A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina.

OBJECTIVE: We sought to determine whether 4000 IU/d (vs 2000 IU/d) of vitamin D during pregnancy is safe and improves maternal/neonatal 25-hydroxyvitamin D [25(OH)D] in a dose-dependent manner. STUDY DESIGN: A total of 257 pregnant women 12-16 weeks' gestation were enrolled. Randomization to 2000 vs 4000 IU/d followed 1-month run-in at 2000 IU/d. Participants were monitored for hypercalciuria, hypercalcemia, and 25(OH)D status. RESULTS: Maternal 25(OH)D (n = 161) increased from 22.7 ng/mL (SD 9.7) at baseline to 36.2 ng/mL (SD 15) and 37.9 ng/mL (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 < .01). No supplementation-related adverse events occurred. Mean cord blood 25(OH)D was 22.1 ± 10.3 ng/mL in 2000 IU and 27.0 ± 13.3 ng/mL in 4000 IU groups (P = .024). After controlling for race and study site, preterm birth and labor were inversely associated with predelivery and mean 25(OH)D, but not baseline 25(OH)D. CONCLUSION: Maternal supplementation with vitamin D 2000 and 4000 IU/d 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.

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.

Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

Profound Vitamin D Deficiency in a Diverse Group of Women during Pregnancy Living in a Sun-Rich Environment at Latitude 32°N.

OBJECTIVE: Determine prevalence of vitamin D deficiency (VDD) in a diverse group of women presenting for obstetrical care at two community health centers in South Carolina at latitude 32°N. METHODS AND DESIGN: Any pregnant woman presenting for care at 2 community health centers was eligible to participate. Sociodemographic and clinical history were recorded. A single blood sample was taken to measure circulating 25(OH)D as indicator of vitamin D status [25(OH)D < 20 ng/mL (50 nmol/L deficiency; <32 ng/mL (80 nmol/L) insufficiency]. Total serum calcium, phosphorus, creatinine, and intact parathyroid hormone also were measured. RESULTS: 559 women, [mean age 25.0 ± 5.4 (range 14-43) years] participated: African American (48%), Hispanic (38%), Caucasian/Other (14%). Mean gestational age was 18.5 ± 8.4 (median 14.6, range 6.4-39.6) weeks' gestation. 48% were VDD; an additional 37% insufficient. Greatest degree was in the African American women (68% deficient; 94% insufficient). In multivariable regression, 25(OH)D retained a significant negative association with PTH (P < .001). CONCLUSIONS: VDD was high in a diverse group of women, greatest in those of darker pigmentation. The negative correlation between 25(OH)D and PTH confirms their corroborative use as biomarkers of VDD. These findings raise the issue of adequacy of current vitamin D recommendations for pregnant women.

Using participatory design to develop structured training in child and adolescent psychiatry.

CONTEXT: Learning during residency in child and adolescent psychiatry (CAP) is primarily work-based and has traditionally been opportunistic. There are increasing demands from both postgraduate trainees and medical organisations for structured programmes with defined learning outcomes. OBJECTIVES: The aim of this study was to partner with postgraduate trainees and consultants in psychiatry to identify key learning issues that should be considered during CAP residency and to use these in designing a structured programme to meet the learning outcome requirements of a competency framework. METHODS: Participatory design was used to structure a learning and assessment programme in CAP. First, during working seminars, consultants and postgraduate trainees were interviewed about the characteristics of the learning and working in CAP. These interviews were audio taped, transcribed and analyzed for recurrent themes to identify key issues. Descriptive results were fed back to the participants for validation. In a subsequent iterative process the researchers and practitioners partnered to construct a learning and assessment programme. RESULTS: The tasks within CAP were poorly described by study participants. Several other types of professionals within the healthcare team perform many of the tasks a CAP postgraduate trainee has to learn. Participants had difficulties describing how learning takes place and what postgraduate trainees need to learn in CAP. The partnership between researchers and practitioners identified three key issues to consider in CAP residencies: (1) Preparation for tasks postgraduate trainees are expected to fulfil, (2) Ensuring acquisition of physician-specific knowledge and skills, and (3) Clarifying roles and professional identity within the team. A structured training programme incorporating the key learning issues identified was created. CONCLUSION: Participatory design was very helpful to structure a contextually suitable training programme in CAP. The researchers speculate that this approach will result in easier implementation of the new training programme.

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.

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.

Accreditation of undergraduate and graduate medical education: how do the standards contribute to quality?

Accreditation organizations such as the Liaison Committee for Medical Education (LCME), the Royal College of Physicians and Surgeons of Canada (RCPSC), and the Accreditation Council for Graduate Medical Education (ACGME) are charged with the difficult task of evaluating the educational quality of medical education programs in North America. Traditionally accreditation includes a more quantitative rather than qualitative judgment of the educational facilities, resources and teaching provided by the programs. The focus is on the educational process but the contributions of these to the outcomes are not at all clear. As medical education moves toward outcome-based education related to a broad and context-based concept of competence, the accreditation paradigm should change accordingly.

A pilot survey of junior doctors' confidence in tasks related to broad aspects of competence.

Medical authorities and society are recommending that postgraduate medical education prepare physicians for broad aspects of competence. The most effective ways to prepare physicians for these are not known. The aim of this pilot study was to survey junior doctors' growth in confidence in different physician roles. A total of 165 junior doctors in internal medicine completed a self-administered survey of confidence levels in physician roles. Confidence levels between training levels were compared. Confidence in the roles of medical expert, communicator and collaborator increased between PRHOs and SHOs. Confidence levels increased in all roles between PRHOs and SpRs, but confidence between SHOs and SpRs increased only in the roles of collaborator and scholar. Confidence in the role of professional was low and did not increase significantly between training levels. The SHO year was rated as only moderately useful in facilitating learning of the tasks. These results suggest that growth of confidence in the physician roles proceeds at different rates during postgraduate training. Additional research is needed to identify effective ways for junior doctors to learn broad aspects of competence. Longitudinal tracking will be important to evaluate the effect of educational interventions on patient care.

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

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.

Periconceptional folic acid and the prevention of neural tube defects: Some food for thought for Canadian paediatricians.

OBJECTIVE: To review the data supporting the periconceptional use of folic acid for the prevention of neural tube defects and to explore how Canadian physicians can help foster preventive strategies. DATA SOURCES: Articles found through a MEDLINE search, 1990 to 1996, and Cochrane Database of Systematic Reviews 1995. Questionnaire survey of selected group of women of childbearing age (November 1994). Chart review of all children with newly diagnosed neural tube defects admitted to the Children's Hospital of Eastern Ontario, Ottawa, Ontario, between 1989 and 1994. DATA SELECTION: Epidemiological studies and randomized trials of supplemental folic acid for prevention of neural tube defects. Epidemio-logical studies and randomized trials of dietary folic acid. DATA SYNTHESIS: An increased periconceptional folic acid intake can prevent the recurrence of and the first occurrence of neural tube defects. However, consumption of adequate folic acid as natural food folate is relatively ineffective. Furthermore, few women are aware of the need for increased folic acid intake, despite Health Canada recommendations, nor do physicians seem to discuss the prevention of neural tube defects with patients. CONCLUSION: Better physician awareness, public education and supplementation of a staple food with folic acid are necessary to make the preventive strategy against neural tube defects effective.

OBJECTIF: Examiner les données soutenant l'utilisation périconception-nelle d'acide folique pour prévenir les anomalies du tube neural et explorer comment les médecins canadiens peuvent aider à favoriser des stratégies de prévention. SOURCES DES DONNÉES: Articles colligés dans le cadre d'une recherche sur MEDLINE, publiés entre 1990 et 1996, et dans la Cochrane Database Systematic Reviews, publiés en 1995. Enquête par questionnaire d'un groupe choisi de femmes en âgede procréer,effectuée ennovembre 1994. Étude du dossier médical de tous les enfants atteints d'une anomalie du tube neural venant d'être diagnostiquée et admis à l'Hôpital pour enfants de l'est de l'Ontario, à Ottawa, entre 1989 et 1994. SÉLECTION DES DONNÉES: Études épidémiologiques et études aléatoires sur l'administration de suppléments d'acide folique pour prévenir les anomalies du tube neural. Études épidémiologiques et aléatoires de l'acide folique alimentaire. SYNTHÈSE DES DONNÉES: Un apport accru d'acide folique pendant la période périconceptionnelle peut prévenir la récurrence ou la première occurrence d'anomalie du tube neural. Cependant, la consommation d'une quantité suffisante de folate, l'acide folique naturel, se révèle relativement inefficace. En outre, peu de femmes savent qu'elles doivent augmenter leur apport en acide folique, malgré les recommandations de Santé Canada, et les médecins ne semblent pas discuter de la prévention des anomalies du tube neural avec leurs patients. CONCLUSION: Une meilleure sensibilisation des médecins, l'éducation publique et des suppléments d'acide folique inclus dans un aliment de base sont nécessaires pour rendre efficace la stratégie contre les anomalies du tube neural.