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Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity
No full textBACKGROUND: We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1-hyperinsulinism by screening a large international cohort of patients living with the condition. METHODS: We screened the HK1 cis-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories. RESULTS: We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses (n = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis-regulatory region from 42 to 46 bp. CONCLUSIONS: Non-coding variants within the HK1 cis-regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy
No full textPURPOSE: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes
No full textAIMS/HYPOTHESIS: Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study. METHODS: Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages. RESULTS: Compared with IA-2A(-) individuals, IA-2A(+) individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A(-) stage 1 individuals. Individuals at highest risk within the single-IA-2A(+) category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A(+) individuals and dysglycaemic IA-2A(-) individuals. CONCLUSIONS/INTERPRETATION: IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A(-). Approaches to incorporate IA-2A(+) status into monitoring strategies for autoantibody-positive individuals should be considered.Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Chest Pain at Rest With Unremarkable ECG and Cardiac Enzymes: Case Study Emphasising the Importance of Clinical Suspicion in the Diagnosis of Coronary Artery Disease
No full textBACKGROUND: Coronary artery disease (CAD), primarily caused by atherosclerosis, is a leading cause of death, presenting as angina or myocardial infarction. Advances in cardiac imaging, angiography, and procedures like percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery have improved early detection and management of this condition. This report presents the case of a man who experienced worsening exertional chest pain and discomfort while at rest. CASE REPORT: A 66-year-old man with a history of neurogenic syncope and asthma presented at the same-day emergency care (SDEC) unit with worsening exertional chest pain and discomfort whilst at rest. Despite normal ECG and cardiac enzyme results, further cardiac computed tomography angiography (CTCA) revealed significant CAD with moderate stenosis in the right coronary artery (RCA) and severe stenosis at the left anterior descending artery (LAD) bifurcation, leading to CABG surgery. Echocardiography showed a left ventricular ejection fraction of 50-54% with mid-inferior and basal to mid-inferoseptal hypokinesia. The cardiology-cardiothoracic multidisciplinary team concluded that CABG surgery would provide the most durable long-term outcome. CONCLUSION: This case demonstrates the high importance of clinical suspicion of CAD despite normal initial investigations in the early identification and timely investigation as well as the role multidisciplinary teams and CABG can play in the timely management of complex CAD, ultimately leading to improved patient outcomes.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international licenseRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Post-colonoscopy pancreatitis: a case report and a systematic review of the literature
No full textBACKGROUND: Colonoscopy represents a commonly performed endoscopic procedure for the study of large bowel. Even though, colonoscopy is considered a safe and well-tolerated procedure, in the literature, it has also been related with in a few cases of acute pancreatitis. METHODS: A systematic PubMed and Scopus search was conducted, a propos of a case report. RESULTS: Twelve patients were included from 11 case reports. The mean age of the patients was 57.4 years (range: 25 - 84). None of the included patients had a history of cholelithiasis or alcoholism. The principal indication for colonoscopy was cancer/polyp surveillance (7 out of 12, 58.3%). Polypectomy was performed in 9 patients (75%). In 4 out of 12 cases (33.3%) the procedure of colonoscopy was characterised as difficult and external manipulation was necessitated. The mean onset of symptoms was 8 hours after colonoscopy (range: 2 - >24). Hospitalization was necessary in 9 out of 12 patients (75%). Regarding the location of the pancreatitis, body/tail (3 out of 12, 25%), body (4 out of 12, 33.3%) and tail (4 out of 12, 33.3%) were most affected. The median duration of symptoms was 7 days (range: 3-12). No complications were reported. The mean follow-up period of the included patients was 15 months (range: 3-36). No fatalities were reported. CONCLUSION: Post-colonoscopy pancreatitis is an extremely rare complication of colonoscopy. After having excluded a surgical emergency, acute pancreatitis should be taken into consideration, especially when endoscopy is technically challenging. Conservative management is indicated in these cases, while no serious sequels have been reported in the literature.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
British Thyroid Association Survey of Graves' Disease Management in the UK
No full textBACKGROUND: Recent years have seen changes and uncertainties in evidence and guideline recommendations in Graves' disease treatment. To understand the impact of these developments on current practice, we undertook a survey of Graves' disease management in the United Kingdom and compared this to other national and international surveys. METHOD: Members of the British Thyroid Association, the UK Society for Endocrinology and regional endocrinology networks, were invited by e-mail to complete a 15-min online survey (October 2022 to March 2023). RESULTS: Out of 158 eligible respondents, 99% were endocrinologists. For a 40-year-old female with a first presentation of Graves' hyperthyroidism, TSH-receptor antibodies (TRAb) were requested at diagnosis and at follow-up by 95% and 76%, respectively. Isotope scans and ultrasound were rarely requested (< 5%). Majority (95%) would treat with antithyroid drugs (ATD), predominantly Carbimazole (CMZ), while radioactive iodine (RAI) was preferred for recurrent disease (81%). Common reasons for avoiding RAI were thyroid eye disease, pregnancy intention, or contact with young children whereas biochemical severity, goitre, or male sex did not influence decision to use RAI. Propylthiouracil (PTU) was preferred in preconception and early pregnancy, but after the first-trimester, 50% would continue PTU while 50% switch back to CMZ. CONCLUSIONS: The survey confirms a growing application of TRAbs, both for diagnostic and prognostic purposes. ATDs remain the preferred first-line therapy for Graves' disease, which is consistent with global trends but contrary to National Institute of Health and Care Excellence (NICE) guidance. Further studies are required to explore the clinical and pragmatic determinants of current treatment approaches.CC BY 4.0 Internationa
Video versus direct laryngoscopy for urgent tracheal intubation in neonates: a systematic review and meta-analysis
No full textINTRODUCTION: Intubation is most often performed electively by anaesthetists in controlled conditions in operating theatres. In neonates, however, it is most often performed by neonatologists or paediatricians in urgent circumstances in the neonatal intensive care unit (NICU) or delivery room (DR). Neonatal intubation is a difficult skill to learn and maintain, and success rates are suboptimal both in the NICU and DR. Video laryngoscopy (VL) has the potential to increase intubation success and safety as it may offer a better view of the airway, which can be shared by the intubator and other clinicians. OBJECTIVES: To compare the efficacy and safety of using VL to direct laryngoscopy (DL) for intubation of neonates in the NICU and DR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and CINAHL up to August 2024 without language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs or cross-over trials that compared VL to DL for intubation of neonates outside of the neonatal operating theatre. MAIN RESULTS: VL improves first attempt intubation success rates, 849 intubations (RR 1.46, 95% CI 1.21 to 1.75), with a number needed to treat (NNT) of 6. CONCLUSIONS: VL improves intubation success rates without increasing adverse events and should be the standard of care for neonatal intubations in the NICU and DR.Non
BSG/ACPGBI guidance on the management of colorectal polyps in patients with limited life expectancy
No full textBACKGROUND: Determining optimal management of colorectal polyps in patients with limited life expectancy of under 10 years can be difficult, due to challenges balancing an uncertain natural history of polyp progression to symptomatic malignancy versus the increased risk and consequences of polypectomy complications. AIM: This British Society of Gastroenterology and Association of Coloproctologists of Great Britain and Ireland guidance aims to help clinicians and patients consider these risks to aid decision-making for polypectomy versus a conservative approach. METHODS: A guidance development group comprising 28 members was established, including gastroenterologists, colorectal surgeons, elderly care physicians, anaesthetists, epidemiologists, nurse endoscopists, a general practitioner and patient representatives. Estimates on life expectancy stratified by age and comorbidity, polyp dwell time for differing polyp sizes, cancer sojourn time and polypectomy complication rates for comorbid/elderly patients both on and off antithrombotic medication were collated from various literature searches. A model was created to compare the risk of symptomatic malignancy in a patient's lifetime against the risk of significant complications. RESULTS: Following a modified Delphi consensus process and after three rounds of voting, 33 recommendations were made within 10 domains (principles, diagnostic investigation, life expectancy, polyp and cancer natural history, polypectomy risks, management recommendations, follow-up, decision-making practicalities, training and education, future research). A table was created, summarising whether polypectomy or conservative management might be the favoured option for 40 clinical scenarios of patients with differing life expectancy, polyp sizes and use of antithrombotic medication. CONCLUSIONS: This guidance provides a framework to facilitate more objective and informed decision-making, from which an individualised plan can be developed between the patient and their clinician.CC BY-NC (non-commercial only
Answer to the letter to the editor of X. Zhang, et al. concerning AI versus the spinal surgeons in the management of controversial spinal surgery scenarios" by Mehmet, S. et al. (Eur spine J [2025]: doi.org/10.1007/s00586-025-08825-w)"
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Assessing the environmental impact of propofol use in anaesthesia: a call for surveillance monitoring
No full textCC BY 4.0 (Creative Commons Attribution