Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

BACKGROUND: Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS: In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group. RESULTS: Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death. CONCLUSIONS: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).

C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study.

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours.

Cost impact of procalcitonin-guided decision making on duration of antibiotic therapy for suspected early-onset sepsis in neonates.

BACKGROUNDS: The large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age. METHODS: Data from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making. RESULTS: In total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category 'infection unlikely' and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age < 37 weeks in the Czech Republic. CONCLUSIONS: Health care costs of PCT-guided decision making of term and late-preterm neonates with suspected EOS are not significantly different from costs of standard care. Significant cost reduction was found for risk category 'infection unlikely,' and is affected by both the price of PCT-testing and (prolonged) hospitalization due to SAEs.

Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns).

BACKGROUND: Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS: We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS: Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI -4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (-5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). INTERPRETATION: Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING: The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.

Hypoxia-induced contraction of chicken embryo mesenteric arteries: mechanisms and developmental changes.

The fetal cardiovascular responses to acute hypoxia include a redistribution of the cardiac output toward the heart and the brain at the expense of other organs, such as the intestine. We hypothesized that hypoxia exerts a direct effect on the mesenteric artery (MA) that may contribute to this response. Using wire myography, we investigated the response to hypoxia (Po2 ~2.5 kPa for 20 min) of isolated MAs from 15- to 21-day chicken embryos (E15, E19, E21), and 1- to 45-day-old chickens (P1, P3, P14, P45). Agonist-induced pretone or an intact endothelium were not required to obtain a consistent and reproducible response to hypoxia, which showed a pattern of initial rapid phasic contraction followed by a sustained tonic contraction. Phasic contraction was reduced by elimination of extracellular Ca2+ or by presence of the neurotoxin tetrodotoxin, the α1-adrenoceptor antagonist prazosin, or inhibitors of L-type voltage-gated Ca2+ channels (nifedipine), mitochondrial electron transport chain (rotenone and antimycin A), and NADPH oxidase (VAS2870). The Rho-kinase inhibitor Y27632 impaired both phasic and tonic contraction and, when combined with elimination of extracellular Ca2+, hypoxia-induced contraction was virtually abolished. Hypoxic MA contraction was absent at E15 but present from E19 and increased toward the first days posthatching. It then decreased during the first weeks of life and P45 MAs were unable to sustain hypoxia-induced contraction over time. In conclusion, the results of the present study demonstrate that hypoxic vasoconstriction is an intrinsic feature of chicken MA vascular smooth muscle cells during late embryogenesis and the perinatal period.

Plasma levels of dimethylarginines in preterm very low birth weight neonates: its relation with perinatal factors and short-term outcome.

Endogenously produced inhibitors of nitric oxide (NO) synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various disease states characterized by reduced NO availability. We investigated the association between plasma levels of ADMA, symmetric dimethylarginine (SDMA), L-arginine, and citrulline and perinatal factors and outcome in 130 preterm (gestational age ≤ 30 weeks) very low birth weight (VLBW, < 1500 g) infants. Plasma samples were collected 6-12 h after birth. We did not find significant correlations between ADMA, SDMA, L-arginine, and citrulline levels and gestational age or birth weight. However, the arginine:ADMA ratio (AAR, a better indicator of NO availability than either arginine or ADMA separately) was positively correlated with gestational age. ADMA and arginine levels were not significantly different between males and females but males showed a negative correlation between ADMA levels and gestational age. Perinatal factors such as preeclampsia, chrorioamnionitis, prolonged rupture of membranes, or form of delivery did not significantly alter dimethylarginine levels or AAR. In contrast, the AAR was significantly reduced in the infants with respiratory distress, mechanical ventilation, and systemic hypotension Therefore, our data suggest that altered NO availability may play a role in the respiratory and cardiovascular adaptation in preterm VLBW infants.

Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial.

BACKGROUND: At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term. METHODS AND FINDINGS: We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34(+0) and 37(+0) wk of gestation. Participants were randomly allocated in a 1:1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate. From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported. Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM. CONCLUSIONS: In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29313500

Management of late-preterm premature rupture of membranes: the PPROMEXIL-2 trial.

OBJECTIVE: The evidence for the management of near term prelabor rupture of membranes is poor. From January 2007 until September 2009, we performed the PPROM Expectant Management versus Induction of Labor (PPROMEXIL) trial. In this trial, we showed that in women with preterm prelabor rupture of membranes (PPROM), the incidence of neonatal sepsis was low, and the induction of labor (IoL) did not reduce this risk. Because the PPROMEXIL trial was underpowered and because of a lower-than-expected incidence of neonatal sepsis, we performed a second trial (PPROMEXIL-2), aiming to randomize 200 patients to improve the evidence in near-term PPROM. STUDY DESIGN: In a nationwide multicenter study, nonlaboring women with PPROM between 34 and 37 weeks' gestational age were eligible for inclusion. Patients were randomized to IoL or expectant management (EM). The primary outcome measure was neonatal sepsis. RESULTS: From December 2009 until January 2011, we randomized 100 women to IoL and 95 to EM. Neonatal sepsis was seen in 3 neonates (3.0%) in the IoL-group versus 4 neonates (4.1%) in the EM group (relative risk, 0.74; 95% confidence interval, 0.17-3.2). One of the sepsis cases in the IoL group resulted in neonatal death because of asphyxia. There were no significant differences in secondary outcomes. CONCLUSION: The risk of neonatal sepsis after PPROM near term is low. Induction of labor does not reduce this risk.

Machine Learning Used to Compare the Diagnostic Accuracy of Risk Factors, Clinical Signs and Biomarkers and to Develop a New Prediction Model for Neonatal Early-onset Sepsis.

BACKGROUND: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. STUDY DESIGN: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. RESULTS: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. CONCLUSIONS: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

Plasma Amino Acid Concentrations at Birth and Patent Ductus Arteriosus in Very and Extremely Preterm Infants.

Background: Amino acids are increasingly recognized as bioactive molecules in numerous physiological and pathophysiological pathways. The non-essential amino acid glutamate is vasoactive in the rat ductus arteriosus (DA) and a decrease in its levels within the 1st days of life has been associated with the presence of patent DA (PDA) in extremely preterm infants. However, these findings have not been confirmed in other studies. Objective: To investigate the possible association between amino acid concentrations in the 1st day of life and the presence of PDA in a cohort of 121 newborns with gestational age (GA) below 30 weeks and birth weight (BW) below 1,500 g. Methods: Plasma samples were collected 6-12 h after birth and amino acid concentrations were determined by tandem mass spectrometry. Besides PDA, we analyzed the potential association of amino acid concentrations with infant sex, small for GA (SGA, defined as BW < third percentile), antenatal corticosteroids, chorioamnionitis, and preeclampsia. Group differences were analyzed by ANOVA adjusted for GA and BW. A Bonferroni significance threshold of P < 0.0024 was used to correct for multiple testing. Results: PDA was found in 48 of the 121 infants examined. We observed higher mean levels of glutamate in infants with PDA (147.0 µmol/L, SD 84.0) as compared with those without (106.7 µmol/L, SD 49.1, P = 0.0006). None of the other amino acid concentrations in the PDA group reached the level of statistical significance that was pre-set to correct for multiple comparisons. Glutamate levels were not significantly affected by infant sex, being SGA, or by exposure to antenatal corticosteroids, clinical chorioamnionitis, or preeclampsia. Conclusion: Our study not only does not confirm the previous findings of low glutamate levels in preterm infants with PDA, but we have even found elevated glutamate concentrations associated with PDA. Nevertheless, despite the high statistical significance, the difference in glutamate levels may lack clinical significance or may be an epiphenomenon associated with the particular clinical condition of infants with PDA.

Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort.

The etiology of necrotizing enterocolitis (NEC) is multifactorial and an underlying genetic predisposition to NEC is increasingly being recognized. A growing number of studies identified single nucleotide polymorphisms (SNPs) of selected genes with potential biological relevance in the development of NEC. However, few of these genetic studies have been replicated in validation cohorts. We aimed to confirm in a cohort of 358 preterm newborns (gestational age <30 weeks, 26 cases of NEC ≥ Bell stage II) the association with NEC of three candidate SNPs: the vascular endothelium growth factor (VEGF) C-2578A polymorphism (rs699947), the interleukin (IL)-18 C-607A polymorphism (rs1946518), and the IL-4 receptor α-chain (IL-4Rα) A-1902G polymorphism (rs1801275). We observed that allele and genotype frequencies of the three SNPs did not significantly differ between the infants with and without NEC. In contrast, the minor G-allele of the IL-4Rα A-1902G polymorphism was significantly less frequent in the group of 51 infants with the combined outcome NEC or death before 34 weeks postmenstrual age than in the infants without the outcome (0.206 vs. 0.331, P = 0.01). In addition, a significant negative association of the G-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.44, 95% CI 0.21-0.92), recessive (aOR 0.15, 95% CI 0.03-0.74), and additive (aOR 0.46, 95% CI 0.26-0.80) genetic models. In conclusion our study provides further evidence that a genetic variant of the IL-4Rα gene may contribute to NEC.

Pentalogy of Cantrell: two patients and a review to determine prognostic factors for optimal approach.

Two patients with incomplete pentalogy of Cantrell are described. The first was a girl with a large omphalocele with evisceration of the heart, liver and intestines with an intact sternum. Echocardiography showed profound intracardiac defects. The girl died 33 h after birth. The second patient was a female fetus with ectopia cordis (EC) without intracardiac anomalies; a large omphalocele with evisceration of the heart, stomach, spleen and liver; a hypoplastic sternum and rib cage; and a scoliosis. The pregnancy was terminated. A review of patients described in the literature is presented with the intention of finding prognostic factors for an optimal approach to patients with the pentalogy of Cantrell. In conclusion the prognosis seems to be poorer in patients with the complete form of pentalogy of Cantrell, EC, and patients with associated anomalies. Intracardial defects do not seem to be a prognostic factor.

Is the C242T Polymorphism of the CYBA Gene Linked with Oxidative Stress-Associated Complications of Prematurity?

The C242T polymorphism of CYBA (cytochrome B-245 alpha chain), the gene encoding the p22phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, has been linked to several conditions in which oxidative stress plays a pathogenic role. We investigated in a cohort of 451 preterm infants [gestational age (GA) ≤30 weeks] the association of the polymorphism with the risk of developing neonatal respiratory distress syndrome (RDS), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, patent ductus arteriosus, or intraventricular hemorrhage. We observed a significant association of the TT/CT genotype with RDS [odds ratio (OR) 2.34, 95% confidence interval (95% CI) 1.28-3.90], ROP (OR 1.72, 95% CI 1.05-2.80), and BPD (OR 1.60, 95% CI 1.05-2.43). When this dominant model was adjusted to account for GA, birth weight, and sex, it remained significant for the three outcomes. This study is the first to address the association of a polymorphism related to the NADPH family with oxidative stress-related complications of prematurity. Since p22phox is essential for reactive oxygen species production by NADPH oxidase, we hypothesize that genetic variations in the protein may lead to differences in susceptibility to oxidative stress-induced damage in preterm infants. Antioxid. Redox Signal. 27, 1432-1438.

Association between the p.Thr1406Asn polymorphism of the carbamoyl-phosphate synthetase 1 gene and necrotizing enterocolitis: A prospective multicenter study.

The p.Thr1406Asn (rs1047891) polymorphism of the carbamoyl-phosphate synthetase 1 (CPS1) gene has been linked to functional consequences affecting the downstream availability of the nitric oxide precursor L-arginine. L-arginine concentrations are decreased in preterm infants with necrotizing enterocolitis (NEC). In this multicenter prospective study, we investigated the association of the p.Thr1406Asn polymorphism with NEC in 477 preterm infants (36 cases of NEC) from 4 European neonatal intensive care units (Maastricht, Las Palmas de Gran Canaria, Mantova, and Milan). Allele and genotype frequencies of the p.Thr1406Asn polymorphism did not significantly differ between the infants with and without NEC. In contrast, the minor A-allele was significantly less frequent in the group of 64 infants with the combined outcome NEC or death before 34 weeks of corrected gestational age than in the infants without the outcome (0.20 vs. 0.31, P = 0.03). In addition, a significant negative association of the A-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.54, 95% CI 0.29-0.99) and the additive (aOR 0.58, 95% CI 0.36-0.93) genetic models. In conclusion, our study provides further evidence that a functional variant of the CPS1 gene may contribute to NEC susceptibility.

Evaluating medical residents as managers of care: a critical appraisal of assessment methods.

INTRODUCTION: The increasing demands for effective and efficient health care delivery systems worldwide have resulted in an expansion of the desired competencies that physicians need to possess upon graduation. Presently, medical residents require additional professional competencies that can prepare them to practice adequately in a continuously changing health care environment. Recent studies show that despite the importance of competency-based training, the development and evaluation of management competencies in residents during residency training is inadequate. The aim of this literature review was to find out which assessment methods are currently being used to evaluate trainees' management competencies and which, if any, of these methods make use of valid and reliable instruments. METHODS: In September 2012, a thorough search of the literature was performed using the PubMed, Cochrane, Embase®, MEDLINE®, and ERIC databases. Additional searches included scanning the references of relevant articles and sifting through the "related topics" displayed by the databases. RESULTS: A total of 25 out of 178 articles were selected for final review. Four broad categories emerged after analysis that best reflected their content: 1) measurement tools used to evaluate the effect of implemented curricular interventions; 2) measurement tools based on recommendations from consensus surveys or conventions; 3) measurement tools for assessing general competencies, which included care-management; and 4) measurement tools focusing exclusively on care-management competencies. CONCLUSION: Little information was found about (validated) assessment tools being used to measure care-management competence in practice. Our findings suggest that a combination of assessment tools should be used when evaluating residents' care-management competencies.

Developmental changes in mesenteric artery reactivity in embryonic and newly hatched chicks.

At birth, the intestine becomes the sole site for nutrient absorption requiring a dramatic increase in blood flow. The vascular changes accompanying this transition have been partly characterized in mammals. We investigated, using wire myography, the developmental changes in chick mesenteric artery (MA) reactivity. Rings of the MA from 15-day (E15) and 19-day (E19) chicken embryos (total incubation 21 days) as well as non-fed 0-3-h-old (NH3h) and first-fed 1-day-old (NH1d) newly hatched chicks contracted in response to KCl, norepinephrine (NE), U46619, and endothelin (ET)-1 and relaxed in response to acetylcholine (ACh), sodium nitroprusside (SNP), and forskolin indicating the presence of electro- and pharmaco-mechanical coupling as well as cGMP- and cAMP-mediated relaxation. In ovo development and transition to ex ovo life was accompanied by alterations in the response of the MAs, but a different developmental trajectory was observed for each reactivity pathway tested. Thus, the contractile efficacy of KCl underwent a linear increase (E15 < E19 < NH3h < NH1d). The efficacy of NE and U46619 increased in ovo, but not ex ovo (E15 < E19 = NH3h = NH1d) and the efficacy of ET-1 peaked at E19 (E15 < E19 > NH3h = NH1d). The relaxations elicited by ACh (endothelium-dependent), SNP, and forskolin did not undergo significant developmental changes. In conclusion, the ability of chick MAs to constrict in response to pharmacological stimuli increases during the embryonic period, but no dramatic changes are induced by hatching or the first feeding. Maturation of vasodilator mechanisms precedes that of vasoconstrictor mechanisms. Alterations of the delicate balance between vasoconstrictors and vasodilators may play an important role in perinatal intestinal diseases.

The T1405N carbamoyl phosphate synthetase polymorphism does not affect plasma arginine concentrations in preterm infants.

BACKGROUND: A C-to-A nucleotide transversion (T1405N) in the gene that encodes carbamoyl-phosphate synthetase 1 (CPS1) has been associated with changes in plasma concentrations of L-arginine in term and near term infants but not in adults. In preterm infants homozygosity for the CPS1 Thr1405 variant (CC genotype) was associated with an increased risk of having necrotizing enterocolitis (NEC). Plasma L-arginine concentrations are decreased in preterm infants with NEC. AIM: To examine the putative association between the CPS1 T1405N polymorphism and plasma arginine concentrations in preterm infants. METHODS: Prospective multicenter cohort study. Plasma and DNA samples were collected from 128 preterm infants (<30 weeks) between 6 and 12 hours after birth. Plasma amino acid and CPS1 T1405N polymorphism analysis were performed. RESULTS: Distribution of genotypes did not differ between the preterm (CC:CA:AA = 55.5%:33.6%:10.9%, n = 128) and term infants (CC:CA:AA = 54.2%:35.4%:10.4%, n = 96). There was no association between the CPS1 genotype and plasma L-arginine or L-citrulline concentration, or the ornithine to citrulline ratio, which varies inversely with CPS1 activity. Also the levels of asymmetric dimethylarginine, and symmetric dimethylarginine were not significantly different among the three genotypes. CONCLUSIONS: The present study in preterm infants did not confirm the earlier reported association between CPS1 genotype and L-arginine levels in term infants.

Response of chicken ductus arteriosus to hypercarbic and normocarbic acidosis.

BACKGROUND: Changes in pH can have profound effects on vascular tone and reactivity, but their influence on the ductus arteriosus (DA) remains unknown. OBJECTIVE: To analyzethe effects of hypercarbic and normocarbic acidosis in the reactivity of the chicken DA. METHODS: DA rings from 19-day chicken fetuses (total incubation time, 21 days) were mounted in a wire myograph for isometric tension recording. RESULTS: In DA rings (pulmonary side) stimulated with O(2), norepinephrine (NE), KCl, or U46619, changes from control conditions (5% CO(2), 24 mM NaHCO(3), pH 7.4) to 7.5% CO(2) (pH 7.25) or 10% CO(2) (pH 7.14) induced a concentration-dependent relaxation that reached 43.0% (SD 21.3) of the O(2)-, 28.6% (SD 23.1) of the NE-, 10.4% (SD 18.7) of the KCl-, and 6.8% (SD 12.6) of the U46619-induced contraction. Hypercarbic-acidosis-induced relaxation was impaired by the non-selective K(+) channel blocker tetraethylammonium or the BK(Ca) channel inhibitor iberiotoxin. Normocarbic acidosis (5% CO(2), 12 mM NaHCO(3), pH 7.13) induced transient relaxation of the DA, which was not affected by the presence of tetraethylammonium or iberiotoxin. Euhydric hypercarbia (10% CO(2), 48 mM NaHCO(3), pH 7.46) induced a transient contraction of the DA. CONCLUSIONS: Our results indicate that the chicken DA is very sensitive to changes in extracellular pH, and that stimulation of BK(Ca) channels may account for the ductal-relaxing effects of hypercarbic acidosis.

Endotoxin induced chorioamnionitis prevents intestinal development during gestation in fetal sheep.

Chorioamnionitis is the most significant source of prenatal inflammation and preterm delivery. Prematurity and prenatal inflammation are associated with compromised postnatal developmental outcomes, of the intestinal immune defence, gut barrier function and the vascular system. We developed a sheep model to study how the antenatal development of the gut was affected by gestation and/or by endotoxin induced chorioamnionitis.Chorioamnionitis was induced at different gestational ages (GA). Animals were sacrificed at low GA after 2d or 14d exposure to chorioamnionitis. Long term effects of 30d exposure to chorioamnionitis were studied in near term animals after induction of chorioamnionitis. The cellular distribution of tight junction protein ZO-1 was shown to be underdeveloped at low GA whereas endotoxin induced chorioamnionitis prevented the maturation of tight junctions during later gestation. Endotoxin induced chorioamnionitis did not induce an early (2d) inflammatory response in the gut in preterm animals. However, 14d after endotoxin administration preterm animals had increased numbers of T-lymphocytes, myeloperoxidase-positive cells and gammadelta T-cells which lasted till 30d after induction of chorioamnionitis in then near term animals. At early GA, low intestinal TLR-4 and MD-2 mRNA levels were detected which were further down regulated during endotoxin-induced chorioamnionitis. Predisposition to organ injury by ischemia was assessed by the vascular function of third-generation mesenteric arteries. Endotoxin-exposed animals of low GA had increased contractile response to the thromboxane A2 mimetic U46619 and reduced endothelium-dependent relaxation in responses to acetylcholine. The administration of a nitric oxide (NO) donor completely restored endothelial dysfunction suggesting reduced NO bioavailability which was not due to low expression of endothelial nitric oxide synthase.Our results indicate that the distribution of the tight junctional protein ZO-1, the immune defence and vascular function are immature at low GA and are further compromised by endotoxin-induced chorioamnionitis. This study suggests that both prematurity and inflammation in utero disturb fetal gut development, potentially predisposing to postnatal intestinal pathology.

Carbamoyl phosphate synthetase polymorphisms as a risk factor for necrotizing enterocolitis.

A C-to-A nucleotide transversion (T1405N) in the gene that encodes carbamoyl-phosphate synthetase 1 (CPS1) has been correlated with low plasma concentrations of L-arginine in neonates. As plasma L-arginine concentrations are decreased in premature infants with necrotizing enterocolitis (NEC), we hypothesized that the CPS1 T1405N polymorphism would correlate with the presence of NEC. We analyzed the CPS1 genotypes for the T1405N polymorphism in 17 preterm infants (