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Mapping the therapeutic landscape in emergency incisional hernia: a scoping review
No full textPURPOSE: Incisional hernias (IH) represent common complications following abdominal surgeries, with emergency repair associated with increased morbidity and mortality. This scoping review aimed to map the existing literature on emergency incisional hernia repair, identify research gaps, and inform future guideline development. METHODS: A comprehensive literature search was conducted in PubMed MEDLINE and SCOPUS for studies published between January 2000 and August 2024. Articles addressing any aspect of emergency incisional hernia repair in adults were included. Data extraction focused on study characteristics, patient demographics, surgical approaches, and outcomes. RESULTS: Of 801 unique articles identified, 73 met the inclusion criteria. Most were cohort studies (73.97%), with only one randomized trial. The primary areas of interest were repair methods (47.95%), operative outcomes (31.51%), risk assessment (16.44%), and diagnosis (5.48%). Pooled analysis revealed a predominantly female (63%), elderly (mean age 62.3 years), and comorbid patient population. The most frequent study endpoints were readmission (18%), surgical site infection (12%), reoperation (8%), and mortality (4%). Significant heterogeneity was observed in defect characterization and surgical techniques. CONCLUSION: This review highlights a paucity of randomized studies guiding emergency incisional hernia management. Key issues identified include inconsistent definitions of emergency presentation, limited data on hernia characteristics, and a lack of standardized outcome reporting. Future research should focus on developing a unified classification system for emergency incisional hernias, evaluating the role of imaging in decision-making, and conducting comparative studies on various treatment strategies across different clinical scenarios.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.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
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
Quantitative hypermorphic FAM111A alleles cause autosomal recessive Kenny-Caffey syndrome type 2 and osteocraniostenosis
No full textKenny-Caffey syndrome (KCS) is a rare genetic disorder characterized by extreme short stature, cortical thickening and medullary stenosis of tubular bones, facial dysmorphism, abnormal T-cell function, and hypoparathyroidism. Biallelic loss-of-function variants in TBCE cause autosomal recessive type 1 KCS (KCS1). By contrast, heterozygous missense variants in a restricted region of the FAM111A gene have been identified in autosomal dominant type 2 KCS (KCS2) and a more severe lethal phenotype, osteocraniostenosis (OCS) that have recently been shown to confer a gain-of-function. In this study, we describe two unrelated children with KCS and OCS who were homozygous for different FAM111A variant alleles that result in replacement of the same residue, Tyr414 (c.1241A>G, p.Y414C and c.1240T>A, p.Y414N), in the mature FAM111A protein. Their heterozygous relatives are asymptomatic. Functional studies of recombinant FAM111AY414C demonstrated normal dimerization and a mild gain-of-function effect. This study provides evidence that both biallelic and monoallelic variants of FAM111A with varying degrees of activation can lead to dominant or recessive KCS2 and OCS.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
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
Clinical and socio-demographic characteristics of people with multiple sclerosis at the time of diagnosis: Influences on outcome trajectories
No full textBACKGROUND: It has long been accepted that multiple sclerosis (MS) is heterogenous regarding presentation and disease course, so that outcomes are diverse; however, there is less data on variation in the immediate period after diagnosis. METHODS: Our objective was to identify the clinical and demographic factors present at diagnosis. Two cohorts were compared from the Trajectories of Outcome in Neurological Conditions-MS study: those joining within one year of diagnosis (inception cohort) compared to 9-11 years following diagnosis (decade cohort). Patient reported outcome data were fitted to the Rasch model to yield interval estimates, longitudinal data were analysed by group-based trajectory models. RESULTS: The inception cohort (n = 813) showed impact on fatigue, disability, health status and quality of life (QOL), although as expected, less than the decade cohort (n = 679), who also had more depressive symptoms. The average trajectory of health status was deceptive, as analysis showed two distinct groups, 13.8 % having much poorer health status, sustained for at least 3 years from diagnosis. Similarly, there were distinct groups with different trajectories identified for disability and QOL. These groups varied for depression, anxiety, sleep problems, employment, comorbidities, smoking history, and deprivation indices, highlighting influences prior to diagnosis. CONCLUSIONS: MS care must be personalised from diagnosis; service design should account for those people with MS experiencing poor health status from diagnosis. Basing capacity planning on average trajectories would be misleading. Furthermore, this evidence shows that service provision to support symptom management and disability clearly needs to be resourced from the diagnostic year.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
Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multi-Ancestry Population Cohorts
No full textType 1 diabetes (T1D) polygenic risk scores (PRS) are effective tools for discriminating T1D from other diabetes types and predicting T1D risk, with applications in screening and intervention trials. A previously published T1D Genetic Risk Score 2 (GRS2) is widely adopted, but challenges in standardization and accessibility have hindered broader clinical and research utility. To address this, we introduce GRS2x, a standardized and cross-compatible method for accurate T1D PRS calculation, demonstrating genotyping and reference panel independent performance across diverse datasets. GRS2x as a unified approach facilitates accessible and portable measurement of T1D polygenic risk.This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.Unpublished eprin
MIKROBE: a feasibility study for a randomised controlled trial of one-stage or two-stage surgery for prosthetic knee infection
No full textBACKGROUND: Total knee replacement surgery is common, with over 107,000 operations performed in the UK in 2019. After surgery, about 1% of patients develop a deep infection, known as a prosthetic joint infection. Two types of operations, one- or two-stage revision surgery, are routinely performed to treat the infection. Re-infection rates are similar, but there is uncertainty regarding longer-term outcomes for patients. The aim of this study was to establish the feasibility of conducting a future randomised controlled trial that will compare clinical and cost-effectiveness of one-stage versus two-stage revision knee surgery for prosthetic joint infection. METHODS: Following eligibility screening, consenting patients took part in an audio-recorded consultation with their surgeon and were then randomised on a 1:1 allocation to one-stage or two-stage revision surgery. Patient-reported outcome measures were administered at baseline and 3 and 6 months postoperatively. Embedded qualitative work with patient participants and nonparticipants and with surgeons to understand the acceptability of trial processes and involvement was undertaken. Patient and public involvement and engagement activities were conducted throughout the study. RESULTS: Of 136 patients screened, only 3 were randomised and had surgery as part of the study. Qualitative data were collected from the three participants, as well as from two eligible patients who declined participation and two who withdrew from participation after the initial patient-surgeon consultation. Five surgeons took part in qualitative interviews prior to study end. CONCLUSION: This study indicated that a larger randomised controlled trial evaluating one-stage versus two-stage revision knee surgery for prosthetic joint infection is not feasible with the current straightforward randomised controlled trial design. Future research needs to consider the most appropriate study design and methodology to address this important research question. TRIAL REGISTRATION: No.: NCT04458961.CC BY 4.0 Internationa
Conservatively managed non-functioning pituitary macroadenomas-cohort study from the UK Non-functioning Pituitary Adenoma Consortium
No full textOBJECTIVE: Surveillance is often adopted for asymptomatic non-functioning pituitary macroadenomas (macroNFPAs). Due to low-quality evidence, uncertainty remains on optimal frequency of imaging/biochemical monitoring and indications for surgery. We assessed the natural history and outcomes of patients with macroNFPA who had monitoring as initial management choice from the UK NFPA Consortium. DESIGN: This was a multicentre, retrospective, cohort study involving 21 UK endocrine departments. METHODS: Clinical, imaging, and hormonal data of 949 patients followed up between January, 1, 2005 and March, 1, 2022 were analysed. RESULTS: Incidence rate for tumour enlargement was 9.8 per 100 patient-years (95% CI, 8.8-10.8), with cumulative probabilities 1.6%, 8.1%, 18.4%, 29.2%, and 43.6% at 6-month, 1-year, 2-year, 3-year, and 5-year follow-up, respectively; rates were higher in tumours abutting/displacing optic chiasm than those not in contact with it. Amongst macroNFPAs not in contact with optic chiasm showing enlargement within 6 months, none impacted visual fields. In tumours with enlargement and continued monitoring (median 2.6 years), further growth occurred in 60.5% (33.8% probability at 2 years), stability in 35.5%, and shrinkage in 4.0%. Rates of new pituitary hormone deficits were 4.0%-4.9%, mainly driven by tumour enlargement. After transsphenoidal surgery, rates of hypopituitarism reversal were 12%-17% and those of additional anterior pituitary hormone deficits were 12%-15% (permanent vasopressin deficiency 3.5%). CONCLUSIONS: Our data provide evidence for monitoring protocols. MacroNFPAs not in contact with optic chiasm require less frequent imaging, and first follow-up scan can be delayed to 1 year. After first enlargement, variable tumour behaviour can occur. New hypopituitarism in stable tumours is rare, challenging necessity of regular pituitary function assessment.CC BY 4.0 (Creative Commons Attribution
COA5 has an essential role in the early stage of mitochondrial complex IV assembly
No full textPathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.This article is available under a Creative Commons License (Attribution 4.0 International, as described at 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