The challenges of optimising glycaemic control in children with type 1 diabetes: a qualitative study of parents’ experiences and views

Aims To explore the difficulties parents encounter in trying to achieve clinically recommended blood glucose levels and how they could be better supported to optimize their child's glycaemic control. Methods In-depth interviews were conducted with 54 parents of children with Type 1 diabetes (≤ 12 years). Data were analysed thematically. Results Parents described being reluctant and finding it difficult to keep their child's blood glucose levels consistently within clinically recommended ranges. As well as worrying about their child's ability to detect/report hypoglycaemia, parents highlighted a multitude of factors that had an impact on their child's blood glucose levels and over which they could exercise little control. These included: leaving their child with other caregivers who could not be trusted to detect hypoglycaemia; difficulties remotely monitoring and regulating their child's food consumption and activity; and physical and social changes accompanying childhood development. Most parents used two sets of blood glucose targets, with clinically recommended targets employed when their child was in their immediate care and higher targets when in the care of others. Parents described health professionals as lacking understanding of the difficulties they encountered keeping blood glucose within target ranges and needing more empathetic, tailored and realistic advice. Conclusion It is not parents' fear of hypoglycaemia in isolation that leads to decisions to raise their child's blood glucose but, rather, parental fear in conjunction with other factors and considerations. Hence, to improve diabetes management in children, these factors may need to be addressed; for instance, by training others in diabetes management and using new technologies. Changes to consultations are also recommended

Electronic band structure and carrier effective mass in calcium aluminates

First-principles electronic band structure investigations of five compounds of the CaO-Al2O3 family, 3CaO.Al2O3, 12CaO.7Al2O3, CaO.Al2O3, CaO.2Al2O3 and CaO.6Al2O3, as well as CaO and alpha-, theta- and kappa-Al2O3 are performed. We find that the conduction band in the complex oxides is formed from the oxygen antibonding p-states and, although the band gap in Al2O3 is almost twice larger than in CaO, the s-states of both cations. Such a hybrid nature of the conduction band leads to isotropic electron effective masses which are nearly the same for all compounds investigated. This insensitivity of the effective mass to variations in the composition and structure suggests that upon a proper degenerate doping, both amorphous and crystalline phases of the materials will possess mobile extra electrons

Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome

Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2.Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis.Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations

PRIM1 Deficiency Causes a Distinctive Primordial Dwarfism Syndrome

DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation

Adolescents’ Experiences of Using a Smartphone Application Hosting a Closed-loop Algorithm to Manage Type 1 Diabetes in Everyday Life: Qualitative Study

Background:: Closed-loop technology may help address health disparities experienced by adolescents, who are more likely to have suboptimal glycemic control than other age groups and, because of their age, find diabetes self-management particularly challenging. The CamAPS FX closed-loop has sought to address accessibility and usability issues reported by users of previous prototype systems. It comprises small components and a smartphone app used to: announce meal-time boluses, adjust (“boost” or “ease-off”) closed-loop insulin delivery, customize alarms, and review/share data. We explored how using the CamAPS FX platform influences adolescents’ self-management practices and everyday lives. Methods:: Eighteen adolescents were interviewed after having ≥6 months experience using the closed-loop platform. Data were analyzed thematically. Results:: Participants reported feeling less burdened and shackled by diabetes because closed-loop components were easier to carry/wear, finger-pricks were not required, the smartphone app provided a discreet and less stigmatizing way of managing diabetes in public, and they were able to customize alarms. Participants also reported checking and reviewing data more regularly, because they did so when using the smartphone for other reasons. Some reported challenges in school settings where use of personal phones was restricted. Participants highlighted how self-management practices were improved because they could easily review glucose data and adjust closed-loop insulin delivery using the “boost” and “ease-off” functions. Some described how using the system resulted in them forgetting about diabetes and neglecting certain tasks. Conclusions:: A closed-loop system with small components and control algorithm on a smartphone app can enhance usability and acceptability for adolescents and may help address the health-related disparities experienced by this age group. However, challenges can arise from using a medical app on a device which doubles as a smartphone. Trial registration:: Closed Loop From Onset in Type 1 Diabetes (CLOuD); NCT02871089; https://clinicaltrials.gov/ct2/show/NCT0287108

Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene

Objective: To report a series of patients with cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma (CBL) gene and examine the functional role of the identified mutant Cbl protein. We hypothesized that mutated Cbl fails to act as a negative regulator of the RAS-mitogen-activated protein kinases (MAPK) signaling pathway, resulting in enhanced vascular fibroblast proliferation and migration and enhanced angiogenesis and collateral vessel formation. Methods: We performed whole-exome sequencing in 11 separate families referred to Great Ormond Street Hospital, London, with suspected genetic cause for clinical presentation with severe progressive cerebral arteriopathy. Results: We identified heterozygous variants in the CBL gene in 5 affected cases from 3 families. We show that impaired CBL-mediated degradation of cell surface tyrosine kinase receptors and dysregulated intracellular signaling through the RAS-MAPK pathway contribute to the pathogenesis of the observed arteriopathy. Mutated CBL failed to control the angiogenic signal relay of vascular endothelial growth factor receptor 2, leading to prolonged tyrosine kinase signaling, thus driving angiogenesis and collateral vessel formation. Mutant Cbl promoted myofibroblast migration and proliferation contributing to vascular occlusive disease; these effects were abrogated following treatment with a RAF-RAS-MAPK pathway inhibitor. Conclusions: We provide a possible mechanism for the arteriopathy associated with heterozygous CBL variants. Identification of the key role for the RAS-MAPK pathway in CBL-mediated cerebral arteriopathy could facilitate identification of novel or repurposed druggable targets for treating these patients and may also provide therapeutic clues for other cerebral arteriopathies.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.Y. Hong was supported for this work by Versus Arthritis (grant 21791) and Rosetrees Trust (grant A1700). D. Eleftheriou was supported by Versus Arthritis (grants 20164 and 21593). A. Keylock was supported by a BHF PhD studentship. B. Jensen is supported by a GOSH Children’s Charity grant (CP_RSRCH_003). P.A. Brogan and D. Eleftheriou also acknowledge support from Great Ormond Street Hospital Children’s Charity. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.accepted version (12 month embargo

The 5x1 DAFNE Study Protocol: A cluster randomised trial comparing a standard 5 day DAFNE course delivered over 1 week against DAFNE training delivered over 1 day a week for 5 consecutive weeks.

Background Structured education programmes are now established as an essential component to assist effective self-management of diabetes. In the case of Type 1 diabetes, the Dose Adjustment For Normal Eating (DAFNE) programme improves both glycaemic control and quality of life. Traditionally delivered over five consecutive days, this format has been cited as a barrier to participation by some patients, such as those who work full-time. Some centres in the UK have organised structured education programmes to be delivered one day a week over several consecutive weeks. This type of format may add benefit by allowing more time in which to practice skills between sessions, but may suffer as a result of weaker peer support being generated compared to that formed over five consecutive days. Methods/design We aim to compare DAFNE delivered over five consecutive days (1 week course) with DAFNE delivered one day a week over five weeks (5 week course) in a randomised controlled trial. A total of 213 patients were randomised to attend either a 1 week or a 5 week course delivered in seven participating centres. Study outcomes (measured at baseline, 6 and 12 months post-course) include HbA1c, weight, self-reported rates of severe hypoglycaemia, psychosocial measures of quality of life, and cost-effectiveness. Generalisability was optimised by recruiting patients from DAFNE waiting lists at each centre, and by mailing eligible patients from hospital clinic lists. The inclusion and exclusion criteria were identical to those used to recruit to a standard DAFNE course (e.g., HbA1c <12%, with no lower limit). Qualitative interviews were undertaken with a sub-sample of n=30 patients and their course educators (n=11) to help understand and interpret differences and similarities in outcomes between the two arms, and to identify logistical problems and unanticipated issues arising from the adaptation and delivery of a 5 week course. Discussion This trial has been designed to test the hypothesis that the benefits of delivering a structured education programme over 5 weeks are comparable to those observed after a 1 week course. The results of the trial and the qualitative sub-study will both inform the design and delivery of future DAFNE courses, and the development of structured education programmes in other fields of medicine

Supporting self-management after attending a structured education programme: a qualitative longitudinal investigation of type 1 diabetes patients’ experiences and views

Background: Structured education programmes for patients with diabetes and other chronic conditions are being widely adopted. However, follow-up studies suggest that course graduates may struggle to sustain the self-care practices taught on their courses over time. This study explored the support needs of patients with type 1 diabetes after attending a structured education programme promoting an empowerment approach and training in use of flexible intensive insulin therapy, a regimen now widely advocated and used to manage this condition. The objective was to inform future support offered to course graduates. Methods: Repeat, in-depth interviews with 30 type 1 diabetes patients after attending Dose Adjustment for Normal Eating (DAFNE) courses in the UK, and six and 12 months later. Data were analysed using an inductive, thematic approach. Results: While the flexible intensive insulin treatment approach taught on DAFNE courses was seen as a logical and effective way of managing one’s diabetes, it was also considered more technically complex than other insulin regimens. To sustain effective disease self-management using flexible intensive insulin treatment over time, patients often expected, and needed, on-going input and support from health care professionals trained in the approach. This included: help determining insulin dose adjustments; reassurance; and, opportunities to trouble-shoot issues of concern. While some benefits were identified to receiving follow-up support in a group setting, most patients stated a preference or need for tailored and individualised support from appropriately-trained clinicians, accessible on an ‘as and when needed’ basis. Conclusions: Our findings highlight potential limitations to group-based forms of follow-up support for sustaining diabetes self-management. To maintain the clinical benefits of structured education for patients with type 1 diabetes over time, course graduates may benefit from and prefer ongoing, one-to-one support from health care professionals trained in the programme’s practices and principles. This support should be tailored and personalised to reflect patients’ specific and unique experiences of applying their education and training in the context of their everyday lives, and could be the subject of future research

PURA syndrome : clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.Peer reviewe

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society