The relation of attachment style to subjective motivations for sex was investigated in an Internet survey of 1999 respondents. The relations of attachment anxiety and avoidance to overall sexual motivation and to the specific motives for emotional closeness, reassurance, self-esteem enhancement, stress reduction, partner manipulation, protection from partner's negative affect and behavior, power exertion, physical pleasure, nurturing one's partner, and procreation were explored. As predicted, attachment anxiety was positively related to overall sexual motivation and to all specific motives for sex, with the exception of physical pleasure. Avoidance was negatively related to emotional closeness and reassurance as goals of sex and positively related to manipulative use of sex but minimally related to most other motives. Sexual passion was positively related to attachment anxiety and negatively related to avoidance, and anxiety was related to the maintenance of passion over time, whereas avoidance was related to loss of passion over time.

Associations between gender, age, emotional involvement, and attachment style and reactions to romantic relationship dissolution were studied in a survey of more than 5,000 Internet respondents. It was hypothesized that individual reactions to breakups would be congruent with characteristic attachment behaviors and affect-regulation strategies generally associated with attachment style. Attachment-related anxiety was associated with greater preoccupation with the lost partner, greater perseveration over the loss, more extreme physical and emotional distress, exaggerated attempts to reestablish the relationship, partner-related sexual motivation, angry and vengeful behavior, interference with exploratory activities, dysfunctional coping strategies, and disordered resolution. Attachment-related avoidance was weakly and negatively associated with most distress/proximity-seeking reactions to breakups and strongly and positively associated with avoidant and self-reliant coping strategies. Security (low scores on the anxiety and avoidance dimensions) was associated with social coping strategies (e.g., using friends and family as "safe havens"). Attachment insecurity, particularly anxiety, was associated with using drugs and alcohol to cope with loss.

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

An Internet survey was conducted to extend the investigation of attachment style to the domains of sexual communication and sexual satisfaction. We hypothesized that insecure attachment would be associated with sexual dissatisfaction, mediated by inhibited communication of sexual needs. Further, the association of attachment with inhibited communication was expected to be mediated by attachment‐related tendencies toward deference to partners’ needs, concern with the relationship implications of sexual choices, general anxiety regarding sex, and feelings for one’s partner. Somewhat different mediational pathways were predicted for each of the 2 dimensions of attachment insecurity: anxiety and avoidance. Respondents (N= 1,989, around half of them involved in a sexual relationship at the time of the study and half not involved but with previous sexual relationship experience) completed measures of attachment‐related anxiety and avoidance, neuroticism (a possible confound), and sexual communication and satisfaction. Results generally supported the hypotheses and provided additional evidence regarding the associations between attachment style, sexual communication, and sexual satisfaction.

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

Objective-To determine whether 4000 IU vitamin D 3 /day (vs. 2000 IU/day) during pregnancy is safe and improves maternal/neonatal 25(OH)D in a dose-dependent manner.Study Design-257 pregnant women 12-16 weeks' gestation were enrolled. Randomization to 2000-vs. 4000 IU/day followed one-month run-in at 2000 IU/day. Participants were monitored for hypercalciuria, hypercalcemia and 25(OH)D status.Results-Maternal 25(OH)D (n=161) increased from 22.7(SD 9.7) at baseline to 36.2(SD 15) and 37.9(SD 13.5) in the 2000-and 4000 IU groups, respectively. While maternal 25(OH)D change from baseline did not differ between groups, 25(OH)D monthly increase differed between groups (p<0.01). No supplementation-related adverse events occurred. Mean cord blood 25(OH)D (ng/mL) was 22.1±10.3 in 2000-and 27.0±13.3 in 4000 IU group (p=0.024). After controlling for race and study site, preterm birth and labor were inversely associated with pre-delivery-and mean 25(OH)D, but not baseline 25(OH)D,.Conclusions-Maternal supplementation with 2000 and 4000 IU vitamin D/day during pregnancy improved maternal/neonatal vitamin D status. Evidence of risk reduction in infection, preterm labor and preterm birth was suggestive, requiring additional studies powered for these endpoints.

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This study provides a sketch of the content and construct validity of the CanMEDS roles in a non-Canadian setting. More research is needed in how these aspects of competence can be best taught and applied across specialties in different jurisdictions.