How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies

Exome Sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making

Majority of dietary glutamine is utilized in first pass in preterm infants

Glutamine is a conditionally essential amino acid for very low-birth weight infants by virtue of its ability to play an important role in several key metabolic processes of immune cells and enterocytes. Although glutamine is known to be used to a great extend, the exact splanchnic metabolism in enterally fed preterm infants is unknown. We hypothesized that preterm infants show a high splanchnic first-pass glutamine metabolism and the primary metabolic fate of glutamine is oxidation. Five preterm infants (mean ± SD birth weight 1.07 ± 0.22 kg and GA 29 ± 2 wk) were studied by dual tracer ([U-C]glutamine and [N2]glutamine) cross-over techniques on two study days (at postnatal week 3 ± 1 wk). Splanchnic and whole-body glutamine kinetics were assessed by plasma isotopic enrichment of [U-C]glutamine and [N2]glutamine and breath CO2 enrichments. Mean fractional first-pass glutamine uptake was 73 ± 6% and 57 ± 17% on the study days. The splanchnic tissues contributed for a large part (57 ± 6%) to the total amount of labeled carbon from glutamine retrieved in expiratory air. Dietary glutamine is used to a great extent by the splanchnic tissues in preterm infants and its carbon skeleton has an important role as fuel source. Copyright © 2010 International Pediatric Research Foundation, Inc

New insights into the methodological issues of the indicator amino acid oxidation method in preterm neonates

Background: We determined the effect of adaptation to the study diet on oxidation of the indicator amino acid and the required tracer washout time in preterms. Methods: Subjects received a study diet for 6 d that entailed a 50% reduction in leucine. Tracer studies using enterally infused [ 13 C]bicarbonate and [1-13 C]phenylalanine were performed on days 1, 2, 4, and 6. Breath samples containing 13 CO 2 were collected during steady state and measured by infrared spectrometric analysis, and the fraction of 13 CO 2 recovery from 13 C oxidation (F 13 CO 2) was calculated. Results: Preterm infants (n = 11, birth weight 1.9 ± 0.1 kg, gestational age 32.6 ± 1.5 wk) received 166 mg/kg/d of leucine. Baseline enrichment changed significantly at day 1 of the study diet. F 13 CO 2 did not change significantly between days 2 and 4 but was significantly lower at day 6. The tracer washout time was determined to be 7.5 h using a biphasic regression analysis. Conclusion: One day of adaptation to a new diet is necessary to adapt to the 13 C enrichment of the study formula before starting infant requirement studies. Adaptation for a period of 5 d results in a protein-sparing response. The minimal time between two studies within the same subject is 7.5 h. © 2013 International Pediatric Research Foundation, Inc

Use of [13C]Bicarbonate for Metabolic Studies in Preterm Infants: Intragastric versus Intravenous Administration

The metabolic fate of substrates in humans can be examined by the use of stable isotopes, one of which, [13C]bicarbonate, may serve to estimate CO2 production rate. In view of minimizing the burden of metabolic studies for preterm infants, the authors determined whether intragastric and intravenous infusions of [13C]bicarbonate would achieve the same 13CO2 enrichment in expired air during steady state. A second aim of this study was to determine the minimum time required to reach steady state during intragastric infusion. Ten preterm infants received a primed continuous [13C]bicarbonate infusion intragastrically, followed by an intravenous infusion the next day. Breath samples were obtained every 30 min by the direct sampling method. 13CO2 isotopic enrichment, expressed as atom percent excess, was measured by isotopic ratio mass spectrometry. Two-tailed t tests were used to detect statistically significant differences between the infusion routes. The isotopic enrichment at plateau did not differ between intragastric and intravenous infusion. A steady state of 13CO2 enrichment was achieved after 60 min of intravenous infusion and after 120 min of intragastric infusion. In conclusion, intragastric infusion of [13C]bicarbonate may serve to estimate the whole-body CO2 production rate in preterm infants. To reach 13CO2 steady state, a minimum of 120 min of bicarbonate administration is require