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OCT-Derived Biomarkers in Optic Disc Pit Maculopathy Are Associated with Age, Visual Function, and Natural History
No full textINTRODUCTION: Optic disc pit maculopathy (ODP-M) describes the variable intra- (IRF) and/or subretinal fluid (SRF) accumulation complicating a congenital optic disc anomaly that is primarily observed in young adults. This study aimed to explore the morphological variance in ODP-M, in order to measure associations between demographic and functional characteristics and investigate the natural course of the disease. METHODS: A single-centre, retrospective, observational study was performed. Subjects with ODP-M were identified through electronic notes review. Demographic characteristics, visual acuity, and anatomical features were analysed with respect to a predefined OCT-based sub-categorisation: type 1a: IRF only; type 1b: IRF + outer lamellar hole (OLH) +/- SRF; type 2: SRF +/- IRF (no OLH). RESULTS: Fifty eyes (50 subjects) were sub-categorised according to fluid distribution into type 1a (34%), type 1b (28%), and type 2 ODP-M (38%). Those with type 2 were found to be significantly younger than those with types 1a/b ODP-M (p < 0.001) and accounted for 93% of cases occurring in subjects ≤20 years old. The presence of OLH (i.e., type 1b) was noted to be independently associated with worse final VA (p = 0.013) and higher likelihood of proceeding to surgery (p = 0.002). CONCLUSION: There appears to be an age-related variation in ODP-M morphology, indicating the possibility of separate pathoanatomical processes, with distinct clinical courses and potentially different optimal management strategies. Sub-categorisation of ODP-M according to the reported structural features may help guide management of this rare condition.All rights reserve
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
Assessing the environmental impact of propofol use in anaesthesia: a call for surveillance monitoring
No full textCC BY 4.0 (Creative Commons Attribution
A novel, dominant disease mechanism of distal renal tubular acidosis with specific variants in ATP6V1B1
No full textBACKGROUND AND HYPOTHESIS: ATP6V1B1 encodes a subunit of the vacuolar H+-ATPase and pathogenic variants are associated with autosomal recessive distal renal tubular acidosis (dRTA) with deafness. Heterozygous variants predicted to affect a specific amino acid, Arg394, have been recurrently reported in dRTA but their significance has been unclear. We hypothesised that these variants are associated with a dominant disease mechanism. METHODS: Retrospective analysis of cases identified in our genetic laboratories and through European nephrology organisations. Data regarding demographics, clinical presentation, laboratory findings, hearing and imaging studies of kidneys were collected from the index patient and, if available, from other family members. The potential disease mechanism was investigated through structural modelling in silico. RESULTS: Twenty index patients in total were included, of which 19 carried the variant c.1181G>A; p.(Arg394Gln) and one c.1180C>G; p.(Arg394Gly). In 7 families, more than one member was affected and the variant segregated with the disease in those with available information (15 affected, 6 unaffected), except for the unaffected mother of 2 affected children, who was mosaic. In no patient was a second causative variant in trans identified. In 8 sporadic patients and 1 affected parent, the variant was confirmed to be de novo. Both variants are absent in gnomAD. Sensorineural hearing loss was reported in 8 of the 22 patients with available information. Structural modelling supports a crucial role for Arg394 in nucleotide binding. CONCLUSION: We provide strong evidence for the pathogenicity of heterozygous variants affecting Arg394 and thus a novel inheritance modus for ATP6V1B1-associated dRTA. Clinically, this form differs from the recessive one by the lower prevalence of hearing loss. The prominent position of Arg394 in the nucleotide binding fold of the H+-ATPase structure is consistent with a dominant negative mechanism. Our findings inform the diagnosis and management of patients with dRTA and variants of Arg394.This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)New Full Text unavailable for 1 year from time of publication. Please click an article to explore additional access options
Assessment of frailty in patients with heart failure: A new Heart Failure Frailty Score developed by Delphi consensus
No full textAIMS: The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF. METHODS AND RESULTS: The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their opinions on specific questions prepared by the Steering Committee. The experts were invited to vote and share their views anonymously, using a 5-point Likert scale over iterative rounds. An 80% threshold was set for agreement or disagreement for each statement. Twenty-two variables from four domains (clinical, functional, psycho-cognitive and social) have been selected for inclusion in the HFFS after the third round of the Delphi process. A shorter version (S-HFFS), including 10 variables, has also been developed for daily clinical use. CONCLUSIONS: The HFFS is a new multidimensional tool for the identification of frailty in patients with HF. It should also enables healthcare providers to identify potential 'red flags' for frailty in order to develop personalized care plans. The next step will be to validate the new score in patients with HF.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.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
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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Water-soluble contrast agents in adhesional small bowel obstruction: meta-analysis and PRECIS-2 assessment of trials
No full textBACKGROUND: Adhesional small bowel obstruction is a common presentation to acute general surgical services. Initial management is typically conservative and includes the use of water-soluble contrast agents. Current trials assessing water-soluble contrast agents are limited by sample size and demonstrate contrasting results. The aim of this review was to systematically appraise the use of water-soluble contrast agents in adhesional small bowel obstruction. METHODS: This systematic review and meta-analysis was registered with PROSPERO (CRD42024573136) and conducted in line with PRISMA guidelines. Searches of Medline, Embase and Central databases were undertaken to include randomized clinical trials reporting the use of water-soluble contrast agents in adhesional small bowel obstruction. Searches were last updated on 26 July 2024. The primary outcome was the need for operative intervention. Secondary outcomes included the rate of intestinal ischaemia, the need for bowel resection, and mortality. A random-effects meta-analysis was conducted for outcomes reported in three or more studies. Risk of bias was assessed using the Cochrane Risk-of-Bias tool, and trial methods were appraised using the PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) tool. RESULTS: In all, 11 randomized controlled trials were included with a median sample size of 88 (range 26-242), nine of which were single-centre studies; only one study used computed tomography imaging to diagnoses adhesional small bowel obstruction. Meta-analysis revealed no significant difference in operative intervention (odds ratio 0.63, 95% confidence interval 0.39 to 1.01; P = 0.053), small bowel ischaemia, small bowel resection, or mortality. Risk of bias raised concerns in several domains. PRECIS-2 assessment showed trials were pragmatic rather than explanatory designs. CONCLUSION: This review does not support the use of therapeutic water-soluble contrast agents in adhesional small bowel obstruction. Further adequately powered trials are needed. Standardization of diagnostic modality and consideration of explanatory designs should be considered.CC BY‑NC‑ND 4.0 (open access
Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Adults and Adolescents with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Extension Study
No full textRATIONALE: Clinical and real-world studies show elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is efficacious and safe in people with cystic fibrosis (CF) ≥12 years of age with at least one F508del allele. OBJECTIVES: Given the potential for life-long ELX/TEZ/IVA use, long-term safety and efficacy of ELX/TEZ/IVA was assessed. METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function genotypes (from 24-week parent study 445-102 [n = 399]) or with the F508del-F508del genotype (from 4-week parent study 445-103 [n = 107]) received ELX/TEZ/IVA (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours) over 192 weeks. MEASUREMENTS AND MAIN RESULTS: Primary endpoint was safety and tolerability. Mean exposure to ELX/TEZ/IVA was 172.6 weeks. Most participants had adverse events classified as mild (12.8%) or moderate (60.7%) in severity. Eighteen participants (3.6%) had adverse events that led to treatment discontinuation. After starting ELX/TEZ/IVA, participants had consistent increases in percent predicted FEV(1) (ppFEV(1)), Cystic Fibrosis Questionnaire-Revised respiratory domain score, and body mass index, with decreases in sweat chloride concentration and pulmonary exacerbations rates; these improvements were maintained through 192 weeks. The mean annualized rate of change in ppFEV(1) was 0.02 percentage points (95% CI, -0.14 to 0.19) after initiation of ELX/TEZ/IVA. CONCLUSIONS: During this 192-week open label extension study, the longest clinical study of a CFTR modulator to date, ELX/TEZ/IVA remained generally safe and well-tolerated. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates, and nutritional status. The estimated annualized rate of change in ppFEV(1) suggests no evidence of pulmonary function loss across the study population over the 4-year treatment period. These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03525574.CC BY 4.0 (Creative Commons Attribution
FUT8 Is a Critical Driver of Prostate Tumour Growth and Can Be Targeted Using Fucosylation Inhibitors
No full textBACKGROUND: An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6-fucose to the innermost GlcNAc residue on N-glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood. METHODS & RESULTS: Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N-glycan MALDI mass spectrometry imaging (MALDI-MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N-glycans in prostate cancer cells and using both in vitro and in vivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours. CONCLUSIONS: Our study cements FUT8-mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.CC BY 4.0 (Creative Commons Attribution
A Time-varying Analysis of General Practice Prescribing in the COVID-19 Era: Lessons from Prescription Dynamics in a Pandemic
No full textBACKGROUND/AIM: Pharmacotherapy is vital in medicine, but inappropriate and inadequate use of medications significantly impacts global mortality and morbidity. Increased prescribing may indicate irrational use or prolonged illness, while decreased prescribing could suggest undertreatment, supply shortages, or the availability of safer and, more effective treatments. The COVID-19 pandemic disrupted health systems, potentially altering prescribing patterns. This study examined its impact on the prescribing patterns of common therapeutic categories and high-risk medicines in general practice in England. MATERIALS AND METHODS: Common therapeutic categories were identified from English General Practice prescription data, and high-risk medicines were identified by mapping the UK pharmacovigilance data onto the English prescribing data. A retrospective analysis compared monthly prescription data pre-pandemic, during the pandemic, and post-pandemic. Significant changes in the prescribing volumes of therapeutic categories and high-risk medicines were tracked to determine persistence, intensification, or diminution post-pandemic. Linear regression models analysed prescribing trends. RESULTS: Among 220 therapeutic categories, 16 experienced significant changes: 14 increased and two decreased during the pandemic. Of 78 high-risk medicines, six showed significant changes: two increased and three decreased. Only three therapeutic categories and two high-risk medicines returned to pre-pandemic levels. CONCLUSION: Despite a reduction in general practice appointments during the pandemic, prescribing for several therapeutic categories and certain high-risk medicines surged, indicating increased treatment, prolonged illness or stockpiling. Post-pandemic downward trends suggest long-term under-treatment or reduced stockpiling. Continuous monitoring, strategic healthcare planning, and regulatory interventions are needed to optimise prescribing. Future research is needed to assess the long-term effects on disease management.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