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Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol
No full textBACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged = 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.Published versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Of oranges and lemons: you are what you eat
No full textA young boy presented with increasing lower limb pain and swelling for a month. At the time of his hospitalisation, he was unable to walk. We report the patient's clinical journey with clinical commentary throughout, highlighting the importance that uncommon diseases may be diagnosed with a high index of suspicion and thorough history taking.Published version, accepted version, submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Availability, cost and affordability of essential medicines for chronic respiratory diseases in low-income and middle-income countries: a cross-sectional study
No full textContemporary data on the availability, cost and affordability of essential medicines for chronic respiratory diseases (CRDs) across low-income and middle-income countries (LMICs) are missing, despite most people with CRDs living in LMICs. Cross-sectional data for seven CRD medicines in pharmacies, healthcare facilities and central medicine stores were collected from 60 LMICs in 2022-2023. Medicines for symptomatic relief were widely available and affordable, while preventative treatments varied widely in cost, were less available and largely unaffordable. There is an urgent need to address these issues if the Sustainable Development Goal 3 is to be achieved for people with asthma by 2030.Published version, accepted version, 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
Detection and characterization of copy-number variants from exome sequencing in the DDD study
No full textPURPOSE: Structural variants such as multiexon deletions and duplications are an important cause of disease but are often overlooked in standard exome/genome sequencing analysis. We aimed to evaluate the detection of copy-number variants (CNVs) from exome sequencing (ES) in comparison with genome-wide low-resolution and exon-resolution chromosomal microarrays (CMAs) and to characterize the properties of de novo CNVs in a large clinical cohort. METHODS: We performed CNV detection using ES of 9859 parent-offspring trios in the Deciphering Developmental Disorders (DDD) study and compared them with CNVs detected from exon-resolution array comparative genomic hybridization in 5197 probands from the DDD study. RESULTS: Integrating calls from multiple ES-based CNV algorithms using random forest machine learning generated a higher quality data set than using individual algorithms. Both ES- and array comparative genomic hybridization-based approaches had the same sensitivity of 89% and detected the same number of unique pathogenic CNVs not called by the other approach. Of DDD probands prescreened with low-resolution CMAs, 2.6% had a pathogenic CNV detected by higher-resolution assays. De novo CNVs were strongly enriched in known DD-associated genes and exhibited no bias in parental age or sex. CONCLUSION: ES-based CNV calling has higher sensitivity than low-resolution CMAs currently in clinical use and comparable sensitivity to exon-resolution CMA. With sufficient investment in bioinformatic analysis, exome-based CNV detection could replace low-resolution CMA for detecting pathogenic CNVs.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo
The Effect of Postoperative Analgesia on the Day-Case Rate of Laparoscopic Cholecystectomy: A Randomised Pilot Study of the Laparoscopic-Assisted Right Subcostal Transversus Abdominis Plane Block plus Local Anaesthetic Wound Infiltration versus Local Anaesthetic Wound Infiltration only
No full textOBJECTIVE: The transversus abdominis plane (TAP) block and local anaesthetic infiltration (LAI) of port sites provide adequate analgesia after laparoscopic cholecystectomy (LC). Little is known if the two techniques affect the day-case (DC) rate of LC. We tested the appropriateness of the research design in view of a larger randomised controlled trial (RCT) - laparoscopic-assisted right subcostal TAP block plus local anaesthetic wound infiltration (STALA) versus LAI. SUBJECTS AND METHODS: Sixty patients having DC LC were randomised into STALA and LAI. Participants received bupivacaine 0.5% 30 mL. Pain scores were evaluated with the Visual Analogue Scale (VAS) score, at 1 h post-surgery and at discharge. Need of postoperative intravenous (IV) opioids, DC rate, and Quality of Recovery-15 questionnaires were compared between groups and were considered as measures of efficacy of the interventions and follow-up in a definitive trial. RESULTS: Twenty-nine participants were randomised to STALA, and 31 to LAI. Subjects in LAI group were all women (p = 0.0007) and younger (43.8 vs. 37.7 years, p = 0.023). Median VAS scores were 0 versus 1 at 1 h (p = 0.60), 0 versus 1.5 at discharge (p = 0.55). The need of IV opioids was 15/29 (51.7%) versus 13/31 (41.9%; p = 0.60). The DC rate was 93.1% versus 93.5% (p = 0.39). Fifty (83.3%) participants responded the questionnaires. CONCLUSIONS: The laparoscopically guided right subcostal TAP block provided no additional benefit to LAI on pain control after LC and DC rate. Despite the appropriate design, our findings do not support a larger RCT.This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.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
Digital innovation for cancer risk assessment allows large-scale service redevelopment of regional cancer genetics service delivery
No full textFamily-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.Unknown1 year embargo from time of publicatio
Unwarranted variation and the goal of net zero for the NHS in England: exploring the link between efficiency working, patient outcomes and carbon footprint
No full textIn 2020 the NHS in England set a target of reaching net zero carbon emissions by 2040. Progress has already been made towards this goal, with substantial reductions in the use of environmentally harmful anaesthetic gases, such as desflurane, in recent years. Where an effective replacement already exists, changing practice to use low carbon alternatives is relatively easy to achieve, but much greater challenges lie ahead. The Getting It Right First Time (GIRFT) programme is a clinically-led, data-driven clinical improvement initiative with a focus on reducing unwarranted variation in clinical practice and patient outcomes. Reducing unwarranted variation can improve patient care and service efficiency, and can also support the drive to net zero. In this article we set out what the GIRFT programme is doing to support sustainable healthcare in England, why it is uniquely positioned to support this goal and what the future challenges, barriers, enablers and opportunities are likely to be in the drive to net zero.Accepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Impact of Reductive Stress on Human Infertility: Underlying Mechanisms and Perspectives
No full textAntioxidants have a well-established effect on general health and are essential in preventing oxidative damage to cells by scavenging free radicals. Free radicals are thought to be neutralized by these substances, which include polyphenols, β-carotene, and vitamins C and E, reducing cellular damage. On the other hand, recent data indicates that consuming excessive amounts of antioxidants may have side effects. Apoptosis and cell signaling are two beneficial physiological processes that are affected by excessive supplementation. Other negative effects include paradoxical enhancement of oxidative stress and unbalanced cellular redox potential. Overdosing on particular antioxidants has been associated with increased medication interactions, cancer progression, and fatality risks. Additionally, the complex impacts they may have on fertility might be both useful and adverse, depending on the quantity and duration of usage. This review delves into the dual role of antioxidants and emphasizes the importance of employing antioxidants in moderation. Antioxidant overconsumption may disrupt the oxidative balance necessary for normal sperm and oocyte function, which is one of the potential negative effects of antioxidants on fertility in both males and females that are also investigated. Although modest usage of antioxidants is generally safe and useful, high levels of antioxidants can upset hormonal balance, impair sperm motility, and negatively impact the outcomes of assisted reproductive technologies (ART). The findings emphasize the need to use antioxidant supplements in a balanced way, the importance of further research to optimize their use in fertility treatments, and the importance of supporting reproductive health to avoid adverse effects.Journal content freely available via Open Access. Some content may be unavailable due to publisher embarg
Recurrent patellar dislocation: personalised therapy or operative treatment? The REPPORT randomised trial protocol
No full textINTRODUCTION: Recurrent patellar dislocation is a debilitating musculoskeletal condition, affecting mainly adolescents and adults under the age of 30. It can persist for many decades, causing pain and cartilage and soft-tissue damage, potentially leading to osteoarthritis. Recurrent patellar dislocation can be managed with physiotherapy or surgery. However, it is not known which treatment is most effective. METHODS AND ANALYSIS: Recurrent Patellar Dislocation: Personalised Therapy or Operative Treatment (REPPORT) is a pragmatic, multicentre, two-arm, superiority, randomised controlled trial. It will compare the clinical and cost-effectiveness of an initial management strategy of personalised, phased and progressive rehabilitation, termed personalised knee therapy versus surgery for recurrent patellar dislocation.The trial's target sample size is 276 participants who will be recruited from approximately 20 sites across the UK. Participants will be randomly allocated to the two treatment groups via a central computer-based minimisation system. Treatment allocation will be in a 1:1 ratio, stratified by age, presence of patella alta and recruitment site.The primary outcome is participant-reported function using the Knee injury and Osteoarthritis Outcome 4-domain score at 18 months post randomisation. Health economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including patellar instability, health utility, work/education status, satisfaction with social roles and treatment, health resource use and adverse events will be collected at 6, 12, 18 and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the East Midlands-Nottingham 2 Research Ethics Committee on 30 March 2023.Results will be disseminated via peer-reviewed publications, presentations at national and international conferences, in lay summaries, and using the REPPORT website and social media channels. TRIAL REGISTRATION NUMBER: ISRCTN17972668.Published version, accepted version, 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
Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
No full textSequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene is commonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiology of this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmental diseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected by the HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore, experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derived cells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstrate that HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability of the autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1 axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 in autophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder and Angelman syndrome.Published versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embarg