Great Ormond Street Hospital for Children NHS Foundation Trust

Objective Magnetic resonance imaging (MRI) is a crucial tool for identifying brain abnormalities in a wide range of neurological disorders. In focal epilepsy, MRI is used to identify structural cerebral abnormalities. For covert lesions, machine learning and artificial intelligence (AI) algorithms may improve lesion detection if abnormalities are not evident on visual inspection. The success of this approach depends on the volume and quality of training data. Methods Herein, we release an open‐source data set of pre‐processed MRI scans from 442 individuals with drug‐refractory focal epilepsy who had neurosurgical resections and detailed demographic information. We also share scans from 100 healthy controls acquired on the same scanners. The MRI scan data include the preoperative three‐dimensional (3D) T1 and, where available, 3D fluid‐attenuated inversion recovery (FLAIR), as well as a manually inspected complete surface reconstruction and volumetric parcellations. Demographic information includes age, sex, age a onset of epilepsy, location of surgery, histopathology of resected specimen, occurrence and frequency of focal seizures with and without impairment of awareness, focal to bilateral tonic–clonic seizures, number of anti‐seizure medications (ASMs) at time of surgery, and a total of 1764 patient years of post‐surgical followup. Crucially, we also include resection masks delineated from post‐surgical imaging. Results To demonstrate the veracity of our data, we successfully replicated previous studies showing long‐term outcomes of seizure freedom in the range of ~50%. Our imaging data replicate findings of group‐level atrophy in patients compared to controls. Resection locations in the cohort were predominantly in the temporal and frontal lobes. Significance We envisage that our data set, shared openly with the community, will catalyze the development and application of computational methods in clinical neurology.

Primary and secondary neurulation – processes that form the spinal cord – are incompletely understood in humans, largely due to the challenge of accessing neurulation-stage embryos (3–7 weeks post-conception). Here, we describe findings from 108 human embryos, spanning Carnegie stages (CS) 10–18. Primary neurulation is completed at the posterior neuropore with neural plate bending that is similar, but not identical, to the mouse. Secondary neurulation proceeds from CS13 with formation of a single lumen as in mouse, not coalescence of multiple lumens as in chick. There is no evidence of a ‘transition zone’ from primary to secondary neurulation. Secondary neural tube ‘splitting’ occurs in 60% of proximal human tail regions. A somite is formed every 7 hr in human, compared with 2 hr in mice and a 5 hr ‘segmentation clock’ in human organoids. Termination of axial elongation occurs after down-regulation of WNT3A and FGF8 in the CS15 embryonic tailbud, with a ‘burst’ of apoptosis that may remove neuro-mesodermal progenitors. Hence, the main differences between human and mouse/rat spinal neurulation relate to timing. Investigators are now attempting to recapitulate neurulation events in stem cell-derived organoids, and our results provide ‘normative data’ for interpretation of such research findings.

Aim To extend the findings of a previous clinical trial suggesting combined abacavir (ABC), lamivudine (3TC), and zidovudine (AZT) reduces type I interferon (IFN) signalling in Aicardi–Goutières syndrome (AGS). Method This was an open label, non‐placebo‐controlled phase II clinical trial (NCT04731103) in patients less than 16 years with any of five AGS genotypes. The effect of ABC or 3TC individually, or of combined ABC + 3TC + AZT, on IFN‐stimulated gene (ISG) expression (primary outcome) and IFN‐alpha protein (secondary outcome) in blood was assessed. Results Thirteen patients were recruited. Compliance was poor in the ABC + 3TC + AZT arm. No statistically significant effects were observed with ABC or 3TC, or with ABC + 3TC + AZT over 6 weeks. A statistically significant reduction of ISG expression was recorded after 3 weeks of ABC + 3TC + AZT, which was not mirrored by changes in IFN‐alpha protein. Interpretation There is insufficient evidence that ABC or 3TC is either effective or ineffective in reducing type I IFN signalling in AGS over 6 weeks. The effect of ABC + 3TC + AZT at 3 weeks supports data from a previous clinical trial of the effect of ABC + 3TC + AZT in reducing type I IFN signalling, although there was insufficient evidence of an effect at 6 weeks. Time to local research and development (R&D) approval, and to sponsor authorization after R&D approval, severely limited patient recruitment.

Background Despite high rates of adolescent mental health problems, there are few effective school-based interventions to address this. Whole-school interventions offer a feasible and sustainable means of promoting mental health, but few have to date been evaluated. Previously we trialled the Learning Together intervention comprising local needs assessment, student and staff participation in decision-making, restorative practice, and a social and emotional skills curriculum. This was effective not only in preventing bullying (primary outcome), but also in promoting mental well-being and psychological functioning (secondary outcomes). Objective We aimed to adapt Learning Together to develop Learning Together for Mental Health, focused on promoting mental health. This paper reports on how we refined and elaborated intervention materials to produce the Learning Together for Mental Health intervention including through patient and public involvement and engagement. Design We reviewed evidence to inform choice of the curriculum component and the contents of our needs assessment survey. We conducted patient and public involvement and engagement with school staff and students, and children and young people from the National Children’s Bureau to adapt the intervention. We also conducted a systematic review of reviews to inform a menu of evidence-based actions, but this is reported separately. Setting Southern England. Participants Patient and public involvement and engagement was conducted with four staff and five students from one secondary school, and a group of two school senior leadership team members from different schools, and about eight children and young people who were members of the Young National Children’s Bureau. Interventions None. Results We refined and elaborated our initial plans for Learning Together for Mental Health to generate an intervention supported by full materials, training and external facilitation. We focused needs assessment on mental health, added a menu of evidence-based whole-school mental health actions, and switched to a different social and emotional skills curriculum. We retained restorative practice and staff/student involvement in decisions. No further refinements were made to the intervention theory of change or overall approach. Patient and public involvement and engagement was useful, but not all suggestions were acted on either because some participants suggested dropping pre-determined elements (e.g. needs survey) or because suggestions (e.g. to include aromatherapy) lacked evidence of effectiveness. Limitations Not all of our engagements with patient and public involvement and engagement stakeholders were sustained over time. Our patient and public involvement and engagement work was affected by its having occurred within the recovery period from COVID-19 when schools were more stressed than normal. We had planned for the school involved in patient and public involvement and engagement to be above average in student free-school-meals eligibility, but the school initially recruited dropped out at the last minute. Its replacement had a lower-than-average rate of free-school-meal entitlement. Conclusions This paper reports on the process of adaptation and reflects on the various ways in which engagement and evidence review were useful in this process. We found that it is possible to refine interventions and elaborate them to provide full materials and support via processes drawing on evidence review and patient and public involvement and engagement. The latter proved valuable in informing refinement of Learning Together for Mental Health in terms of ensuring its feasibility, acceptability, and inclusiveness. However, in our opinion, not all suggestions from patient and public involvement and engagement can or should be acted on, especially when they do not align with the evidence base. Future work A feasibility study to optimise the intervention and assess whether progression to a full trial is justified. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131594.

This Viewpoint summarizes key takeaways for pediatricians from the 2024 Kidney Disease: Improving Global Outcomes guidelines.

Objective We examined the risk of adverse neonatal outcomes among children born to mothers with anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS). Design Cohort study. Setting Population‐based using Danish national registers. Population We included 1 517 839 singletons born between 1991 and 2015 in Denmark. Methods For each ED subtype, we compared children born to mothers with a recent (≤ 2 years before conception and during pregnancy) or past (> 2 years before conception) diagnosis, with children born to mothers who had not been diagnosed with the ED of interest before the index delivery. Main Outcome Measures Using multinomial logistic regression, we estimated relative risk ratios (RRRs) and 95% confidence intervals (CIs) for gestational age, birthweight, weight‐for‐gestational age, low Apgar score, Caesarean section, congenital malformations and postpartum haemorrhage. Results Both recent and past AN were associated with increased risk of low birthweight (recent: RRR = 2.36 [95% CI = 1.76–3.18]; past: 1.22 [1.04–1.43]), small‐for‐gestational age (recent: 1.52 [1.01–2.26]; past: 1.37 [1.16–1.62]), and preterm birth (recent: 1.83 [1.37–2.45]; past: 1.17 [1.00–1.36]), with more pronounced risks in recent AN. Recent (but not past) BN was associated with increased risk of low Apgar score (1.44 [1.03–2.00]). Recent (but not past) EDNOS was associated with increased risk of SGA (1.53 [1.04–2.27]). Conclusions Children born to mothers with EDs have an increased risk of some adverse neonatal outcomes, with more pronounced risks in recent than past EDs. These results underscore the need for improved prevention of maternal EDs and enhanced monitoring throughout pregnancy to mitigate adverse outcomes.

Background Antisense oligonucleotides (AON) represent a promising treatment for Duchenne muscular dystrophy (DMD) carrying out-of-frame deletions, but also show limitations. In a completed clinical trial golodirsen, approved by FDA to induce skipping of DMD gene exon 53 in eligible patients, we demonstrated increase in DMD expression and protein production, albeit with inter-patient variability. Methods Here, we investigate further the golodirsen mechanism of action using myotubes derived from MyoD transfected fibroblasts isolated from DMD patients at the baseline of the clinical trial SRP-4053. Results We confirm golodirsen’s selectivity and efficiency in removing only exon 53. For the first time in human cells, we revealed a significant reduction in the so called DMD “transcript imbalance”, in golodirsen-treated DMD muscle cultures. The transcript imbalance is a unique DMD phenomenon characterized by non-homogeneous transcript expression along its entire length and responsible for the reduced stability of the transcript. Our in-vivo study also showed that the efficiency of exon skipping did not always correspond to a proportional restoration of the dystrophin protein. Predominant nuclear localization of the DMD transcript, observed in patients and animal models, persists even after exon skipping. Conclusion All these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition.

Background Previous research has shown that genetics and maternal medical, sociodemographic, lifestyle and psychosocial factors affect maternal and perinatal outcomes. Substantial research has been done on ethnic differences and maternal and perinatal outcomes in hospital settings. To our knowledge there are no studies about the associations between ethnicity and maternal and perinatal outcomes in a midwife-led care setting among low-risk women. Therefore, our study aimed to investigate possible ethnic associations between non-Western and Dutch women, and maternal and perinatal outcomes in a midwife-led care setting. Methods A retrospective cohort study was performed of low-risk pregnant women (n = 977) in midwife-led care. Data was collected from a medium-sized midwifery practice in an urban region near Amsterdam, the Netherlands. Regression analyses were performed to examine the effect of ethnicity on maternal and perinatal outcomes. Outcomes of interest were gestational age, mode of birth, perineal status, postpartum hemorrhage, birthweight, perinatal death and low Apgar score. Associations were corrected for deprived areas, body mass index (BMI), parity and maternal educational level. Potential effect modification for prenatal referral to obstetrician and parity were assessed. Results The study included 977 women, of whom 483 were non-Western, and 494 were Dutch. Regarding characteristics, compared to Dutch women, non-Western women were more likely to be multiparous (respectively 58.6% versus 49.2%; p = 0.003), live in a deprived area (34.0% versus 8.1%; p < 0.001), have limited formal education (medium: 46.0% versus 49.2%; low: 15.6% versus 7.4%; p < 0.001), have a higher BMI (overweight: 28.6% versus 22.9%; obese: 14.9% versus 12.0%; p = 0.045), make inadequate/intermediate use of prenatal care (7.2% versus 2.4%, p < 0.001) and suffer from gestational diabetes (17.2% versus 9.9%, p < 0.001). Whereas Dutch women were more likely to suffer from psychosocial problems during and/or before pregnancy (34.8% versus 23.0%, p < 0.001) and drink alcohol during pregnancy (5.9% versus 1.9%, p = 0.001). Regarding maternal and perinatal outcomes, non-Western women had increased odds of perineal laceration (OR 1.59, 95%CI 1.14–2.21) and decreased odds of high birthweight (0.50, 95%CI 0.29–0.84). The mode of birth differed by ethnicity. The interaction of prenatal referral and ethnicity was significant for the mode of birth. Therefore, for mode of birth the groups were stratified by prenatal referral (yes/no). In the prenatally referred group (n = 474), non-Western ethnicity was significantly associated with decreased odds of cesarean Sect. (0.63, 0.40–0.98). No other associations were significantly associated with ethnicity. Conclusions Maternal and perinatal outcomes differed between low-risk non-Western and Dutch women in a midwife-led care setting. Among non-Western women, perineal laceration occurred more often, and fewer children with high birthweight were born. In the prenatally referred group, women of non-Western ethnicity had decreased odds of cesarean section. Gestational age and postpartum hemorrhage were not significantly associated with ethnicity.

Infective endocarditis, or inflammation of the endocardium, is a relatively rare condition with a reported incidence of between 3–10 cases per 100000. However, it is associated with poor patient outcomes including increased morbidity and mortality, increased length of hospital stay, and reduced quality of life, resulting in a significant burden on the healthcare system. Nurses and allied health professionals must be familiar with contemporary evidence-based guidelines to optimise patient care and improve outcomes. This article provides an overview of the European Society of Cardiology 2023 guidelines and recommendations for the management of patients with endocarditis.

Objective Scaphocephaly represents the most frequent single-suture craniosynostosis, with a male prevalence. In many cases, prominent frontal bossing (sphenocephaly) is the major aesthetic concern, typically in school-aged children. This aspect is also usually found in patients with late presentation (after 1 year of age). Several techniques have been described for the correction of frontal bossing in these patients, most involving wide frontal bone exposure and reconstruction. The authors describe a different, less invasive technique, useful in severe sphenocephalic patients, independently from age. Methods Thirteen children aged from 3.5 to 22 months were operated on in our institution between 2016 and 2023 using the snails technique, in addition to the treatment for the craniosynostosis itself. The technique is described, consisting in spiral frontal impacted craniotomies. Transfusional rate and duration of surgery are reported and compared with 15 randomly selected patients treated at the same time without Snails technique. Postoperative follow-up is almost 1 year. Results Cosmetic postoperative results, based on parental and clinician’s satisfaction as well as on radiographic and photographic assessment, showed rapid improvement of frontal bossing, which remains stable during years. Transfusion rate during scaphocephaly repair with Snails technique is not different from control, even if time of procedure is longer. Conclusion Among several techniques described to directly correct frontal bossing, the snail technique is more simple and less invasive, avoiding further craniotomies over the superior sagittal sinus, and does not imply consistent blood loss.

Griscelli syndrome type 2 (GS2) is a rare, life-threatening immunodysregulatory disorder characterised by impaired cytotoxic activity leading to susceptibility to haemophagocytic lymphohistiocytosis (HLH) and hypopigmentation. We completed a literature review and analysis of clinical data of 149 patients with GS2 including 8 new patients. We identified three founder mutations which show diverse phenotypic profiles (RAB27A c.244 C > T, p.R82C, c.514_518delCAAGC, p.Q172NfsX2, c.550 C > T, p.R184X). The most common presentation was HLH (119/149, 80%), with high proportion of central nervous system involvement (68/149, 46%). Features of partial albinism were present in 105 of 149 cases (70%). Hypopigmentation can be absent in GS2 and should not exclude the diagnosis. Patients with biallelic protein truncating variants (PTV) were more likely to have systemic HLH (44/56, 79%) and partial albinism (45/56, 80%), in comparison to hypomorphic variants (9/41, 22%; 20/41, 49%). Patients with hypomorphic variants presented later (5.4 years cf. 0.4 years, p = < 0.0001) and were more likely to have isolated CNS HLH (2% cf. 42%, p = 0.001). Mortality was high in the cohort (50/149, 34%). Survival of cases post-HLH who underwent transplantation is superior to un-transplanted patients, suggesting adequate HLH control followed by early HSCT is highly beneficial. Mortality was reduced in HSCT recipients versus the un-transplanted group where follow-up data was available (14% compared to 58%). Asymptomatic cases identified through family history/genetic screening may benefit from pre-emptive HSCT, but access and development of robust functional testing are required. High mortality related to HLH remains concerning and emphasises the need for improved molecular characterisation and clinical prognostic factors to guide management decisions.

Background Patient-reported outcome measures (PROMs) measure people’s views of their health status whereas patient-reported experience measures (PREMs) are questionnaires measuring perceptions of their experience whilst receiving healthcare. PROMs/PREMs have the potential to enable children and young people (CYP) to be involved in decisions about their care and improve the quality of their care but it is not clear how often PROMs/PREMs are incorporated as part of standard care of CYP in the hospital setting. The aims of this scoping review were to understand the extent of the literature and map available evidence on the use, benefits, barriers and facilitators of PROMs/PREMs as part of standard care and treatment of CYP in hospitals. Methods The Joanna Briggs Institute review process was used to map existing evidence on the use of PROMs/PREMs in routine care of CYP in different hospital settings worldwide. Key search terms were developed and Ovid (Emcare, Embase MEDLINE, APA PsychInfo), Scopus and Web of Science were searched. Data were analysed using frequency counts and basic content analysis for thematic mapping according to the research questions. We undertook an initial search in February 2021 and updated this in April 2023. Results The search yielded 68,004 studies, 388 were eligible for full text review and 172 met the inclusion criteria. PROMs were more commonly used than PREMs in routine care of CYP in hospitals; these were mostly collected using electronic collection and concentrated in specific specialities, settings, contexts and countries. The findings mapped the use of PROMs/PREMs, including how data are applied in clinical practice and used for service development, but this was not consistently reported. There are specific challenges in the implementation of PROMs/PREMs in routine care of CYP that need to be considered. Conclusion PROMs/PREMs have the potential to improve care for CYP in hospital settings contributing to different aspects of care. A better understanding of their use, how results can be applied in clinical practice and contribute to service development will enable meaningful employment. The popularity of electronically collected and captured PROMS/PREMs warrants further investigation to enable their meaningful use in routine care of CYP. Systematic review registration Not pre-registered.

Introduction Non-invasive ventilation (NIV) is a known effective and safe treatment for children and young people with sleep disordered breathing (SDB). Adherence can be challenging and poor adherence risks undertreatment of SDB. While the risk factors for non-adherence have been widely reported, very few interventions have been tested in any capacity to address barriers to adherence. Methods and analysis We will conduct a mixed methods study over three phases. The aim is to identify the components of a toolkit of interventions to address some of the barriers to NIV usage in children and young people who have SDB. We will test these components for their feasibility and acceptability to families. We will also aim to identify health outcomes from NIV use that are important to families. Qualitative data will be managed using NVivo software and analysed using the Framework method. Quantitative data will be analysed using descriptive statistics. Ethics and dissemination The study will run from January 2023 to October 2025. This study has ethics and local site approval. Data will be stored and accessed only by the research team, stored on a secure server. Data will be pseudo-anonymised prior to analysis and presented in a way that no individual can be identified. We will disseminate widely to relevant stakeholders including peer-reviewed journals, presentations to academic and clinical audiences at conferences and meetings and a lay report. Trial registration number ISRCTN56845190 .

Objective To employ the neonatal seizure framework developed by the International League Against Epilepsy (ILAE) Neonatal Task force to assess its usefulness in determining the etiology of neonatal seizures. Methods The members of the ILAE Neonatal Task Force evaluated 157 seizures from 146 neonates to determine internal validity and associations between semiology and a specific etiology. Results Provoked neonatal electrographic and electroclinical seizures were due to multiple etiologies. For electroclinical seizures, unilateral clonic seizures were typically seen with vascular etiologies, focal tonic seizures and sequential seizures with genetic etiologies, and myoclonic seizures with inborn errors of metabolism. Electrographic seizures were often seen in hypoxic–ischemic encephalopathy or vascular etiologies. Significance These data suggest that the ILAE neonatal seizure classification may be used as a bedside tool to aid and guide workup to determine the etiology of seizures.

Background Powerful new genomic technologies are transforming the way healthcare is delivered, shaping medical practice across all specialties. In this rapidly changing landscape, there is an urgent need to equip the clinical workforce with knowledge and skills to navigate the new healthcare terrain. Co-design of healthcare resources with end users is increasingly gaining traction as a method of ensuring that educational content and delivery are tailored to users’ needs, increasing likelihood of use and resulting in better outcomes for patients. Here we describe the co-design and ongoing co-creation of GeNotes – an NHS England National Genomics Education flagship online resource providing genomics education at the point of patient care. Methods To understand the barriers to implementation of genomic medicine and the training needs of the diverse NHS workforce, we adopted a co-design approach with clinicians from both primary and secondary care who are uniquely placed to understand the context in which they are working and identify their own training needs. Concept design, initial user research and subsequent ‘alpha’ and ‘private beta’ phase user research was conducted in a series of co-design iterations employing a mixed methodology integrating quantitative and qualitative data collection and analysis. Results User evaluation data demonstrated excellent feedback across the tested domains (content, navigation, likelihood of use and recommendation to colleagues). We identified several key themes from user testing that shaped the resource’s development. Conclusions The co-design approach to the development of this point-of-care genomics education resource for clinicians has allowed insight into the education needs, challenges and learning styles of end-users. The utility of this approach was supported by excellent user feedback across the tested domains, and we recommend it to others involved in developing healthcare resources in a fast-paced environment.

Patient choice consent for whole genome sequencing (WGS) through the Genomic Medicine Service in England covers consent to diagnostic testing and an invitation to the National Genomic Research Library (NGRL). Little is known about what consent conversations for WGS look like in practice. We audio-recorded and analysed the content and structure of consent appointments ( n = 26) between healthcare professionals (HCPs) and parents of children with rare disease across seven NHS Trusts. Appointments frequently covered the potential findings from testing, implications for family members, and DNA storage, but often omitted that data may be reanalysed in the future if a diagnosis is not made. Consent to the NGRL was typically sought during the same appointment; these discussions varied in content, but frequently included a background to the NGRL and data security. HCPs often tempered expectations around what WGS can achieve and asked questions to clarify parents’ understanding, but less commonly elicited parents’ values and concerns. Administrative tasks were time-consuming, but took less time when consent was recorded digitally. Future training should emphasise how to elicit patients’ values and concerns. Digital infrastructure and hiring roles such as genomic associates to support consent may be important strategies to meet the workload demands of WGS.