Anatomic accuracy, physiologic characteristics, and fidelity of very low birth weight infant airway simulators.

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.

The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes.

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.

Active perinatal care of preterm infants in the German Neonatal Network.

OBJECTIVE: To determine if survival rates of preterm infants receiving active perinatal care improve over time. DESIGN: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016. SETTING: 43 German level III neonatal intensive care units (NICUs). PATIENTS: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care. INTERVENTIONS: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (

Inherited Thrombotic Thrombocytopenic Purpura (Upshaw Schulman Syndrome) as Differential Diagnosis to Neonatal Septicaemia with Disseminated Intravascular Coagulation - a Case Series.

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<5%, compound heterozygous mutations were found in all patients. USS constitutes a differential diagnosis to thrombocytopenia caused by disseminated intravascular coagulation in neonatal septicaemia. Administration of fresh frozen plasma usually resolves acute bouts of the disease. In some cases of thrombocytopenia of unknown origin in infancy, the resolution of signs and symptoms after infusion of plasma may point towards the diagnosis.

Clinical Relevance of Pathogens Detected by Multiplex PCR in Blood of Very-Low-Birth Weight Infants with Suspected Sepsis - Multicentre Study of the German Neonatal Network.

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.

Neurological involvement in children with E. coli O104:H4-induced hemolytic uremic syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Successful outcome of severe Amanita phalloides poisoning in children.

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.

An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children.

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.

Intestinal glucose transport: evidence for a membrane traffic-based pathway in humans.

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.

Long-term survival after radical operations for cancer treatment-induced sarcomas: how two survivors invite reflection on oncologic treatment concepts.

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.