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Objective: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes., Design: Superiority, double-blind randomised controlled trial., Setting: A total of 20 UK fetal medicine units., Population: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22 +0 and 29 +6  weeks of gestation., Methods: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation., Main Outcome Measures: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85., Results: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm)., Conclusions: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies., Design: Cross-sectional survey., Setting: International., Population: Clinicians involved in the management of MCDA twin pregnancies with sFGR., Methods: A structured, self-administered survey., Main Outcome Measures: Clinical practices and attitudes to diagnostic criteria and management strategies., Results: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide., Conclusions: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: During Coronavirus disease 2019 pandemic, the general public used any face-worn products they could get to overcome the shortage of N95 respirators and surgical masks. These products, often not meeting any standards, raised concerns about their effectiveness in reducing the spread of respiratory viruses., Methods: This study quantified total outward leakage (TOL) of units from 9 face-worn product categories used by members of the general public. A benchtop system was devised to test 2 units from each category on 2 different-sized headforms with silicone elastomer skin. Each unit was donned 5 times per headform., Results: Both face-worn product category and headform size significantly affected TOL (P value < .05). The TOL of tested face-worn products varied from 10% to 58% depending on both model and headform size. Face-worn products donned on the medium headform had a higher mean TOL compared to those donned on the larger headform., Conclusions: Overall, single-layer cloth masks are the least effective measure for source control due to their highest TOL among the tested face-worn products. Three-layer disposable face masks may be a favorable option for source control among the public. A standard should be developed for face-worn product design and manufacturing to accommodate different facial sizes., (Published by Elsevier Inc.)

Background: Neonatal neurocritical care (NNCC) is a rapidly advancing field with limited fellowship training available in locally developed, non-accredited programs. A standardized survey aimed to understand the training backgrounds of individuals practicing NNCC, the structure of existing clinical NNCC services/training programs, and suggested clinical competencies for new graduates., Methods: We developed an anonymous survey electronically sent to members of societies related to NNCC. Using the survey results as a guide, we discuss a competence by design (CBD) curriculum as a complementary approach to traditional time-based training., Results: There were 82 responses to the survey from 30 countries; 95% of respondents were physicians. Thirty-one (42%) institutions reported having an NNCC service, 24 (29%) individuals reported formal NNCC training, 81% reported "significant variability" across NNCC training programs, and 88% were both in favor of standardizing training programs and pursuing formal accreditation for NNCC in the next 5 years., Conclusions: The survey results demonstrate international interest in standardizing NNCC training and development of an accreditation or certification process. We propose consideration of a CBD-type curriculum as a training approach to focus on the development of specific NNCC competencies, rather than assuming the acquisition of these competencies based on time as a surrogate., Impact: Continued growth and development in the field of NNCC has led to increasing need for training programs suited to meet the diverse needs of trainees from varied backgrounds. We present the results of an international survey that assessed the structure of existing training programs and the priority areas in which graduates must demonstrate competence, highlighting the combination of CBD and time-based training as one approach to address these recommendations. The survey results support interest in translating published training competencies, existing expertise, and infrastructure across centers into a standardized curriculum for NNCC including certification opportunities., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin <10th centile and EFW discordance ≥25%, is associated with stillbirth and neurodisability for both twins. The condition poses unique management difficulties: on the one hand, continuation of the pregnancy carries a risk of death of the smaller twin, with a high risk of co-twin demise (40%) or co-twin neurological sequelae (30%). On the other, early delivery to prevent the death of the smaller twin may expose the larger twin to prematurity, with the associated risks of long-term physical, emotional and financial costs from neurodisability, such as cerebral palsy.When there is severe and early sFGR, before viability, delivery is not an option. In this scenario, there are currently three main management options: (1) expectant management, (2) selective termination of the smaller twin and (3) placental laser photocoagulation of interconnecting vessels. These management options have never been investigated in a randomised controlled trial (RCT). The best management option is unknown, and there are many challenges for a potential RCT. These include the rarity of the condition resulting in a small number of eligible pregnancies, uncertainty about whether pregnant women will agree to participate in such a trial and whether they will agree to be randomised to expectant management or active fetal intervention, and the challenges of robust and long-term outcome measures. Therefore, the main objective of the FERN study is to assess the feasibility of conducting an RCT of active intervention vs expectant management in monochorionic twin pregnancies with early-onset (prior to 24 weeks) sFGR., Methods and Analysis: The FERN study is a prospective mixed-methods feasibility study. The primary objective is to recommend whether an RCT of intervention vs expectant management of sFGR in monochorionic twin pregnancy is feasible by exploring women's preference, clinician's preference, current practice and equipoise and numbers of cases. To achieve this, we propose three distinct work packages (WPs). WP1: A Prospective UK Multicentre Study, WP2A: a Qualitative Study Exploring Parents' and Clinicians' Views and WP3: a Consensus Development to Determine Feasibility of a Trial. Eligible pregnancies will be recruited to WP1 and WP2, which will run concurrently. The results of these two WPs will be used in WP3 to develop consensus on a future definitive study. The duration of the study will be 53 months, composed of 10 months of setup, 39 months of recruitment, 42 months of data collection, and 5 months of data analysis, report writing and recommendations. The pragmatic sample size for WP1 is 100 monochorionic twin pregnancies with sFGR. For WP2, interviews will be conducted until data saturation and sample variance are achieved, that is, when no new major themes are being discovered. Based on previous similar pilot studies, this is anticipated to be approximately 15-25 interviews in both the parent and clinician groups. Engagement of at least 50 UK clinicians is planned for WP3., Ethics and Dissemination: This study has received ethical approval from the Health Research Authority (HRA) South West-Cornwall and Plymouth Ethics Committee (REC reference 20/SW/0156, IRAS ID 286337). All participating sites will undergo site-specific approvals for assessment of capacity and capability by the HRA. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. The results from the FERN project will be used to inform future studies., Trial Registration Number: This study is included in the ISRCTN Registry (ISRCTN16879394) and the NIHR Central Portfolio Management System (CPMS), CRN: Reproductive Health and Childbirth Specialty (UKCRN reference 47201)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists., Competing Interests: Declaration of competing interest The authors report no conflict of interest or competing financial interests in relation to the work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Susceptibility weighted imaging (SWI) of neonatal hypoxic-ischemic brain injury can provide assistance in the prognosis of neonatal hypoxic-ischemic encephalopathy (HIE). We propose a convolutional neural network model to classify SWI images with HIE., Materials and Methods: Due to the lack of a large dataset, transfer learning method with fine-tuning a pre-trained ResNet 50 is introduced. We randomly select 11 datasets from patients with normal neurology outcomes (n = 31) and patients with abnormal neurology outcomes (n = 11) at 24 months of age to avoid bias in classification due to any imbalance in the data., Results: We develop a rule-based system to improve the classification performance, with an accuracy of 0.93 ± 0.09. We also compute heatmaps produced by the Grad-CAM technique to analyze which areas of SWI images contributed more to the classification patients with abnormal neurology outcome., Conclusion: Such regions that are important in the classification accuracy can interpret the relationship between the brain regions affected by hypoxic-ischemic and neurodevelopmental outcomes of infants with HIE at the age of 2 years., (© 2024. The Author(s), under exclusive licence to European Society for Magnetic Resonance in Medicine and Biology (ESMRMB).)

Herpesviruses remain a burden for animal and human health, including the medically important varicella-zoster virus (VZV). Membrane fusion mediated by conserved core glycoproteins, the fusogen gB and the heterodimer gH-gL, enables herpesvirus cell entry. The ectodomain of gB orthologs has five domains and is proposed to transition from a prefusion to postfusion conformation but the functional relevance of the domains for this transition remains poorly defined. Here we describe structure-function studies of the VZV gB DIII central helix targeting residues 526 EHV 528 . Critically, a H527P mutation captures gB in a prefusion conformation as determined by cryo-EM, a loss of membrane fusion in a virus free assay, and failure of recombinant VZV to spread in cell monolayers. Importantly, two predominant cryo-EM structures of gB[H527P] are identified by 3D classification and focused refinement, suggesting they represented gB conformations in transition. These studies reveal gB DIII as a critical element for herpesvirus gB fusion function., (© 2023. The Author(s).)

Background: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition., Methods: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2 -only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German., Results: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition., Conclusions: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objective: The purpose of this study is to evaluate venous vascular structure and distribution as prognostic indicators of developmental outcomes for infants with neonatal hypoxic-ischaemic encephalopathy (HIE) by detecting and analysing ridges representing vessels on susceptibility-weighted magnetic resonance images (SWIs)., Methods: Forty-two infants with neonatal HIE underwent SWI in the neonatal period and neurodevelopmental assessment at age 2 years. Normalised histograms of the width, intensity, length and Hessian eigenvalues extracted from the ridge analysis of each patient's SWI are applied as feature vectors to feed into supervised classifiers such as the kNN and random forest (RF) classifiers to predict their neurodevelopmental outcomes. Here we also propose a supervised classifier for automatic prognosis of automated detection of SWI signs of HIE. Our classifier proposed in this paper demonstrates a superior performance in HIE prognosis for the datasets associated with cognitive and motor outcomes and it also enables to determination of brain regions which have been affected by hypoxia-ischaemia by extracting appropriate features from SWI images., Results: The feature vectors containing width, intensity, length, and eigenvalue show a promising classification accuracy of 78.67% ± 2.58Linear regression, polynomial regression, and support vector regression (SVR) models predicted outcomes and the lower mean relative errors (MRE) for motor and cognitive outcomes are 0.088 ± 0.073 and 0.101 ± 0.11 respectively., Conclusion: The features derived from the vascular ridges improve the prognostic value of SWI in HIE. Our findings suggest that it is possible to predict neurological, motor, and cognitive outcomes by numerical analysis of neonatal SW images and to identify brain regions on SWI affected by hypoxia-ischaemia., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has magnified systemic vulnerabilities and made the global and Canadian newcomer experience even more fragile. In 2022, the Kitchener, Waterloo, Wellesley, Wilmot and Woolwich (KW4) Ontario Health Team launched a journey-mapping initiative with the aim to better understand newcomers' lived experiences with regard to their health and wellness within the first two years of their arrival in the region. We interviewed 17 newcomers from 11 different countries. The outcomes of this project are helping to inform a people-centred integrated health system approach toward service redesign and the creation of technological solutions to improve newcomers' abilities to self-navigate local services toward more equitable population health outcomes., (Copyright © 2023 Longwoods Publishing.)

The membrane surface of enveloped viruses contains dedicated proteins enabling the fusion of the viral with the host cell membrane. Working with these proteins is almost always challenging because they are membrane-embedded and naturally metastable. Fortunately, based on a range of different examples, researchers now have several possibilities to tame membrane fusion proteins, making them amenable for structure determination and immunogen generation. This review describes the structural and functional similarities of the different membrane fusion proteins and ways to exploit these features to stabilise them by targeted mutational approaches. The recent determination of two herpesvirus membrane fusion proteins in prefusion conformation holds the potential to apply similar methods to this group of viral fusogens. In addition to a better understanding of the herpesviral fusion mechanism, the structural insights gained will help to find ways to further stabilise these proteins using the methods described to obtain stable immunogens that will form the basis for the development of the next generation of vaccines and antiviral drugs.

Successful sample preparation is the foundation to any structural biology technique. Membrane proteins are of particular interest as these are important targets for drug design, but also notoriously difficult to work with. For electron cryo-microscopy (cryo-EM), the biophysical characterization of sample purity, homogeneity, and integrity as well as biochemical activity is the prerequisite for the preparation of good quality cryo-EM grids as these factors impact the result of the computational reconstruction. Here, we present a quality control pipeline prior to single particle cryo-EM grid preparation using a combination of biophysical techniques to address the integrity, purity, and oligomeric states of membrane proteins and its complexes to enable reproducible conditions for sample vitrification. Differential scanning fluorimetry following the intrinsic protein fluorescence (nDSF) is used for optimizing buffer and detergent conditions, whereas mass photometry and dynamic light scattering are used to assess aggregation behavior, reconstitution efficiency, and oligomerization. The data collected on nDSF and mass photometry instruments can be analyzed with web servers publicly available at spc.embl-hamburg.de. Case studies to optimize conditions prior to cryo-EM sample preparation of membrane proteins present an example quality assessment to corroborate the usefulness of our pipeline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Niebling, Veith, Vollmer, Lizarrondo, Burastero, Schiller, Struve García, Lewe, Seuring, Witt and García-Alai.)

Impaired neurodevelopmental outcome, in particular cognitive impairment, after neonatal hypoxic-ischemic encephalopathy is a major concern for parents, clinicians, and society. This study aims to investigate the potential benefits of using advanced quantitative electroencephalography analysis (qEEG) for early prediction of cognitive outcomes, assessed here at 2 years of age. EEG data were recorded within the first week after birth from a cohort of twenty infants with neonatal hypoxic-ischemic encephalopathy (HIE). A proposed regression framework was based on two different sets of features, namely graph-theoretical features derived from the weighted phase-lag index (WPLI) and entropies metrics represented by sample entropy (SampEn), permutation entropy (PEn), and spectral entropy (SpEn). Both sets of features were calculated within the noise-assisted multivariate empirical mode decomposition (NA-MEMD) domain. Correlation analysis showed a significant association in the delta band between the proposed features, graph attributes (radius, transitivity, global efficiency, and characteristic path length) and entropy features (Pen and SpEn) from the neonatal EEG data and the cognitive development at age two years. These features were used to train and test the tree ensemble (boosted and bagged) regression models. The highest prediction performance was reached to 14.27 root mean square error (RMSE), 12.07 mean absolute error (MAE), and 0.45 R -squared using the entropy features with a boosted tree regression model. Thus, the results demonstrate that the proposed qEEG features show the state of brain function at an early stage; hence, they could serve as predictive biomarkers of later cognitive impairment, which could facilitate identifying those who might benefit from early targeted intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alotaibi, Bakheet, Konn, Vollmer and Maharatna.)

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services., (© 2021 Mac Keith Press.)

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling., (© 2021 Mac Keith Press.)

Herpesviruses cause severe diseases particularly in immunocompromised patients. Both genome packaging and release from the capsid require a unique portal channel occupying one of the 12 capsid vertices. Here, we report the 2.6 Å crystal structure of the pentameric pORF19 of the γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) resembling the portal cap that seals this portal channel. We also present the structure of its β-herpesviral ortholog, revealing a striking structural similarity to its α- and γ-herpesviral counterparts despite apparent differences in capsid association. We demonstrate pORF19 pentamer formation in solution and provide insights into how pentamerization is triggered in infected cells. Mutagenesis in its lateral interfaces blocked pORF19 pentamerization and severely affected KSHV capsid assembly and production of infectious progeny. Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases., Competing Interests: The authors have declared that no competing interests exist.

Background: Research investigating neuromotor function in the absence of cerebral palsy (CP) for children who had neonatal HIE is limited., Aims: To investigate school-age neurological and neuromotor function, and correlations with attention, neonatal Magnetic Resonance Imaging (MRI), and neuromotor assessments at toddler age., Methods: Twenty-seven children with neonatal HIE without CP who underwent hypothermia treatment and a comparison group of 20 children were assessed at age 5-7 years for Minor Neurological Dysfunction (MND; simplified Touwen), motor skills (Movement Assessment Battery for Children-2; MABC-2), parental concern over motor function (MABC Checklist), general cognition (Wechsler Preschool and Primary Scale of Intelligence-IV, WPPSI), and attention (DuPaul ADHD Rating Scale). Neurological examination and motor development, using Bayley-3 scales, at age 24-months was extracted from the clinical database. Clinical neonatal MRI was assessed for hypoxic-ischaemic injury., Results: In the HIE group, MND was more prevalent (p = 0.026) and M-ABC performance (total score p = 0.006; balance subtest p = 0.008) was worse; parents were more concerned about children's motor function (p = 0.011). HIE group inattention scores were higher (p = 0.032), which correlated with lower MABC-2 scores (rs = -0.590, p = 0.004). Neurological examination at 24-months correlated with MND (rs = 0.437, p = 0.033); Bayley-3 motor scores did not correlate with M-ABC-2 scores (rs = 368, p = 0.133). Neonatal MRI findings were not associated with school-age MND (rs = 0.140, p = 0.523) or MABC-2 (rs = 0.300, p = 0.165)., Conclusions: Children with neonatal HIE, without CP, treated with hypothermia may be more likely to develop MND and motor difficulties than typically developing peers. Inattention may contribute to motor performance. In the absence of CP, neonatal MRI and toddler age assessment of motor development have limited predictive value for school-age outcome. Since this was an exploratory study with a small sample size, findings should be confirmed by a definite larger study., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Ltd.)