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Longitudinal Study on Clinical Predictors for Allergic Bronchopulmonary Aspergillosis in Children and Young People with Cystic Fibrosis Highlights the Impact of Infection with Aspergillus and Pseudomonas and Ivacaftor Treatment
No full textAllergic bronchopulmonary aspergillosis (ABPA) is a well-known complication in children and young people with cystic fibrosis (CF) and without treatment causes structural lung damage. We performed a longitudinal observational study to identify clinical risk factors for ABPA in a cohort of children and young people with CF aged 8 to 17 years at baseline. Anonymised annual review UK CF Registry data from 2009 to 2019 for patients aged 8-17 years in 2009 were collected, with lung transplant recipients excluded. Baseline characteristics are presented for the whole group and cross-sectional comparisons made according to the presence of ABPA or not in 2009. Longitudinal analysis from 2009 to 2019 was completed on the group without ABPA in 2009 to identify predictors for the subsequent development of ABPA using a complementary log-log regression model. In 2009, there were 1612 patients, of which 1420 were ABPA-negative and 192 ABPA-positive. Aspergillus colonisation (p = 0.01) and IV antibiotic use (p < 0.0001) were associated with having ABPA in 2009. Longitudinal analysis of the group without ABPA in 2009 identified male gender, younger age, lower lung function, Pseudomonas aeruginosa infection, and Aspergillus colonisation to be significantly associated with the development of ABPA (p < 0.0001). Ivacaftor was significantly associated with reduced ABPA (OR 0.46, p = 0.01) but not lumacaftor/ivacaftor (OR 0.64, p = 0.28). Chronic oral macrolide use was significantly associated with increased risk of development of ABPA (OR 1.30, p < 0.0001). This study shows that lower lung function, Aspergillus colonisation, and Pseudomonas aeruginosa infection in children with CF were associated with the development of ABPA, highlighting the need for enhanced surveillance in these patients. This is the first study to show a protective association of ivacaftor and ABPA.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://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
CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans
No full textFour genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects. While the knockout of Ciroz in mice also leads to situs anomalies, we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies. Moreover, CIROZ is absent or obsolete in select animals with motile cilia at their LRO, including Carnivora, Atherinomorpha fish, or jawless vertebrates. In summary, this evo-devo study identifies CIROZ as an essential gene for breaking bilateral embryonic symmetry in humans and mice, whereas we witness its contemporary pseudogenization in discrete vertebrate species.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
An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants
No full textThe role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR edited cell lines and mouse models, we have identified a silencer element that is lost in ADLD patients and that specifically targets expression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving LMNB1 and the recruitment of the PRC2 transcriptional repressor complex. Loss of the silencer element in ADLD identifies a role for non-coding regulatory elements in tissue specificity and disease causation.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. You do not have permission under this licence to share adapted material derived from this article or parts of it.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
Practical Approaches to Continuous Glucose Monitoring in Primary Care: A UK-Based Consensus Opinion
No full textINTRODUCTION: Type 2 diabetes (T2D) imposes significant personal challenges and societal costs. Continuous glucose monitoring (CGM) is recognised as a state-of-the-art tool, but remains underutilised. Adoption of CGM in primary care should be informed by a broader understanding of the technology's capabilities and limitations. METHODS: An expert panel was convened to review current literature and clinical experience to provide practical approaches to CGM for primary care practitioners and discuss the technology's value in the routine management of T2D. The goals were to review and reach consensus on the current state of CGM in non-specialist practice settings and on strategies for successfully initiating and maintaining people on CGM. RESULTS: Initiation and maintenance of CGM therapy can be successfully conducted in primary care settings. CGM therapy should include proper patient selection, proper setting of expectations, and evidence-based adjustments to therapy. Most patients are likely to see quick, meaningful, and lasting improvements in their diabetes, along with a better understanding of their condition and greater motivation for successful management. Retrospective report interpretation is feasible and intuitive. Barriers to adoption and sustained use include cost, technological limitations, behavioural or psychological factors, and therapeutic inertia. Addressing these barriers is critical to enable better access to CGM. Continuous glucose monitoring can be leveraged by primary care teams to inform treatment decisions and also by patients to inform diabetes self-management. CONCLUSION: CGM should be considered for all people with T2D. The recommendations provided here should simplify adoption and maintenance use of CGM in primary care and maximise the glycaemic and psychosocial benefits of the technology.Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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
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
Hiding in plain sight: a partial deletion of BRCA1 exon 7 undetectable by MLPA is a Nepali founder variant
No full textThis is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://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
I Live With Lynch. Cancer Worry Ebbs Into the Background, Then Something Brings It to the Fore.' A Qualitative Interview Study Exploring How Lynch Syndrome Carriers Make Sense of Their Cancer Risks and Implications to Support Decision Making
No full textBACKGROUND: Lynch syndrome carriers ('carriers') are presented with complex, emotionally laden choices regarding management of increased genetic cancer risks. Decision aids encourage active involvement in values-based health decisions. This paper aimed to address the research question: How do Lynch syndrome carriers make sense of their chances of developing cancer, and what are the implications for providing support with decision making about genetic cancer risk management? METHODS: Adult carriers were recruited through a genetics service or involvement with Lynch Syndrome UK. Semi-structured interviews explored lived experiences of carriers' access to care with a focus on decision support. Themes were constructed using framework analysis. These were developed into a conceptual model with recommendations for codevelopment of improved information and support including a tailored decision aid to complement integrated healthcare. RESULTS: Twenty participants included 12 women and eight men, half with a history of cancer. Six overarching themes were: (1) finding balance with Lynch; (2) living 'on higher alert'; (3) managing uncertainty: 'I've thought about it a lot'; (4) burden of responsibility: 'It's on me'; (5) access to joined-up care and support: 'There's something missing'; and (6) influence/pressure from others. CONCLUSIONS: This qualitative interview study provided in-depth insights from Lynch syndrome carriers about their lived experiences, informed by their values. Recommendations to empower carriers to make sense of genetic cancer risks and support decisions included accessible, trusted information, educated healthcare professionals, shared decision making, and joined-up integrated care pathways complemented by tailored decision aids.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.New Full Text unavailable for 1 year from time of publication. Please click an article to explore additional access options
New therapeutic perspectives for vascular and valvular calcifications in chronic kidney disease
No full textPURPOSE OF REVIEW: Vascular and valvular calcification are associated with cardiovascular morbidity and mortality in people with chronic kidney disease (CKD). Uncertainty exists regarding therapeutic strategies to attenuate calcification. This review outlines the pathophysiological mechanisms contributing to vascular and valvular calcification, considers the mechanisms of action of therapeutic interventions, and reports the latest outcomes from interventional studies. RECENT FINDINGS: Conventional therapies targeted at CKD-mineral and bone disorder (MBD) modulation have yielded conflicting or inconclusive results. Magnesium and vitamin K supplementation appear to offer attenuation of coronary artery calcification but inconsistent findings justify the need for further studies. Strategies targeting hydroxyapatite formation such as sodium thiosulphate and hexasodium fytate show promise and are worthy of further evaluation. The serum calcification propensity assay (T50) correlates with severity and progression; it holds promise as a potential future clinical tool for screening monitoring calcification risk. SUMMARY: Whilst knowledge of the pathophysiology of vascular calcification has grown and therapeutic approaches appear promising, as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis.UnknownNot hel
Culture-independent Multilocus sequence typing screening for Haemophilus influenzae cross-infection in non-cystic fibrosis bronchiectasis
No full textWhether cross-infection of respiratory pathogens between patients with non-cystic fibrosis bronchiectasis occurs is debated. Investigation with traditional microbiological culture risks simplifying the lung microbiome. We demonstrate the use of culture-independent Multilocus sequence typing to screen for Haemophilus influenzae strain types in a cohort of twenty-eight patients with non-cystic fibrosis bronchiectasis.Published version, accepted version (12 month embargo), submitted versionNot hel
Are the cardiovascular properties of GLP-1 receptor agonists differentially modulated by sulfonylureas? Insights from post-hoc analysis of EXSCEL
No full textAIMS: To examine whether the cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are attenuated by concurrent sulfonylurea (SU) therapy in a post-hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). METHODS: We investigated whether SUs, as a class or by specific type, modulated the effects of once-weekly exenatide (EQW) on EXSCEL cardiovascular outcomes in intent-to-treat analyses of all trial participants, categorized as SU users or nonusers. Marginal structural models were used to evaluate whether there were differential EQW effects by SU category on major adverse cardiovascular events (MACE), depending on duration of SU use (6, 12, and 18 months). EQW-by-SU type interaction p-values and hazard ratios (95 % CIs) for EQW versus placebo for each baseline SU type (glibenclamide, gliclazide, glimepiride, other SUs) were calculated. RESULTS: Neither SU use nor baseline SU type modified the effect of EQW on time to MACE (p(interaction) = 0.88 and 0.78, respectively), nor did individual SU types, including glibenclamide (a systemically wide-acting SU). CONCLUSIONS: SUs did not modulate the effect of EQW on cardiovascular outcomes, suggesting that SU treatment choices need not be altered to optimize the cardiovascular effects of GLP-1 receptor agonists in people with type 2 diabetes.Published version, accepted version (12 month embargo), submitted versionJournal 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