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De novo variants in KDM2A cause a syndromic neurodevelopmental disorder
No full textGermline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo variants in KDM2A, a lysine demethylase crucial for embryonic development, in 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe intellectual disability. Other core symptoms included feeding difficulties, growth issues such as intrauterine growth restriction, short stature and microcephaly as well as recurrent facial features like epicanthic folds, upslanted palpebral fissures, thin lips, and low-set ears. Expression of human disease-causing KDM2A variants in a Drosophila melanogaster model led to neural degeneration, motor defects, and reduced lifespan. Interestingly, pathogenic variants in KDM2A affected physiological attributes including subcellular distribution, expression and stability in human cells. Genetic epistasis experiments indicated that KDM2A variants likely exert their effects through a potential gain-of-function mechanism, as eliminating endogenous KDM2A in Drosophila did not produce noticeable neurodevelopmental phenotypes. Data from Enzymatic-Methylation sequencing supports the suggested gene-disease association by showing an aberrant methylome profiles in affected individuals' peripheral blood. Combining our genetic, phenotypic and functional findings, we establish de novo variants in KDM2A as causative for a syndromic neurodevelopmental disorder.CC BY 4.0 Internationa
Correction: High patient acceptance of immediately sequential bilateral cataract surgery (ISBCS) as part of a one-stop see-and-treat pathway within an innovative NHS cataract unit
No full textCC BY 4.0 (Creative Commons Attribution
Directed acyclic graphs to minimise bias and optimise causal inference in SNAP-3: an observational cohort study of frailty, multimorbidity, and delirium in older surgical patients
No full textBACKGROUND: The 3rd Sprint National Anaesthesia Project (SNAP-3) aims to describe the impact of frailty, multimorbidity, and delirium, and their management, on outcomes after surgery within the older surgical population. Causal diagrams, such as directed acyclic graphs (DAGs), are a useful tool for visually representing relationships between variables and for clarifying the causal assumptions underlying a chosen statistical model. METHODS: A description of how the SNAP-3 cohort study's DAGs were developed is provided. DAGs have been created for the exposure-outcome relationships between frailty, multimorbidity, and delirium (as an exposure) with postoperative outcomes (length of hospital stay, delirium, morbidity, mortality). DAGs were created following the approach of 'Evidence synthesis for constructing directed acyclic graphs', and revised after independent clinical expert input. RESULTS: DAGs provide visual representations of assumptions made, and provide an objective approach to appropriate statistical adjustments. Key nodes within all the DAGs included age, dementia, genetic predisposition, hearing and visual impairment, length of stay, malignancy, operative severity, polypharmacy, postoperative perioperative medicine service, preoperative clinic review, sex, social deprivation, urgency, with delirium, frailty, multimorbidity, interaction, morbidity acting as exposures, or outcomes in certain DAGs. CONCLUSIONS: DAGs provide a transparent framework for statistical decision-making in observational research. We provide an overview of DAGs using the SNAP-3 DAGs as examples to explain fundamental concepts for developing and using causal diagrams. This overview acknowledges the complexities of exploring clinical relationships and the assumptions that are necessary, providing an opportunity for critique of the relationships described and refinements for future studies.CC BY‑NC‑ND 4.0 (open access
A Multi-Sector Mixed Methods Study of Stroke Services in the Philippines: Insights From Government Officials and Organisational Leaders
No full textOBJECTIVES: This study aimed to illustrate the state of stroke care and rehabilitation in the Philippines through the perspectives of local government officials, policymakers, and organisational leaders. It sought to identify challenges, opportunities, and recommendations for improving stroke policies and services across different administrative levels. METHODS: Mixed-methods approach involving a structured survey of 131 local government officials and in-depth interviews with eight key stakeholders. Survey participants included Department of Health (DoH) officials, local chief executives, policymakers, Local Government Unit (LGU) employees, and representatives from non-government agencies. Interviewees comprised leads and managers from the DoH and representatives from organisations including the Philippine Academy of Rehabilitation Medicine (PARM), Physicians for Peace Philippines, and the Philippine Council for Health Research and Development (PCHRD). Quantitative survey data were analysed using descriptive statistics and qualitative interview data were thematically analysed, then the two types of data were triangulated and organised by theme. RESULTS: Findings revealed significant gaps in funding, healthcare infrastructure, and policy implementation. Challenges included inadequate facilities, lack of qualified staff, financial barriers, and regional disparities in service provision. Survey and interview participants emphasised the need for increased government support, comprehensive policies, and community-based rehabilitation (CBR) programmes. Improving stroke survivors' quality of life was ranked as the most critical aspect of rehabilitation programmes. CONCLUSIONS: The study highlights the critical need for more equitable and accessible stroke care and rehabilitation in the Philippines. This can be facilitated by sustained government support, inter-agency collaboration, community engagement, and the implementation of holistic, evidence-based, and cost-effective CBR initiatives.CC BY 4.0 (Creative Commons Attribution
A modified Delphi consensus statement on the role of biopsy in small renal masses
No full textOBJECTIVE: To understand the variable utilisation of diagnostic biopsy for small renal masses (SRM) across the urology community, we worked with expert clinicians and patients to produce a consensus statement on the role of biopsy and to identify research gaps. METHODS: In phase I, qualitative interviews were performed to identify potential statements on the role of biopsy and research gaps. In phase II, an expert panel including patients scored statements on a 9-point scale through a modified Delphi process involving three rounds of web-based surveys. Consensus was considered to have been reached when 70% of participants scored a statement greater than or equal to seven. Panel members could propose additional statements for consideration after the first round. Following the second round, a moderation meeting was held to discuss statements where threshold of agreement was not met. RESULTS: In total, 35 participants were involved in this project and consisted of 23 clinicians and 12 patients, with 29 participants completing all three rounds. Overall, 18 statements reached consensus, 11 of which pertained to when and how a biopsy should be used in SRM management and 7 research recommendations to improve the evidence base for biopsy use. CONCLUSIONS AND CLINICAL IMPLICATIONS: This Delphi consensus statement, co-produced by patients and clinicians, provides best-practice guidance on the current role of renal tumour biopsy, including offering biopsy prior to active treatment if the outcome would affect management and offering a second attempt should the first biopsy be non-diagnostic. Priority areas for future research included studies to evaluate how a biopsy affects choice of treatment and patient anxiety.CC BY 4.0 Internationa
A survey of perioperative medicine services with a focus on provision for older surgical patients in the UK and Republic of Ireland: SNAP-3
No full textBACKGROUND: Perioperative medicine aims to improve care for high-risk patients, and is endorsed by national guidelines in the UK and Republic of Ireland (ROI). However, comprehensive perioperative medicine services are not yet uniformly available. This survey addressed the current state of perioperative medicine services for older surgical patients in the UK and ROI and how these services align with current national guidance. METHODS: A survey was distributed electronically to all publicly administered UK and ROI hospitals performing surgical procedures. The survey examined perioperative care against national recommendations regarding service organisation and conduct. RESULTS: Of 339 eligible hospitals, 54.9% (186/339) responded. A hospital frailty lead was appointed in 54% (101/186) of hospitals, and 9% (16/186) had a designated anaesthetist for cognitive impairment. Hospital anaesthetic services outside the theatre were focused on preoperative assessment clinics (146/172), with few reporting routine postoperative involvement (17/166). Nurse-led preoperative assessments of frailty, cognition, and delirium risk were conducted in 49.5% (90/182), 44.3% (78/176), and 13.7% (24/175) of hospitals, respectively. The Clinical Frailty Scale was used in 87.0% (147/169) of hospitals for frailty screening. The 4 'A's Test (45.7% [85/186]) and Abbreviated Mental Test (43.0% [80/186]) were the preferred cognitive assessment tools. CONCLUSIONS: The survey highlights the variation in perioperative medicine services that exist for older surgical patients despite national guidelines advocating their widespread implementation. Opportunity exists to develop interspecialty perioperative services further and promote identification of frailty, cognitive impairment, and delirium, all of which negatively impact postoperative outcomes for older surgical patients.Creative Commons CC BY 4.0 (open access
A multimodal approach to reduce the incidence of peripheral venous cannula bacteraemias and improve patient safety
No full textBACKGROUND: Incidence of peripheral venous cannula (PVC) bacteraemia have been rising in a trust in the south-west of England, with a 267% increase noted over the 2022/23 financial year compared with the previous year. AIM: To use a multimodal approach to reduce the incidence of PVC bacteraemia and improve patient safety. METHODS: The initiative consisted of an educational poster highlighting the severity of infection associated with PVCs alongside key prevention messages rooted in Trust policy. Teaching sessions, complementing the poster, were delivered by the infection prevention and control team to each clinical area. FINDINGS: The data showed that the provision of further educational resources and wider support resulted in a 54.5% decrease in the incidence of PVC bacteraemia in 2023/24 compared with the previous year. An audit undertaken in the fourth quarter of 2023/24 (January-March) found zero cases of PVC bacteraemia for the first time in 2 years. CONCLUSION: Dedication and collaborative working are vital for securing the success of quality improvement projects. PVC-related bacteraemias and the severity of infection remain an under-acknowledged and under-recognised topic within health care, with further research required.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
Zonal Characteristics of Collagen Ultrastructure and Responses to Mechanical Loading in Articular Cartilage
No full textThe biomechanical properties of articular cartilage arise from a complex bioenvironment comprising hierarchically organised collagen networks within the extracellular matrix (ECM) that interact with the proteoglycan-rich interstitial fluid. This network features a depth-dependent fibril organisation across different zones. Understanding how collagen fibrils respond to external loading is key to elucidating the mechanisms behind lesion formation and managing degenerative conditions like osteoarthritis. This study employs polarisation-resolved second harmonic generation (pSHG) microscopy to quantify the ultrastructural organisation of collagen fibrils and their spatial gradient along the depth of bone-cartilage explants under a close-to-in vivo condition. By combining with in-situ loading, we examined the responses of collagen fibrils by quantifying changes in their principal orientation and degree of alignment. The spatial gradient and heterogeneity of collagen organisation were captured at high resolution (1 μm) along the longitudinal plane of explants (0.5 mm by 2 mm). Zone-specific ultrastructural characteristics were quantified to aid in defining zonal borders, revealing consistent zonal proportions with varying overall thicknesses. Under compression, the transitional zone exhibited the most significant re-organisation of collagen fibrils. It initially allowed large deformation through the re-orientation of fibrils, which then tightened fibril alignment to prevent excessive deformation, indicating a dynamic adaptation mechanism in response to increasing strain levels. Our results provide comprehensive, zone-specific baselines of cartilage ultrastructure and micromechanics, crucial for investigating the onset and progression of degenerative conditions, setting therapeutic intervention targets, and guiding cartilage repair and regeneration efforts. STATEMENT OF SIGNIFICANCE: Achieved unprecedented quantification of the spatial gradient and heterogeneity of collagen ultrastructural organisation at a high resolution (1 μm) along the full depth of the longitudinal plane of osteochondral explants (0.5 mm by 2 mm) under close-to-in vivo condition. Suggested new anatomical landmarks based on ultrastructural features for determining zonal borders and found consistent zonal proportions in explants with different overall thicknesses. Demonstrated that collagen fibrils initially respond by reorienting themselves at low strain levels, playing a significant role in cartilage deformation, particularly within the transitional zone. At higher strain levels, more collagen fibrils re-aligned, indicating a dynamic shift in the response mechanism at varying strain levels.This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.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
High patient acceptance of immediately sequential bilateral cataract surgery (ISBCS) as part of a one-stop see-and-treat pathway within an innovative NHS cataract unit
No full textBACKGROUND: Constituting ~0.5% of all NHS cataract operations, national provision of immediately sequential bilateral cataract surgery (ISBCS) is limited. Combining offering ISBCS within a novel one-stop see-and-treat (S&T) cataract pathway would offer patients the opportunity for two cataract operations in a single hospital visit. Patient acceptance of ISBCS amongst urban populations has been investigated. However, little is understood about ISBCS acceptance rurally. METHODS: Retrospective observational study at the Nightingale Hospital, Exeter investigating patient acceptance of ISBCS within S&T; following the implementation of a S&T cataract pathway entailing a pre-operative patient-clinician telephone consultation and subsequently scheduled single date of assessment and surgery. Patient acceptance and factors potentially influencing decisions were investigated. RESULTS: 200 patient telephone consultations between 22nd August 2023 and 9th January 2024 were evaluated. 198 (99%) patients referred were suitable for S&T cataract surgery, of whom 109 (54.5%) were deemed eligible for offering ISBCS S&T cataract surgery. Of the eligible participants, 78 (71.56%) favoured ISBCS. No significant differences in age, sex, distance from hospital or refractive data were identified between ISBCS accepting and declining participants. CONCLUSIONS: Our results illustrate a high patient acceptance rate (71.56%) of ISBCS within our population in contrast with published national rates. Offering ISBCS within a S&T model would allow patients to benefit from having both cataracts assessed and treated within a single hospital visit.This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.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
Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder
No full textPURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a(-/-) mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.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