Alternative Markers of Performance in Simulation: Where We Are and Where We Need To Go

This article on alternative markers of performance in simulation is the product of a session held during the 2017 Academic Emergency Medicine Consensus Conference â Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes.â There is a dearth of research on the use of performance markers other than checklists, holistic ratings, and behaviorally anchored rating scales in the simulation environment. Through literature review, group discussion, and consultation with experts prior to the conference, the working group defined five topics for discussion: 1) establishing a working definition for alternative markers of performance, 2) defining goals for using alternative performance markers, 3) implications for measurement when using alternative markers, identifying practical concerns related to the use of alternative performance markers, and 5) identifying potential for alternative markers of performance to validate simulation scenarios. Five research propositions also emerged and are summarized.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142535/1/acem13321_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142535/2/acem13321.pd

Dynamics of direct inter-pack encounters in endangered African wild dogs

Aggressive encounters may have important life history consequences due to the potential for injury and death, disease transmission, dispersal opportunities or exclusion from key areas of the home range. Despite this, little is known of their detailed dynamics, mainly due to the difficulties of directly observing encounters in detail. Here, we describe detailed spatial dynamics of inter-pack encounters in African wild dogs (Lycaon pictus), using data from custom-built high-resolution GPS collars in 11 free-ranging packs. On average, each pack encountered another pack approximately every 7 weeks and met each neighbour twice each year. Surprisingly, intruders were more likely to win encounters (winning 78.6% of encounters by remaining closer to the site in the short term). However, intruders did tend to move farther than residents toward their own range core in the short-term (1 h) post-encounter, and if this were used to indicate losing an encounter, then the majority (73.3%) of encounters were won by residents. Surprisingly, relative pack size had little effect on encounter outcome, and injuries were rare (<15% of encounters). These results highlight the difficulty of remotely scoring encounters involving mobile participants away from static defendable food resources. Although inter-pack range overlap was reduced following an encounter, encounter outcome did not seem to drive this, as both packs shifted their ranges post-encounter. Our results indicate that inter-pack encounters may be lower risk than previously suggested and do not appear to influence long-term movement and ranging

Alternative Markers of Performance in Simulation: Where We Are and Where We Need To Go.

This article on alternative markers of performance in simulation is the product of a session held during the 2017 Academic Emergency Medicine Consensus Conference Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes. There is a dearth of research on the use of performance markers other than checklists, holistic ratings, and behaviorally anchored rating scales in the simulation environment. Through literature review, group discussion, and consultation with experts prior to the conference, the working group defined five topics for discussion: 1) establishing a working definition for alternative markers of performance, 2) defining goals for using alternative performance markers, 3) implications for measurement when using alternative markers, identifying practical concerns related to the use of alternative performance markers, and 5) identifying potential for alternative markers of performance to validate simulation scenarios. Five research propositions also emerged and are summarized

Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors

On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1′ alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa <i>K</i>_i = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC_2<i>x</i> = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors

Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa <i>K</i>_i was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability

Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1­(2<i>H</i>)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency