the joint pharmacophore space (JPS) model to identify and generate potential TDP-43 inhibitors. Five JPS-designed molecules are evaluated using both experimental and computational methods: ion mobility mass spectrometry, thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that all five molecules can prevent the amyloid fibril formation of TDP-43307-319, but their efficacy varies significantly. Furthermore, among the five molecules, [AC0101] is the most efficient in preventing the formation of higher-order oligomers and dissociating preformed higher-order oligomers. Molecular dynamics simulations show that [AC0101] both is the most flexible and forms the most hydrogen bonds with the TDP-43307-319 monomer. The JPS-designed molecules can insert themselves between the ß-strands in the hexameric cylindrin structure of TDP-43307-319 and can open its structure. Possible mechanisms for JPS-designed molecules to inhibit and dissociate TDP-43307-319 oligomers on an atomistic scale are proposed.

Use of Simulation-Based Mastery Learning Curriculum to Improve Difficult Conversation Skills Among Anesthesiologists: A Pilot Study.

Background: Breaking bad news (BBN) is an important clinical task for physicians. Unfortunately, there is no standard method to teach and assess these skills of anesthesiologists. Although anesthesiology has become a relatively safe medical specialty, complications still occur that require disclosure to patients and their families. Disclosure of bad news can be a significant source of stress for clinicians, especially for those who have low confidence in their BBN skills. Anesthesiologists' skills in BBN can be improved with simulation-based mastery learning (SBML), an intense form of competency-based learning. Methods: An SBML curriculum was developed using the SPIKES (Situation, Perception, Invitation, Knowledge, Emotion, Summarize) framework for BBN and the NURSE (Naming, Understanding, Respecting, Supporting, Exploring) statements for expressing empathy. A pretest-posttest study was conducted from March 2020 to June 2022 to evaluate anesthesiologists' performance in BBN. Participants completed a 2-hour curriculum consisting of a pretest, didactic session, deliberate practice with feedback, and a posttest. Anesthesiologists were assessed using a 16-item skills checklist. Results: Six anesthesiology attendings and 14 anesthesiology fellows were enrolled in the study. Three of 20 participants met the minimum passing score (MPS) at the time of their pretest. All study participants met the MPS on their first posttest (P < .001). The median participant confidence in BBN significantly increased (3 to 4, P < .001). Overall course satisfaction in the curriculum was high, with a median score of 5. Conclusions: Our study demonstrates that a BBN SBML curriculum for anesthesiologists significantly improved communication skills and confidence in a simulated environment. Because only 3 participants met the MPS before training, our results suggest that anesthesiologists could benefit from further education to gain effective communication skills and that SBML training may be effective to achieve this result.

Use of an ultrasound-guided intravenous catheter insertion simulation-based mastery learning curriculum to improve paediatric anaesthesia care.

Background: We previously showed that an ultrasound-guided i.v. catheter insertion (USGIV) simulation-based mastery learning (SBML) curriculum improves the simulated USGIV skills of paediatric anaesthesiologists. It remains unclear if improvements in simulated USGIV skills translate to improved patient care. Methods: A cohort study was conducted from August 2018 to August 2020 to evaluate paediatric anaesthesiologists' USGIV performance in the operating theatre before and after they participated in the USGIV SBML curriculum. Paediatric anaesthesiologists' use of ultrasound for successful i.v. insertion and first-attempt i.v. insertion success rate with ultrasound were compared before and after training. Results: Twenty-nine paediatric anaesthesiologists completed training. Unadjusted analysis showed a significant increase in the percentage of i.v. catheters inserted with ultrasound for successful i.v. catheter insertion (9.5-14.5%; P<0.001) and first i.v. catheter insertion attempt success with ultrasound (5.5-8.9%; P<0.001) from before to after training. Multivariable regression analysis showed higher odds of ultrasound use for a successful i.v. catheter attempt (1.79; 95% confidence interval [CI]: 1.11-2.90; P=0.018) and first-attempt success with ultrasound (4.11; 95% CI: 2.02-8.37; P<0.001) after training. Conclusions: After completing the USGIV SBML curriculum, paediatric anaesthesiologists increased their ultrasound use for successful i.v. catheter insertion and first-attempt success rate with ultrasound for patients in the operating theatre.

Use of a simulation-based mastery learning curriculum to improve ultrasound-guided vascular access skills of pediatric anesthesiologists.

BACKGROUND: Pediatric vascular access is inherently challenging due to the small caliber of children's vessels. Ultrasound-guided intravenous catheter insertion has been shown to increase success rates and decrease time to cannulation in patients with difficult intravenous access. Although proficiency in ultrasound-guided intravenous catheter insertion is a critical skill in pediatric anesthesia, there are no published competency-based training curricula. AIMS: The objective of this study was to evaluate the performance of pediatric anesthesiologists who participated in a novel ultrasound-guided intravenous catheter insertion simulation-based mastery learning curriculum. METHODS: Pediatric anesthesia attendings, fellows, and rotating residents participated in the ultrasound-guided intravenous catheter insertion simulation-based mastery learning curriculum from August 2019 to February 2020. The 2-hour curriculum consisted of participants first undergoing a simulated skills pretest followed by watching a video on ultrasound-guided intravenous catheter insertion and deliberate practice on a simulator. Subsequently, all participants took a post-test and were required to meet or exceed a minimum passing standard. Those who were unable to meet the minimum passing standard participated in further practice until they could be retested and met this standard. We compared pre to post-test ultrasound-guided intravenous catheter insertion skills and self-confidence before and after participation in the curriculum. RESULTS: Twenty-six pediatric anesthesia attendings, 12 fellows, and 38 residents participated in the curriculum. At pretest, 16/76 (21%) participants were able to meet or exceed the minimum passing standard. The median score on the pretest was 21/25 skills checklist items correct and improved to 24/25 at post-test (95% CI 3.0-4.0, P < .01). Self-confidence significantly improved after the course from an average of 3.2 before the course to a postcourse score of 3.9 (95% CI 0.5-0.9, P < .01; 1 = Not all confident, 5 = Very confident). CONCLUSIONS: Simulation-based mastery learning significantly improved anesthesiologists' ultrasound-guided intravenous catheter insertion performance in a simulated setting.

Pediatric airway management devices: an update on recent advances and future directions.

INTRODUCTION: Structural and physiologic differences between pediatric and adult patients make management of the pediatric airway a challenge. Many initial airway device designs were modeled for adult patients and simply downsized for the pediatric population. This paper reviews the last decade's design improvements in video laryngoscopes and supraglottic airway devices (SGAs), as well as advances in noninvasive oxygenation/ventilation techniques for pediatric airway management. AREAS COVERED: Topic areas reviewed include basic principles of common and newer devices for video laryngoscopy, supraglottic airway management, and alternate ventilation techniques. A literature search was conducted in PubMed using device-specific keywords and limited to neonatal, infant, and pediatric populations. Articles were reviewed for evidence deemed high yield by the authors. Device specifications were obtained from manufacturer correspondences. Features, comparisons, advantages, and disadvantages are provided for each device class. We give expert commentary regarding the current state of clinical application, research considerations, as well as a 5-year outlook on potential areas of device design and development. EXPERT COMMENTARY: Video laryngoscopes and SGAs are safe and effective for use in children and improvements continue to be made for neonates and infants. The most significant area of new research is in the area of noninvasive airway devices for oxygenation and ventilation in difficult airways.