A Feasibility Randomized Trial Evaluating Safe Peds: A Virtual Reality Training Program to Teach Children When to Cross Streets Safely.

OBJECTIVE: Injury as pedestrians is a leading contributor to childhood deaths. This study evaluated the effectiveness of Safe Peds, a fully immersive virtual reality training program to teach children when to cross street safely, with the focus on a number of foundational skills and practicing these in traffic situations of varying complexity. METHODS: Children 7-10 years old were randomly assigned to a control (N = 31) or intervention (N = 26) group. Eligibility criteria included English speaking and typically developing. Testing took place on campus. All children completed pre- and post-testing measures, with those in the intervention group receiving training in between. Training comprised 1 session with 3 phases for a total of up to 1.5 hr and was tailored to each child's performance over trials. On each trial, children decided when to cross and fully executed this crossing, with measures automatically taken by the system as they did so. RESULTS: Negative binomial regression and analysis of covariance tests were applied, predicting post-test scores while controlling for pre-test scores, age, and sex. The intervention was effective in improving children's street crossing skills, including stopping and checking skills (stop at the curb, look left/right/left, check for traffic before crossing the yellow line), and choosing safe inter-vehicle gaps. Children in the control group did not show significant improvements in any crossing skills. CONCLUSIONS: The Safe Peds program effectively teaches children skills to support their deciding when to safely cross in a variety of traffic situations. Implications for pedestrian injury are discussed.

Adolescents at the skatepark: identifying design features and youth behaviours that pose risk for falls.

BACKGROUND: Skateboarding is an increasingly popular leisure activity for youth, yet injuries due to falls are common. This study aimed to identify the features at skateparks and tricks performed by youth that pose an increased risk of falls in skateboarders. METHOD: Video recordings were unobtrusively taken at a large skatepark of youth designated as young (11-15 years) or old (16-20 years). Videos were coded to identify the popular skatepark features used and tricks performed, and to assign a fall severity outcome rating for each feature and each type of trick attempted. RESULTS: The results identify features and tricks that pose increased risk of falling for youth at skateparks. CONCLUSIONS: Implications for injury prevention are discussed, including a consideration of environmental (skatepark design) and individual (youth behaviour) factors relevant to reducing skateboarding injuries due to falls among youth.

Sex Differences in the Relation Between Supervision and Injury Risk Across Motor Development Stages: Transitioning From Infancy Into Toddlerhood.

RATIONALE: Addressing a notable gap in research on injuries during infancy, this longitudinal study examined sex differences in the relationship between parents' typical levels of supervision and infants' injuries across motor development stages. METHOD: Parents were recruited and completed biweekly phone calls about their infant's motor skills. Once the infant was able to sit up independently, then a home visit was scheduled. Applying a participant-event monitoring method, parents were taught to complete diary forms (injury, supervision), which they started doing once the child could move from their seated location on the floor in some way (e.g., roll, crawl). Recordings continued until a month after the child could walk independently. Data (injury, supervision) were averaged within each motor development stage (low, high), and associations across stages were examined. RESULTS: Model testing indicated that supervision level moderated the relation between injury rate across motor development stages, but the strength of this association varied by sex of the child. More intense supervision predicted lower injury rates for girls more so than for boys. CONCLUSIONS: Although the emergence of motor milestones has been associated with increased risk of injury during infancy, the current findings indicate that greater supervision can reduce this risk. However, supervision alone is not as effective to moderate injury risk for boys as it is for girls. Thus, for boys, additional strategies (e.g., hazard removal) may also be warranted to maximize reduction in their risk of injury as they acquire increasing motor skills.

Characterization of false positive, contaminant-driven mutagenicity in impurities associated with the sotorasib drug substance.

Sotorasib (Lumakras™) is a first-in-class, non-genotoxic, small molecule inhibitor of KRAS G12C developed as an anticancer therapeutic for treatment of patients that have a high unmet medical need. Anticancer therapeutics are considered out of scope of ICH M7 guidance for control of mutagenic impurities; however, based on ICH S9 Q&A, mutagenicity assessments are needed for impurities that exceed the qualification threshold, consistent with ICH Q3A/B, and non-mutagenic drugs. Here, we carried out hybrid-based mutagenicity assessment of sotorasib drug substance (DS) impurities using in silico quantitative structure-activity relationship (QSAR) modelling and Ames tests (for in silico positive mutagens). We encountered contradictive mutagenicity results for 2 impurities (Beta-Chloride and PAC). PAC was negative initially by QSAR but positive in a GLP full plate Ames test and Beta-Chloride was positive by QSAR, negative in a non-GLP micro-Ames but positive in a GLP full plate Ames assay. Root cause analyses identified and characterized mutagenic contaminants, 3-chloropropionic acid in batches of Beta-Chloride and 3-chloropropionic acid and Chloro-PAC in batches of PAC, used in initial GLP full-plate Ames tests. Significant reduction of these contaminants in re-purified batches resulted in no induction of mutagenicity in follow-up GLP micro-Ames tests. In summary, root-cause analyses led to accurate mutagenicity assessment for sotorasib DS-associated impurities.

Understanding Infants' In-Home Injuries: Context and Correlates.

RATIONALE: Infancy is a time of elevated risk of injury. Past research has focused mostly on the type of injuries, leaving many gaps in knowledge about contextual information that could aid in injury prevention planning. METHODS: In this longitudinal study, a participant-event recording method was used in which mothers tracked their infants' home injuries through three motor development stages (sitting up independently, crawling, and walking). A contextual analysis elucidated where injuries occurred, their type and severity, the infant's and parent's behaviors at the time, if the infant had done the risk behavior before and been injured, the level of supervision, and the nature of any safety precautions parents implemented following these injuries. RESULTS: Injuries occurred as often in play as in nonplay areas and were due to physically-active nonplay activities more so than play activities; mothers were often doing chores. Bumps and bruises were the most common types of injuries. As infants became more mobile, supervision scores declined and injury severity scores increased. Infants had done the risk behavior leading to injury previously about 60% of the time, with higher scores associated with parents implementing fewer preventive actions in response to injury. When mothers did implement a safety precaution, greater injury severity was associated with more modifications to the environment and increased supervision; teaching about safety was infrequent. CONCLUSION: Implications of these results for injury prevention messaging are discussed.

Understanding Sex Differences in Children's Injury Risk as Pedestrians.

OBJECTIVE: Boys experience more injuries as pedestrians than girls. The aim of this study was to compare how boys and girls cross streets in order to identify factors that differentially influence their injury risk as pedestrians. METHODS: Using a fully immersive virtual reality (VR) system interfaced with a 3D movement measurement system, various measures of children's street-crossing behaviors were taken. RESULTS: At the start of the crossing, boys selected smaller (riskier) inter-vehicle gaps to cross into than girls. Subsequently, as they crossed, they showed greater attention to traffic, shorter start delay, and more evasive action than girls, which are strategies that could reduce risk as a pedestrian. Despite these efforts, however, boys experienced more hits and close calls than girls. CONCLUSION: To enhance their safety as pedestrians, girls adopt a proactive approach and select larger inter-vehicle gaps to cross into, whereas boys apply a reactive approach aimed at managing the risk created by having selected smaller (riskier) gaps. Girls' proactive approach yielded safer outcomes than boys' reactive strategy.

Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis-Pinnick Tandem Transformation.

A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).

Two-Phase Improves Performance of Anaerobic Membrane Bioreactor Treatment of Food Waste at High Organic Loading Rates.

Anaerobic membrane bioreactors (AnMBRs) are in use at the full-scale for energy recovery from food waste (FW). In this study, the potential for two-phase (acid/gas) AnMBR treatment of FW was investigated as a strategy to increase microbial diversity, thereby improving performance. Two bench-scale AnMBRs were operated in single-phase (SP) and two-phase (TP) mode across incremental increases in organic loading rate (OLR) from 2.5 to 15 g total chemical oxygen demand (COD) L·d-1. The TP acid-phase (TP-AP) enriched total VFAs by 3-fold compared to influent FW and harbored a distinct microbial community enriched in fermenters that thrived in the low pH environment. The TP methane phase (TP-MP) showed increased methane production and resilience relative to SP as OLR increased from 3.5 to 10 g COD L·d-1. SP showed signs of inhibition (i.e., rapid decrease in methane production per OLR) at 10 g COD L·d-1, whereas both systems were inhibited at 15 g COD L·d-1. At 10 g COD L·d-1, where the highest difference in performance was observed (20.3% increase in methane production), activity of syntrophic bacteria in TP-MP was double that of SP. Our results indicate that AnMBRs in TP mode could effectively treat FW at OLRs up to 10 g COD·L day-1 by improving hydrolysis rates, microbial diversity, and syntroph activity, and enriching resistant communities to high OLRs relative to AnMBRs in SP mode.

Effects of Peers on Child Pedestrian Behaviors in a Virtual Traffic Context.

OBJECTIVES: Research shows that school-aged children are at high risk of pedestrian injury when they cross streets with peers. How peers exert their influence is unknown. Using a fully immersive virtual reality pedestrian environment, this study examined the impact of peers on children's pedestrian behaviors. METHODS: 137 children were assigned either to a control, peer observer, or peer-safety or peer-risky modeling condition. Street-crossing behaviors were measured twice (baseline, postbaseline), with group comparisons (control vs. test condition) of postbaseline scores conducted. RESULTS: Children who observed a peer modeling risky behaviors imitated this. No significant influences were found in the peer observation or safe modeling conditions. CONCLUSIONS: Peers may elevate other children's risk of pedestrian injury through modeling risky crossings. Implications for prevention are discussed.

A Pilot Randomized Controlled Trial Testing the Effectiveness of a Pedestrian Training Program That Teaches Children Where and How to Cross the Street Safely.

Objective: Pedestrian injury is a leading cause of injury-related mortality for children. This pilot randomized controlled trial tested the efficacy of a training program to teach where and how to cross safely. Methods: Using fully immersive virtual reality technology, 142 children 7-10 years of age were recruited, with 130 completing crossing measures before (pretest) and immediately after (posttest) training. Training comprised 1.5 hr, was tailored to each child's performance over trials, and focused on either where to cross (n = 44 children completed testing) or how to cross safely (n = 43); corresponding control groups comprised 22 and 21 children, respectively. Following training, children in the intervention groups completed additional tasks to test conceptual knowledge and generalization of learning. Children in the control groups spent the same time as those in training groups but played a video game that used the same game controller but provided no training in street crossing. Results: The primary outcomes were errors in crossing at posttest, controlling for pretest error scores. Children in the intervention group made from 75% to 98% fewer errors at posttest than control children for all pedestrian safety variables related to where and how to cross safely, with effect sizes (incidence rate ratios) varying between 0.02 and 0.25. They also showed a generalization of what they had learned and applied this knowledge to novel posttraining situations. Conclusion: Training within a virtual pedestrian environment can successfully improve children's conceptual understanding and crossing behaviors for both where and how to cross streets safely.

Do All X-ray Structures of Protein-Ligand Complexes Represent Functional States? EPOR, a Case Study.

Based on differences between the x-ray crystal structures of ligand-bound and unbound forms, the activation of the erythropoietin receptor (EPOR) was initially proposed to involve a cross-action scissorlike motion. However, the validity of the motions involved in the scissorlike model has been recently challenged. Here, atomistic molecular dynamics simulations are used to examine the structure of the extracellular domain of the EPOR dimer in the presence and absence of erythropoietin and a series of agonistic or antagonistic mimetic peptides free in solution. The simulations suggest that in the absence of crystal packing effects, the EPOR chains in the different dimers adopt very similar conformations with no clear distinction between the agonist and antagonist-bound complexes. This questions whether the available x-ray crystal structures of EPOR truly represent active or inactive conformations. The study demonstrates the difficulty in using such structures to infer a mechanism of action, especially in the case of membrane receptors where just part of the structure has been considered in addition to potential confounding effects that arise from the comparison of structures in a crystal as opposed to a membrane environment. The work highlights the danger of assigning functional significance to small differences between structures of proteins bound to different ligands in a crystal environment without consideration of the effects of the crystal lattice and thermal motion.

Using a Virtual Environment to Examine How Children Cross Streets: Advancing Our Understanding of How Injury Risk Arises.

PURPOSE: To examine how risk of injury can arise for child pedestrians. METHODS: Using a highly immersive virtual reality system interfaced with a 3-D movement measurement system, younger (M = 8 years) and older (M = 10 years) children's crossing behaviors were measured under conditions that introduced variation in vehicle speed, distance, and intervehicle gaps. RESULTS: Children used distance cues in deciding when to cross; there were no age or sex differences. This increased risk of injury in larger intervehicle gaps because they started late and did not monitor traffic or adjust walking speed as they crossed. In contrast, injury risk in smaller intervehicle gaps of equal risk (i.e., same time to contact) occurred because crossing behavioral adjustments (starting early, increasing walking speed while crossing) were not sufficient. CONCLUSIONS: Dependence on distance cues increases children's risk of injury as pedestrians when crossing in a variety of traffic situations.

Using a Virtual Environment to Study Pedestrian Behaviors: How Does Time Pressure Affect Children's and Adults' Street Crossing Behaviors?

OBJECTIVE: The aim of this study was to examine how crossing under time pressure influences the pedestrian behaviors of children and adults. METHODS: Using a highly immersive virtual reality system interfaced with a 3D movement measurement system, various indices of children's and adults' crossing behaviors were measured under time-pressure and no time-pressure conditions. RESULTS: Pedestrians engaged in riskier crossing behaviors on time-pressure trials as indicated by appraising traffic for a shorter period before initiating their crossing, selecting shorter more hazardous temporal gaps to cross into, and having the car come closer to them (less time to spare). There were no age or sex differences in how time pressure affected crossing behaviors. CONCLUSIONS: The current findings indicate that, at all ages, pedestrians experience greater exposure to traffic dangers when they cross under time pressure.

Using a virtual environment to study child pedestrian behaviours: a comparison of parents' expectations and children's street crossing behaviour.

OBJECTIVE: The aim of this study was to compare parents' expectations for their children crossing streets with children's actual crossing behaviours and determine how accurately parents judge their own children's pedestrian behaviours to be. METHOD: Using a fully immersive virtual reality system interfaced with a 3D movement measurement system, younger (7-9 years) and older (10-12 years) children's crossing behaviours were assessed. The parent viewed the same traffic conditions and indicated if their child would cross and how successful she/he expected the child would be when doing so. RESULTS: Comparing children's performance with what their parents expected they would do revealed that parents significantly overestimated the inter-vehicle gap threshold of their children, erroneously assuming that children would show safer pedestrian behaviours and select larger inter-vehicle gaps to cross into than they actually did; there were no effects of child age or sex. Child and parent scores were not correlated and a logistic regression indicated these were independent of one another. CONCLUSIONS: Parents were not accurate in estimating the traffic conditions under which their children would try and cross the street. If parents are not adequately supervising when children cross streets, they may be placing their children at risk of pedestrian injury because they are assuming their children will select larger (safer) inter-vehicle gaps when crossing than children actually do.

Innovations in using virtual reality to study how children cross streets in traffic: evidence for evasive action skills.

PURPOSE: Children in middle childhood are at an increased risk for injury in pedestrian environments. This study examined whether they are capable of showing evasive action (ie, adjusting crossing speed) to avoid injury when crossing streets. METHODS: The study used a fully immersive virtual reality (VR) system interfaced with a three-dimensional movement measurement system so that the actual crossing behaviour of 7-10-year-old children under different traffic conditions could be precisely measured. Relating outcomes to that which would have been obtained based on using the approach of estimating walking speed and assuming a constant speed provided insights into the realised benefits of the current movement monitoring VR system. RESULTS: Controlling for age and sex, children showed evasive action, crossing more quickly as traffic conditions became more risky. Using an average and assuming a constant walking speed underestimated actual walking speed, failing to capture evasive action and leading to overestimation of children being hit compared with the actual incidence of hits. CONCLUSIONS: VR technology is a valuable tool for assessing child pedestrian behaviour. However, systems need to allow the child to cross the street so their level of pedestrian skill is appropriately measured. The current findings provide the first evidence that children are capable of implementing evasive action in reaction to risky traffic conditions.

Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase.

The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.

Dynamic kinetic asymmetric transformations of ß-stereogenic α-ketoesters by direct aldolization.

Dynamic kinetic asymmetric transformations (DyKAT) of racemic ß-bromo-α-keto esters by direct aldolization of nitromethane and acetone provide access to fully substituted α-glycolic acid derivatives bearing a ß-stereocenter. The aldol adducts are obtained in excellent yield with high relative and absolute stereocontrol under mild reaction conditions. Mechanistic studies determined that the reactions proceed through a facile catalyst-mediated racemization of the ß-bromo-α-keto esters under a DyKAT Type I manifold.

Diametric stereocontrol in dynamic catalytic reduction of racemic acyl phosphonates: divergence from α-keto ester congeners.

An unexpected dichotomy was observed in the Ru-catalyzed asymmetric transfer hydrogenation of acyl phosphonates: reduction proceeded from the opposite face relative to that observed in the analogous reduction of α-keto esters. The first highly selective catalytic hydrogenation of acyl phosphonates was utilized in the dynamic kinetic resolution of α-aryl acyl phosphonates, providing ß-stereogenic α-hydroxy phosphonic acid derivatives.

Asymmetric synthesis of diverse glycolic acid scaffolds via dynamic kinetic resolution of α-keto esters.

The dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation has been developed as a technique for the highly stereoselective construction of structurally diverse ß-substituted-α-hydroxy carboxylic acid derivatives. Through the development of a privileged m-terphenylsulfonamide for (arene)RuCl(monosulfonamide) complexes with a high affinity for selective α-keto ester reduction, excellent levels of chemo-, diastereo-, and enantiocontrol can be realized in the reduction of ß-aryl- and ß-chloro-α-keto esters.

A longitudinal study of boys' and girls' injury-risk behaviors and parent supervision during infancy.

In most developed nations worldwide, unintentional injury is the leading cause of death for youth 1 through 18 years. Infants are a particularly vulnerable group because motor development enables increased access to hazards, yet they are poorly equipped to assess danger. The current study compared when infants possessed low versus high motor development skills and examined the frequency and type of injury-risk behaviors and parent supervision patterns, as well as modeling how supervision influences injury-risk behaviors across motor development stages and if it does so differentially for boys and girls. Applying a participant-event monitoring method, parents were trained in completing injury-risk behavior diary forms, which they did once the child could move from their seated location on the floor in some way and continued until a month after the child could walk independently. Results revealed few differences between boys and girls in risk behaviors. The overall rate of risk behaviors was greater at high than low motor development stages and there was stability in the rate of individual infant injury-risk behaviors across motor development stages. The same general types of risk behaviors occurred over motor development stages, though about 88% of risk behaviors per se were novel and unfamiliar to parents. Parents supervised boys and girls similarly. However, model testing indicated that greater supervision increased the rate of risk behaviors longitudinally for boys but not girls. Implications for preventing injuries to boys and girls during infancy are discussed.