Background Mice are well suited for modeling human congenital heart defects (CHD), given their four-chamber cardiac anatomy. However, mice with CHD invariably die prenatally/neonatally, causing CHD phenotypes to be missed. Therefore, we investigated the efficacy of noninvasive micro-computed tomography (micro-CT) to screen for CHD in stillborn/fetal mice. These studies were carried out using chemically mutagenized mice expected to be enriched for birth defects including CHD. Methods and Results Stillborn/fetal mice obtained from the breeding of N-ethyl-N-nitrosourea (ENU) mutagenized mice were formalin-fixed and stained with iodine, then micro-CT scanned. Those diagnosed with CHD and some CHD-negative pups were necropsied. A subset of these were further analyzed by histopathology to confirm the CHD/no-CHD diagnosis. Micro-CT scanning of 2105 fetal/newborn mice revealed an abundance of ventricular septal defects (VSD) (n=307). Overall, we observed an accuracy of 89.8% for VSD diagnosis. Outflow tract anomalies identified by micro-CT included double outlet right ventricle (n=36), transposition of the great arteries (n=14), and persistent truncus arteriosus (n=3). These were diagnosed with a 97.4% accuracy. Aortic arch anomalies also were readily detected with an overall 99.6% accuracy. This included right aortic arch (n=28) and coarctation/interrupted aortic arch (n=12). Also detected by micro-CT were atrioventricular septal defects (n=22), tricuspid hypoplasia/atresia (n=13), and coronary artery fistulas (n=16). They yielded accuracies of 98.9%, 100%, and 97.8% respectively. Conclusions Contrast enhanced micro-CT imaging in neonatal/fetal mice can reliably detect a wide spectrum of CHD. We conclude micro-CT imaging can be used for routine rapid assessments of structural heart defects in fetal/newborn mice.

There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population.

BACKGROUND: Pharmacogenetic testing can provide predictive insights about the efficacy and safety of drugs used in cancer treatment. Although many drug-gene associations have been reported in the literature, the strength of evidence supporting each association can vary significantly. Even among the subgroup of drugs classified by the PharmGKB database to have a high or moderate level of evidence, there is limited information regarding the economic value of pharmacogenetic testing.OBJECTIVES: To: (a) summarize the available pharmacoeconomic evidence assessing the value of pharmacogenetic testing for cancer drugs with clinically relevant drug-gene associations; (b) determine the quality of the studies that contain this evidence; and (c) discuss the quality of this evidence with respect to the level of evidence of the drug-gene associations. METHODS:The PharmGKB database was used to identify cancer drugs with clinically relevant drug-gene associations graded high (1A, 1B) or moderate (2A, 2B). A systematic literature review was conducted using these drugs. Ovid MEDLINE and Embase databases were searched to identify costeffectiveness, cost-utility, or cost-minimization studies comparing pharmacogenetic testing to an alternative. Cost and effect values from every relevant comparison within the studies were extracted, and the incremental cost-effectiveness ratio (ICER) was either extracted or calculated for each comparison. Quality assessment was conducted for each study using the Quality of Health Economic Studies (QHES) instrument. Qualitative synthesis was used to summarize the data.