Amniotic fluid content in children with kidney and urinary tract anomalies determines pre- and postnatal development.

BACKGROUND: Renal oligohydramnios (ROH) describes an abnormally low volume of amniotic fluid (AF) during pregnancy. ROH is mostly caused by congenital fetal kidney anomalies. The ROH diagnosis frequently implies an increased risk of peri- and postnatal fetal mortality and morbidity. The present study aimed to evaluate the impact of ROH on pre-and postnatal development in children with congenital kidney anomalies. METHODS: This retrospective study included 168 fetuses with anomalies in the kidney and urinary tract. Based on the amount of AF measured by ultrasound, patients were divided into three groups: normal amniotic fluid (NAF), amniotic fluid in the lower normal range (LAF), and ROH. These groups were compared with respect to prenatal sonographic parameters, perinatal outcomes, and postnatal outcomes. RESULTS: Among the 168 patients with congenital kidney anomalies, 26 (15%) had ROH, 132 (79%) had NAF, and 10 (6%) had LAF. Of the 26 families affected by ROH, 14 (54%) decided to terminate pregnancy. Of 10 live-born children in the ROH group, 6 (60%) survived the observation time; of these, 5/6 presented with chronic kidney disease, stages I-III, at their last examination. The main differences in postnatal development between the ROH group and the NAF and LAF groups were: restricted height and weight gain, respiratory issues, complicated feeding, and the presence of extrarenal malformations. CONCLUSIONS: ROH is not a mandatory indicator of severe postnatal kidney function impairment. However, children with ROH have complicated peri-and postnatal periods, due to the presence of concomitant malformations, which must be considered in prenatal care. A higher resolution version of the Graphical abstract is available as Supplementary information.

Potential Benefit of Probiotic E. Coli Nissle in Term Neonates.

BACKGROUND: Probiotics are often viewed as an immunity enhancing agent. The objective of this study was to investigate whether oral administration of Escherichia coli Nissle 1917 reduces the number of infections, their duration, and severity in the first 24 months after parturition in healthy neonates. SUBJECTS AND METHODS: This prospective, confirmatory, randomised, double-blind, placebo-controlled study enrolled 567 healthy neonates from four German and two Polish sites. Neonates received 10e8 viable E. coli Nissle (n=283) or placebo (n=284) daily in the first week and every second day in week 2 and 3. After 6 and 12 months, the subjects received additional instillations on ten subsequent days. The overall efficacy was assessed by the number of infections per observation period. RESULTS: Incidence rates of infection, infection duration and severity showed no statistically significant difference between groups after 24 months. Post-hoc analyses, however, revealed a short-term benefit of E. coli Nissle four weeks after treatment start which became less pronounced after eight weeks. E. coli Nissle was safe and well tolerated. CONCLUSIONS: A long-term effect after colonising the healthy neonate´s gut with E. coli Nissle to protect against infections could not be shown. Additional studies are needed to confirm a transitory, yet clinically significant role of probiotics in the first four weeks after parturition.

Evaluation of the post-processing algorithms SimGrid and S-Enhance for paediatric intensive care patients and neonates.

BACKGROUND: Post-processing software can be used in digital radiography to achieve higher image quality, especially in cases of scattered radiation. SimGrid is a grid-like software based on a Convolutional Neuronal Network that estimates the distribution and degree of scattered radiation in radiographs and thus improves image quality by simulating an anti-scatter grid. S-Enhance is an algorithm programmed to improve contrast visibility of foreign material. OBJECTIVE: The objective of this study was to evaluate the SimGrid and S-Enhance digital radiography post-processing methods for neonatology and paediatric intensive care. MATERIALS AND METHODS: Two hundred and ten radiographs from the neonatal (n = 101, 0 to 6 months of age) and paediatric (n = 109, 6 months to 18 years of age) intensive care units performed in daily clinical routine using a mobile digital radiography system were post-processed with one of the algorithms, anonymized and then evaluated comparatively by two experienced paediatric radiologists. For every radiograph, patient data and exposure data were collected and analysed. RESULTS: Analysis of different radiographs showed that SimGrid significantly improves image quality for patients with a weight above 10 kg (range: 10-30 kg: odds ratio [OR] = 6.683, P < 0.0001), especially regarding the tracheobronchial system, intestinal gas, and bones. Utilizing S-Enhance significantly advances the assessment of foreign material (OR = 136.111, P < 0.0001) and bones (OR = 34.917, P < 0.0001) for children of all ages and weight, whereas overall image quality decreases. CONCLUSION: SimGrid offers a differentiated spectrum in image improvement for children beyond the neonatal period whereas S-Enhance especially improves visibility of foreign material and bones for all patients.

Epidemiology of Sepsis Among Children and Neonates in Germany: Results From an Observational Study Based on Nationwide Diagnosis-Related Groups Data Between 2010 and 2016.

OBJECTIVES: Worldwide, more than half of all sepsis cases occur in pediatric and adolescent patients, particularly in neonates. Previous population-based studies in these age groups often were limited to either neonatal or pediatric patients admitted to ICUs. We aimed to investigate the overall and age-specific incidence and case fatality of sepsis in children in Germany, a high-income country with a total population of 82 million. DESIGN: Retrospective observational study based on the German Diagnosis-related Groups statistics of the years 2010-2016. SETTING: All acute care hospitals in Germany except for prison and psychiatric hospitals. PATIENTS: Pediatric patients less than or equal to 19 years with International Classification of Diseases, 10th Revision-coded sepsis, neonates with International Classification of Diseases, 10th Revision-coded neonatal sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed pediatric sepsis incidence in patients aged birth to less than or equal to 19 years old, case fatality, and underlying comorbidities, and neonatal sepsis incidence and case fatality within the neonatal period. We identified 14,635 pediatric sepsis cases among 15.4 million pediatric hospitalizations between 2010 and 2016 (= 0.1% of pediatric hospitalizations). The incidence of pediatric sepsis was 14 cases per 100,000 children between 0 and 19 years. Case fatality was 16.6% and decreased from 17.8% (2010) to 15.0% (2016). A total of 11.5% of hospital deaths in the age group 0-19 years were associated with pediatric sepsis. Sepsis incidence and case fatality were highest in children less than 1 year old and declined in older children and adolescents. Admissions with pediatric sepsis were more common in children with preexisting comorbidities compared with those without (0.52% vs 0.03% of pediatric admissions). In neonates, the incidence of neonatal sepsis was 1,006 cases per 100,000 live births. Case fatality was 3.9%. While 17.7% of very low birth weight infants had neonatal sepsis, only 2.1% of low birth weight and 0.6% of normal birth weight neonates were affected, respectively. CONCLUSIONS: Sepsis is also in Germany a common and frequently fatal condition in pediatric patients, particularly among neonates and children with comorbidities.

Comparison of image quality in brain MRI with and without MR compatible incubator and predictive value of brain MRI at expected delivery date in preterm babies.

Objectives MR compatible incubators (MRcI) offer the examination of preterm and critically ill infants in controlled environment. The aim of the study was to compare objective and subjective image quality as well as diagnostic value of MRI brain examinations with and without using the MRcI. Thus, predictive value of brain MRI at expected delivery date in general was investigated. Methods This retrospective study included MRI brain examinations conducted at patients' corrected age ≤6 months and presence of four standard sequences (PD TSE transversal, T2 TSE transversal, T2 TSE sagittal and T1 SE transversal). Signal-to-Noise Ratio (SNR) and Contrast-to-Noise Ratio (CNR) was calculated. Subjective image quality was estimated using a 5-point Likert scale. Findings of MRI were compared with those of previous transfontanellar ultrasound because of additional diagnostic information. Severe brain abnormality scaled by score of Kidokoro was related to results of Munich Functional Developmental Diagnostics (MFDD) within first year. Results One hundred MRI brain examinations (76 with MRcI, 24 without MRcI) were performed in 79 patients. Using the MRcI SNR and CNR were significantly higher in PD- and in T2-weighted sequences (p<0.05). TSE PD transversal demonstrated a higher risk of non-diagnostic quality using MRcI (OR 5.23; 95%-CI 1.86-14.72). MRcI revealed additional diagnostic information (OR 5.69; 95%-CI 1.15-28.24). Severe brain abnormality was associated with walking deficits (r=0.570; p=0.021). Conclusions The MRcI increased objective image quality and revealed additional diagnostic information to transfontanellar ultrasound. Nevertheless, prediction of infants' future development remains limited.

[Bone Analysis in the Newborn - Quantitative Ultrasound of the Peripheral Skeleton]. / Alternative Knochenanalyse bei Neugeborenen ­ Quantitativer Ultraschall des peripheren Skeletts.

PURPOSE: The aim was to determine whether the quantitative ultrasound (QUS) parameter speed of sound (SOS) is sufficient for evaluation of reference data in the newborn and how they are influenced. MATERIALS AND METHODS: 219 full-term and 14 preterm infants (gestational age 28-41 weeks (GA), birth weight 590-4,930 g) were evaluated by Omnisense 7000 P on their tibia. Reference values were sampled in 178 eutrophic infants. RESULTS: SOS reference values at the tibia were 3028 m/s for GA<40 and 3057 m/s for ≥ 40 weeks. There was a significant correlation between SOS and gestational age. SOS was significantly higher in male (3058.3±93.3 vs. 3022.8±93.4 m/s; p 0.012) infants. If birth weight was below 3,800 g, there was a correlation between SOS and weight (p<0.05). Preterm infants showed lower SOS than term babies (p<0.05). CONCLUSION: Speed of sound can be evaluated sufficiently in preterm and term infants on the tibia. The estimated reference data can be used to identify osteopenia in the preterm infant with low birth weight.

[Intrauterine Growth Restriction: Transsectoral, Interdisciplinary and Multiprofessional Care for Pregnant Women and Newborns in a Feto-neonatal Pathway: A Project of the Innovationsfonds]. / Intrauterine Wachstumsrestriktion: Transsektorale, interdisziplinäre und multiprofessionelle Betreuung von Schwangeren und Neugeborenen im Feto-Neonat-Pfad: Ein Projekt des Innovationsfonds.

Intrauterine growth restriction (IUGR) is present in fetuses that do not achieve their full in-utero growth potential. IUGR needs to be discriminated from small for gestational age (SGA) because IUGR newborns in particular experience long-term side effects from their small growth. IUGR fetuses have a significantly increased risk of prematurity and a distinct risk profile compared to adequate-for-gestational-age preterm newborns. Complications of prematurity are more frequent, including bronchopulmonary dysplasia, intraventricular hemorrhage, and meconium ileus. IUGR newborns are at risk of long-term health issues like cerebral palsy, impaired lung function, and delayed speech development. Interdisciplinary and interprofessional care of IUGR pregnancies in the context of a standardized health care research project is feasible: Pregnant women at risk are identified, early therapy with acetylsalicylic acid is started as indicated, risk-adapted care at level III centers is organized including psychosocial interventions and neonatal consultations. Postnatally, integrated neonatal care focusing on parent-child interaction and optimized nutrition is a hallmark. Afterwards, in-depth pediatric follow-up visits with local pediatricians help to identify growth and neurodevelopment problems early. The effects, acceptance. and cost efficiency of this approach are evaluated prospectively as part of an Innovationsfonds project.

[Infection Prevention in Premature Infants and Newborns in Thuringia: Implementation of Recommendation of the Commission for Hospital Hygiene and Infection Prevention (KRINKO)]. / Infektionsprävention bei Früh- und Neugeborenen in Thüringen: Umsetzung der Empfehlung der Kommission für Krankenhaushygiene und Infektionsprävention (KRINKO).

Systematic recording of practical implementation of current recommendations of KRINKO for the prevention of nosocomial infections in premature and newborn infants in children's hospitals in Thuringia. All neonatal treatment centers in Thuringia (n=18) were included in this survey. Answer were received from 83% (15/18). Degree of compliance was 100% in level-1 (3/3) and level-2 centers (5/5), and 70% in level-3 centers (7/10). The aim of the questionnaire was to evaluate infection prevention measures as well as structural/organizational parameters in neonatal centers in Thuringia. Preventive measures as well as weekly screening for colonization was fully performed in patients with a birth weight <1 500 g (n=205) at all centers. Additionally, prolonged screening and colonization surveillance measures were performed in 60% of all units until discharge from the hospital. Results related to structural/organizational parameters and especially structural conditions in neonatal centers in Thuringia pointed up challenges (2 m minimum distance between incubators in 27% (n=4/15), isolation in single room in 53% (n=8/15)). Insufficient number of staff also hamper the complete implementation of KRINKO recommendations (intensive care unit: patient/staff ratio (MW±SD) 2.5±1.1; newborn area 4.3±0.9). Analysis shows actual rate of implementation of KRINKO recommendations as well as structural/organizational parameters in neonatal treatment centers in Thuringia. It provides important points for discussion regarding necessary staff numbers and structural conditions. Analysis could also be used for future surveys in other regions in Germany.

Intensified colonisation screening according to the recommendations of the German Commission for Hospital Hygiene and Infectious Diseases Prevention (KRINKO): identification and containment of a Serratia marcescens outbreak in the neonatal intensive care unit, Jena, Germany, 2013-2014.

PURPOSE: In 2013, the German Commission for Hospital Hygiene and Infectious Disease Prevention (KRINKO) stated that extending weekly colonisation screening from very low birth weight (VLBW) infants (<1500 g) to all patients in the Neonatal Intensive Care Unit (NICU) might be useful. METHODS: After implementing this recommendation, we detected a previously unnoticed cluster of Serratia marcescens. Strains were typed by Pulsed Field Gel Electrophoresis (PFGE). RESULTS: Over 6 months, 19 out of 159 infants acquired S. marcescens. Twelve of the nineteen patients with S. marcescens were non-VLBW infants, and they were colonised significantly earlier than were VLBW infants (median 17 vs. 28 days; p < 0.01). Molecular typing revealed a polyclonal outbreak with multiple strain types leading to one or two transmissions each and a dominating outbreak strains being involved in an explosive outbreak involving eight neonates. CONCLUSION: The revised KRINKO recommendation may help identify unnoticed outbreaks. Colonised non-VLBW patients may be an underestimated source of S. marcescens.

Birth weight-related percentiles of brain ventricular system as a tool for assessment of posthemorrhagic hydrocephalus and ventricular enlargement.

Besides remarkable improvements of neonatal medical therapy, neurological morbidity remains a major concern in preterm infants. In particular, intracranial hemorrhage is a severe complication strongly correlated to poor neurological outcome. For early clinical assessment of intracranial hemorrhage and its impact on the ventricular system, cranial sonography is an important bedside diagnostic tool. Reference values of ventricular sizes are available in relation to gestational age (GA). So far, it has not been demonstrated that ventricular size values are also reliable in relation to birth weight (BW). In this study, we performed cranial ultrasonography in 250 preterm and term newborn infants. Measurements of the intracranial ventricular system by cranial ultrasound examination were performed within 72 h after birth. We determined ventricular index, anterior horn width, width of the third ventricle, width and length of the fourth ventricle for statistical analysis in relation to BW and GA. GA ranged from 23 weeks, 3 days to 42 weeks, 1 day (mean: 33 weeks), BW ranged from 345 to 5620 g (mean: 2146 g). Ventricular index and fourth ventricle width revealed a significant correlation to birth weight with r=0.75, each. A significant correlation to birth weight was also obtained for width and length of the third ventricle (r=0.55 and 0.47, respectively). Correlations obtained for ventricular measures in relation to GA were similar to those referring to BW. In preterm and term infants, ventricular sizes in relation to BW seem reliable for assessment and monitoring of ventricular pathologies, i.e. after intracranial hemorrhage.

Molecular typing of toxic shock syndrome toxin-1- and Enterotoxin A-producing methicillin-sensitive Staphylococcus aureus isolates from an outbreak in a neonatal intensive care unit.

Outbreaks of Staphylococcus aureus are common in neonatal intensive care units (NICUs). Usually they are documented for methicillin-resistant strains, while reports involving methicillin-susceptible S. aureus (MSSA) strains are rare. In this study we report the epidemiological and molecular investigation of an MSSA outbreak in a NICU among preterm neonates. Infection control measures and interventions were commissioned by the Local Public Health Authority and supported by the Robert Koch Institute. To support epidemiological investigations molecular typing was done by spa-typing and Multilocus sequence typing; the relatedness of collected isolates was further elucidated by DNA SmaI-macrorestriction, microarray analysis and bacterial whole genome sequencing. A total of 213 neonates, 123 healthcare workers and 205 neonate parents were analyzed in the period November 2011 to November 2012. The outbreak strain was characterized as a MSSA spa-type t021, able to produce toxic shock syndrome toxin-1 and Enterotoxin A. We identified seventeen neonates (of which two died from toxic shock syndrome), four healthcare workers and three parents putatively involved in the outbreak. Whole-genome sequencing permitted to exclude unrelated cases from the outbreak and to discuss the role of healthcare workers as a reservoir of S. aureus on the NICU. Genome comparisons also indicated the presence of the respective clone on the ward months before the first colonized/infected neonates were detected.

Dead space reduction by Kolobow's endotracheal tube does not justify the waiving of volume monitoring in small, ventilated lungs.

In ventilated preterm infants the flow sensor contributes significantly to the total apparatus dead space, which may impair gas exchange. The aim of the study was to quantify to which extent a dead space reduced Kolobow tube (KB) without flow sensor improves the gas exchange compared with a conventional ventilator circuit with flow sensor [Babylog 8000 (BL)]. In a cross-over trial in 14 tracheotomized, surfactant-depleted (saline lavage) and mechanically ventilated newborn piglets (age <12 h; body weight 705-1200 g) BL and KB was applied alternately for 15 min and blood gases were recorded. The inner diameter of the endotracheal tube was 3.6 mm and the apparatus dead space of BL and KB including the endotracheal tube were 3.0 and 1.34 mL. Despite a 50 % apparatus dead space reduction with KB compared to BL statistically significant improvements were only observed for body weights <900 g. In this weight group median paCO2 was decreased by 5 mmHg (p < 0.01), whereas the improvement decreased with decreasing baseline paCO2. Furthermore, median paO2 was increased by 4 mmHg (p < 0.05) and O2 saturation was increased by 2.5 % (p < 0.05). No significant changes were seen in the circulatory parameters. In very small, ventilated lungs the use of KB improved the gas exchange; however, the improvement was moderate and does not justify the waiving of volume monitoring.

Gestational age at birth, birth weight, and gestational age when intrauterine brain sparing occurs determines the neonatal outcome in growth-restricted infants born before 32 weeks of gestation: a retrospective cohort analysis.

Background: Preterm birth and fetal growth restriction are the main determinants of perinatal mortality. In the absence of therapeutic interventions, management is restricted to the observation of fetal growth and fetoplacental perfusion to determine the timing of delivery. Fetal circulatory redistribution, known as "brain sparing," represents a sign of fetal hypoxia and has been implemented in algorithms for when to deliver. In the absence of any other option, the nitric oxide donor pentaerythrityl tetranitrate (PETN), which has been shown to improve fetoplacental flow and reduce preterm birth in high-risk patients, is offered to patients as a personal therapy attempt. The aim of this study was to evaluate determinants related to pregnancy, including PETN intake during pregnancy, on immediate neonatal outcomes in a cohort of growth-restricted infants born before 32 completed weeks of gestation. Methods: We performed a retrospective cohort study of 98 infants born with a birth weight below the 10th percentile before 32 completed weeks of gestation at our tertiary care center between 2010 and 2019. PETN was offered to all mothers with a history of severe adverse pregnancy outcomes who were at high risk of developing fetal growth restriction as an individual therapy attempt. Results: The mean gestational age at birth was 188.5 days, and the mean birth weight was 549 g, corresponding to a median percentile of three. In 73 (79.3%) cases, brain sparing occurred during pregnancy. A total of 22 (22.4%) neonates were stillborn, 20 died postnatally, and 37.3% developed a severe complication. Multivariable analysis revealed birth weight percentile, gestational age at birth, and gestational age when brain sparing first occurred to be robust predictors of mortality or severe neonatal morbidity. In 39 neonates of mothers taking PETN, this impact of brain sparing was not observed. Conclusion: Our study is the first to demonstrate a significant association between the early occurrence of brain-sparing and severe neonatal outcomes in a cohort of very early preterm, growth-restricted newborns. The data suggest that PETN intake may ameliorate the effect of brain sparing in the affected neonates.

Contactless assessment of heart rate in neonates within a clinical environment using imaging photoplethysmography.

Introduction: In neonatology, the accurate determination of vital parameters plays a pivotal role in monitoring critically ill newborns and premature infants, as well as aiding in disease diagnosis. In response to the limitations associated with contact-based measurement methods, substantial efforts have been directed toward developing contactless measurement techniques, particularly over the past decade. Methods: Building upon the insights gained from our pilot study, we realized a new investigation to assess the precision of our imaging photoplethysmography-based system within a clinical environment of the neonatal intermediate care unit. We conducted measurements in 20 preterm infants or newborns requiring therapeutic interventions. As a point of reference, we employed a conventional pulse oximeter. To analytically predict measurement artifacts, we analyzed the potential influence of confounding factors, such as motion artifacts, illumination fluctuations (under- and overexposure), and loss of region of interest prior to heart rate evaluation. This reduced the amount of data we evaluated for heart rate to 56.1% of its original volume. Results: In artifact-free time segments, the mean difference between the pulse oximetry and the imaging photoplethysmography-based system for 1 s sampling intervals resulted in -0.2 bpm (95% CI -0.8 to 0.4, LOA ±â€…12.2). For the clinical standard of 8 s averaging time, the mean difference resulted in -0.09 bpm (95% CI -0.7 to 0.6, LOA ±â€…10.1). These results match the medical standards. Discussion: While further research is needed to increase the range of measurable vital parameters and more diverse patient collectives need to be considered in the future, we could demonstrate very high accuracy for non-contact heart rate measurement in newborn infants in the clinical setting, provided artifacts are excluded. In particular, performing a priori signal assessment helps make clinical measurements safer by identifying unreliable readings.

Fetal and neonatal samples of a precursor surfactant protein B inversely related to gestational age.

BACKGROUND: Alveolar-capillary membrane leaks can increase the amount of surfactant protein B (SP-B) in the bloodstream. The purpose of this study was to measure the concentration of C-proSP-B, a SP-B precursor that includes C-terminal domains, in various body fluids of newborn infants and determine its dependence on gestational age. METHODS: C-pro-SPB was measured in amniotic fluid and umbilical cord blood at birth, and in peripheral blood and urine on postnatal day 3 in 137 newborn infants with a median birth weight of 2015 g (range, 550-4475 g) and gestational age of 34 weeks (range, 23-42 weeks). RESULTS: C-proSP-B levels differed more than 100-fold among samples. The levels (median; interquartile range) were highest in peripheral blood (655.6 ng/mL; 419.0-1467.0 ng/mL) and lowest in urine (3.08 ng/mL; 2.96-3.35 ng/mL). C-proSP-B levels in amniotic fluid (314.9 ng/mL; 192.7-603.6 ng/mL) were approximately half of those in peripheral blood. In cord blood C-proSP-B was slightly lower (589.1 ng/mL; 181.2-1129.0 ng/mL) compared with peripheral blood. C-proSP-B levels significantly increased in all the fluids sampled except urine with decreasing gestational age (p < 0.001). CONCLUSIONS: This novel assay allows for the quantitative measurement of C-proSP-B in blood and amniotic fluid. The dependence of C-proSP-B on gestational age may hamper its use for the detection of alveolar leaks in preterm newborns.

Value of Doppler sonography near term: can umbilical and uterine artery indices in low-risk pregnancies predict perinatal outcome?

AIM: The goal of this study was to evaluate the umbilical and uterine Doppler velocimetry waveforms for predicting the perinatal outcome of low-risk pregnancies at term. METHODS: We prospectively recruited 514 women with low risk pregnancies and performed umbilical and uterine artery Doppler assessments between 37 and 41 weeks of gestation. Ultrasound measurements (completed in 365 patients) were correlated with the perinatal outcome. RESULTS: The velocimetry waveforms of the umbilical artery were significantly associated with birthweight, placental weight, and postpartal umbilical artery pH. Low pH, placental weight, and birthweight were correlated with increasing pulsatility index (PI) and resistance index (RI). An umbilical artery PI > 1.2 and a uterine artery RI > 0.5 were associated with statistically higher rates of infants that were small for gestational age (SGA). Also, high cesarean delivery rates were correlated with an umbilical artery PI > 1.2. CONCLUSIONS: In our low-risk pregnancies population, the elevated umbilical artery indices at term appeared to be associated with the higher rates of infants that were SGA and cesarean deliveries. The Doppler waveforms at term had low prognostic value for predicting neonatal acidosis or decreased Apgar scores.

Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells.

PURPOSE: Ewing's sarcoma is a highly malignant childhood tumour whose outcome has hardly changed over the past two decades despite numerous attempts at chemotherapy intensification. It is therefore essential to identify new treatment options. The present study was conducted to explore the effectiveness of combined inhibition of two promising targets, ATR and ribonucleotide reductase (RNR), in Ewing's sarcoma cells. METHODS: Effects of the ATR inhibitor VE821 in combination with the RNR inhibitors triapine and didox were assessed in three Ewing's sarcoma cell lines with different TP53 status (WE-68, SK-ES-1, A673) by flow cytometric analysis of cell death, mitochondrial depolarisation and cell cycle distribution as well as by caspase 3/7 activity determination, by immunoblotting and by real-time RT-PCR. Interactions between inhibitors were evaluated by combination index analysis. RESULTS: Single ATR or RNR inhibitor treatment produced small to moderate effects, while their combined treatment produced strong synergistic ones. ATR and RNR inhibitors elicited synergistic cell death and cooperated in inducing mitochondrial depolarisation, caspase 3/7 activity and DNA fragmentation, evidencing an apoptotic form of cell death. All effects were independent of functional p53. In addition, VE821 in combination with triapine increased p53 level and induced p53 target gene expression (CDKN1A, BBC3) in p53 wild-type Ewing's sarcoma cells. CONCLUSION: Our study reveals that combined targeting of ATR and RNR was effective against Ewing's sarcoma in vitro and thus rationalises an in vivo exploration into the potential of combining ATR and RNR inhibitors as a new strategy for the treatment of this challenging disease.

Similar adverse outcome rates with high or low oxygen saturation targets in an area with low background mortality.

Background: Randomized controlled trials have indicated reduced mortality rates in very preterm infants assigned to high compared to low oxygen saturation (SpO2) target levels, accompanied by higher rates of retinopathy of prematurity and bronchopulmonary dysplasia. However, the benefit-to-harm ratio may depend on the local background mortality risk. We therefore aimed to quantify the risk-benefit ratios of different SpO2 target ranges in 10 tertiary newborn intensive care units (NICUs) in East Germany. Methods: In a retrospective multicenter study, 1,399 infants born between 2008 and 2012 at a gestational age between 24 0/7 and 27 6/7 weeks and with a birthweight below 1,250 g were grouped according to the hospital's target SpO2 range [high oxygen saturation group (HOSG) above 90%], low oxygen saturation group (LOSG) below 90%] and the compliance of units with their target SpO2 range. The association between neonatal morbidities, neurodevelopmental outcomes, selected treatment strategies, and target SpO2 ranges was calculated using chi-squared and Mann Whitney U tests. Results: Nine of the ten participating NICUs met their SpO2 target ranges. Five units were considered as HOSG, and five units were considered as LOSG. Necrotizing enterocolitis and intraventricular hemorrhage grade ≥ 2 occurred significantly more frequently in the HOSG than in the LOSG (8.4% vs. 5.1%, p = 0.02; and 26.6% vs. 17.7%, p < 0.001). No significant differences in the mortality rate and the rate of retinopathy of prematurity were found. Conclusion: In our patient population, a lower SpO2 target range was not associated with increased safety risks in extremely preterm infants. We cannot be sure that our outcome differences are associated with differences in oxygen saturations due to the retrospective study design and the differences in site practices.