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Background Medical simulation training requires realistic simulators with high fidelity. This prospective multi-center study investigated anatomic precision, physiologic characteristics, and fidelity of four commercially available very low birth weight infant simulators. Methods We measured airway angles and distances in the simulators Premature AirwayPaul (SIMCharacters), Premature Anne (Laerdal Medical), Premie HAL S2209 (Gaumard), and Preterm Baby (Lifecast Body Simulation) using computer tomography and compared these to human cadavers of premature stillbirths. The simulators’ physiologic characteristics were tested, and highly experienced experts rated their physical and functional fidelity. Results The airway angles corresponded to those of the reference cadavers in three simulators. The nasal inlet to glottis distance and the mouth aperture to glottis distance were only accurate in one simulator. All simulators had airway resistances up to 20 times higher and compliances up to 19 times lower than published reference values. Fifty-six highly experienced experts gave three simulators (Premature AirwayPaul: 5.1 ± 1.0, Premature Anne 4.9 ± 1.1, Preterm Baby 5.0 ± 1.0) good overall ratings and one simulator (Premie HAL S2209: 2.8 ± 1.0) an unfavorable rating. Conclusion The simulator physiology deviated significantly from preterm infants’ reference values concerning resistance and compliance, potentially promoting a wrong ventilation technique. Impact Very low birth weight infant simulators showed physiological properties far deviating from corresponding patient reference values. Only ventilation with very high peak pressure achieved tidal volumes in the simulators, as aimed at in very low birth weight infants, potentially promoting a wrong ventilation technique. Compared to very low birth weight infant cadavers, most tested simulators accurately reproduced the anatomic angular relationships, but their airway dimensions were relatively too large for the represented body. The more professional experience the experts had, the lower they rated the very low birth weight infant simulators.

Aims/hypothesis The mammalian enzyme glucokinase (GK), expressed predominantly in liver and pancreas, plays an essential role in carbohydrate metabolism. Monogenic GK disorders emphasise the role of GK in determining the blood glucose set point. Methods A family with congenital hyperinsulinism (CHI) was examined for GCK gene variants by Sanger sequencing. A combined approach, involving kinetic analysis (also using GK activators and inhibitors), intracellular translocation assays, insulin secretion measurements and structural modelling, was used to investigate the novel variant compared with known variants. Results We report on the novel gain-of-function GCK variant p.Val455Leu (V455L), inherited as an autosomal dominant trait in a German family with CHI and concomitant obesity (fasting blood glucose 2.1 mmol/l, BMI 45.0 kg/m2, HOMA-IR 1.5 in an adult female family member); one male family member developed type 2 diabetes until age 35 years (with fasting glucose 2.8–3.7 mmol/l, BMI 38.9 kg/m2, HOMA-IR 4.6). Kinetic characterisation of the V455L variant revealed a significant increase in glucose affinity (glucose concentration at which reaction rate is half its maximum rate [S0.5]: mutant 2.4 ± 0.3 mmol/l vs wild-type 7.6 ± 1.0 mmol/l), accompanied by a distinct additive susceptibility to both the endogenous activator fructose 2,6-bisphosphatase and the synthetic allosteric activator RO-28-1675. The effect of RO-28-1675 was more pronounced when compared with the previously known GK variants V455M and V455E. Binding to the inhibitor glucokinase regulatory protein was unimpaired for V455L and V455E but was reduced for V455M, whereas mannoheptulose inhibited all GK variants and the wild-type enzyme. Structural analyses suggested a role for residue 455 in rearrangements between the inactive and active conformations of GK and also in allosteric activation. Comparison with V455M and V455E and an overview of activating GK variants provided a context for the novel sequence aberration in terms of altered GK enzyme characteristics caused by single amino acid changes. Conclusion/interpretation We provide new knowledge on the structure–function relationship of GK, with special emphasis on enzyme activation, potentially yielding fresh strategic insights into breaking the vicious circle of fluctuating blood glucose levels and the attendant risk of long-lasting metabolic changes in both CHI and type 2 diabetes. Graphical abstract

ObjectiveTo determine if survival rates of preterm infants receiving active perinatal care improve over time.DesignThe German Neonatal Network is a cohort study of preterm infants with birth weight Setting43 German level III neonatal intensive care units (NICUs).Patients8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care.InterventionsParticipating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25–P75) and low (Main outcome measuresDeath by any cause before discharge.ResultsTotal survival increased from 85.8% in 2011–2013 to 87.4% in 2014–2016. This increase was due to reduced mortality of NICUs with low survival rates in 2011–2013. Survival increased in these centres from 53% to 64% in the 22–24 weeks strata and from 73% to 84% in the 25–26 weeks strata.ConclusionsOur data support previous reports that active perinatal care of very immature infants improves outcomes at the border of viability and survival rates at higher gestational ages. The high total number of surviving infants below 24 weeks of gestation challenges national recommendations exclusively referring to gestational age as the single criterion for providing active care. However, more data are needed before recommendations for parental counselling should be reconsidered.Trial registrationApproval by the local institutional review board for research in human subjects of the University of Lübeck (file number 08–022) and by the local ethic committees of all participating centres has been given.

We report on 3 male neonates with hereditary ADAMTS13 deficiency (Upshaw Schulman syndrome, USS), the inherited form of thrombotic thrombocytopenic purpura (TTP). 2 presented shortly after birth with thrombocytopenia followed by microangiopathic Coombs-negative haemolytic anaemia. Both initially received antibiotic treatment for suspected infection-associated thrombocytopenia. In one patient's brother, the first bout of incipient TTP did not occur before 6 months of age, despite the same genetic defect. ADAMTS13 activity was

Introduction In the German Neonatal Network (GNN) 10% of very-low-birth weight infants (VLBWI) suffer from blood-culture confirmed sepsis, while 30% of VLBWI develop clinical sepsis. Diagnosis of sepsis is a difficult task leading to potential over-treatment with antibiotics. This study aims to investigate whether the results of blood multiplex-PCR (SeptiFast®) for common sepsis pathogens are relevant for clinical decision making when sepsis is suspected in VLBWI. Methods We performed a prospective, multi-centre study within the GNN including 133 VLBWI with 214 episodes of suspected late onset sepsis (LOS). In patients with suspected sepsis a multiplex-PCR (LightCycler SeptiFast MGRADE-test®) was performed from 100 μl EDTA blood in addition to center-specific laboratory biomarkers. The attending neonatologist documented whether the PCR-result, which was available after 24 to 48 hrs, had an impact on the choice of antibiotic drugs and duration of therapy. Results PCR was positive in 110/214 episodes (51%) and blood culture (BC) was positive in 55 episodes (26%). Both methods yielded predominantly coagulase-negative staphylococci (CoNS) followed by Escherichia coli and Staphylococcus aureus. In 214 BC—PCR paired samples concordant results were documented in 126 episodes (59%; n = 32 were concordant pathogen positive results, n = 94 were negative in both methods). In 65 episodes (30%) we found positive PCR results but negative BCs, with CoNS being identified in 43 (66%) of these samples. Multiplex-PCR results influenced clinical decision making in 30% of episodes, specifically in 18% for the choice of antimicrobial therapy and in 22% for the duration of antimicrobial therapy. Conclusions Multiplex-PCR results had a moderate impact on clinical management in about one third of LOS-episodes. The main advantage of multiplex-PCR was the rapid detection of pathogens from micro-volume blood samples. In VLBWI limitations include risk of contamination, lack of resistance testing and high costs. The high rate of positive PCR results in episodes of negative BC might lead to overtreatment of infants which is associated with risk of mortality, antibiotic resistance, fungal sepsis and NEC.

Objective To assess whether breastmilk feeding is associated with a reduced risk of bronchopulmonary dysplasia (BPD). Secondary outcome measures analyzed were retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC). Study design In an ongoing multicenter cohort study, the data of 1433 very low birth weight infants born before 32 weeks of gestation and discharged in 2013 were analyzed. We compared growth and neonatal complications of infants who received breastmilk exclusively (N = 223) with those who received formula feedings exclusively (N = 239). Logistic regression models were estimated for BPD, ROP, and NEC using nutrition as an independent variable. The Firth logistic regression model and Lasso were used for sensitivity analyses. Results Exclusively breastmilk-fed infants gained less weight compared with formula-fed infants. SDS for weight decreased between birth and discharge (median (Q1-Q3): formula −0.9 (−1.4 to [−0.5]) vs breastmilk −1.1 (−1.7 to [−0.6])). Exclusive formula feeding of very low birth weight infants was associated with increased risks of BPD (OR 2.6) as well as NEC (OR 12.6) and ROP (OR 1.80) after controlling for known risk factors. Conclusions Exclusive breastmilk feeding was associated with lower growth rates and a reduced risk of BPD as well as NEC and ROP.

Background In May and June 2011 the largest known outbreak of hemolytic uremic syndrome (HUS) occurred in northern Germany. Because, quite unusually, a large number of adults was affected and the causative Escherichia coli strain, serotype O104:H4, showed an atypical virulence factor pattern, it was speculated that this outbreak was associated with an aggressive course and an unfavorable prognosis also in children. Methods Retrospective analysis of medical records of 90 children and comparison to previous outbreak and sporadic case series. Results Median age was unusually high (11.5 years) compared with that in historical series. Only 1 patient (1.1%) died in the acute phase. Most patients (67/90 [74%]) received supportive care only. Renal replacement therapy was required in 64 of 90 (71%) of the children. Neurological complications, mainly seizures and altered mental stage, were present in 23 of 90 (26%) patients. Ten patients received plasmapheresis, 6 eculizumab, and 7 a combination of both. After a median follow-up of 4 months, renal function normalized in 85 of 90 (94%) patients, whereas 3 patients had chronic kidney disease stage 3 or 4, and 1 patient (1.1%) still requires dialysis. Complete neurological recovery occurred in 18 of 23 patients. Mild to moderate and major residual neurological changes were present in 3 patients and 1 patient, respectively, although all patients were still improving. Conclusions E. coli O104:H4 caused the largest HUS outbreak in children reported in detail to date and most patients received supportive treatment only. Initial morbidity, as well as short-term outcome, due to this pathogen, is comparable to previous pediatric series of Shiga toxin-producing E. coli HUS.

Getrag hat die Entwicklung eines neuen Antriebsstrang-Konzepts begonnen, das sich Boosted Range Extender nennt. Beinhaltet ist damit zum einen eine Reichweitenverlaengerung (Range Extender) fuer das Elektrofahrzeug, zum anderen kann der Verbrennungsmotor im Parallelbetrieb mit dem Elektromotor unterstuetzt werden (Boosted). Ziel ist, die bekannten Fahrfunktionen mit einem kostenguenstigen Antriebsstrang darzustellen, insbesondere soll die Reichweite im gewohnten Bereich von circa 600 km liegen. Auch fuer weite Strecken soll der Kraftstoffverbrauch unterhalb dem eines konventionellen Antriebsstrangs liegen. Nach ersten Konzeptbewertungen wurde mit der Entwicklung und Konstruktion eines neuen Hybridgetriebes begonnen. Dieses Antriebsstrangkonzept ist als funktionsfaehiger Prototyp in einem Fahrzeug eingebaut und im Versuchsbetrieb. Es konnte nachgewiesen werden, dass das vorgestellte Boosted Range-Extender-Konzept die wesentlichen Attribute bezueglich Fahrbarkeit, Dynamik und Steigfaehigkeit erfuellt. Insbesondere kann durch die gute Regelbarkeit und Dynamik des Elektromotors trotz des grossen Stufensprungs eine sehr gute Schaltqualitaet dargestellt werden. Insbesondere im parallelen Hybridmodus zeigt das Versuchsfahrzeug ein sehr agiles Verhalten, weil der leistungsschwache Verbrennungsmotor durch den dynamischen Elektromotor unterstuetzt wird. In einem ersten Praxistest konnte der Boosted Range Extender seine Leistungsfaehigkeit auch unter schwierigen Fahrbedingungen unter Beweis stellen. In weiteren Versuchen sollen die prognostizierten Emissionswerte von nur 36 g CO2/km im Neuen Europaeischen Fahrzyklus (NEFZ) nachgewiesen werden. Insgesamt ist der Boosted Range Extender ein vollwertiger Antriebsstrang.

The aim of this study was to analyze the neurological involvement and outcome in pediatric patients with hemolytic uremic syndrome (HUS) during the 2011 epidemic caused by Escherichia coli O104:H4.Clinical data and data from magnetic resonance imaging (MRI) scans and electroencephalography (EEG) during the acute phase of the disease and during follow-up at 3 and 6 months were analyzed in 50 patients. Twenty-five of these patients underwent neuropsychological testing (WISC IV) during follow-up.Neurological involvement (stupor or coma, seizures, visual disturbances, paresis, myocloni) was initially observed in 14/50 (28%) patients. One patient died. EEG abnormalities were more frequent in patients with neurological involvement than in those without (12/14 vs. 13/25, respectively). Cranial MRI scans were analyzed in nine patients with neurological involvement, of whom five showed abnormal findings. At the 3- and 6-month follow-ups, EEG abnormalities were found in 14/40 (35%) and 7/36 (19%) patients, respectively, whereas 28/42 (67%) and 17/39 (44%) patients, respectively, complained about on-going reduced performance. Neuropsychological testing showed a slightly lower global intelligence quotient in patients with neurological involvement versus those without (113.4 ± 2.8 vs. 119.4 ± 1.8, respectively).Neurological involvement was frequent in our cohort. Accordingly, the incidence of pathological EEG findings was high, even in patients without clinical signs of neurological involvement. Nevertheless, major neurological sequelae were rare, and neuropsychological outcome was favorable after 6 months.

Amanita phalloides intoxication can lead to FHF with high mortality, especially in children. There is still ongoing discussion about the optimal treatment and decision criteria for emergency liver transplantation (LTx). Here, we summarize our experience with outcomes in five children. Five children with severe A. phalloides intoxication were treated at our tertiary center from 1995 to 2010 and studied retrospectively with respect to clinical and laboratory aspects that might help to decide between LTx or conservative therapy only. The findings are discussed with regard to recommended treatment and transplantation criteria for adults. All patients survived, of whom two of five received emergency LTx. Three patients survived with conservative treatment consisting of intravenous silibinin, NAC, detoxification measures, and intensive care. Indications for LTx in two children were progressive brain edema and cardiovascular failure. Children with FHF due to A. phalloides intoxication should be considered early for emergency LTx but should be monitored closely for the necessity of definite LTx. Early detoxification with active charcoal as well as silibinin and NAC seems to improve the outcome. Late recovery of liver function after day 4 post-ingestion is possible.

Background & Aims: The presence of glucose transporter 2 (GLUT2) molecules in the basolateral membrane of enterocytes has long been considered to be of major importance for intestinal glucose absorption. The aim of this study was to reevaluate the role of GLUT2 in a patient with congenital GLUT2 deficiency (Fanconi-Bickel syndrome, FBS). Methods: Oral mono- and disaccharide tolerance tests including gaschromatographic determination of breath hydrogen concentrations were performed in an FBS patient. For comparison, a patient with a microsomal carbohydrate transport defect, glucose-6-phosphate translocase 1 (G6PT1) deficiency, and a control individual were investigated. Results: No increase in breath hydrogen concentration was found in the GLUT2-deficient patient after a glucose load. In G6PT1 deficiency, basal hydrogen concentrations were repeatedly found to be elevated. Conclusions: From the fact that a GLUT2-deficient patient does not show any impairment of intestinal monosaccharide transport measurable by the hydrogen breath test, we conclude that mechanisms other than facilitative glucose transport by GLUT2 must be involved in the transport of monosaccharides at the basolateral membrane of enterocytes. When relating this observation to the high intestinal expression of human hexokinase, G6PT1, and glucose-6-phosphatase and to our results of oral carbohydrate tolerance tests in a G6PT1-deficient patient, there is evidence that a microsomal membrane traffic-based transport pathway, as recently suggested for GLUT2-deficient animals, also plays a major role in transcellular monosaccharide transport of the human intestine. GASTROENTEROLOGY 2003;124:34-39

Extent and radicality of surgical oncologic treatment has changed in the past 30 years. Two patients with node-positive breast cancer are presented, who underwent (total or radical) mastectomy with lymphadenectomy and postoperative radiation 24 and 40 years ago. A radiation-associated sarcoma of the parascapular soft tissue developed in one patient 9 years after treatment; the other one sought treatment for a lymphedema-associated Stewart-Treves lymphangiosarcoma 16 years after initial therapy. Both patients underwent a forequarter amputation for their treatment-associated high-grade sarcoma. Both are currently alive and cancer-free 15 and 24 years after amputation. These reports remind us that radical locoregional treatment can cure some solid cancers in the absence of systemic therapy; that such extensive treatment may induce significant disability or secondary malignancies long-term; that even advanced treatment-associated sarcomas can be cured with aggressive resection; that today's multimodality therapy approaches and appropriate patient selection have rendered such extensive locoregional treatment for many tumors obsolete or unnecessary; and that if no effective alternative treatment exists and organ or limb preservation is not feasible, an aggressive resection approach for high-grade cancer should not be discounted unless systemic failure is certain or imminent.