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Neonatal chronic lung disease lacks standardized assessment of lung structural changes. We addressed this clinical need by the development of a novel scoring system [UNSEAL BPD (UNiforme Scoring of the disEAsed Lung in BPD)] using T2-weighted single-shot fast-spin-echo sequences from 3 T MRI in very premature infants with and without bronchopulmonary dysplasia (BPD). Quantification of interstitial and airway remodeling, emphysematous changes, and ventilation inhomogeneity was achieved by consensus scoring on a five-point Likert scale. We successfully identified moderate and severe disease by logistic regression [area under the curve (AUC), 0.89] complemented by classification tree analysis revealing gestational age-specific structural changes. We demonstrated substantial interreader reproducibility (weighted Cohen’s κ 0.69) and disease specificity (AUC = 0.91). Our novel MRI score enables the standardized assessment of disease-characteristic structural changes in the preterm lung exhibiting significant potential as a quantifiable endpoint in early intervention clinical trials and long-term disease monitoring.

Zusammenfassung Hintergrund Die Frühgeborenenretinopathie („retinopathy of prematurity“ [ROP]) zählt in Deutschland und weltweit zu den häufigsten Erblindungsursachen im Kindesalter; ein adäquates Screening ist essenziell. Der telemedizinische Ansatz mit objektiver Dokumentation des Netzhautbefundes eröffnet die Möglichkeit, untersucherunabhängig alle ROP-Stadien sicher zu diagnostizieren, wenn die Befundung durch ein ROP-geschultes Augenärzteteam erfolgt. Ziel der Arbeit 10-Jahres-Vergleich des ROP-Screenings an 2 deutschen Level-1-Perinatalzentren: universitär und vor Ort vs. nichtuniversitär und telemedizinisch. Material und Methoden Retrospektive Analyse der Screeninguntersuchungen stratifiziert nach Gestationsalter (GA), Geburtsgewicht (GG), Geschlecht, Mehrlingsgeburten, ROP-Zeitpunkt, Behandlungsbedürftigkeit, -zeitpunkt und Untersuchungshäufigkeit. Ergebnisse Von 2009 bis 2019 wurden 1191 Frühgeborene gescreent, davon 29 Externe. Bei den verbleibenden 1162 wurden 3713 Netzhautuntersuchungen durchgeführt; 34 % hatten eine ROP, 5,4 % wurden behandelt (Gießen 3,7 %, Siegen 7,2 %). Mittleres GA war 28,9 SSW (± 2,5), mittleres GG 1155 g (± 417,5). Die Zahl der ROP-Diagnosen stieg in Gießen um 227,3 % und in Siegen um 111,1 % aufgrund zunehmender Zahlen der betreuten Kinder. Diskussion Die vergleichende Analyse bestätigte national und international steigende ROP-Screening-Untersuchungen und Kinder mit akuter ROP. Das telemedizinische Screening war dem Vor-Ort-Screening gleichwertig und sicher. Mit beiden Screeningmethoden wurden alle Behandlungsbedürftigen zeitgerecht erkannt. Kein Kind mit einem GA > 29 SSW benötigte eine Behandlung, analog zu Ergebnissen des schwedischen Registers. Im deutschen ROP-Register waren aber einzelne Frühgeborene mit einem GA ≥ 30 SSW behandlungsbedürftig.

To evaluate safety and clinical outcome of rapid enteral feeding advances in preterm infants1500 g birthweight (BW).In this single-center retrospective cohort study, 293 preterm infants born during 2015-2018 were comparatively analyzed before (n = 145) and after (n = 148) the implementation of a rapid enteral feeding protocol with daily milk increments of 20-30 ml/kg of body weight. Major outcome parameters were focused toward pulmonary morbidities and nutritional variables.Preterm infants in the rapid feeding advancement group were more successfully stabilized on noninvasive ventilation (p 0.001) never requiring mechanical ventilation. Duration of respiratory support (0.465) and frequency of bronchopulmonary dysplasia (BPD) (p = 0.341) and severe BPD (0.273) did not differ between both groups. Furthermore, patients in the rapid feeding group achieved full volume feedings faster (p 0.001), regained BW earlier (p = 0.009), and displayed significantly improved somatic growth at 36 weeks gestational age (p 0.001). There was no increased risk for further morbidities of prematurity including feeding intolerance, necrotizing enterocolitis (NEC), and focal intestinal perforation.Rapid enteral feeding advancements in preterm infants1500 g BW are safe and do not impede stabilization on noninvasive ventilation.

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Purpose: Sensitivity of tumor cells toward chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemosensitivity remain poorly understood. Here, we aimed at characterizing the role of caspase-8 for chemosensitivity of B- and T-ALL cells.Experimental Design: Primary tumor cells from children with ALL were evaluated for expression levels of the caspase-8 protein, were amplified in nonobese diabetic/severe combined immunodeficient mice, transfected with siRNA, and evaluated for their chemosensitivity in vitro.Results: Effective cell death in B- and T-ALL cells depended on the presence of caspase-8 for the majority of cytotoxic drugs routinely used in antileukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of caspase-8 protein correlated with cell death sensitivity toward defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells, with low expression of caspase-8, methotrexate (MTX) upregulated the expression of caspase-8 mediated by the transcription factor p53, suggesting epigenetic silencing of caspase-8. RNA interference in patient-derived B- and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving MTX depended on the presence of caspase-8.Conclusion: Our results indicate that caspase-8 is crucial for the high antileukemic efficiency of numerous routine cytotoxic drugs. Reexpression of epigenetically downregulated caspase-8 represents a promising approach to increase efficiency of antileukemic therapy. Clin Cancer Res; 17(24); 7605–13. ©2011 AACR.

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Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) might represent a future cytotoxic drug to treat cancer as it induces apoptosis in tumor cells without toxicity in animal trials. We recently described that in contrast to apoptosis, TRAIL mediates tumor cell survival and proliferation in certain tumor cells. Here we studied the effect of TRAIL on 18 cell lines and 53 primary leukemia cells and classified these tumor cells into four groups: TRAIL, anti-DR4 or anti-DR5 induced apoptosis in group A cells, whereas they had no effect on group 0 cells and mediated proliferation in group P cells. To our surprise, TRAIL induced simultaneous apoptosis and proliferation in group AP cells. More than 20% of all cells tested belonged to group P and showed TRAIL-mediated proliferation even in the presence of certain cytotoxic drugs but not inhibitors of nuclear factor-κB. Transfection with B-cell leukemia/lymphoma protein 2 transformed group A cells into group 0 cells, whereas transfection with Fas-associated polypeptide with death domain (FADD)–like interleukin-1-converting enzyme–inhibitory protein (FLIP) transformed them into group AP cells. Loss of caspase-8 or transfection of dominant-negative FADD transformed group A cells into group P cells. Taken together, our data suggest that proliferation is a frequent effect of TRAIL on tumor cells, which is related to receptor-proximal apoptosis defects at the level of the death-inducing signaling complex and should be prevented during antitumor therapy with TRAIL.

Supplementary Figures 1-3 from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Summary of recommendations Corticosteroids should be administered to women at a gestational age between 24+0 and 33+6 weeks, when preterm birth is anticipated in the next seven days, as these have been consistently shown to reduce neonatal mortality and morbidity. (Strong-quality evidence; strong recommendation). In selected cases, extension of this period up to 34+6 weeks may be considered (Expert opinion). Optimal benefits are found in infants delivered within 7 days of corticosteroid administration. Even a single-dose administration should be given to women with imminent preterm birth, as this is likely to improve neurodevelopmental outcome (Moderate-quality evidence; conditional recommendation). Either betamethasone (12 mg administered intramuscularly twice, 24-hours apart) or dexamethasone (6 mg administered intramuscularly in four doses, 12-hours apart, or 12 mg administered intramuscularly twice, 24-hours apart), may be used (Moderate-quality evidence; Strong recommendation). Administration of two “all” doses is named a “course of corticosteroids”. Administration between 22+0 and 23+6 weeks should be considered when preterm birth is anticipated in the next seven days and active newborn life-support is indicated, taking into account parental wishes. Clear survival benefit has been observed in these cases, but the impact on short-term neurological and respiratory function, as well as long-term neurodevelopmental outcome is still unclear (Low/moderate-quality evidence; Weak recommendation). Administration between 34 + 0 and 34 + 6 weeks should only be offered to a few selected cases (Expert opinion). Administration between 35+0 and 36+6 weeks should be restricted to prospective randomized trials. Current evidence suggests that although corticosteroids reduce the incidence of transient tachypnea of the newborn, they do not affect the incidence of respiratory distress syndrome, and they increase neonatal hypoglycemia. Long-term safety data are lacking (Moderate quality evidence; Conditional recommendation). Administration in pregnancies beyond 37+0 weeks is not indicated, even for scheduled cesarean delivery, as current evidence does not suggest benefit and the long-term effects remain unknown (Low-quality evidence; Conditional recommendation). Administration should be given in twin pregnancies, with the same indication and doses as for singletons. However, existing evidence suggests that it should be reserved for pregnancies at high-risk of delivering within a 7-day interval (Low-quality evidence; Conditional recommendation). Maternal diabetes mellitus is not a contraindication to the use of antenatal corticosteroids (Moderate quality evidence; Strong recommendation). A single repeat course of corticosteroids can be considered in pregnancies at less than 34+0 weeks gestation, if the previous course was completed more than seven days earlier, and there is a renewed risk of imminent delivery (Low-quality evidence; Conditional recommendation).

(1) Background: ABO blood group incompatibility between the mother and fetus protects against anti-D immunization by pregnancy. The possible role of ABO incompatibility in protecting against anti-human platelet antigen-1a immunization is unclear. (2) Methods: This study retrospectively screened 817 families (mother-father-neonate trios) of suspected fetal and neonatal alloimmune thrombocytopenia for inclusion. ABO genotypes were determined in 118 mother-child pairs with confirmed alloimmune thrombocytopenia due to anti-HPA-1a antibodies, and 522 mother-child pairs served as the control group. The expression of blood group antigen A on platelets was determined in 199 consecutive newborns by flow cytometry and compared with adult controls. (3) Results: ABO incompatibility between mother and fetus did not protect against anti-human platelet antigen-1a immunization by pregnancy. ABO blood groups of mothers and/or fetuses were not associated with the severity of fetal and neonatal alloimmune thrombocytopenia. The expression pattern of blood group A antigens on the platelets of newborns mirrored that of adults, albeit on a lower level. Blood group A antigen was detected on a subpopulation of neonatal platelets, and some newborns revealed high platelet expression of A determinants on all platelets (type II high-expressers). (4) Conclusion: The lack of a protective effect of ABO incompatibility between mother and fetus against anti-human platelet antigen-1a immunization by pregnancy may indicate that fetal platelets are not the cellular source by which the mother is immunized.

Paediatric hydrocephalus is a result of a dysfunction of cerebrospinal fluid circulation, and it has diverse pathogeneses. This study investigates the epidemiology of paediatric hydrocephalus, as well as the influences of primary aetiology and implant type on treatment complications and the development of new therapeutic approaches and strategies.Between 2013 and 2018, a retrospective analysis of 131 children, who were suffering from hydrocephalus, was conducted. Medical charts, operative reports and clinical follow-up visits were reviewed. Statistical analysis was performed using t-test/ANOVA and Kruskal-Wallis test/Mann-Whitney U test.The most common pathogeneses of hydrocephalus among our patients were meningomyelocele-associated and posthaemorrhagic. The majority of patients received a programmable differential pressure valve (PPV, 77.8%) or a fixed differential pressure valve with a gravitational unit (FPgV, 14.8%). Among 333 shunt-associated surgeries, 66% of surgeries were revision surgeries and were performed because of mechanical shunt dysfunction (61%), infection (12%), or other reasons (27%). The median rate of revisions within one year for each patient was 0.15 (IQR25-75: 0.00-0.68) and was influenced by aetiology (p = 0.045) and valve type (p = 0.029). The highest rates were seen in patients with posthaemorrhagic hydrocephalus and in those with FPgVs; the lowest rates were seen in patients with meningomyelocele-associated hydrocephalus and PPVs. The occurrence of mechanical dysfunctions was correlated with FPgV patients (p = 0.014). Furthermore, the median time interval between initial shunt surgery and onset of infection was shorter than that between initial surgery and mechanical dysfunction (p = 0.033).Based on this research, we can state several factors that influence revision surgeries in paediatric shunt patients. With the assessment of patients' risk profiles, physicians can classify paediatric shunt patients and thus avoid unnecessary examinations or invasive procedures. Furthermore, medical providers can prevent revision surgeries if they choose shunt material in accordance with a patient's associated shunt complications.

HINTERGRUND Trotz uber 50 psychometrisch validierter Beobachtungsverfahren gibt es bisher keinen Konsens uber das praktikabelste Schmerzassessment bei Neugeborenen. Die Items von NFCSshort und PIPP wurden mit der Schmerzeinschatzung der prozedurbeteiligten Behandler verglichen und es wurde evaluiert, ob eine Itemreduktion zu Gunsten der Alltagsanwendung moglich ware. MATERIAL UND METHODEN 52 Neugeborene wurden in unserer Beobachtungsstudie einer klinisch indizierten peripheren Venenpunktion unterzogen. Patient und Monitordaten wurden standardisiert auf Video aufgezeichnet. Die Schmerzintensitat wurden durch sieben unabhangige Untersucher mittels NFCSshort und PIPP bewertet und hinsichtlich der Variabilitat zwischen den Untersuchern verglichen. ERGEBNISSE Nur vier Items des PIPP (Herzfrequenz, Augenbrauenvorwolbung, zusammengekniffene Augen, betonte Nasolabialfalte) wiesen einen signifikanten Zusammenhang mit der geschatzten Schmerzhaftigkeit der Prozedur auf. Die Items 1 (Gestationsalter), 2 (Wachheitsgrad) und 4 (Sauerstoffsattigung) hatten bei keinem Untersucher Einfluss auf das Schmerzmessergebnis. Die Auswertung des NFCSshort zeigte bei zwei Untersuchern fur das Item 1 (Vorwolbung der Augenbrauen) und bei einem Untersucher fur das Item 2 (zusammengekniffene Augen) keine Einflusse auf das Messergebnis. DISKUSSION Die Ergebnisse der Studie legen eine Kurzung des PIPP um drei Items nahe, da diese keinen Einfluss auf das Schmerzmessergebnis zeigten. Eine Reduktion des PIPP um das Item Gestationsalter erscheint fraglich, da es in weiteren Studien als bedeutsames Item bewertet wurde. Ein Verzicht auf das Item Sauerstoffsattigung geht mit einem geringeren Messaufwand einher. Eine weitere Kurzung der bereits gekurzten Version (NFCSshort) auf weniger als funf Items ist auf Basis unserer Ergebnisse nicht zu empfehlen. BACKGROUND Despite more than 50 laboratory-evaluated measurement systems, there is no consensus on the most practicable pain assessment in newborns in daily practice. For this purpose, the items of NFCSshort and PIPP were compared to the pain assesment of the involved medical practitioner. The aim of the study was to evaluate whether an item reduction of the assesments in favor of everyday use is feasible. METHODS In 52 neonates of a paediatric ward venous blood collection was performed in this observational study. Cameras recorded patients and monitor in a standardized way. The pain intensity was assessed with NFCSshort and PIPP by seven independent observers. The ratings were compared for variability between observers. RESULTS Of the seven PIPP items, only four were significantly associated with procedural pain assessment for all seven observers (heart rate, brow bulge, eye squeeze, nasolabial furrow). For the NFCSshort, no significant association with procedural pain assessment was found for two observers for the item "brow bulge" and for one observer for the item "eye squeeze". CONCLUSION The results of the study suggest a possible reduction of the PIPP by three items. Disregarding item 1 (gestational age) appears questionable, since its impact as context variable has been proven repeatedly. The waiver of item 4 (oxygen saturation) is associated with less measuring effort. A further reduction of the already shortened version of the NFCS with ten items (NFCSshort, five items) is not recommended by our results.

ZusammenfassungDie fetale und neonatale Alloimmunthrombozytopenie (FNAIT) wird durch mütterliche Antikörper hervorgerufen, die gegen ein vom Vater ererbtes Blutgruppenmerkmal an fetalen Thrombozyten gerichtet sind. Während Teil 1 des Beitrags Ausgabe die Ätiologie, die Pathogenese und die Diagnostik der FNAIT thematisiert hatte, widmet sich dieser 2. Teil der Risikostratifizierung und Behandlung 1.

ZusammenfassungDie fetale und neonatale Alloimmunthrombozytopenie (FNAIT) wird durch mütterliche Antikörper hervorgerufen, die gegen ein vom Vater ererbtes Blutgruppenmerkmal an fetalen Thrombozyten gerichtet sind. Teil 1 des Beitrags stellt die Ätiologie, die Pathogenese und die Diagnostik der FNAIT dar, während Teil 2 die Risikostratifizierung und Behandlung der FNAIT thematisiert 1.

Intra-amniotic infection (IAI) is one major driver for preterm birth and has been demonstrated by clinical studies to exert both beneficial and injurious effects on the premature lung, possibly due to heterogeneity in the microbial type, timing, and severity of IAI. Due to the inaccessibility of the intra-amniotic cavity during pregnancies, preclinical animal models investigating pulmonary consequences of IAI are indispensable to elucidate the pathogenesis of bronchopulmonary dysplasia (BPD). It is postulated that on one hand imbalanced inflammation, orchestrated by lung immune cells such as macrophages, may impact on airway epithelium, vascular endothelium, and interstitial mesenchyme, resulting in abnormal lung development. On the other hand, excessive suppression of inflammation may as well cause pulmonary injury and a certain degree of inflammation is beneficial. So far, effective strategies to prevent and treat BPD are scarce. Therapeutic options targeting single mediators in signaling cascades and mesenchymal stromal cells (MSCs)-based therapies with global regulatory capacities have demonstrated efficacy in preclinical animal models and warrant further validation in patient populations. Ante-, peri- and postnatal exposome analysis and therapeutic investigations using multiple omics will fundamentally dissect the black box of IAI and its effect on the premature lung, contributing to precisely tailored and individualized therapies.

Aim This study determined the prenatal and postnatal risk factors for pulmonary interstitial emphysema (PIE) in preterm infants born at up to 32 weeks of gestational age (GA) and their contribution to severe complications. Methods We studied 179 preterm infants, who had undergone chest X-rays during the first five days of life at Justus Liebig University Giessen, Germany, between 2016 and 2017. Of these, 33 were retrospectively classified as PIE and 146 as non-PIE. The PIE cases were also matched with 33 non-PIE cases by GA and gender. Risk factors were identified by univariate analyses and multivariable logistic regression. Results Previously known risk factors for pulmonary interstitial emphysema were confirmed, including GA and birthweight and the associations with adverse outcomes like intraventricular haemorrhage and mortality. We identified preeclampsia and haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome as additional risk factors for PIE (P = .027), and lung impairment was associated with respiratory distress syndrome (P = .001), higher maximum inspired oxygen (P = .014) and needing surfactant (P = .006). Conclusion Preeclampsia and HELLP syndrome were identified as possible additional risk factors for PIE in preterm infants. These conditions should be included in future studies, to identify preterm infants at risk of PIE straight after birth.

IntroductionIn pregnant women with a history of fetal and neonatal alloimmune thrombocytopenia (FNAIT), prenatal intervention in subsequent pregnancies may be required to prevent fetal bleeding. Several invasive and non-invasive protocols have been published: amniocentesis for fetal genotyping, fetal blood sampling for the determination of fetal platelet count, intrauterine platelet transfusions, and weekly maternal i.v. immunoglobulin (IVIG) infusion with or without additional corticosteroid therapy. This is the first retrospective study that report the experience with a non-invasive protocol focused on side effects of maternal IVIG treatment and neonatal outcome.MethodsPregnant women with proven FNAIT in history and an antigen positive fetus were treated with IVIG (1 g/kg/bw) every week. To identify potential IVIG-related hemolytic reactions isoagglutinin titer of each IVIG lot and maternal blood count were controlled. IVIG-related side effects were prospectively documented and evaluated. Furthermore, ultrasound examination of the fetus was performed before starting IVIG administration and continued regularly during treatment. Outcome of the index and subsequent pregnancy was compared. Corresponding data of the newborns were analyzed simultaneously.ResultsIVIG was started at 20 weeks of gestation (median). Compared to the index pregnancy, platelet counts of the newborns were higher in all cases. No intracranial hemorrhage occurred (Index pregnancies: 1 case). Platelet counts were 187 × 109/l (median, range 22–239, 95% CI) and one newborn had mild bleeding. No severe hemolytic reaction was observed and side effects were moderate.ConclusionAmong pregnant women with FNAIT history, the use of non-invasive fetal risk determination and maternal IVIG resulted in favorite outcome of all newborns. Invasive diagnostic or therapeutic procedures in women with a history of FNAIT should be abandoned.

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX+PBS, or HYX+FGF10. scRNAseq between rMC-Sca1Pos isolated from NOX and HYX+PBS were also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de-novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1Pos niche cells potentially representing its cellular target.

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX-PBS, or HYX-FGF10. scRNAseq between rMC-Sca1Pos isolated from NOX and HYX-PBS was also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1Pos niche cells potentially representing its cellular target.

Objective This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. Methods Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. Results All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. Conclusion Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The importance of nutritional supply for somatic growth and neurodevelopmental outcome in very-low-birthweight infants is an established medical strategy for reducing long-term morbidities. Our cohort study on rapid enteral feeding advances using a standardized protocol (STENA) previously demonstrated a 4-day reduction of parenteral nutrition. STENA did not impede the success of noninvasive ventilations strategies but significantly less infants required mechanical ventilation. Most importantly, STENA resulted in improved somatic growth at 36 weeks of gestation. Here, we evaluated our cohort for psychomotor outcomes and somatic growth at 2 years of age. n = 218 infants of the original cohort were followed-up (74.4%). Z-scores for weight and length did not differ but the benefits of STENA for head circumference persisted until the age of 2 years (p = 0.034). Concerning the psychomotor outcome, we neither found any statistically significant differences in the mental developmental index (MDI) (p = 0.738), norin the psychomotor developmental index (PDI) (p = 0.122). In conclusion, our data adds important insights on the topic of rapid enteral feeding advances and confirms the safety of STENA with respect to somatic growth and psychomotor outcome measures.

Paediatric hydrocephalus is a result of cerebrospinal fluid circulatory dysfunction and has diverse pathogeneses. This study investigates the epidemiology of paediatric hydrocephalus and influences of primary aetiology, type of implants, and of complications to develope new therapeutic approaches and strategies. Between 2013-2018 a retrospective analysis of 131 children, suffering from hydrocephalus, was conducted. Medical charts, operative reports and clinical follow-up visits were reviewed. Statistical analysis was performed using t-test/ANOVA and Kruksal-Wallis-test/ Mann-Whitney-U test. Most common pathogeneses of hydrocephalus among our patients were meningomyelocele associated and posthaemorrhagic. The majority received a programmable differential pressure valve (PP valve, 77.8%) or a fixed differential pressure valve with gravitational unit (FPG valve, 14.8%). Among 333 shunt associated surgeries 66% were performed because of mechanical shunt dysfunction (61%), infection (12%), or due to other reasons (27%). The median rate of revisions for each patient within one year was 0.15 (IQR25-75:0.00-0.68) and was influenced by aetiology (p=0.045) and used valves (p=0.029). The highest rates were seen in patients with posthaemorrhagic hydrocephalus and in those with FPG valve, the lowest in meningomyelocele associated hydrocephalus and PP valve. The occurrence of mechanical dysfunctions showed a relation to FPG valve (p=0.014). Furthermore, the median time interval between initial shunt surgery and infections was shorter than in mechanical dysfunctions (p=0.033). Conclusion: We could state several influence factors on revision surgeries in paediatric shunt patients. With the assessment of patients’ risk profiles, we can classify paediatric shunt patients and could avoid unnecessary examinations or invasive procedures. Furthermore, we could prevent revisions surgeries, if we choose shunt material in accordance with the patients’ associated shunt complications.

Introduction: Bronchopulmonary dysplasia (BPD) represents a tremendous disease burden following preterm birth. The strong association between compromised gas exchange after birth and BPD demands particular focus on the perinatal period. The mode of delivery can impact on lung fluid clearance and microbial colonization, but its impact on BPD and potential trade-off effects between death and BPD are not established. Methods: A total of 7,435 live births (24+0 to 31+6 weeks postmenstrual age) in 19 regions of 11 European countries were included. Principal outcomes were death and BPD at 36 weeks. We estimated unadjusted and adjusted associations with mode of delivery using multilevel logistic regression to account for clustering within units and regions. Sensitivity analyses examined effects, taking into consideration regional variations in C-section rates. Results: Compared to vaginal delivery, delivery by C-section was not associated with the incidence of BPD (OR 0.92, 95% CI: 0.68–1.25) or the composite outcome of death or BPD (OR 0.94, 95% CI: 0.74–1.19) after adjustment for perinatal and neonatal risk factors in the total cohort and in pregnancies for whom a vaginal delivery could be considered. Sensitivity analyses among singletons, infants in cephalic presentation, and infants of ≥26+0 weeks of gestation did not alter the results for BPD, severe BPD, and death or BPD, even in regions with a high C-section rate. Conclusions: In our population-based cohort study, the mode of delivery was not associated with the incidence of BPD. The intention to reduce BPD does not justify a C-section in pregnancies where a vaginal delivery can be considered.

Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD.

Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.