Pediatric drug data in Canadian drug monographs: a descriptive analysis.

BACKGROUND: Optimal drug therapy in children relies on the availability of pediatric-specific information. We aimed to describe the current status of pediatric pharmacotherapy data in monographs of new drugs approved by Health Canada. METHODS: In this descriptive analysis, we reviewed the quality and quantity of monographs of new drugs approved by Health Canada between Jan. 1, 2007, and Dec. 31, 2016. We excluded drugs withdrawn from the Canadian market and drugs with primary indications irrelevant to pediatrics. We determined the percentage of included drug monographs that listed pediatric-specific information. RESULTS: During this study period, Health Canada approved 281 drugs, 270 of which met our inclusion criteria. Pediatric-specific information and indication were present in 127 (47.1%) and 75 (27.8%) of the drug monographs, respectively. Of all pediatric age groups, neonates had the lowest number of indications listed in the product monographs (7, 2.6%). Only 9 (60%) oral drugs indicated for children 6 years of age or younger were available in child-friendly, age-appropriate dosage forms. INTERPRETATION: Most of the new drugs approved by Health Canada do not contain pediatric or neonatal indications in their product monographs, and therefore, are used "off-label." Regulatory mechanisms are required to promote both neonatal and pediatric drug development and submission of available pediatric data by manufacturers to Health Canada.

Physiological adjustment to postnatal growth trajectories in healthy preterm infants.

BACKGROUND: International guidelines suggest that growth of preterm infants should match intrauterine rates. However, the trajectory for extrauterine growth may deviate from the birth percentile due to an irreversible, physiological loss of extracellular fluid during postnatal adaptation to extrauterine conditions. To which "new" physiological growth trajectory preterm infants should adjust to after completed postnatal adaptation is unknown. This study analyzes the postnatal growth trajectories of healthy preterm infants using prospective criteria defining minimal support, as a model for physiological adaptation. METHODS: International, multi-center, longitudinal, observational study at five neonatal intensive care units (NICUs). Daily weights until day of life (DoL) 21 of infants with undisturbed postnatal adaptation were analyzed (gestational ages: (i) 25-29 wk, (ii) 30-34 wk). RESULTS: 981 out of 3,703 admitted infants included. Maximum weight loss was 11% (i) and 7% (ii) by DoL 5, birth weight regained by DoL 15 (i) and 13 (ii). Infants transitioned to growth trajectories parallel to Fenton chart percentiles, 0.8 z-scores below their birth percentiles. The new trajectory after completed postnatal adaptation could be predicted for DoL 21 with R(2) = 0.96. CONCLUSION: This study provides a robust estimate for physiological growth trajectories of infants after undisturbed postnatal adaptation. In the future, the concept of a target postnatal trajectory during NICU care may be useful.

Rapid measurement of macronutrients in breast milk: How reliable are infrared milk analyzers?

BACKGROUND & AIMS: Significant biological variation in macronutrient content of breast milk is an important barrier that needs to be overcome to meet nutritional needs of preterm infants. To analyze macronutrient content, commercial infrared milk analyzers have been proposed as efficient and practical tools in terms of efficiency and practicality. Since milk analyzers were originally developed for the dairy industry, they must be validated using a significant number of human milk samples that represent the broad range of variation in macronutrient content in preterm and term milk. Aim of this study was to validate two milk analyzers for breast milk analysis with reference methods and to determine an effective sample pretreatment. Current evidence for the influence of (i) aliquoting, (ii) storage time and (iii) temperature, and (iv) vessel wall adsorption on stability and availability of macronutrients in frozen breast milk is reviewed. METHODS: Breast milk samples (n = 1188) were collected from 63 mothers of preterm and term infants. Milk analyzers: (A) Near-infrared milk analyzer (Unity SpectraStar, USA) and (B) Mid-infrared milk analyzer (Miris, Sweden) were compared to reference methods, e.g. ether extraction, elemental analysis, and UPLC-MS/MS for fat, protein, and lactose, respectively. RESULTS: For fat analysis, (A) measured precisely but not accurately (y = 0.55x + 1.25, r(2) = 0.85), whereas (B) measured precisely and accurately (y = 0.93x + 0.18, r(2) = 0.86). For protein analysis, (A) was precise but not accurate (y = 0.55x + 0.54, r(2) = 0.67) while (B) was both precise and accurate (y = 0.78x + 0.05, r(2) = 0.73). For lactose analysis, both devices (A) and (B) showed two distinct concentration levels and measured therefore neither accurately nor precisely (y = 0.02x + 5.69, r(2) = 0.01 and y = -0.09x + 6.62, r(2) = 0.02 respectively). Macronutrient levels were unchanged in two independent samples of stored breast milk (-20 °C measured with IR; -80 °C measured with wet chemistry) over a period of 14 months. CONCLUSIONS: Milk analyzers in the current configuration have the potential to be introduced in clinical routine to measure fat and protein content, but will need major adjustments.

Glycogen synthase kinase 3α deficiency attenuates atherosclerosis and hepatic steatosis in high fat diet-fed low density lipoprotein receptor-deficient mice.

Studies have implicated signaling through glycogen synthase kinase (GSK) 3α/ß in the activation of pro-atherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3α in the development and progression of accelerated atherosclerosis. We crossed Gsk3a/GSK3α-knockout mice with low-density lipoprotein receptor (Ldlr) knockout mice. Five-week-old Ldlr(-/-);Gsk3a(+/+), Ldlr(-/-);Gsk3a(+/-), and Ldlr(-/-);Gsk3a(-/-) mice were fed a chow diet or a high-fat diet for 10 weeks and then sacrificed. GSK3α deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat-diet fed Ldlr(-/-) mice that were deficient for GSK3α had significantly less hepatic lipid accumulation and smaller atherosclerotic lesions (60% smaller in Ldlr(-/-);Gsk3a(+/-) mice, 80% smaller in Ldlr(-/-);Gsk3a(-/-) mice; P < 0.05), compared with Ldlr(-/-);Gsk3a(+/+) controls. GSK3α deficiency was associated with a significant increase in plasma IL-10 concentration and IL-10 expression in isolated macrophages. A twofold to threefold enhancement in endoplasmic reticulum stress-induced IL-10 expression was observed in Thp-1-derived macrophages that were pretreated with the GSK3α/ß inhibitor CT99021. Together, these results suggest that GSK3α plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways.

Nutritional status in sick children and adolescents is not accurately reflected by BMI-SDS.

OBJECTIVE: Nutritional status provides helpful information of disease severity and treatment effectiveness. Body mass index standard deviation scores (BMI-SDS) provide an approximation of body composition and thus are frequently used to classify nutritional status of sick children and adolescents. However, the accuracy of estimating body composition in this population using BMI-SDS has not been assessed. Thus, this study aims to evaluate the accuracy of nutritional status classification in sick infants and adolescents using BMI-SDS, upon comparison to classification using percentage body fat (%BF) reference charts. DESIGN: BMI-SDS was calculated from anthropometric measurements and %BF was measured using dual-energy x-ray absorptiometry (DXA) for 393 sick children and adolescents (5 months-18 years). Subjects were classified by nutritional status (underweight, normal weight, overweight, and obese), using 2 methods: (1) BMI-SDS, based on age- and gender-specific percentiles, and (2) %BF reference charts (standard). Linear regression and a correlation analysis were conducted to compare agreement between both methods of nutritional status classification. %BF reference value comparisons were also made between 3 independent sources based on German, Canadian, and American study populations. RESULTS: Correlation between nutritional status classification by BMI-SDS and %BF agreed moderately (r (2) = 0.75, 0.76 in boys and girls, respectively). The misclassification of nutritional status in sick children and adolescents using BMI-SDS was 27% when using German %BF references. Similar rates observed when using Canadian and American %BF references (24% and 23%, respectively). CONCLUSIONS: Using BMI-SDS to determine nutritional status in a sick population is not considered an appropriate clinical tool for identifying individual underweight or overweight children or adolescents. However, BMI-SDS may be appropriate for longitudinal measurements or for screening purposes in large field studies. When accurate nutritional status classification of a sick patient is needed for clinical purposes, nutritional status will be assessed more accurately using methods that accurately measure %BF, such as DXA.

Misclassification of newborns due to systematic error in plotting birth weight percentile values.

OBJECTIVES: Higher than expected small for gestational age (SGA) rates and lower than expected large for gestational age (LGA) rates have been observed. A possible explanation is a leftward shift of percentile curves for birth weight due to a systematic error in plotting birth weight values in charts (ie, plotting weekly mean birth weight data at the beginning of the weeks). Our objectives were to assess how common this plotting error is and to analyze the effect of this error on SGA and LGA classification based on data from the German perinatal survey. METHODS: First, a systematic literature search for birth weight charts was performed, and the charts were analyzed for the plotting error. Second, percentile values (10th, 50th, and 90th) for 25 to 42 completed weeks of gestation were calculated from the data of 1181200 male singleton newborns (German perinatal survey, 1995-2000). Birth weight percentile curves were calculated with and without the plotting error, and the resulting SGA and LGA rates were analyzed. RESULTS: Fourteen of the 16 identified publications contained the systematic error in plotting. Using our calculated percentile curves, a leftward shift caused by the plotting error led to an SGA rate of 12.5% and an LGA rate of 7.7%; ∼5% of newborns were misclassified. CONCLUSIONS: Percentile charts should be examined for the described systematic error and, if necessary, corrected.