The UCL Great Ormond Street Institute of Child Health (ICH) is an academic department of the Faculty of Population Health Sciences of University College London (UCL) and is located in London, United Kingdom. It was founded in 1946 and together with its clinical partner Great Ormond Street Hospital (GOSH), forms the largest concentration of children's health research in Europe. In 1996 the Institute merged with University College London. Current research focusses on broad biomedical topics within child health, ranging from developmental biology, to genetics, to immunology and epidemiology.
In 2024, an unprecedented outbreak of H5N1 high pathogenicity avian influenza was detected in dairy cattle in the USA resulting in spillbacks into poultry, wild birds and other mammals including humans. Here, we present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses rapidly accumulated adaptations in polymerase genes that enabled better replication in bovine cells and tissues, as well as cells of other mammals including humans. We find evidence of several mammalian adaptations in cattle including PB2 M631L, which is found in all cattle sequences, and PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, an essential host factor for viral genome replication. We show that this mutation adapts the polymerase to better interact with bovine ANP32 proteins, particularly ANP32A, and thereby enhances virus replication in bovine mammary systems and primary human airway cultures. We show that ongoing evolution in the PB2 gene, including E627K and a convergently arising D740N substitution, further increase polymerase activity and virus replication in a range of mammalian cells. Thus, circulation of H5N1 in dairy cattle allows virus adaption improving replicative ability in cattle and poses a continued risk of zoonotic spillover.
The reduction of health inequalities has been a priority of researchers, decision-makers and practitioners for many years. Advances in causal mediation analysis offer great promise for identifying intervention targets and inferring how policy actions might alter health inequalities. However, these methods are sometimes presented in a manner that is not accessible to the wider community of health researchers. Causal mediation methods also have a range of limitations and assumptions that have implications for their application and the interpretation of results. In this paper, we consider three types of questions that can be used to guide policy actions to reduce health inequalities, addressed using causal mediation methods: (1) which mediating pathways offer most promise for the reduction of health inequalities and should be the focus of further, more indepth analysis? 2) In the face of two competing pathways, which one is most likely to lead to a narrowing of health inequalities? 3) What would be the impact of a hypothetical intervention on one specific mediating pathway when implemented under different scenarios? Focusing on early years' health, we use real life examples of the application of causal mediation methods to address these three types of question. In doing so, we discuss the relative strengths and limitations of these methods and introduce key mediation concepts relevant to health inequalities researchers.
INTRODUCTION:The development of approaches and interventions to achieve HIV remission continues to accelerate. Children living with HIV who started antiretroviral therapy (ART) at a young age and sustain viral suppression are an ideal clinical trial population. Trials may require analytic treatment interruptions (ATIs). Paediatric trials depend on the willingness of guardians to consent to child participation, yet there are few data about guardian willingness or attitudes. Here, we investigated the opinions of guardians of children likely to be eligible for ATI trials. METHODS:Children and youth who started ART ≤ 3 months of age, and who remained well-controlled on ART older than 7 years, were recruited in South Africa, Mozambique, Uganda, Mali and Thailand. A survey was conducted among guardians of these paediatric participants. The survey utilized a vignette describing a trial with ATI and assessed attitudes and intentions (measured on 7-point scales) of the guardians regarding their children's participation in a hypothetical trial. RESULTS:Guardians of 99 children were recruited. Guardians' median age was 45 years (range 24-73) and most (89.9%) were female. The median age of the child or youth with HIV was 13.2 years (range 7-18.5 years). Most respondents endorsed a positive intention to enrol their child in a future HIV remission trial (mean 6.5 [SD:1.3] on a 7-point scale), with significant variation across the sites (p = 0.0024). Most respondents strongly endorsed a range of trial benefits, including better future HIV treatments (93.8%) and access to better care (88.0%). Some endorsed concern about the trial burden to themselves (33.3%) and the child (35.4%). Almost half strongly believed that the trial would result in the child no longer needing ART (48%) and the child being cured of HIV (46.5%). CONCLUSIONS:Across multiple countries, guardians of children and youth who were treated early were positive about participation in trials with ATI. Only a third expressed some concern about trial burden, while almost half had unrealistic expectations about potential benefits. Recruitment into trials involving ATI will need to include effective communication strategies to ensure that participants and caregivers are adequately informed about burden, potential risks and the likelihood of personal benefit.
Abstract Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3 , and CELSR3 . Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.
The cystic fibrosis (CF) causing variant G542X harbours a premature translation stop signal in the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA. This results in nonsense-mediated decay and loss of functional CFTR protein which leads to defective anion transport and the development of CF disease pathology. Currently available CF modulator therapies cannot be used to treat this variant. We used an adenine base editor (ABE8e Cas9) and guide RNA (sgRNA)/enhanced green fluorescent protein (EGFP) plasmids encapsulated in receptor targeted nanoparticles (RTN), delivered to Bmi-1 transduced basal human CF nasal epithelial cells harbouring the homozygous CFTR G542X variant, to convert the stop codon to G542R, a variant which is amenable to modulator therapy. ABE resulted in 17% of alleles edited to G542R and further selection of GFP fluorescent cells by FACS liberated a population with 52% G542R edited alleles with no editing of neighbouring adenines (A) and few off target edits using a gRNA homology-based approach. In cells differentiated at air-liquid-interface (ALI), 17% and 52% editing of CFTR G542X increased mRNA abundance. 52% editing alone or 17% and 52% editing of CFTR G542X plus treatment with CFTR modulators (VX-445/VX-661/VX-770; ETI/Trikafta/Kaftrio) increased epithelial CFTR protein expression, CFTR protein band C abundance, CFTR172 inhibitable anion transport, and changes in airway surface liquid height and pH in response to vasoactive intestinal peptide (VIP) stimulation. Epithelial scratch repair speed and directionality was also improved. These data provide proof-of-concept that ABE of G542X to G542R in human CF airway epithelial cells could provide a feasible therapy for this variant.
