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Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial
No full textPoly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m(2), weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.CC BY 4.0 (Creative Commons Attribution
Experiences of the Management of Uncertainty Amongst Musculoskeletal First Contact Practitioners Working in Primary Care
No full textAIM: To develop a deeper understanding of strategies used to manage uncertainty by Musculoskeletal First Contact Practitioners (MSK FCPs), including barriers to and facilitators for these strategies. BACKGROUND: MSK FCP services provide patients with an alternative to seeing their GP regarding MSK complaints. Research suggests that the role demands different skills and attributes from traditional physiotherapy roles, including the ability to deal with greater clinical uncertainty. There is a lack of research evaluating the strategies FCPs find most helpful for managing uncertainty. METHOD: A qualitative study using semi-structured online interviews. Participants were recruited using convenience sampling. Data was analysed using Braun & Clarke's reflexive approach to thematic analysis. The research was underpinned by a theoretical framework of hermeneutic phenomenology. FINDINGS: Nine participants were recruited. Three main themes were developed: (1) Being comfortable with being uncomfortable; (2) Teamwork makes the dream work and (3) Navigating uncertainty with patients. CONCLUSION: This study provides further insight into how FCPs manage uncertainty. Management of uncertainty was influenced by many factors, including: clinician experience, patient complexity and wider medical knowledge, fear of over-medicalising patients, communication and consultation styles and having protected non-clinical time. Recommendations for clinical practice include: consideration of the challenges facing FCPs, and what support is needed to maintain staff retention, health and wellbeing; consideration of how FCPs might best approach meeting the needs of an ageing population and supporting change in health and wellness behaviour. The key to successful management of uncertainty was having a supportive team which encouraged open non-judgemental discussions about uncertainty.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits 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
Chest Pain at Rest With Unremarkable ECG and Cardiac Enzymes: Case Study Emphasising the Importance of Clinical Suspicion in the Diagnosis of Coronary Artery Disease
No full textBACKGROUND: Coronary artery disease (CAD), primarily caused by atherosclerosis, is a leading cause of death, presenting as angina or myocardial infarction. Advances in cardiac imaging, angiography, and procedures like percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery have improved early detection and management of this condition. This report presents the case of a man who experienced worsening exertional chest pain and discomfort while at rest. CASE REPORT: A 66-year-old man with a history of neurogenic syncope and asthma presented at the same-day emergency care (SDEC) unit with worsening exertional chest pain and discomfort whilst at rest. Despite normal ECG and cardiac enzyme results, further cardiac computed tomography angiography (CTCA) revealed significant CAD with moderate stenosis in the right coronary artery (RCA) and severe stenosis at the left anterior descending artery (LAD) bifurcation, leading to CABG surgery. Echocardiography showed a left ventricular ejection fraction of 50-54% with mid-inferior and basal to mid-inferoseptal hypokinesia. The cardiology-cardiothoracic multidisciplinary team concluded that CABG surgery would provide the most durable long-term outcome. CONCLUSION: This case demonstrates the high importance of clinical suspicion of CAD despite normal initial investigations in the early identification and timely investigation as well as the role multidisciplinary teams and CABG can play in the timely management of complex CAD, ultimately leading to improved patient outcomes.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
Mapping the Microbial Landscape and Variations Based on Biological Sex, Age and Biopsy Location in the Shoulder Skin Microbiome
No full textBACKGROUND: The organisms responsible for periprosthetic joint infections (PJI) of the shoulder are often skin pathogens originating from the patient's own skin flora at the time of surgery. Understanding the normal skin flora around the shoulder is an important step to identify the range of organisms that could be responsible for PJI, and ensure optimization of culture mediums to identify them. This study aimed to provide the first description of the shoulder skin microbiome using high-throughput next-generation sequencing methodology, and explore variations by age, biological sex and biopsy location. METHODS: Patients undergoing arthroscopic surgery were approached for informed consent to have punch biopsies taken from anterior, lateral and posterior arthroscopy portal sites. DNA extraction was undertaken followed by Illumina sequencing, focusing on the V3-V4 regions of the 16S rRNA gene. Amplicon sequence variants (ASV) were generated using Deblur workflow and used for taxonomic assignment. Variation in the microbiota community based on age, biological sex and biopsy location was assessed through alpha and beta diversity metric calculations using phyloseq R package. RESULT: Sixty-two patients (24 female, 38 male) aged 18 to 80 were recruited, resulting in 186 punch biopsy samples for analysis. Following removal of low-prevalence taxa, 606 ASVs were aggregated at genus level resulting in 214 genera across 13 phyla. The top 20 most abundant genera accounted for 73.5% of the overall sequence count. Cutibacterium was the most abundant genus within the study population, followed by Ralstonia, Staphylococcus, Bacteroides and Streptococcus. Significant differences were observed in beta diversity metrics when comparing by biological sex, which accounted for 3.9%-5.3% of variation in the microbial community, but not age or biopsy location. Males displayed a greater proportion of Gram-positive and aerobic bacteria while females exhibited a greater proportion of Gram-negative and stress tolerant bacteria. CONCLUSION: This is the first study to look specifically at the microbiome of the cutaneous shoulder and describe the most abundant genera and compositional differences based on age, biological sex and biopsy location. Biological sex was the only host co-variant studied which reached significance in explaining microbiota variation. The top 20 most abundant genera, accounting for 74% of the overall sequence count, would be isolated with standard microbiological culture. As such this study does not highlight a need to change current culture investigation practice for shoulder PJI, but serves as an important catalogue of skin commensals around the operative site in shoulder surgery.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
Impact of NICE Guideline NG241 'Ovarian Cancer: identifying and managing familial and genetic risk' on a regional NHS family history and clinical genetics service
No full textBACKGROUND: NICE Guideline NG241: identifying and managing familial and genetic risk of ovarian cancer (OC) was published by the National Institute for Health and Care Excellence (NICE) in March 2024. NG241 advises germline genetic testing of genes predisposing to OC in unaffected individuals with an OC family history at different mutation likelihood thresholds depending on age and sex, ranging from 2% to 10% likelihood of finding a germline pathogenic variant (GPV). Prior to implementation of NG241, updates to the NHS England National Genomic Test Directory would be required. Clinical genetics services have to consider equity of access to assessment and testing across all familial cancer types, best use of their limited resources and other factors such as complexity of delivery of clinical pathways. METHODS: We analysed data from 8011 patients who provided digital family histories to the South West Thames Centre for Genomics between October 2019 and June 2024. RESULTS: We estimate 527/782 (68%) females and 28/77 (36%) males would meet test criteria for NICE NG241. We estimate we would reject 2919/5485 (53%) females and 135/1208 (11%) males with the same likelihood of carrying a GPV, but with a breast cancer rather than OC family history. Testing the familial OC cohort at a universal 5% threshold in OC families would detect ~11 carriers for 229 tests compared with ~8 carriers for 278 tests following NG241 criteria. CONCLUSION: Our data highlight additional factors needing to be considered before the NICE Guideline NG241 can be implemented by regional genetics services.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/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
Digital tools in cardiac reperfusion pathways: A systematic review
No full textWith health and surgery increasingly aided by digital technologies, there exists a growing impetus to understand how such tools must integrate into existing clinical pathways to ensure a positive impact on patient and organisational outcomes. Consequently, this study sought to collate evidence on the use of digital technology in cardiac reperfusion surgeries. We systematically searched three scientific databases for relevant articles. In total, 1,092 articles were retrieved, with 126 screened using inclusion/exclusion criteria, and 21 selected for analysis. Articles reported on the use of virtual reality, mHealth and telehealth in cardiovascular reperfusion procedures, ranging from surgical training regimens to postoperative rehabilitation. Here, despite clinical advantages, limitations were highlighted, including cost, ineffective interfaces and extensive training needed to operate novel digital tools. Nevertheless with further development and input from patient stakeholders, many limitations look set to dematerialise and provide tangible improvements to the benefit of patients and hard-pressed health institutions.Published version (12 month embargo), accepted version (12 month embargo)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
Use of immunomodulators in combination with infliximab in Crohn's disease: time for a reappraisal?
No full textPublished version, accepted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Developmentally dynamic changes in DNA methylation in the human pancreas
No full textDevelopment of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.Published version, accepted 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
Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone
No full textPharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10(-5)). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.Published version, accepted version (6 month embargo), 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 (12 month embargo)
The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification
No full textBACKGROUND: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity. METHODS: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1). RESULTS: PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation. CONCLUSION: PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.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