The evolution of inverted magnetic fields through the inner heliosphere

Local inversions are often observed in the heliospheric magnetic field (HMF), but their origins and evolution are not yet fully understood.Parker Solar Probe has recently observed rapid, Alfvénic, HMF inversions in the inner heliosphere, known as ‘switchbacks’, which have been interpreted as the possible remnants of coronal jets. It has also been suggested that inverted HMF may be produced by near-Sun interchange reconnection; a key process in mechanisms proposed for slow solar wind release. These cases suggest that the source of inverted HMF is near the Sun, and it follows that these inversions would gradually decay and straighten as they propagate out through the heliosphere. Alternatively, HMF inversions could form during solar wind transit, through phenomena such velocity shears, draping over ejecta, or waves and turbulence. Such processes are expected to lead to a qualitatively radial evolution of inverted HMF structures. Using Helios measurements spanning 0.3–1 AU, we examine the occurrence rate of inverted HMF, as well as other magnetic field morphologies, as a function of radial distance r, and find that it continually increases. This trend may be explained by inverted HMF observed between 0.3–1 AU being primarily driven by one or more of the above in-transit processes, rather than created at the Sun. We make suggestions as to the relative importance of these different processes based on the evolution of the magnetic field properties associated with inverted HMF. We also explore alternative explanations outside of our suggested driving processes which may lead to the observed trend

An exploration into identity formation in young people living with a chronic illness

Section A critically reviews relevant theoretical literature and empirical studies exploring the particular impact of chronic illness on identity formation in adolescents. Theoretical conceptualisations of the adolescent period and of the process of identity formation are explored. Following this, empirical literature regarding the impact of chronic illness on the developmental tasks of adolescence and in particular identify formation will be critically examined. A number of clinical implications are discussed to enable clinicians to effectively support young people and future research directions are outlined. Section B reports a narrative analysis of young people's experiences of forming an identity with a diagnosis of an adolescent-onset chronic illness (CI). Identity formation is argued to be one of the key developmental tasks of adolescence. Despite implications for adolescent development, research into CI onset during this period has been notably sparse. This study aimed to explore how diagnosis impacts on the developmental tasks of adolescence, what role adolescent-onset CI plays in identity formation, and how adolescents incorporate the diagnosis into their identity. Individual semi-structured interviews were carried out with 8 young people aged 14-19 who lived with a diagnosis of a CI diagnosed between the ages of 12-16 years. Two illness types were studied; crohn’s disease and juvenile idiopathic arthritis. Interviews were audio-recorded, transcribed and analysed using narrative analysis. Participant narratives contained five core narrative themes: Walking a different path, tolerating contradiction, a changed interface with others, locating power and a fluid relationship. Narratives were considered to have been influenced by factors such as the interview context and dominant social narratives concerning health and illness. Adolescent-onset CI was found to have a significant, though not exclusively negative, impact on developmental tasks. The findings are discussed in relation to existing literature and potential clinical implications. Section C critically appraises the narrative study. A discussion begins with reflections on the research skills developed and insights into the research process. Areas of further learning are identified. Implications of clinical practice are explored and the section concludes with considerations for further research in this area.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Synthesis and evaluation of symmetrical biphenyltetrols as aggregation inhibitors for Alzheimer’s amyloid-β peptide

Inhibiting the aggregation of amyloid-beta peptide (Aβ) is one therapeutic target for the prevention and treatment of Alzheimer’s disease. We have previously demonstrated that biphenyl-3,3′,4,4′-tetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations. To investigate molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we have synthesized four additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- and 3,5-BPT). We have evaluated these inhibitors by means of Congo red and Thioflavin T dye-binding assays to monitor Aβ aggregation as a function of time and to determine inhibitor IC50 values for reducing equilibrium levels of aggregation. 2,3- and 2,5-BPT were observed to be promising inhibitors of Aβ aggregation: we have qualitatively assessed their IC50 values to be approximately 7X and 3-4X, respectively. In contrast, 2,4- and 3,5-BPT showed little to no inhibition. Thus, 2,5-BPT was the most successful of the four inhibitors evaluated, however; it was not as effective as 3,4-BPT, studied previously (IC50 = 1.0 ± 0.3X). The four isomers we have characterized exhibit a range of IC50 values spanning more than one order of magnitude, likely due to varying abilities to bind to A assemblies. Future work will involve further evaluation of the symmetrical biphenyltetrols, by methods including circular dichroism and transmission electron microscopy, which will afford greater insight into the Aβ assemblies formed in the presence and absence of inhibitors. These results will aid in the rational design of additional small-molecule aggregation inhibitors, including unsymmetrical biphenyltetrols and other architectures bearing hydroxyl substituents in those positions associated with the greatest inhibitory efficacy

Administration of aspirin tablets using a novel gel-based swallowing aid: an open-label randomised controlled cross-over trial

Introduction To ease administration of medicines to people with dysphagia we developed and patented a gel formulation within which whole tablets could be inserted. The aim was to determine whether the gel would affect bioequivalence of uncoated aspirin tablet. Method A gel containing gelatin, hydroxypropylmethylcellulose, citric acid, potassium sorbate and water was developed to maintain structure on tablet insertion and increase saliva production to lubricate the swallow. In an open-label cross-over trial 12 healthy male volunteers were administered a 300 mg uncoated aspirin tablet with and without gel with a 7-day washout period. Blood salicylate levels, platelet activity and patient satisfaction were measured over 2 hours. Analysis was based on a random effects cross-over model. Results The estimated mean ratio (90% CI) of effect on salicylate levels when comparing administration with and without gel was 0.77 (90% CI 0.40 to 1.47) for amount absorbed and 0.76 (90% CI 0.44 to 1.31) and on total ASP-arachidonic acid platelet activity 1.16 (90% CI 0.88 to 1.53) and maximum ASP arachidonic platelet activity 0.98 (90% CI 0.79 to 1.22). These results are outside of the range allowable for the assumption of bioequivalence. Participants rated the taste of aspirin tablets significantly better when encapsulated in the gel (p<0.05). Discussion We cannot assume that uncoated aspirin administration with and without gel is bioequivalent. Administration with gel resulted in reduced salicylate levels and therefore increased platelet function. Further research is required to determine the exact reason for this result. The results bring into question current processes for providing marketing authorisation for medical devices which are designed to aid swallowing

Neuropsychiatric risk in children with intellectual disability of genetic origin:IMAGINE, a UK national cohort study

Background: Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. Methods: IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. Findings: We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.Interpretation: Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services. Funding: UK Medical Research Council and Medical Research Foundation.</p

Neuropsychiatric risk in children with intellectual disability of genetic origin:IMAGINE, a UK national cohort study

Background: Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. Methods: IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. Findings: We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.Interpretation: Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services. Funding: UK Medical Research Council and Medical Research Foundation.</p

Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study

BACKGROUND: Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. METHODS: IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4-19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. FINDINGS: We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9-36·5), ADHD RR 13·5 (95% CI 11·1-16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV. INTERPRETATION: Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services. FUNDING: UK Medical Research Council and Medical Research Foundation

The People's Trial : supporting the public's understanding of randomised trials

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Simone Lepage, Aoife O’Shaughnessy, and Louise Foley for their support with the research project. We would also like to thank Rob & Paul Digital Design™, Galway, Ireland. In addition, we would like to thank Marina Zaki for her support of The People’s Trial, in particular her expertise in promoting The People’s Trial through social media channels. Funding This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award (grant reference KEDS-2018-012) 2018. The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD

Does reading a book in bed make a difference to sleep in comparison to not reading a book in bed? : The People's Trial- an online, pragmatic, randomised trial

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Claire O’Connell, Simone Lepage, Aoife O’Shaughnessy and Louise Foley for their support with the research project. Trial funder This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award 2018 (grant reference KEDS-2018-012). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD

SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools

Background: Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing. Results: We present the Systems Biology Markup Language (SBML) Qualitative Models Package (“qual”), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models. Conclusions: SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks