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Integrated care systems join up health and care services, so that people have the support they need, in the right place, at the right time. The aims include improving outcomes in healthcare, tackling inequalities in access and enhancing productivity and value for money. This is needed for neuroscience care as the traditional delivery of neuroscience care is inefficient, outdated and expensive, and can involve complex referral pathways and long waiting times.In preparation for the formation of the integrated care system (ICS), a novel innovative collaboration across multiple NHS trusts developed across North Central London in 2021. We developed a model where neuroscience specialists engage in collaborative care with clinicians outside the specialist hospital setting. Pivotal to the pathway is a multidisciplinary meeting, and collaborative working enables joint clinical reviews, diagnostics and medication initiation.This innovative collaboration has already significantly improved access, addressed inequalities due to borough variation and enhanced the delivery and quality of neuroscience care in our ICS. It is a translatable model that can be adapted to suit other regions in the UK. It fulfils many of the objectives of the integrated care system and these benefits are seen without the need for significantly more resource.

Objective Identify the proportion of patients referred with putative functional seizures (FS) that were subsequently re-diagnosed as epileptic seizures (ES), or an alternative diagnosis, following video telemetry EEG (VTEEG). In addition, describe the characteristics of those seizures.Methods The VTEEG reports from patients admitted to the Chalfont Centre for Epilepsy between 2019 and 2022 were reviewed. Pre-VTEEG and post-VTEEG diagnoses were compared to identify whether a diagnostic revision was made from suspected FS to ES or another diagnosis. Diagnostic revision cases were then grouped into cohorts with associated features and reviewed to characterise and describe FS mimics.Results 444 VTEEG reports where patients had habitual events were identified. 4.7% of patients were referred with FS and were subsequently diagnosed with ES or another diagnosis. In this group, several cohorts could be identified including frontal lobe epileptic seizures, ES with functional overlay, insular or temporal lobe epileptic seizures associated with autonomic or marked experiential peri-ictal symptoms, and individuals who had both ES and FS but whose ES were revealed on medication withdrawal.Conclusion In patients referred to a tertiary epilepsy unit, a small minority of cases had seizures diagnosed as functional and reclassified as epileptic or an alternative diagnosis. It is clinically important to be aware of these FS mimics.

Uncovering the mechanisms that establish naïve pluripotency in humans is crucial for the future applications of pluripotent stem cells including the production of human blastoids. However, the regulatory pathways that control the establishment of naïve pluripotency by reprogramming are largely unknown. Here, we use genome-wide screening to identify essential regulators as well as major impediments of human primed to naïve pluripotent stem cell reprogramming. We discover that factors essential for cell state change do not typically undergo changes at the level of gene expression but rather are repurposed with new functions. Mechanistically, we establish that the variant Polycomb complex PRC1.3 and PRDM14 jointly repress developmental and gene regulatory factors to ensure naïve cell reprogramming. In addition, small-molecule inhibitors of reprogramming impediments improve naïve cell reprogramming beyond current methods. Collectively, this work defines the principles controlling the establishment of human naïve pluripotency and also provides new insights into mechanisms that destabilize and reconfigure cell identity during cell state transitions.

Heterochromatin maintains genome integrity and function, and is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation of HP1ɑ. Mouse heterochromatin contains noncoding major satellite repeats (MSR), which are highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive the formation of HP1ɑ droplets in vitro, and modulate heterochromatin into dynamic condensates in ESCs, contributing to the formation of large nuclear domains that are characteristic of pluripotent cells. Depleting MSR transcripts causes heterochromatin to transition into a more compact and static state. Unexpectedly, changing heterochromatin's biophysical properties has severe consequences for ESCs, including chromosome instability and mitotic defects. These findings uncover an essential role for MSR transcripts in modulating the organisation and properties of heterochromatin to preserve genome stability. They also provide insights into the processes that could regulate phase separation and the functional consequences of disrupting the properties of heterochromatin condensates.

Abstract Successful epilepsy surgery depends on localizing and resecting cerebral abnormalities and networks that generate seizures. Abnormalities, however, may be widely distributed across multiple discontiguous areas. We propose spatially constrained clusters as candidate areas for further investigation and potential resection. We quantified the spatial overlap between the abnormality cluster and subsequent resection, hypothesizing a greater overlap in seizure‐free patients. Thirty‐four individuals with refractory focal epilepsy underwent pre‐surgical resting‐state interictal magnetoencephalography (MEG) recording. Fourteen individuals were totally seizure‐free (ILAE 1) after surgery and 20 continued to have some seizures post‐operatively (ILAE 2+). Band power abnormality maps were derived using controls as a baseline. Patient abnormalities were spatially clustered using the k‐means algorithm. The tissue within the cluster containing the most abnormal region was compared with the resection volume using the dice score. The proposed abnormality cluster overlapped with the resection in 71% of ILAE 1 patients. Conversely, an overlap only occurred in 15% of ILAE 2+ patients. This effect discriminated outcome groups well (AUC = 0.82). Our novel approach identifies clusters of spatially similar tissue with high abnormality. This is clinically valuable, providing (a) a data‐driven framework to validate current hypotheses of the epileptogenic zone localization or (b) to guide further investigation.

Birth cohorts are those among observational studies that provide understanding of the natural history and causality of diseases since early in life. Discussions during an International Association for Dental Research symposium in London, United Kingdom, in 2018, followed by a workshop in Bangkok, Thailand, in 2019, concluded that there are few birth cohort studies that consider oral health and that a broader discussion on similarities and differences among those studies would be valuable. This article aims to 1) bring together available long-term data of oral health birth cohort studies from the low, middle, and high-income countries worldwide and 2) describe similarities and differences among these studies. This work comprises 15 studies from all 5 continents. The most studied dental conditions and exposures are identified; findings are summarized; and methodological differences and similarities among studies are presented. Methodological strengths and weaknesses are also highlighted. Findings are summarized in 1) the negative impact of detrimental socioeconomic status on oral health changes over time, 2) the role of unfavorable patterns of dental visiting on oral health, 3) associations between general and oral health, 4) nutritional and dietary effects on oral health, and 5) intergenerational influences on oral health. Dental caries and dental visiting patterns have been recorded in all studies. Sources of fluoride exposure have been documented in most of the more recent studies. Despite some methodological differences in the way that the exposures and outcomes were measured, some findings are consistent. Predictive models have been used with caries risk tools, periodontitis occurrence, and permanent dentition orthodontic treatment need. The next steps of the group's work are as follows: 1) establishing a consortium of oral health birth cohort studies, 2) conducting a scoping review, 3) exploring opportunities for pooled data analyses to answer pressing research questions, and 4) promoting and enabling the development of the next generation of oral health researchers.

Here the authors show satellite transcripts in mouse embryonic stem cells drive HP1α into droplets in vitro and also control HP1α organisation and association with chromatin in vivo. Depleting the satellite transcripts converts heterochromatin into a less dynamic and more static state and leads to chromosome instability.

The role of transcriptional enhancers and 3D chromatin organisation in coordinating the transition from naive to primed pluripotency remains poorly understood. Here the authors generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells to provide insights into these developmental processes.

Objective: To assess the evidence presented in a set of articles that use the Canadian Maternal–Infant Research on Environmental Chemicals (MIREC) study database to claim that community water fluoridation (CWF) is associated with harm to foetal and infant cognitive development. Methods: Critical appraisal of measurements and processes in the MIREC database, and articles derived therefrom. MIREC's cohort is approximately 2000 pregnant women recruited in 10 centres across Canada, 2008–2011, leading to measuring 512 children aged 3–6 years in six cities. Fluoride exposure was measured by city fluoridation status, self‐reports and maternal spot urine samples. Intelligence Quotient (IQ) was measured using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI‐III) by different assessors in each city. Results: MIREC's fluoride and IQ measurements are invalid and therefore cannot support the claim that CWF is associated with IQ decline in children. Conclusions: The MIREC fluoride‐IQ articles' results should be considered unacceptable for legal and policy purposes; other water fluoridation studies and systematic reviews show no effect of fluoridation on cognition. [ABSTRACT FROM AUTHOR]

Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus. Careful and timely intervention is required to optimise glycaemic control and reduce the risk of mortality and devastating complications. Of these, cerebral oedema is the leading cause of death, with a mortality rate of approximately 25%. This article highlights the recent updates to UK fluid therapy guidelines for DKA and provides clinical context for the benefit of paediatricians and junior doctors in light of this new guidance.

The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGFβ/Activin/Nodal signalling. In contrast, the signalling requirements of naïve human pluripotency have not been fully established. Here, we demonstrate that TGFβ signalling is required to maintain naïve hPSCs. The downstream effector proteins – SMAD2/3 – bind common sites in naïve and primed hPSCs, including shared pluripotency genes. In naïve hPSCs, SMAD2/3 additionally bind to active regulatory regions near to naïve pluripotency genes. Inhibiting TGFβ signalling in naïve hPSCs causes the downregulation of SMAD2/3-target genes and pluripotency exit. Single-cell analyses reveal that naïve and primed hPSCs follow different transcriptional trajectories after inhibition of TGFβ signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naïve hPSCs transition into trophectoderm. These results establish that there is a continuum for TGFβ pathway function in human pluripotency spanning a developmental window from naïve to primed states.

Background Asthma is the most common chronic condition of childhood. Leukotriene receptor antagonists (LTRAs) are included in international guidelines for children and young people (CYP), but there have been highly publicised concerns about potential adverse effects. The aim was to identify and understand the reported frequency of adverse drug reactions (ADRs) attributed to LTRAs in CYP with asthma.Methods Embase, MEDLINE, PubMed and CINAHL were searched up to October 2020. Reference lists of eligible papers were manually screened. Eligible studies identified adverse events attributed to an LTRA in individuals aged between 0 and 18 years diagnosed with asthma. Four different tools were used to assess risk of bias or quality of data to accommodate the papers assessed.Results The search identified 427 papers after deduplication; 15 were included (7 case reports, 7 case–controlled or cohort studies and 1 randomised control trial (RCT)). 7012 patients were recorded, of which 6853 received an LTRA. 13 papers examined the ADRs attributed to montelukast, one to pranlukast and one to unspecified LTRAs. After language standardisation, 48 ADRs were found, 20 of which were psychiatric disorders. Across all studies, the most commonly reported ADRs were ‘anxiety’, ‘sleep disorders’ and ‘mood disorders’. The frequency of ADRs could be calculated in seven of the eight studies. Applying standardised frequency terms to the prospective studies and RCT, there were 14 ‘common’ and ‘uncommon’ ADRs. ‘Common’ ADRs included ‘agitation/hyperactivity/irritability/nervousness’, ‘aggression’ and ‘headache’. The case reports showed a similar pattern, describing 46 different ADRs experienced by a total of eight patients.Conclusions LTRAs have a wide range of suspected ADRs in CYP, predominantly gastrointestinal and neuropsychiatric disorders. Careful monitoring of CYP with asthma is required, both to assess and manage ADRs and to step treatment down when clinically stable.PROSPERO registration number CRD42020209627.

Faithful replication of the entire genome requires replication forks to copy large contiguous tracts of DNA, and sites of persistent replication fork stalling present a major threat to genome stability. Understanding the distribution of sites at which replication forks stall, and the ensuing fork processing events, requires genome-wide methods that profile replication fork position and the formation of recombinogenic DNA ends. Here, we describe Transferase-Activated End Ligation sequencing (TrAEL-seq), a method that captures single-stranded DNA 3' ends genome-wide and with base pair resolution. TrAEL-seq labels both DNA breaks and replication forks, providing genome-wide maps of replication fork progression and fork stalling sites in yeast and mammalian cells. Replication maps are similar to those obtained by Okazaki fragment sequencing; however, TrAEL-seq is performed on asynchronous populations of wild-type cells without incorporation of labels, cell sorting, or biochemical purification of replication intermediates, rendering TrAEL-seq far simpler and more widely applicable than existing replication fork direction profiling methods. The specificity of TrAEL-seq for DNA 3' ends also allows accurate detection of double-strand break sites after the initiation of DNA end resection, which we demonstrate by genome-wide mapping of meiotic double-strand break hotspots in a dmc1Δ mutant that is competent for end resection but not strand invasion. Overall, TrAEL-seq provides a flexible and robust methodology with high sensitivity and resolution for studying DNA replication and repair, which will be of significant use in determining mechanisms of genome instability.

Objective: To investigate whether MEG network connectivity was associated with epilepsy duration, to identify functional brain network hubs in patients with refractory focal epilepsy, and assess if their surgical removal was associated with post-operative seizure freedom.Methods: We studied 31 patients with drug refractory focal epilepsy who underwent resting state magnetoencephalography (MEG), and structural magnetic resonance imaging (MRI) as part of pre-surgical evaluation. Using the structural MRI, we generated 114 cortical regions of interest, performed surface reconstruction and MEG source localization. Representative source localized signals for each region were correlated with each other to generate a functional brain network. We repeated this procedure across three randomly chosen one-minute epochs. Network hubs were defined as those with the highest intra-hemispheric mean correlations. Post-operative MRI identified regions that were surgically removed.Results: Greater mean MEG network connectivity was associated with a longer duration of epilepsy. Patients who were seizure free after surgery had more hubs surgically removed than patients who were not seizure free (AUC = 0.76, p = 0.01) consistently across three randomly chosen time segments.Conclusion: Our results support a growing literature implicating network hub involvement in focal epilepsy, the removal of which by surgery is associated with greater chance of post-operative seizure freedom.

The neuronal ceroid lipofuscinoses (NCL) are a collection of lysosomal storage diseases characterised by the accumulation of characteristic inclusions containing lipofuscin in various tissues of the body and are one of the causes of progressive myoclonic epilepsy. Mutations in at least thirteen genes have been identified as causes of NCL, which can present as infantile, late-infantile, juvenile or adult forms. CLN6 codes for an endoplasmic reticulum transmembrane protein of unknown function. Homozygous and compound heterozygous mutations of the gene are associated with both late-infantile (LINCL) and adult onset (ANCL) forms of NCL, including Kufs disease, comprising ANCL without associated visual loss. Moyamoya, a rare vasculopathy of the circle of Willis, has been reported in conjunction with a number of inflammatory and other diseases, as well as a handful of lysosomal storage diseases. To our knowledge, this is the first reported case of Moyamoya in the context of the neuronal ceroid lipofuscinoses or a CLN6-related disease.

Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are a widely used model to study cardiac genomics. Here, Choy et al. perform promoter capture Hi-C to map long-range chromosomal interactions of hESC-CMs and to study overlap of such regions with genetic loci associated with cardiac phenotypes.

Summary: Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs). We found that SEs form complex, spatial networks in which individual SEs contact multiple promoters, and a rewiring of promoter-SE interactions occurs between pluripotent states. We also show that long-range promoter-SE interactions are more prevalent in ESCs than in epiblast stem cells (EpiSCs) or Nanog-deficient ESCs. We conclude that SEs form cell-type-specific interaction networks that are partly dependent on core transcription factors, thereby providing insights into the gene regulatory organization of pluripotent cells. : Novo et al. use promoter-capture Hi-C to map the target promoters of super-enhancers (SEs) in mouse pluripotent cells. SEs form complex networks, and a subset of promoter-SE interactions was rewired between ESCs and EpiSCs. In ESCs, many SEs form long-range contacts that are not detected in EpiSC or Nanog-deficient ESCs. Keywords: epigenetics, genome organization, chromatin looping, gene regulation, pluripotency, differentiation, promoter capture Hi-C