Royal Devon and Exeter Research Repository
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Delivery Models and Health Economics of Supportive Care Services in England: A Multicentre Analysis
No full textAIMS: Improvements in cancer treatment have led to more people living with and beyond cancer. These patients have symptom and support needs unmet by current services. The development of enhanced supportive care (ESC) services may meet the longitudinal care needs of these patients, including at the end of life. This study aimed to determine the impact and health economic benefits of ESC for patients living with treatable but not curable cancer. MATERIALS AND METHODS: A prospective observational evaluation was undertaken over 12 months across eight cancer centres in England. ESC service design and costs were recorded. Data relating to patients' symptom burden were collected using the Integrated Palliative Care Outcome Scale (IPOS). For patients in the last year of life, secondary care use was compared against an NHS England published benchmark. RESULTS: In total, 4594 patients were seen by ESC services, of whom 1061 died during follow-up. Mean IPOS scores improved across all tumour groups. In total, £1,676,044 was spent delivering ESC across the eight centres. Reductions in secondary care usage for the 1061 patients who died saved a total of £8,490,581. CONCLUSIONS: People living with cancer suffer with complex and unmet needs. ESC services appear to be effective at supporting these vulnerable people and significantly reduce the costs of their care.Published version, accepted version (12 month embargo)The article is available via Open Access. Click on the 'Additional link' above to access the full-text
Penetrance and expressivity of mitochondrial variants in a large clinically unselected population
No full textBACKGROUND: Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. METHOD: Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. RESULTS: We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5 respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. CONCLUSION: Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.Published version, accepted version (12 month embargo), submitted versionThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site
Incretin hormone responses to carbohydrate and protein/fat are preserved in adults with sulfonylurea-treated KCNJ11 neonatal diabetes
No full textThe incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes) for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.unknownThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Anesthesia and Critical Care for the Prediction and Prevention for Small-for-size Syndrome: Guidelines from the ILTS-iLDLT-LTSI Consensus Conference
No full textBACKGROUND: During the perioperative period of living donor liver transplantation, anesthesiologists and intensivists may encounter patients in receipt of small grafts that puts them at risk of developing small for size syndrome (SFSS). METHODS: A scientific committee (106 members from 21 countries) performed an extensive literature review on aspects of SFSS with proposed recommendations. Recommendations underwent a blinded review by an independent expert panel and discussion/voting on the recommendations occurred at a consensus conference organized by the International Liver Transplantation Society, International Living Donor Liver Transplantation Group, and Liver Transplantation Society of India. RESULTS: It was determined that centers with experience in living donor liver transplantation should utilize potential small for size grafts. Higher risk recipients with sarcopenia, cardiopulmonary, and renal dysfunction should receive small for size grafts with caution. In the intraoperative phase, a restrictive fluid strategy should be considered along with routine use of cardiac output monitoring, as well as use of pharmacologic portal flow modulation when appropriate. Postoperatively, these patients can be considered for enhanced recovery and should receive proactive monitoring for SFSS, nutrition optimization, infection prevention, and consideration for early renal replacement therapy for avoidance of graft congestion. CONCLUSIONS: Our recommendations provide a framework for the optimal anesthetic and critical care management in the perioperative period for patients with grafts that put them at risk of developing SFSS. There is a significant limitation in the level of evidence for most recommendations. This statement aims to provide guidance for future research in the perioperative management of SFSS.Published version, accepted version (12 month embargo)
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
No full textPathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.UnknownThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Improving the quality of rehabilitation following anterior cruciate ligament reconstruction surgery, in an outpatient physiotherapy department
No full textAnterior cruciate ligament reconstruction (ACLR) is a type of orthopaedic knee surgery and physiotherapy rehabilitation is undertaken for several months postoperatively, often with the aim of returning the patient to sport. Variations in postoperative protocols to guide rehabilitation exist between National Health Service (NHS) Trusts. Although there is no single guideline to guide clinicians, strong evidence does support several clinical measures to be included post-ACLR, to improve outcomes and reduce the need for revision surgery. This project aimed to align our NHS Trust's ACLR physiotherapy care with best-evidence.A literature review was completed to establish key quality standards for ACLR rehabilitation. A retrospective notes audit was then undertaken to quantify the baseline quality of care, measured against these standards. Quality improvement methods were used to improve the quality of care and postoperative rehabilitation processes for ACLR patients. A new evidence-based, postoperative rehabilitation protocol was created, a core group of clinicians was formed to see ACLR patients and a rehabilitation class, solely for ACLR patients was also implemented.The key process measure for the project was patients engaging in 'criteria-driven progressions of rehabilitation'. This 'criteria-driven progressions' rate increased from 0% at baseline to 100% during the project period. Overall, non-attendance rates maintained at a similar level from 5.4% at baseline to a final rate of 4.8%. There was also an increase in mean 'return to sport' times, from 6 to 9.9 months, which is in line with best-evidence recommendations.The previous rehabilitation provided in our trust was not aligned with current evidence. This quality improvement project has led to improvements in patient care and lessons from the project will allow other trusts to learn from the changes made, to improve their own care pathways.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Differential impact of COVID-19 on mental health and burnout
No full textBACKGROUND: There may be differential impact of the COVID-19 pandemic on mental health and burnout rates of healthcare professionals (HCPs) performing different roles. AIMS: To examine mental health and burnout rates, and possible drivers for any disparities between professional roles. METHODS: In this cohort study, online surveys were distributed to HCPs in July-September 2020 (baseline) and re-sent 4 months later (follow-up; December 2020) assessing for probable major depressive disorder (MDD), generalized anxiety disorder (GAD), insomnia, mental well-being and burnout (emotional exhaustion and depersonalization). Separate logistic regression models (at both phases) compared the risk of outcomes between roles: healthcare assistants (HCAs), nurses and midwives (nurses), allied health professionals (AHPs) and doctors (reference group). Separate linear regression models were also developed relating the change in scores to professional role. RESULTS: At baseline (n = 1537), nurses had a 1.9-fold and 2.5-fold increased risk of MDD and insomnia, respectively. AHPs had a 1.7-fold and 1.4-fold increased risk of MDD and emotional exhaustion, respectively. At follow-up (n = 736), the disproportionate risk between doctors and others worsened: nurses and HCAs were at 3.7-fold and 3.6-fold increased risk of insomnia, respectively. Nurses also had a significantly increased risk of MDD, GAD, poor mental well-being and burnout. Nurses also had significantly worsened anxiety, mental well-being and burnout scores over time, relative to doctors. CONCLUSIONS: Nurses and AHPs had excess risk of adverse mental health and burnout during the pandemic, and this difference worsened over time (in nurses especially). Our findings support adoption of targeted strategies accounting for different HCP roles.Published version, accepted version (12 months embrago)1 year embargo from time of publicatio
Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial (RACER-knee): a study protocol
No full textINTRODUCTION: Robotic-assisted knee replacement systems have been introduced to healthcare services worldwide in an effort to improve clinical outcomes for people, although high-quality evidence that they are clinically, or cost-effective remains sparse. Robotic-arm systems may improve surgical accuracy and could contribute to reduced pain, improved function and lower overall cost of total knee replacement (TKR) surgery. However, TKR with conventional instruments may be just as effective and may be quicker and cheaper. There is a need for a robust evaluation of this technology, including cost-effectiveness analyses using both within-trial and modelling approaches. This trial will compare robotic-assisted against conventional TKR to provide high-quality evidence on whether robotic-assisted knee replacement is beneficial to patients and cost-effective for healthcare systems. METHODS AND ANALYSIS: The Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial-Knee is a multicentre, participant-assessor blinded, randomised controlled trial to evaluate the clinical and cost-effectiveness of robotic-assisted TKR compared with TKR using conventional instruments. A total of 332 participants will be randomised (1:1) to provide 90% power for a 12-point difference in the primary outcome measure; the Forgotten Joint Score at 12 months postrandomisation. Allocation concealment will be achieved using computer-based randomisation performed on the day of surgery and methods for blinding will include sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will be reported in line with the Consolidated Standards of Reporting Trials statement. A parallel study will collect data on the learning effects associated with robotic-arm systems. ETHICS AND DISSEMINATION: The trial has been approved by an ethics committee for patient participation (East Midlands-Nottingham 2 Research Ethics Committee, 29 July 2020. NRES number: 20/EM/0159). All results from the study will be disseminated using peer-reviewed publications, presentations at international conferences, lay summaries and social media as appropriate. TRIAL REGISTRATION NUMBER: ISRCTN27624068.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Renal failure as a complication of defunctioning ileostomy: more complexity to a complex decision-making process
No full textPublished version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Total Talus Replacements
No full textBACKGROUND: Total talus replacements are a surgical treatment for talar avascular necrosis (AVN) replacing the entire talus. The potential for total talus replacements has increased with the advent of patient-specific implants using 3D printing based on computed tomographic scanning of the ipsilateral or contralateral talus. The primary aim of this review is to summarize the literature on total talus replacements, providing a historical survey, indications, controversies, complications, survival, and functional outcomes. METHODS: A systematic review was performed. Articles with survival of total talus replacements were included. Basic percentages and a critical review of the literature was performed. RESULTS: Nine articles with 115 patients were included. The mean age ranged from 27.6 to 72 years, but with 5 studies having a mean age of <50 years. Mean follow-up ranged from 12.8 to 152 months. The most common indication was avascular necrosis in 67 patients (58%). Five studies used customized implants and 4 studies used 3D printing. Four studies used ceramic prostheses, 3 cobalt chromium, 1 stainless steel, and 1 titanium with ceramic surface. Three studies involved a talus replacement in conjunction with an ankle replacement. Postoperative complications ranged from 0% to 33%. Of 24 functional outcomes scores, 66.7% demonstrated significant improvement. CONCLUSION: Total talus replacements are a promising alternative to tibiotalocalcaneal fusion for patients with avascular necrosis of the talus; however, further studies are required to ensure reliable outcomes prior to widespread adoption of this technology. LEVEL OF EVIDENCE: Level IV, review of case series.UnknownSupports Open Acces