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Understanding how spatially remote brain regions interact to form functional brain networks, and how these develop during the neonatal period, provides fundamental insights into normal brain development, and how mechanisms of brain disorder and recovery may function in the immature brain. A key imaging tool in characterising functional brain networks is examination of T2*-weighted fMRI signal during rest (resting state fMRI, rs-fMRI). The majority of rs-fMRI studies have concentrated on slow signal fluctuations occurring at <0.1 Hz, even though neuronal rhythms, and haemodynamic responses to these fluctuate more rapidly, and there is emerging evidence for crucial information about functional brain connectivity occurring more rapidly than these limits. The characterisation of higher frequency components has been limited by the sampling frequency achievable with standard T2* echoplanar imaging (EPI) sequences. We describe patterns of neonatal functional brain network connectivity derived using accelerated T2*-weighted EPI MRI. We acquired whole brain rs-fMRI data, at subsecond sampling frequency, from preterm infants at term equivalent age and compared this to rs-fMRI data acquired with standard EPI acquisition protocol. We provide the first evidence that rapid rs-fMRI acquisition in neonates, and adoption of an extended frequency range for analysis, allows identification of a substantial proportion of signal power residing above 0.2 Hz. We thereby describe changes in brain connectivity associated with increasing maturity which are not evident using standard rs-fMRI protocols. Development of optimised neonatal fMRI protocols, including use of high speed acquisition sequences, is crucial for understanding the physiology and pathophysiology of the developing brain. Hum Brain Mapp 36:2483-2494, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Single-strand conformational polymorphism (SSCP) is still a frequently used genotyping method across different fields for the detection of single nucleotide polymorphisms (SNPs) due to its simplicity, requirement for basic equipment accessible in most laboratories and low cost. This technique was previously used to detect rs4354668:A > C (g.-181A > C) SNP in the promoter of astroglial glutamate transporter (EAAT2) and the same approach was initially used here to investigate this promoter region in a cohort of newborns. Results: Unexpectedly, four distinct DNA migration patterns were identified by SSCP. Sanger sequencing revealed two additional SNPs: g.-200C > A and g.-168C > T giving a rise to a total of ten EAAT2 promoter variants. SSCP failed to distinguish these variants reliably and thus pyrosequencing assays were developed. g.-168C > T was found in heterozygous form in one infant only with minor allele frequency (MAF) of 0.0023. In contrast, g.-200C > A and -181A > C were more common (with MAF of 0.46 and 0.49, respectively) and showed string evidence of linkage disequilibrium (LD). In a systematic comparison, 16% of samples were miss-classified by SSCP with 25-31% errors in the identification of the wild-type and homozygote mutant genotypes compared to pyrosequencing or Sanger sequencing. In contrast, SSCP and pyrosequencing of an unrelated single SNP (rs1835740:C > T), showed 94% concordance. Conclusion: Our data suggest that SSCP cannot always detect reliably several closely located SNPs. Furthermore, caution is needed in the interpretation of the association studies linking only one of the co-inherited SNPs in the EAAT2 promoter to human diseases. [ABSTRACT FROM AUTHOR]

Background Genotyping requires biological sample collection that must be reliable, convenient and acceptable for patients and clinicians. Finding the most optimal procedure of sample collection for premature neonates who have a very limited blood volume is a particular challenge. The aim of the current study was to evaluate the use of umbilical cord (UC) tissue and newborn dried blood spot (DBS)-extracted genomic DNA (gDNA) as an alternative to venous blood-derived gDNA from premature neonates for molecular genetic analysis. Methods All samples were obtained from premature newborn infants between 24-32 weeks of gestation. Paired blood and UC samples were collected from 31 study participants. gDNA was extracted from ethylenediaminetetraacetic acid (EDTA) anticoagulant-treated blood samples (~500 µl) and newborn DBSs (n = 723) using QIAamp DNA Micro kit (Qiagen Ltd., Crawley, UK); and from UC using Qiagen DNAeasy Blood and Tissue kit (Qiagen Ltd., Crawley, UK). gDNA was quantified and purity confirmed by measuring the A260:A280 ratio. PCR amplification and pyrosequencing was carried out to determine suitability of the gDNA for molecular genetic analysis. Minor allele frequency of two unrelated single nucleotide polymorphisms (SNPs) was calculated using the entire cohort. Results Both whole blood samples and UC tissue provided good quality and yield of gDNA, which was considerably less from newborn DBS. The gDNA purity was also reduced after 3 years of storage of the newborn DBS. PCR amplification of three unrelated genes resulted in clear products in all whole blood and UC samples and 86%-100% of newborn DBS. Genotyping using pyrosequencing showed 100% concordance in the paired UC and whole blood samples. Minor allele frequencies of the two SNPs indicated that no maternal gDNA contamination occurred in the genotyping of the UC samples. Conclusions gDNAs from all three sources are suitable for standard PCR and pyrosequencing assays. Given that UC provide good quality and quantity gDNA with 100% concordance in the genetic analysis with whole blood, it can replace blood sampling from premature infants. This is likely to reduce the stress and potential side effects associated with invasive sample collection and thus, greatly facilitate participant recruitment for genetic studies. [ABSTRACT FROM AUTHOR]

GABAB receptors (GABABRs) are involved in early events during neuronal development. The presence of GABABRs in developing oligodendrocytes has not been established. Using immunofluorescent co-localization, we have identified GABABR proteins in O4 marker-positive oligodendrocyte precursor cells (OPCs) in 4-day-old mouse brain periventricular white matter. In culture, OPCs, differentiated oligodendrocytes (DOs) and type 2 astrocytes (ASTs) express both the GABAB1abcdf and GABAB2 subunits of the GABABR. Using semiquantitative PCR analysis with GABABR isoform-selective primers we found that the expression level of GABAB1abd was substantially higher in OPCs or ASTs than in DOs. In contrast, the GABAB2 isoform showed a similar level of expression in OPCs and DOs, and a significantly higher level in ASTs. This indicates that the expression of GABAB1 and GABAB2 subunits are under independent control during oligodendroglial development. Activation of GABABRs using the selective agonist baclofen demonstrated that these receptors are functionally active and negatively coupled to adenylyl cyclase. Manipulation of GABABR activity had no effect on OPC migration in a conventional agarose drop assay, whereas baclofen significantly increased OPC migration in a more sensitive transwell microchamber-based assay. Exposure of cultured OPCs to baclofen increased their proliferation, providing evidence for a functional role of GABABRs in oligodendrocyte development. The presence of GABABRs in developing oligodendrocytes provides a new mechanism for neuronal–glial interactions during development and may offer a novel target for promoting remyelination following white matter injury. [ABSTRACT FROM AUTHOR]

Oligodendrocytes (OLs) are responsible for axon myelination and are the principal cells targeted in preterm white matter injury. The cellular and molecular mechanisms involved in white matter development and immature OL injury are incompletely understood. Metabotropic glutamate receptors (mGluRs) modulate neuronal development and survival, and have recently been identified in oligodendrocyte progenitor cells (OPCs). Using the highly homogeneous CG-4 OPC line and O4 marker-immunoselected primary OLs, we established the differentiation stage-specific expression profile of mGluR3 and mGluR5 mRNAs and proteins in the oligodendroglial lineage and type-2-astrocytes (ASTs). Our quantitative analysis indicated no changes in mGluR3, but a significant down-regulation of mGluR5a mRNA and protein expression during differentiation of OPCs into OLs or ASTs. The down-regulation of mGluR5a had functional consequences, with significantly fewer OLs and ASTs than OPCs responding to the group I mGluR agonist ( RS)-3,5-dihydroxyphenylglycine with intracellular Ca2+ concentration oscillations. Neither stimulation nor inhibition of mGluR3 or mGluR5 altered OPC migration, suggesting that these receptors do not play prominent roles in the regulation of OPC motility. The activation of mGluR5 completely protected OPCs and substantially reduced staurosporine-induced apoptosis in OLs. This suggests that the down-regulation of mGluR5 in premyelinating OLs is likely to contribute to their increased vulnerability, and that the targeting of mGluR5 may be a potential therapeutic strategy for future development. [ABSTRACT FROM AUTHOR]

Glial precursor cells (GPCs) are present in the adult human central nervous system (CNS) and they can be isolated and maintained in culture for in vitro studies. This study analysed expression of mGluR3 and mGluR5 metabotropic glutamate receptor (mGluR) mRNAs in GPCs. A2B5 surface antigen positive GPCs were isolated using immunomagnetic selection from dissociated temporal lobe subcortical white matter cells. The separated GPCs were maintained in cultures and characterised by immunoreactivity for the differentiation markers A2B5 and human platelet-derived growth factor-α receptor (PDGFαR). Reverse transcription followed by multiplex PCR analysis showed that the GPCs expressed both mGluR3 and mGluR5a mRNAs. Double immunostaining for glial progenitor markers and mGluR5 proteins demonstrated that all A2B5 and PDGFαR-positive cells were also positive for mGluR5. The results indicate that GPCs present in the adult human CNS express mGluR3 and mGluR5a. These neurotransmitter receptors may be involved in the proliferation and differentiation of glial cells. [Copyright &y& Elsevier]

Abstract We investigated the expression of metabotropic glutamate receptor (mGluR) isoforms in CG-4 rodent oligodendroglial progenitor cells (OPC) and rat brain oligodendrocytes. Our RT-PCR analysis detected mRNAs for mGluR3 and mGluR5 isoforms in OPCs. Although neurons express both mGluR5a and mGluR5b splice variants, only mGluR5a was identified in OPCs. Antibodies to mGluR2/3 and mGluR5 detected the corresponding receptor proteins in immunoblots of OPC membrane fractions. Furthermore, immunocytochemical analysis identified mGluR5 in oligodendrocyte marker O4-positive OPCs. The expression of mGluR5 was also demonstrated in oligodendrocyte marker (O4 and O1) positive cells in white matter of postnatal 4- and 7-day-old rat brain sections using immunofluorescent double labelling and confocal microscopy. The mGluR5 receptor function was assessed in CG-4 OPCs with fura-2 microfluorometry. Application of the mGluR1/5 specific agonist (S )-3,5-dihydroxyphenylglycine (DHPG) induced calcium oscillations, which were inhibited by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP). The DHPG induced calcium oscillations required Ca2+ release from intracellular stores. In OPCs the group II mGluR agonist (2S ,2′R ,3′R )-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) decreased forskolin-stimulated cAMP synthesis, indicating the presence of functional mGluR3. The newly identified mGluR3 and mGluR5a may be involved in the differentiation of oligodendrocytes, myelination and the development of white matter damage. [ABSTRACT FROM AUTHOR]

Preterm birth remains the leading cause of mortality among under‐5's and is a major contributor to the reduction in quality‐of‐life adjusted years and reduction in human capital. Globally, there are many interventions and care bundles that aim to reduce the impact of preterm birth once preterm labor has ensued and into the neonatal period; not all of these are applicable in all settings. Here, we introduce the FIGO PremPrep‐5 initiative, which aims to disseminate key information on the most simple and effective interventions with the aim of increasing implementation globally. Before delivery, we recommend a course of antenatal corticosteroids, and intrapartum magnesium sulfate. At delivery, we recommend delayed cord clamping. Postnatally, we recommend early feeding with breast milk and immediate kangaroo care. While there are many other interventions that may improve outcomes at the time of labor and after preterm birth, these are clinically effective and relatively inexpensive options that can be practiced in most settings and supplemented with more advanced care. We include examples of a training video and infographics that will be used for dissemination. Synopsis: An introduction to simple interventions to reduce the impact of preterm birth in low‐ and middle‐income country settings. [ABSTRACT FROM AUTHOR]

Objective: To compare two quality improvement (QI) interventions to improve antenatal magnesium sulphate (MgSO4) uptake in preterm births for the prevention of cerebral palsy. Design: Unblinded cluster randomised controlled trial. Setting: Academic Health Sciences Network, England, 2018. Sample: Maternity units with ≥10 preterm deliveries annually and MgSO4 uptake of ≤70%; 40 (27 NPP, 13 enhanced support) were included (randomisation stratified by MgSO4 uptake). Methods: The National PReCePT Programme (NPP) gave maternity units QI materials (clinical guidance, training), regional support, and midwife backfill funding. Enhanced support units received this plus extra backfill funding and unit‐level QI coaching. Main outcome measures: MgSO4 uptake was compared using routine data and multivariable linear regression. Net monetary benefit was estimated, based on implementation costs, lifetime quality‐adjusted life‐years and societal costs. The implementation process was assessed through qualitative interviews. Results: MgSO4 uptake increased in all units, with no evidence of any difference between groups (0.84 percentage points lower uptake in the enhanced group, 95% CI −5.03 to 3.35). The probability of enhanced support being cost‐effective was <30%. NPP midwives gave more than their funded hours for implementation. Units varied in their support needs. Enhanced support units reported better understanding, engagement and perinatal teamwork. Conclusions: PReCePT improved MgSO4 uptake in all maternity units. Enhanced support did not further improve uptake but may improve teamwork, and more accurately represented the time needed for implementation. Targeted enhanced support, sustainability of improvements and the possible indirect benefits of stronger teamwork associated with enhanced support should be explored further. [ABSTRACT FROM AUTHOR]

Background: Post-haemorrhagic ventricular dilatation (PHVD) is commonly seen in extremely preterm babies, carries significant morbidity, and may cause neonatal mortality. There is a lack of literature on the subsequent health-related quality of life (HRQoL) in childhood. The aim of this work was to assess the quality of life of preterm babies after PHVD at 10 years of age using two validated questionnaires. Methods: Children with PHVD were assessed as part of the 10-year follow-up of the drainage, irrigation, and fibrinolytic therapy trial. The HRQoL outcome was measured using parent-reported EQ-5D-5L and HUI-3 questionnaires. Both questionnaires produce a summary score anchored at 1 (best health) and 0 (equivalent to death). Results: Median scores at follow-up were 0.65 (IQR 0.36–0.84; n = 44) for the EQ-5D-5L and 0.52 (IQR 0.22–0.87; n = 51) for the HUI-3. Similar proportions had a score below 0.2 (HRQoL [20%], HUI-3 [21%]), while 20% had a HRQoL score above 0.80 compared to 34% using HUI-3. The most severe problems from the EQ-5D-5L were reported in the self-care, mobility, and activity domains, while the HUI-3 reported worse problems in ambulation, cognition, and dexterity domains. Infants with worse (grade 4) intraventricular haemorrhage had poorer HRQoL than those with grade 3 bleeds. Conclusion: Children who survive to 10 years of age after PHVD have on average lower HRQoL than their peers. However, the reported range is wide, with a quarter of the children having scores above 0.87 (similar to population norms), while a fifth have very low HRQol scores. Impact was not uniform across domains, with mobility/ambulation a concern across both measures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mothers are increasingly given greater control over many of the choices around birth, although there is little robust evidence to inform these choices. After an infant is born with HIE the question of whether it was predictable, or preventable, is often raised. Intrapartum 'sentinel' events and antenatal predictors of HIE have been well described, however there is little evidence how antenatal and intrapartum factors interact. This is particularly important when elective delivery by lower segment caesarean section (LSCS) has been shown to be beneficial in high risk groups. AIM: To develop a clinical risk score to identify women with a higher risk of having an infant with HIE. PATIENTS AND METHODS: This study is based on the Avon Longitudinal Study of Parents and Children (ALSPAC). This dataset was split into two halves: with each infant being randomly allocated to either cohort one or two. The first cohort was used for the derivation of the model, while it was tested exclusively on the second. Logistic regression modelling was then performed to develop a predictive model. The final model was used to predict the outcome of infants in the second cohort and infants divided into four risk quartiles. To give some indication of possible avoidable disease, the proportion of infants with HIE, potentially avoided by earlier delivery, was estimated by assuming that medicalized delivery by elective LSCS at 37 weeks would remove intrapartum risk of HIE for those infants undelivered at this point. RESULTS: In the final model seven covariates remained (parity, preeclampsia, polyhydramnios, prelabor rupture of membranes, gender, concerns over fetal growth and prematurity). When applied to the second cohort, a ROC curve for the prediction of developing HIE in the newborn period showed good evidence for association (AUC 0.68 (0.60 to 0.77)) and the risk score derived was strongly associated with the risk of HIE, resuscitation and stillbirth, and neonatal death (all p < 0.05). Elective delivery of high risk infants at 37 weeks gestation could prevent 14% of all HIE, with a NNT of 41. CONCLUSION: It is possible to combine routine antenatal findings to identify infants at higher risk of neonatal HIE, thereby recognizing those infants who may benefit most from delivery by elective caesarean section. This work suggests a clinical risk score permits antenatal identification of high-risk infants whose outcome may be amenable to changes in clinical practice to potentially reduce HIE rates, and its devastating consequences. [ABSTRACT FROM AUTHOR]

Background: A quality improvement strategy (PReCePT) was used in a standard and enhanced format to scale up a clinical intervention (administering magnesium sulphate to women in preterm labour) across all maternity units in England to protect prematurely born infants from neurodevelopmental disabilities. Formal evaluations reported the effectiveness of the standard package alone in increasing the administration of magnesium sulphate. In this paper, we focus on the findings of the process evaluations, using normalisation process theory to explain how different implementation contexts generated the observed outcomes relating to normative and relational restructuring and sustainment. Methods: Interviews were conducted with key individuals in implementation of leadership positions nationally and locally. Interviews were analysed initially using the framework method. We then engaged recursively with NPT constructs to generate generalisable insights with pragmatic applicability in other settings. Results: In total, 72 interviews were conducted with good representation from units across England and staff from the National Academic Health Science Network. We found that all units irrespective of whether they received a standard or enhanced QI package were successful in the 'normative restructuring' of their setting to enable magnesium sulphate to be administered. This suggests that this implementation outcome is necessary to achieve improvements. However, it may not be sufficient to sustain the changes once additional resources have been withdrawn. Sustainment, our findings suggest, required 'relational restructuring' to accommodate altered workflows and facilitate the sharing of responsibilities and tasks in daily practice. Relational restructuring was more likely to have been achieved units receiving enhanced QI support but also happened in units with standard QI support, especially in those where perinatal team working was already well established. Conclusion: Unlike other large QI-focused spread-and-scale programmes which failed to show any impact on outcomes, the PReCePT programme in both the enhanced and standard support packages led to improvements in the uptake of magnesium sulphate. The findings suggest that QI programmes interact with the enabling factors, such as strong interprofessional team working, already present in the setting. A standard package with minimal support was therefore sufficient in settings with enabling factors, but enhanced support was required in units where these were absent. [ABSTRACT FROM AUTHOR]

Background: Postmenstrual age for surviving infants without congenital anomalies born at 24–29 weeks' gestational age from 2005 to 2018 in the USA increased 8 days, discharge weight increased 316 grams, and median discharge weight z-score increased 0.19 standard units. We asked whether increases were observed in other countries. Methods: We evaluated postmenstrual age, weight, and weight z-score at discharge of surviving infants without congenital anomalies born at 24–29 weeks' gestational age admitted to Vermont Oxford Network member hospitals in Austria, Ireland, Italy, Switzerland, the UK, and the USA from 2012 to 2020. Results: After adjustment, the median postmenstrual age at discharge increased significantly in Austria (3.6 days, 99% CI [1.0, 6.3]), Italy (4.0 days [2.3, 5.6]), and the USA (5.4 days [5.0, 5.8]). Median discharge weight increased significantly in Austria (181 grams, 99% CI [95, 267]), Ireland (234 [143, 325]), Italy (133 [83, 182]), and the USA (207 [194, 220]). Median discharge weight z-score increased in Ireland (0.24 standard units, 99% CI [0.12, 0.36]) and the USA (0.15 [0.13, 0.16]). Discharge on human milk increased in Italy, Switzerland, and the UK, while going home on cardiorespiratory monitors decreased in Austria, Ireland, and USA and going home on oxygen decreased in Ireland. Conclusions: In this international cohort of neonatal intensive care units, postmenstrual discharge age and weight increased in some, but not all, countries. Processes of care at discharge did not change in conjunction with age and weight increases. [ABSTRACT FROM AUTHOR]

Background: Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium‐sized studies. Objectives: This study aimed to investigate the epidemiology of ACC, using data from a large European network of population‐based registries for congenital anomalies (EUROCAT). Methods: Twenty‐eight EUROCAT population‐based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5‐year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9‐BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. Results: Five hundred cases were identified in the period 1998–2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5‐year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams–Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. Conclusion: To our knowledge, this is the only population‐based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies. [ABSTRACT FROM AUTHOR]

Aim: We examined children 10 to 11 years after grade 3 or 4 intraventricular haemorrhage and ventricular dilation (IVHVD) and investigated whether the grade of IVHVD affected their visual outcome. We explored associations between visual outcomes with cognitive outcomes and extra support at school. Method: The visual examinations were part of a 10‐year follow‐up study for children in a randomized trial. Testers followed a protocol and were masked to whether the child had experienced grade 3 or grade 4 IVHVD and all other data. Results: Thirty‐two children were tested: 24 were male and mean (standard deviation) age was 10 years 5 months (1 year 2 months); range 8 years 9 months to 12 years 9 months. All had at least one visual impairment. The median (interquartile range) number of impairments per child was six (six to nine) for children who experienced a grade 4 IVHVD compared with three (two to four) for children who experienced a grade 3 IVHVD (p = 0.003). Each extra vision impairment per child was associated with increased educational support at school, after adjustment for developmental age equivalence (odds ratio = 1.7 [95% confidence interval 1.1–2.6], p = 0.015). Interpretation: Children who experience grade 3 or 4 IVHVD have a high level of visual morbidity at age 10 to 11 years. These children may have unmet visual needs and their outcomes might improve if these needs could be addressed. What this paper adds: Parent‐reported questionnaire responses underestimated directly assessed visual morbidity.Grade 4 intraventricular haemorrhage and ventricular dilatation (IVHVD) was followed by more vision impairments than grade 3 IVHVD.Simple tests of visual perceptual skills correlated with the neuropsychology tests.Children with supranuclear eye movement disorders were more likely to be receiving extra help at school.Each additional visual impairment increased the likelihood of extra educational support. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between superior vena cava flow (SVCF) measurements within the first 24 h of life, and development of intraventricular haemorrhage (IVH) in extremely preterm infants. Study Design: Single centre retrospective cohort study of 108 preterm infants born less than 28 weeks' gestation. Main outcome measure was degree of IVH at day 7 postnatal age. Results: The mean GA of the study group was 25.4 weeks. Mean SVCF was lower (75 ml/kg/min) in infants later diagnosed with IVH (n = 46) compared to infants, who did not develop IVH (87.7 ml/kg/min, p = 0.055). PDA diameter was inversely associated with SVCF (p = 0.024) and reversal of flow in the descending aorta (p = 0.001). Sensitivity analysis did not confirm an independent association of SVCF with development of IVH [OR 0.990 (0.978-1.002), p = 0.115]. Conclusion: Our study describes early SVCF in extremely preterm infants is associated with the extent of ductal shunting, but insensitive in predicting IVH. [ABSTRACT FROM AUTHOR]

The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has evolved in recent years, improving both quality of life and survival for patients. One of the potential agents for this condition is sildenafil, a phosphodiesterase-V inhibitor with proven efficacy within the idiopathic PH population. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This review summarises the evidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improved patient outcomes. We conclude that sildenafil is both safe and effective in this utility. Doses should be started at 0.5 mg/kg every 8 h before titrating up towards 2 mg/kg every 6 h to effect reductions in pulmonary vascular resistance and arterial pressure. Evidence suggests that if continued until PH resolution, this improves survival from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered. [ABSTRACT FROM AUTHOR]

Background: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden. Objective: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population‐based registries of congenital anomalies. Methods: We analysed cases of PRS born in the period 1998‐2017 collected by 29 population‐based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model. Results: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub‐period 2008‐2017. The prevalence rate ratio of non‐chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%). Conclusions: This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS. [ABSTRACT FROM AUTHOR]

Objective: The PARENTS 1 study (Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death) found that parents would endorse the opportunity to give feedback into the perinatal mortality review (PNMR) process. In subsequent focus groups, healthcare professionals were positive about parental engagement, although they considered that there may be significant challenges. The objective of this study was to develop core principles and recommendations for parental engagement in PNMR in the UK.Methods: A two-round Delphi technique was followed to reach consensus on core principles for parental engagement in the PNMR process; Round 1 included a national consensus workshop and Round 2 an online questionnaire. The consensus meeting was attended by a national panel of stakeholders (clinical and academic experts, parent advocates, managers and commissioners) in stillbirth and neonatal and bereavement care. To develop recommendations for parental engagement, participants discussed four key areas comprising: communication with parents, including receiving feedback; the format of the PNMR meeting; the parental engagement pathway; and challenging aspects of engaging with parents in reviews. Content analysis was conducted to generate recommendations from the meeting for a subsequent anonymous web-based survey. Attendees of the consensus workshop and members of the PARENTS 2 Project Advisory Board were asked to rank recommendations using a 9-point Likert scale from 1 (not important) to 9 (critically important). It had been agreed a priori, in compliance with established Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, that 'consensus' would be achieved if over 70% of participants scored the principle as 'critical' (score of 7-9) and fewer than 15% scored the principle as 'not important' (score of 1-3). Principles for which consensus was achieved were included in the core recommendations.Results: Of the 29 invited stakeholders, 22 participated in the consensus meeting and 25 (86% response rate) in the subsequent online questionnaire in June 2017. Consensus was agreed on 12 core principles. Of the 25 participants, 96% agreed that a face-to-face explanation of the PNMR process was of critical importance, 72% considered that parents should be offered the opportunity to nominate a suitable advocate, 92% believed that responses to parents' comments should be formally documented, 96% indicated that it was vital for action plans to be translated into lessons learnt and that this process should be monitored, and 100% of stakeholders voted that a plain-English summary should be produced for the parents following the meeting. There was good agreement on a further seven principles.Conclusions: Key national stakeholders were unanimously supportive of parental engagement in the PNMR process and agreed on core principles to make this process feasible, meaningful and robust. A 6-month pilot of parental engagement in the PNMR process (PARENTS 2 study) in two UK units took place after the consensus on core principles. In collaboration with the National Perinatal Epidemiology Unit, the findings will inform the national standardized PNMR tool. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Following low incidence of invasive group A streptococcal (iGAS) infections during the COVID-19 pandemic, marked increases were noted in many countries during 2022, particularly in children. In November 2022, severe presentations of lower respiratory tract infections (LRTIs), including empyema, were notified by clinicians across the UK. UKHSA investigated this rise with the aim of informing clinical management and public health response. We undertook a case-series analysis using multiple routine data sources, exempted from ethics approval or patient consent. We identified iGAS cases in England in children younger than 15 years with an LRTI reported between Oct 1 and Dec 21, 2022, using UKHSA laboratory surveillance data (GAS detected in LRT specimens) and notifications by clinicians and Health Protection Teams (HPTs). Symptoms, diagnoses, health-care interactions, and outcome (death or recovery) data were obtained from HPT case management notes, the National Child Mortality Database, and the NHS Digital Emergency Care Dataset. We identified 147 cases of LRTI iGAS in children across England (77 [52%] male, 70 [48%] female; median age 4 years [IQR 2–6]). Predominant ethnicities were White (74 [65%] of 113 with known ethnicity) and Asian (18 [16%] of 113). Most reported symptoms were fever (90 [75%] of 120 children with ≥1 symptom) and cough (60 [50%] of 120), and 71 (48%) of all 147 children had a diagnosed respiratory viral coinfection (most commonly hMPV and RSV). 127 (86%) of children attended an emergency department, 31% (n=36/114 with onset date) at least twice within 21 days after symptom onset. 37 (25%) of 147 children died, with a median time from symptom onset to death of 4 days (IQR 3–7). Of 32 children with sample dates, 16 (84%) were tested for GAS on or after the day they died. Over half of deaths (21 [57%] of 37 deaths) occurred in the community after rapid deterioration, of whom 18 had previous contact with health-care services documented. The UK saw an unusual rise in iGAS LRTIs in children in late 2022. One in four cases died, over half in the community. Non-specific symptoms, viral symptoms, or positive virology might have lowered suspicion of bacterial infection. Although the use of multiple available data sources expedited the analysis, varying data completeness limited interpretation. Our study highlights the need for earlier detection and identification of effective measures to prevent death. None. [ABSTRACT FROM AUTHOR]

Abstract Septo-optic nerve dysplasia is a rare congenital anomaly with optic nerve hypoplasia, pituitary hormone deficiencies and midline developmental defects of the brain. The clinical findings are visual impairment, hypopituitarism and developmental delays. The aim of this study was to report prevalence, associated anomalies, maternal age and other epidemiological factors from a large European population based network of congenital anomaly registries (EUROCAT). Data from 29 full member registries for the years 2005–2014 were included, covering 6.4 million births. There were 99 cases with a diagnosis of septo-optic dysplasia. The prevalence of septo-optic dysplasia in Europe was calculated to lie between 1.9 and 2.5 per 100,000 births after adjusting for potential under-reporting in some registries. The prevalence was highest in babies of mothers aged 20–24 years of age and was significantly higher in UK registries compared with other EUROCAT registries (P = 0.021 in the multilevel model) and the additional risk for younger mothers was significantly greater in the UK compared to the rest of Europe (P = 0.027). The majority of septo-optic dysplasia cases were classified as an isolated cerebral anomaly (N = 76, 77%). Forty percent of diagnoses occurred in fetuses with a prenatal diagnosis. The anomaly may not be visible at birth, which is reflected in that 57% of the postnatal diagnoses occurred over 1 month after birth. This is the first population based study to describe the prevalence of septo-optic dysplasia in Europe. Septo-optic dysplasia shares epidemiological patterns with gastroschisis and this strengthens the hypothesis of vascular disruption being an aetiological factor for septo-optic dysplasia. [ABSTRACT FROM AUTHOR]

Background: The parameters of the optic disc and peripapillary retinal nerve fibre layer (pRNFL) in premature children may vary with disease processes that contribute to visual impairment and blindness and so could be useful as an objective measure in at-risk children. Methods: A systematic review of current literature on the range of pRNFL and optic disc parameters in children aged less than 18 years, who were born before 37 weeks gestation, will be performed. The bibliographic databases MEDLINE, CINAHL, EMBASE, Scopus and Web of Science will be systematically searched. Where possible and appropriate, study-specific estimates will be combined using meta-analysis to obtain an overall summary estimate of pRNFL thickness and cup-disc ratio across studies, and results will be presented by age of population. Discussion: This review aims to improve understanding of what might be considered within/outside the range of normality for this high-risk group. [ABSTRACT FROM AUTHOR]

Aim: The aim of this work was to test whether three single nucleotide polymorphisms (SNPs) implicated in glutamate homoeostasis or signalling and cellular survival are associated with birth condition.Methods: This study is drawn from the Avon Longitudinal Study of Parents and Children. A total of 7611 term infants were genotyped and patient outcome data retrieved from routine medical records. Exposure measures were the presence of one or more minor alleles in one of 3 SNPs (rs2284411, rs2498804, rs1835740). The primary outcome was the need for resuscitation at birth.Results: For SNP rs1835740, infants homozygous for the minor allele compared to wild type were more likely to need resuscitation (9.2% vs. 7.0%, p = 0.041), while the odds ratio for resuscitation was associated with each increasing minor allele [OR 1.17 (1.01-1.35)]. Population attributable risk fraction was 6.5%. There was no evidence that the other two SNPs investigated were associated with birth condition.Conclusion: We have tested three candidate SNPs to measure any association with birth condition. The study revealed that the rs1835740 was associated with the need for resuscitation and Apgar scores, with a substantial population impact. [ABSTRACT FROM AUTHOR]

Aim To determine the aetiological associations, neurological sequelae and role of magnetic resonance imaging ( MRI) in term newborn infants with seizures. Methods Cohort study of infants ≥37 weeks' gestation delivered in a tertiary level centre, prospectively identified and followed longitudinally for 18-24 months. Results An underlying aetiology was found in 95% of the 77 infants identified with seizures (3.0/1000 live births). The most common diagnosis was hypoxic-ischaemic encephalopathy ( HIE) (65%), followed by neonatal stroke (12%). Nine infants died, 28 of the 68 survivors developed neurodevelopmental impairment ( NDI), and 15 had recurrent seizures in the first 2 years, with both outcomes more likely in those with a diagnosis other than HIE. Abnormal MRI findings were found in 45 of the 70 infants imaged. The absence of major cerebral lesions was highly predictive of a normal neurological outcome. Conclusion We report the first cohort of term infants with seizures fully investigated by MRI. The universal use of MRI enabled a cause to be identified in 95% of cases. The probability of having NDI or recurrence of seizures was extremely low with absence of major cerebral lesions on MRI. This study demonstrates the added value of MRI for diagnosis of aetiology and the prediction of neurological outcome. [ABSTRACT FROM AUTHOR]

Objective: Therapeutic hypothermia (HT) is the standard treatment for newborns after perinatal asphyxia. Preclinical studies report that HT is more effective when started early. Methods: Eighty cooled newborns were analyzed and grouped according to when cooling was started after birth: early (≤180 min) or late (>181 min). For survivors we analyzed whether starting cooling early was associated with a better psychomotor or mental developmental index (PDI or MDI, Bayley Scales of Infant Development II) than late cooling. Results: Forty-three newborns started cooling early and 37 started late. There was no significant difference in the severity markers of perinatal asphyxia between the groups; however, nonsurvivors (n = 15) suffered more severe asphyxia and had significantly lower centiles for weight (BWC; p = 0.009). Of the 65 infants that survived, 35 were cooled early and 30 were cooled late. There was no difference in time to start cooling between those who survived and those who did not. For survivors, median PDI (IQR) was significantly higher when cooled early [90 (77-99)] compared to being cooled later [78 (70-90); p = 0.033]. There was no increase in cardiovascular adverse effects in those cooled early. There was no significant difference in MDI between early and late cooling [93 (77-103) vs. 89 (76-106), p = 0.594]. Conclusion: Starting cooling before 3 h of age in surviving asphyxiated newborns is safe and significantly improves motor outcome. Cooling should be initiated as soon as possible after birth in eligible infants. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]