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.

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.

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.

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.

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2. MATERIALS AND METHODS: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 µg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms. RESULTS: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 µg/kg/h, mean TDSS improved by -7.5 ± 1.9 (or -25.7%, p = 0.009), with all monitored symptoms improving. CONCLUSION: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03613129.

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.

Investigation of Fats, Oils, and Grease Co-digestion With Food Waste in Anaerobic Membrane Bioreactors and the Associated Microbial Community Using MinION Sequencing.

Co-digestion of fats, oils, and grease (FOG) with food waste (FW) can improve the energy recovery in anaerobic membrane bioreactors (AnMBRs). Here, we investigated the effect of co-digestion of FW and FOG in AnMBRs at fat mass loading of 0.5, 0.75, and 1.0 kg m-3 day-1 with a constant organic loading rate of 5.0 gCOD L-1 day-1 in both a single-phase (SP) and two-phase (TP) configuration. A separate mono-digestion of FW at an identical organic loading rate was used as the benchmark. During co-digestion, higher daily biogas production, ranging from 4.0 to 12.0%, was observed in the two-phase methane phase (TP-MP) reactor compared to the SP reactor, but the difference was statistically insignificant (p > 0.05) due to the high variability in daily biogas production. However, the co-digestion of FW with FOG at 1.0 kg m-3 day-1 fat loading rate significantly (p < 0.05) improved daily biogas production in both the SP (11.0%) and TP (13.0%) reactors compared to the mono-digestion of FW. Microbial community analyses using cDNA-based MinION sequencing of weekly biomass samples from the AnMBRs revealed the prevalence of Lactobacillus (92.2-95.7% relative activity) and Anaerolineaceae (13.3-57.5% relative activity), which are known as fermenters and fatty acid degraders. Syntrophic fatty acid oxidizers were mostly present in the SP and TP-MP reactors, possibly because of the low pH and short solid retention time (SRT) in the acid phase digesters. A greater abundance of the mcrA gene copies (and methanogens) was observed in the SP and MP reactors compared to the acid-phase (AP) reactors. This study demonstrates that FW and FOG can be effectively co-digested in AnMBRs and is expected to inform full-scale decisions on the optimum fat loading rate.

The effect of a heavy backpack on children's street-crossing performance.

PURPOSE: The current study examined how wearing a heavy backpack influences children's street crossing behaviors. METHOD: Using a fully-immersive virtual reality system, numerous indices of children's street crossing behaviors (7-13 years) were measured both when wearing a heavy backpack (12% of bodyweight) and when not doing so. RESULTS: A heavy backpack slowed walking speed. However, any potential increase in risk from this was counteracted by compensatory actions that included: the selection of larger inter-vehicle gaps to cross into; greater efficiency in initiating the crossing (reduced start delay); and increased walking speed when in the path of the approaching vehicle. Ultimately, there was no greater risk outcome (time left to spare) compared to children's performance when not wearing a backpack. There were no age or sex differences. CONCLUSION: When tested in ways that preserve perceptual-motor coupling in traffic situations, children strategically responded to maintain their safety despite wearing a heavy backpack that slowed their walking speed. Previous conclusions that a backpack increases pedestrian injury risk is likely an artifact of the testing method used.

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.

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.

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).

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.

Photoredox ketone catalysis for the direct C-H imidation and acyloxylation of arenes.

The photoexcited aryl ketone-catalyzed C-H imidation of arenes and heteroarenes is reported. Using 3,6-dimethoxy-9H-thioxanthen-9-one as a catalyst in combination with a bench-stable imidating reagent, C-N bond formation proceeds with high efficiency and a broad substrate scope. A key part of this method is that the thioxanthone catalyst acts as an excited-state reductant, thus establishing an oxidative quenching cycle for radical aromatic substitution. The synthetic potential of this photoexcited ketone catalysis is further demonstrated by application to the direct C-H acyloxylation of arenes.

Examining how different measurement approaches impact safety outcomes in child pedestrian research: Implications for research and prevention.

There has been a great deal of research aimed at understanding the causes of child pedestrian injury. Many different methods have been employed with the goal of designing simulations that produce rigorous assessment of children's behaviors without putting children at risk of actual pedestrian injury. Most research has assessed children's pre-crossing decision making and extrapolated crossing outcome measures from estimates of mean walking speed. This study explores the nature and extent of measurement bias that is introduced when average walking speed is used to produce estimates of outcomes versus measuring actual in-road behavior directly. Using a within-subjects design and a fully immersive virtual reality pedestrian simulator, both measures were taken. Comparisons based on regression models revealed the extent of differences in results produced by measurement bias. Results indicated that measurement bias is produced when average walking speed is used such that hits and high risk crossings are overestimated and missed opportunities are underestimated, resulting in an overall overestimate of children's risk for pedestrian injury. The discussion highlights how these two measurement approaches emphasize different underlying processes as determinants of child pedestrian injury risk.

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.

A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin.

Bovine papular stomatitis virus (BPSV) is a Parapoxvirus that induces acute pustular skin lesions in cattle and is transmissible to humans. Previous studies have shown that BPSV encodes a distinctive chemokine-binding protein (CBP). Chemokines are critically involved in the trafficking of immune cells to sites of inflammation and infected tissue, suggesting that the CBP plays a role in immune evasion by preventing immune cells reaching sites of infection. We hypothesised that the BPSV-CBP binds a wide range of inflammatory chemokines particularly those involved in BPSV skin infection, and inhibits the recruitment of immune cells from the blood into inflamed skin. Molecular analysis of the purified protein revealed that the BPSV-CBP is a homodimeric polypeptide with a MW of 82.4 kDa whilst a comprehensive screen of inflammatory chemokines by surface plasmon resonance showed high-affinity binding to a range of chemokines within the CXC, CC and XC subfamilies. Structural analysis of BPSV-CBP, based on the crystal structure of orf virus CBP, provided a probable explanation for these chemokine specificities at a molecular level. Functional analysis of the BPSV-CBP using transwell migration assays demonstrated that it potently inhibited chemotaxis of murine neutrophils and monocytes in response to CXCL1, CXCL2 as well as CCL2, CCL3 and CCL5 chemokines. In order to examine the effects of CBP in vivo, we used murine skin models to determine its impact on inflammatory cell recruitment such as that observed during BPSV infection. Intradermal injection of BPSV-CBP blocked the influx of neutrophils and monocytes in murine skin in which inflammation was induced with lipopolysaccharide. Furthermore, intradermal injection of BPSV-CBP into injured skin, which more closely mimics BPSV lesions, delayed the influx of neutrophils and reduced the recruitment of MHC-II+ immune cells to the wound bed. Our findings suggest that the CBP could be important in pathogenesis of BPSV infections.

Revisiting the scissor-like mechanism of activation for the erythropoietin receptor.

An interpretation of alternative crystal structures of the erythropoietin receptor, with and without ligand, led to the proposal of a scissor-like mechanism of activation. This model has been propagated in the literature and is still being used to interpret crystal structures of related type-I cytokine receptors. Here, we assess whether the model remains compatible with current knowledge on the family of type-I cytokine receptors, and consider whether the model, as initially presented, is truly supported by the crystal structures on which it was originally based.

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.