A Framework for the Analysis of Communication Errors in Health Care.

Objectives: The goal of this study was to develop a systematic method to identify and classify different types of communication failures leading to patient safety events. We aimed to develop a taxonomy code sheet for identifying communication errors and provide a framework tool to classify the communication error types.

Methods: This observational study used the Delphi method to develop a taxonomy code sheet for identifying communication errors reported in the Veterans Health Administration patient safety databases between April 2018 and March 2021.

Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold.

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions.

Combined Proactive Risk Assessment: Unifying Proactive and Reactive Risk Assessment Techniques In Health Care.

Background: Reactive risk assessments (RRAs) such as incident reporting and root cause analysis (RCA), as well as proactive risk assessments (PRAs) such as failure mode and effects analysis, are generally conducted independently in health care. Literature promotes combining risk assessment techniques. This concept builds on previous methodologies and presents an innovative, scalable, and generalizable risk assessment methodology.

Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor BMS-986097.

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile.

How cockroaches exploit tactile boundaries to find new shelters.

Animals such as cockroaches depend on exploration of unknown environments, and their strategies may inspire robotic approaches. We have previously shown that cockroach behavior, with respect to shelters and the walls of an otherwise empty arena, can be captured with a stochastic state-based algorithm. We call this algorithm RAMBLER, randomized algorithm mimicking biased lone exploration in roaches.

Automated image-based tracking and its application in ecology.

The behavior of individuals determines the strength and outcome of ecological interactions, which drive population, community, and ecosystem organization. Bio-logging, such as telemetry and animal-borne imaging, provides essential individual viewpoints, tracks, and life histories, but requires capture of individuals and is often impractical to scale. Recent developments in automated image-based tracking offers opportunities to remotely quantify and understand individual behavior at scales and resolutions not previously possible, providing an essential supplement to other tracking methodologies in ecology.

Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase.

BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a.

Identification of a novel series of potent HCV NS5B Site I inhibitors.

Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Many of the propellane analogs described in this work exhibited better than targeted potency (less than 20 nM).

Discovery and development of hepatitis C virus NS5A replication complex inhibitors.

Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials.

A neuromechanical simulation of insect walking and transition to turning of the cockroach Blaberus discoidalis.

A neuromechanical simulation of the cockroach Blaberus discoidalis was developed to explore changes in locomotion when the animal transitions from walking straight to turning. The simulation was based upon the biological data taken from three sources. Neural circuitry was adapted from the extensive literature primarily obtained from the studies of neural connections within thoracic ganglia of stick insect and adapted to cockroach.

Inhibitors of HIV-1 attachment. Part 11: the discovery and structure-activity relationships associated with 4,6-diazaindole cores.

A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this mechanism in human clinical studies but required high doses and concomitant administration of a high fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the discovery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure over 2 in a rat PK studies.

Inhibitors of HIV-1 attachment. Part 10. The discovery and structure-activity relationships of 4-azaindole cores.

A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7.

Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043).

BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation.

Information transmission in cercal giant interneurons is unaffected by axonal conduction noise.

What are the fundamental constraints on the precision and accuracy with which nervous systems can process information? One constraint must reflect the intrinsic "noisiness" of the mechanisms that transmit information between nerve cells. Most neurons transmit information through the probabilistic generation and propagation of spikes along axons, and recent modeling studies suggest that noise from spike propagation might pose a significant constraint on the rate at which information could be transmitted between neurons. However, the magnitude and functional significance of this noise source in actual cells remains poorly understood.

Kinematic and behavioral evidence for a distinction between trotting and ambling gaits in the cockroach Blaberus discoidalis.

Earlier observations had suggested that cockroaches might show multiple patterns of leg coordination, or gaits, but these were not followed by detailed behavioral or kinematic measurements that would allow a definite conclusion. We measured the walking speeds of cockroaches exploring a large arena and found that the body movements tended to cluster at one of two preferred speeds, either very slow (<10 cm s(-1)) or fairly fast (∼30 cm s(-1)). To highlight the neural control of walking leg movements, we experimentally reduced the mechanical coupling among the various legs by tethering the animals and allowing them to walk in place on a lightly oiled glass plate.

Computer-assisted 3D kinematic analysis of all leg joints in walking insects.

High-speed video can provide fine-scaled analysis of animal behavior. However, extracting behavioral data from video sequences is a time-consuming, tedious, subjective task. These issues are exacerbated where accurate behavioral descriptions require analysis of multiple points in three dimensions.

Neural activity in the central complex of the insect brain is linked to locomotor changes.

Animals negotiating complex natural terrain must consider cues around them and alter movement parameters accordingly. In the arthropod brain, the central complex (CC) receives bilateral sensory relays and sits immediately upstream of premotor areas, suggesting that it may be involved in the context-dependent control of behavior. In previous studies, CC neurons in various insects responded to visual, chemical, and mechanical stimuli, and genetic or physical lesions affected locomotor behaviors.

Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects.

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4).

A comparison of visual and haltere-mediated feedback in the control of body saccades in Drosophila melanogaster.

The flight trajectories of fruit flies consist of straight flight segments interspersed with rapid turns called body saccades. Although the saccades are stereotyped, it is not known whether their brief time course is due to a feed-forward (predetermined) motor program or due to feedback from sensory systems that are reflexively activated by the rapid rotation. Two sensory modalities, the visual system and the mechanosensory halteres, are likely sources of such feedback because they are sensitive to angular velocities within the range experienced during saccades.

Visual stimulation of saccades in magnetically tethered Drosophila.

Flying fruit flies, Drosophila melanogaster, perform ;body saccades', in which they change heading by about 90 degrees in roughly 70 ms. In free flight, visual expansion can evoke saccades, and saccade-like turns are triggered by similar stimuli in tethered flies. However, because the fictive turns in rigidly tethered flies follow a much longer time course, the extent to which these two behaviors share a common neural basis is unknown.