Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia

The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX₁R and OX₂R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX₁R or OX₂R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models.     

Configuring retroreflective markings to enhance the night-time conspicuity of road workers

This study investigated whether the night-time conspicuity of road workers can be enhanced by positioning retroreflective strips on the moveable joints in patterns that convey varying degrees of biological motion. Participants were 24 visually normal adults (12 young M = 26.8 years; 12 older M = 72.9 years). Visual acuity, contrast sensitivity and glare sensitivity were recorded for each participant. Experimenters acting as road workers walked in place on a closed road circuit within simulated road work sites, facing either the oncoming driver or the roadway (presenting sideways to the driver) and wearing one of four clothing conditions: (i) standard road worker vest; (ii) standard vest plus thigh-mounted retroreflective strips; (iii) standard vest plus retroreflective strips on ankles and knees; (iv) standard vest plus retroreflective strips positioned on the extremities in a configuration that conveyed biological motion (“biomotion”). As they drove along the closed road participants were instructed to press a button to indicate when they first recognized that a road worker was present. The results demonstrated that regardless of the direction of walking, road workers wearing biomotion clothing were recognized at significantly (p < 0.05) longer distances (3×), relative to the standard vest alone. Response distances were significantly shorter for the older drivers. Contrast sensitivity was a better predictor of the ability to recognize road workers than was visual acuity or glare sensitivity. We conclude that adding retroreflective strips in the biomotion configuration can significantly improve road worker conspicuity regardless of the road worker's orientation and the age of the driver.     

Older drivers' insight into their hazard perception ability

Even though the driving ability of older adults may decline with age, there is evidence that some individuals attempt to compensate for these declines using strategies such as restricting their driving exposure. Such compensatory mechanisms rely on drivers’ ability to evaluate their own driving performance. This paper focuses on one key aspect of driver ability that is associated with crash risk and has been found to decline with age: hazard perception. Three hundred and seven drivers, aged 65–96, completed a validated video-based hazard perception test. There was no significant relationship between hazard perception test response latencies and drivers’ ratings of their hazard perception test performance, suggesting that their ability to assess their own test performance was poor. Also, age-related declines in hazard perception latency were not reflected in drivers’ self-ratings. Nonetheless, ratings of test performance were associated with self-reported regulation of driving, as was self-rated driving ability. These findings are consistent with the proposal that, whileself-assessments of driving ability may be used by drivers to determine the degree to which they restrict their driving, the problem is that drivershave little insight into their own driving ability. This may impact on the potential road safety benefits of self-restriction of driving because drivers may not have the information needed to optimally self-restrict. Strategies for addressing this problem are discussed.     

Visual search for features and conjunctions in development.

Visual search performance was examined in 24 7–8 yr olds, 22 9–10 yr olds, 15 11–12 yr olds, and in 10 young adults (aged 23–30 yrs). Color and orientation feature searches and a conjunction search were conducted. Reaction time (RT) showed expected improvements in processing speed with age. Comparisons of RTs on target-present and target-absent trials were consistent with parallel search on the 2 feature conditions and with serial search in the conjunction condition. The RT results indicate that searches for feature arid conjunctions were treated similarly for children and adults. However, the youngest children missed more targets at the largest array sizes, most strikingly in conjunction search. Based on an analysis of speed/accuracy trade-offs, we suggest that low target-distractor discriminability leads to an undersampling of array elements, and is responsible for the high number of misses in the youngest children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Responses to interpersonal transgressions in families: Forgivingness, forgivability, and relationship-specific effects.

Social relations analyses examined the relative importance of forgivingness (disposition to forgive others), forgivability (tendency to obtain forgiveness from others), and relationship effects in determining family members' transgression-related interpersonal motivations (TRIMs) and their perceptions of others' TRIMs toward them (PTRIMs). In 2 studies, the individual and dyadic predictors of these components and their relative importance differed by family role (father, mother, or early adolescent child). Dispositional tendencies accounted for the most variance in father and child forgiveness, whereas mothers' TRIMs and PTRIMs were more strongly determined by relationship and partner effects. Personality correlates of forgivingness and forgivability were moderated by family role. The findings point to the need to embed the study of forgiveness in more complex psychosocial contexts. The theoretical, methodological, and applied implications of this conclusion are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Children's Fright Reactions to Television News

In a random survey of parents of kindergarten, second, fourth, and sixth grade children, 37% of the children were reported to have been frightened or upset by a news story on television. The percentage of children being frightened by news increased from kindergarten to the elementary school years, whereas the tendency to be frightened by fantastic, unreal content showed a decreasing trend. The top categories of stories producing fear were violence between strangers, foreign wars and famines, and natural disasters. me tendency to respond with fright to violence between strangers increased with age, and the tendency to be upset by natural disasters decreased with age. Proposed explanations for the observed age differences were based on developmental differences in children's understanding of the fantasy-reality distinction and in their responsiveness to perceptually salient stimuli.     

Module reuse by interface adaptation

This paper describes a language called Nimble that allows designers to declare how the actual parameters in a procedure call are to be transformed at run time. Normally, programmers must edit an application's source in order to adapt it for reuse in some new context where the interfaces fail to match exactly (e.g. the parameters may appear in a different order, data types may not exactly match, and some data may need to be either initialized or masked out when the reusable module is integrated within a new application.) But Nimble allows programmers to adapt the interfaces of existing software without having to operate on the source manually. As a result, existing software may be easily reused in a broader range of applications, and software libraries do not need to store many variants of a component that differ only in how the interfaces are used. Nimble has been implemented on a variety of Unix hosts, and is part of a broader reuse project at the University of Maryland. Our current system is suitable for use either in conjunction with existing module interconnection languages, or stand-alone with C, Pascal and Ada source programs.     

A screening inventory for assessing psychiatric impairment in children 6 to 18.

Administered a structured questionnaire to a cross-sectional sample of 1,034 mothers and a welfare sample of 1,000 mothers of 6-18 yr olds in New York City. One or more psychiatrists rated each of the children on a 5-point scale of total psychiatric impairment. Factor analysis of the questionnaire items of child behavior yielded 18 factors. The 7 factors with the highest correlations with total psychiatric impairment were selected for the inventory, each represented by 5 items. The correlation of the total 35-item score and total psychiatric impairment was .82. The screening inventory significantly and substantially improved over chance in assigning children to impairment statuses in the cross-sectional sample and the sample used for cross-validation, the welfare sample. Correlations of the total score with child's treatment status and a direct clinical examination rating were expectedly low. In its present form, the instrument is recommended only for comparisons of different child and adolescent groups. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Columbia Mental Maturity Scale as a test of concept formation.

Examined the construct validity of the Columbia Mental Maturity Scale (CMMS) in terms of dimensions derived from conceptual behavior research, i.e., abstract or concrete exemplars and an oddity or pairing rule. The CMMS scores of 2 groups of 30 9-13 yr. old children of normal or borderline IQs were separated by type of card into 4 groups: concrete-oddity, abstract-oddity, abstract-pairing, and concrete-pairing. Significant differences between the percentage correct scores for each type of card were obtained. The order of difficulty for the type of card from easiest to hardest as listed above were reliable for Ss as a whole. The CMMS performance of Ss with normal IQs was superior to that of Ss with borderline IQs on all measures. Implications of findings for the diagnosis of disabilities in conceptual behavior are discussed. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)