Methionine is an indispensable sulfur amino acid that functions as a key precursor for the synthesis of homocysteine and cysteine. Studies in adult humans suggest that splanchnic tissues convert dietary methionine to homocysteine and cysteine by means of transmethylation and transsulfuration, respectively. Studies in piglets show that significant metabolism of dietary indispensable amino acids occurs in the gastrointestinal tissues (GIT), yet the metabolic fate of methionine in GIT is unknown. We show here that 20% of the dietary methionine intake is metabolized by the GIT in piglets implanted with portal and arterial catheters and fed milk formula. Based on analyses from intraduodenal and intravenous infusions of [1-13 C]methionine and [ 2 H3]methionine, we found that the whole-body methionine transmethylation and remethylation rates were significantly higher during duodenal than intravenous tracer infusion. First-pass splanchnic metabolism accounted for 18% and 43% of the whole-body transmethylation and remethylation, respectively. Significant transmethylation and transsulfuration was demonstrated in the GIT, representing Ϸ27% and Ϸ23% of whole-body fluxes, respectively. The methionine used by the GIT was metabolized into homocysteine (31%), CO 2 (40%), or tissue protein (29%). Cystathionine ␤-synthase mRNA and activity was present in multiple GITs, including intestinal epithelial cells, but was significantly lower than liver. We conclude that the GIT consumes 20% of the dietary methionine and is a significant site of net homocysteine production. Moreover, the GITs represent a significant site of whole-body transmethylation and transsulfuration, and these two pathways account for a majority of methionine used by the GITs.cystathionine ␤-synthase ͉ homocysteine ͉ intestine

There is no evidence for limited endogenous cyst(e)ine synthesis in 4-wk-old LBW preterm infants born at gestational ages from 32 to 34 wk. It is safe to conclude that the cyst(e)ine requirement is <18 mg kg(-1) d(-1) providing generous amounts of methionine and that cyst(e)ine is probably not a conditionally essential amino acid in fully enterally fed LBW preterm infants born at 32-34 wk.

Respiratory syncytial virus (RSV) bronchiolitis causes substantial morbidity and mortality in young children, but insight into the burden of RSV bronchiolitis on pediatric intensive care units (PICUs) is limited. We aimed to determine the burden of RSV bronchiolitis on the PICUs in the Netherlands. Therefore, we identified all children ≤ 24 months of age with RSV bronchiolitis between 2003 and 2016 from a nationwide PICU registry. Subsequently we manually checked their patient records for correct diagnosis and collected patient characteristics, additional clinical data, respiratory support modes, and outcome. In total, 2161 children were admitted to the PICU for RSV bronchiolitis. The annual number of admissions increased significantly during the study period (β 4.05, SE 1.27, p = 0.01), and this increase was mostly driven by increased admissions in children up to 3 months old. Concomitantly, non-invasive respiratory support significantly increased (β 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (β 6.69, SE 0.96, p < 0.01), whereas the use of invasive ventilation remained stable.Conclusion: The burden of severe RSV bronchiolitis on PICUs has increased in the Netherlands. Concomitantly, the use of non-invasive respiratory support, especially HFNC, has increased. What is Known:• RSV bronchiolitis is a major cause of childhood morbidity and mortality and may require pediatric intensive care unit admission.• The field of pediatric critical care for severe bronchiolitis has changed due to increased non-invasive respiratory support options. What is New:• The burden of RSV bronchiolitis for the Dutch PICUs has increased. These data inform future strategic PICU resource planning and implementation of RSV preventive strategies.• There was a significant increase in the use of high flow nasal cannula at the PICU, but the use of invasive mechanical ventilation did not decrease.

ABSTRACT:The intestine is a major site of amino acid metabolism, especially in neonates. The energy needed for the metabolic processes in neonatal animals is derived from dietary glucose and amino acids. No data are available showing that dietary amino acids function as intestinal fuel source in human neonates as well. We hypothesized that preterm infants show a high splanchnic first-pass glutamate metabolism and the primary metabolic fate of glutamate is oxidation. Five preterm infants (birth weight 1.2 Ϯ 0.2 kg, gestational age 29 Ϯ 1 wk) were studied by dual tracer ([U- T he splanchnic tissues have much higher energy expenditure and protein synthesis rates than expected based on their weight. Studies in neonatal animals found that up to 50% of the dietary protein intake in the portal drained viscera (intestines, pancreas, spleen, and stomach) is used for protein turnover and biosynthetic pathways; from 10% to 20% is used for whole-body energy expenditure (1-3). Humans also show considerable intestinal amino acid metabolism (4,5) and the metabolic rate is even higher in preterm infants. Previous studies showed that first-pass metabolism of leucine in newborns is twice that of adults (6) and that in preterm infants, a great amount of dietary lysine is used in first pass as well (7).Glutamate plays a pivotal role in human metabolism. It provides a critical link between carbohydrate and amino acid metabolism. Glutamate is the obligatory precursor of glutamine; it plays a central role in all transamination reactions in the body and also functions as a neurotransmitter. In addition, dietary glutamate is a major substrate for glutathione (GSH) synthesis (8). Animal studies showed that the gut of infant piglets metabolizes virtually all the enteral glutamate during absorption (9) and that glutamate it is an important oxidative substrate for the intestinal mucosa (10). In human adults, most of the dietary glutamate (88%) is metabolized in first-pass as well (11) and is oxidized to a great extent in the splanchnic region (12). These studies in animals and adult humans suggest that dietary glutamate serves as an important metabolic fuel source in the intestine. If so, this may have a particular impact on the nutritional needs of preterm infants. The intestine of preterm infant is immature and has a low tolerance to enteral feeding. Yet, enteral feeding is a must for intestinal maturation and the growth and development of other organs. Much effort should be directed toward understanding the nutritional needs of the intestine of preterm infants. The present study was developed to extend the previously mentioned observations made in animals and adult humans and thus gain more insight into the nutritional needs of infants.In the present study, we, therefore, investigated 1) the effect of first-pass splanchnic uptake of glutamate and 2) the metabolic fate of the used glutamate in the splanchnic bed of enterally fed preterm infants. Glutamate kinetics in the splanchnic region were studied by dual, primed, constant i.v. and en...

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The metabolic fate of substrates in humans can be examined by the use of stable isotopes, one of which, [13 C]bicarbonate, may serve to estimate CO 2 production rate. In view of minimizing the burden of metabolic studies for preterm infants, the authors determined whether intragastric and intravenous infusions of [13 C]bicarbonate would achieve the same 13 CO 2 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 [13 C]bicarbonate infusion intragastrically, followed by an intravenous infusion the next day. Breath samples were obtained every 30 min by the direct sampling method.13 CO 2 isotopic enrichment, expressed as atom percent excess, was measured by isotopic ratio mass spectrometry. Twotailed 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 13 CO 2 enrichment was achieved after 60 min of intravenous infusion and after 120 min of intragastric infusion. In conclusion, intragastric infusion of [13 C]bicarbonate may serve to estimate the whole-body CO 2 production rate in preterm infants. The past two decades have seen the increased use of stable isotopes to study amino acid metabolism in humans. These isotopic tracer techniques have greatly enhanced our understanding of nutrient daily requirements and metabolism (1).For determining the oxidation rates of specifically labeled substrates such as amino acids or glucose, we need to quantify substrate oxidation in each individual by measuring the 13 CO 2 production rate during IV infusion of labeled bicarbonate (2). The production of 13 CO 2 is made up of total CO 2 production rate and 13 CO 2 enrichment in expired breath. Although total CO 2 production rate is traditionally assessed by indirect calorimetry, 13 CO 2 enrichment is measured by isotopic ratio mass spectrometry. A certain amount of CO 2 , and thus 13 CO 2 as well, is retained in the body. Because this amount is related to caloric intake, a correction factor is necessary to calculate substrate oxidation rates (3). A method that makes correction factors and indirect calorimetry superfluous is the infusion of NaH 13 CO 3 before the labeled substrate infusion (4). Kien et al. (5) compared IG infusion of [13 C]bicarbonate with indirect calorimetry by the use of a correction factor. This study showed the validation of the use of dilution stable tracer technique to estimate CO 2 production. However, those authors did not compare the 13 CO 2 enrichment during IV infusion with IG infusion of [ 13 C]bicarbonate. The general purpose of this study was to determine whether in preterm infants IG infusion of NaH 13 CO 3 yields the same enrichment as IV infusion at steady state. To this aim, we compared 13 CO 2 enrichment in expired breath during IG and IV infusion of labeled bicarbonate at plateau...

These data do not support the hypothesis that endogenous cyst(e)ine synthesis is limited in very low birth weight preterm infants with gestational ages of <29 weeks, both at 32 and 35 weeks postmenstrual age. It is safe to conclude that cyst(e)ine requirement is <18 mg/kg per day in enterally fed very low birth weight preterm infants who are older than 32 weeks' postmenstrual age and whose methionine intake is adequate. Therefore, cyst(e)ine is probably not a conditionally essential amino acid in these infants.

Entrustable professional activities (EPAs), as a focus of learner assessment, are supported by validity evidence. An EPA is a unit of professional practice requiring proficiency in multiple competencies simultaneously, that can be entrusted to a sufficiently competent learner. Taken collectively, a set of EPAs define and inform the curriculum of a specialty training. The goal of this study was to develop a set of EPAs for Dutch PICU fellows. A multistage methodology was employed incorporating sequential input from task force members, a medical education expert, PICU fellowship program directors, and PICU physicians and fellows via a modified three-round Delphi study. In the first modified Delphi round, experts rated indispensability and clarity of preliminary EPAs. In the subsequent rounds, aggregated scores for each EPA and group comments were provided. In round two, respondents rated indispensability and clarity of revised EPAs. Round three was used to gain explicit confirmation of suitability to implement these EPAs. Based on median ratings and content validity index (CVI) analysis for indispensability in the first two rounds, all nine preliminary EPAs covered activities that were deemed essential to the clinical practice of PICU physicians. Based on median ratings and CVI analysis for clarity however, four EPAs needed revision. With an agreement percentage of 93–100% for all individual EPAs as well as the set as a whole, a high degree of consensus among experts was reached in the third round. The resulting nine PICU EPAs provide a succinct overview of the core tasks of Dutch PICU physicians. These EPAs were created as an essential first step towards developing an assessment system for PICU fellows, grounded in core professional activities. The robust methodology used, may have broad applicability for other (sub)specialty training programs aiming to develop specialty specific EPAs.