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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Effect of a Laparoscopic Donor Nephrectomy in Healthy Living Kidney Donors on the Acute Phase Response Using Either Propofol or Sevoflurane Anesthesia
Surgical trauma elicits a complex inflammatory stress response, contributing to postoperative morbidity and recovery variability. This response is influenced by patient-specific factors and surgical and anesthetic techniques. To isolate the impact of anesthesia on the acute phase response, we investigated plasma proteomic changes in a uniquely homogeneous cohort of healthy, living kidney donors (n = 36; propofol = 19; sevoflurane = 17) undergoing laparoscopic donor nephrectomy. Proteomic profiling of plasma samples collected preoperatively and at 2 and 24 h postoperatively revealed 633 quantifiable proteins, of which 22 showed significant perioperative expression changes. Eight proteins exhibited over two-fold increases, primarily related to the acute phase response (CRP, SAA1, SAA2, LBP), tissue repair (FGL1, A2GL), and anti-inflammatory regulation (AACT). These changes were largely independent of anesthetic type, though SAA2 and MAN1A1 showed anesthetic-specific expression. The upregulation of these proteins implicates the activation of immune pathways involved in host defense, tissue remodeling, and inflammation resolution. Our findings provide a molecular reference for the surgical stress response in healthy individuals and highlight candidate biomarkers for predicting and managing postoperative outcomes. Understanding these pathways may support the development of strategies to mitigate surgical stress and enhance recovery, particularly in vulnerable patient populations.
Size Matters: Micro v. Nanobubbles in Ultrasound Imaging and Therapy Dataset
This data was created using a mix of theoretical modelling, computational analysis of images, sizing instruments and ultrasound data. Full details are in the associated paper.
Associations Between Lactate Thresholds and 2000 m Rowing Ergometer Performance: Implications for Prediction-A Systematic Review.
BACKGROUND: Various exercise thresholds have been evaluated to predict athlete performance. However, a systematic review of the literature assessing the association between lactate-based exercise thresholds and 2000 m rowing ergometer performance is still lacking. These may have utility in the prediction of 2000 m rowing ergometer performance due to the close relationship between metabolic parameters and development of endurance capacity. The aim of the present study is to review and assess the extent, quality, and reliability of lactate-based exercise testing and methodologies in their association with 2000 m rowing ergometer performance, and to discuss the potential implications for performance prediction. METHODS: The systematic review was performed following PRISMA 2020 guidelines. The databases searched were EMBASE, MEDLINE and SPORTDiscus. The initial search took place in July 2022, with an update search performed in September 2023, and again in August 2024. Studies which reported a lactate test and its correlation to 2000 m ergometer performance were included. No meta-analysis was performed. RESULTS: Twenty-four studies comprising 797 athletes (513 male, 257 female, 27 not stated) met the eligibility criteria for inclusion in the review. The most commonly used testing protocol involved the use of incremental step-tests. A range of exercise intensity parameters, lactate-based exercise thresholds and interpretation methodologies were employed. Of these, the power or velocity at a blood lactate concentration of 4 mmol l-1 was the most common test, with correlation coefficients ranging from 0.53 to 0.96 suggesting that 28-92% of the variance in rowing performance can be explained by this metric. Six studies that rated as GOOD on the risk of bias assessment found very strong correlations > 0.85 (p
The 6 Minute Walk Test as a predictor of mortality in idiopathic pulmonary fibrosis: A systematic review.
BACKGROUND: The 6-min walk test (6MWT) is frequently used in pulmonary fibrosis (PF) research. It evaluates an individual's sub-maximal exercise performance by measuring the distance they walk and their vital signs across 6 min. In research studies, the 6-min walk distance (6MWD) is often used as a surrogate marker for disease progression. The aim of this study was to systematically assess the association between 6MWT parameters and mortality in PF. METHODS: MEDLINE, EMBASE, CINAHL, and CENTRAL databases were searched for studies reporting mortality and 6MWD in patients with PF. Study quality was assessed using a modified Newcastle-Ottawa Scale. Studies were included if they reported associations between the 6MWT in pulmonary fibrosis and mortality. Results were presented as a narrative synthesis. RESULTS: 2312 studies were identified, 22 studies met the pre-defined inclusion criteria, comprising 5940 Idiopathic PF patients. Baseline 6MWD was found to be loosely associated with mortality (Ranges: univariate HR 0.89-4.72, multivariate HR 0.96-2.65), while a decrease in 6MWD across 24-weeks was correlated with a higher risk of mortality (Ranges: univariate HR 2.25-4.81, multivariate HR 1.72-4.3). DISCUSSION: This review found that a low baseline 6MWD, and a 6-month decrease in 6MWD were strongly correlated with increased mortality in Idiopathic PF patients. As the 6MWT is a safe, easy-to-conduct test, it is appropriate for use as a marker of patient prognosis, in both clinical and research settings. OPEN SCIENCE FRAMEWORK PROTOCOL REGISTRATION: DOI 10.17605/OSF.IO/3D7BV.
Identification of recurrences in women diagnosed with early invasive breast cancer using routinely collected data in England.
BACKGROUND: Breast cancer is the commonest cancer in the UK, with around 55,000 women diagnosed annually. Information is routinely available on breast cancer mortality but not on recurrence. METHODS: We used a database compiled by the West Midlands Cancer Intelligence Unit during 1997-2011 to develop and train a deterministic algorithm to identify recurrences in routinely collected data (RCD) available within NHS England. We trained the algorithm further using 150 women with stage II-III breast cancer who were recruited into the AZURE trial during 2003-2006 and invited to approximately 24 clinic follow-up visits over ten years. We then evaluated its performance using data for the remaining 1930 women in England in the AZURE trial. RESULTS: The sensitivity of the RCD to detect distant recurrences recorded in the AZURE trial during the ten years following randomisation was 95.6% and its sensitivity to detect any recurrence was 96.6%. The corresponding specificities were 91.9% for distant recurrence and 77.7% for any recurrence. CONCLUSIONS: These findings demonstrate the potential of routinely collected data to identify breast cancer recurrences in England. The algorithm may have a role in several settings and make long-term follow-up in randomised trials of breast cancer treatments more cost-effective.
Regulatory T cell therapy is associated with distinct immune regulatory lymphocytic infiltrates in kidney transplants.
BACKGROUND: Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study (ClinicalTrials.gov: NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression. METHODS: We present 7 years of follow-up data on patients treated with adoptive Treg therapy early post-transplantation who exhibited focal lymphocytic infiltrates on a 9-month protocol biopsy. We phenotyped their adoptively transferred and peripherally circulating Treg compartments using CITE-seq and investigated the focal lymphocytic infiltrates with spatial proteomic and transcriptomic technologies. FINDINGS: Graft survival rates were not significantly different between Treg-treated patients and the control reference group. None of the Treg-treated patients experienced clinical rejection episodes or developed de novo donor-specific antibodies, and three of ten successfully reduced their immunosuppression to tacrolimus monotherapy. All Treg-treated patients who underwent a protocol biopsy 9 months post-transplantation exhibited focal lymphocytic infiltrates. Spatial profiling analysis revealed prominent CD20+ B cell and regulatory (IKZF2, IL10, PD-L1, TIGIT) signatures within cell-therapy-associated immune infiltrates, distinct from the pro-inflammatory myeloid signature associated with rejection biopsies. CONCLUSIONS: We demonstrate for the first time that immune cell infiltrates in transplanted kidneys can occur following adoptive Treg therapy in humans, potentially facilitating within-graft T:B cell interactions that promote local immune regulation. FUNDING: This work was funded by the 7th EU Framework Programme, grant/award no. 260687, and the National Institute for Health Research (NIHR).
Gene editing of CD3 epsilon to redirect regulatory T cells for adoptive T cell transfer.
Adoptive transfer of antigen-specific regulatory T cells (Tregs) is a promising strategy to combat immunopathologies in transplantation and autoimmune diseases. However, their low frequency in peripheral blood poses challenges for both manufacturing and clinical application. Chimeric antigen receptors have been used to redirect the specificity of Tregs, using retroviral vectors. However, retroviral gene transfer is costly, time consuming, and raises safety issues. Here, we explored non-viral CRISPR-Cas12a gene editing to redirect Tregs, using human leukocyte antigen (HLA)-A2-specific constructs for proof-of-concept studies in transplantation models. Knock-in of an antigen-binding domain into the N terminus of CD3 epsilon (CD3ε) gene generates Tregs expressing a chimeric CD3ε-T cell receptor fusion construct (TRuC) protein that integrates into the endogenous TCR/CD3 complex. These CD3ε-TRuC Tregs exhibit potent antigen-dependent activation while maintaining responsiveness to TCR/CD3 stimulation. This enables preferential enrichment of TRuC-redirected Tregs over CD3ε knockout Tregs via repetitive CD3/CD28 stimulation in a good manufacturing practice-compatible expansion system. CD3ε-TRuC Tregs retained their phenotypic, epigenetic, and functional identity. In a humanized mouse model, HLA-A2-specific CD3ε-TRuC Tregs demonstrate superior protection of allogeneic HLA-A2+ skin grafts from rejection compared with polyclonal Tregs. This approach provides a pathway for developing clinical-grade CD3ε-TRuC-based Treg cell products for transplantation immunotherapy and other immunopathologies.
Barriers to Treg therapy in Europe: From production to regulation.
There has been an increased interest in cell based therapies for a range of medical conditions in the last decade. This explosion in novel therapeutics research has led to the development of legislation specifically focused on cell and gene based therapies. In Europe, the European medicines agency (EMA) designates any medicines for human use which are based on genes, tissues, or cells as advanced therapy medicinal products or advanced therapy medicinal products (ATMPs). In this article we discuss the hurdles to widespread adoption of ATMPs in Europe, with a focus on regulatory T cells (Tregs). There are numerous barriers which must be overcome before mainstream adoption of Treg therapy becomes a reality. The source of the cells, whether to use autologous or allogenic cells, and the methods through which they are isolated and expanded, must all meet strict good manufacturing practice (GMP) standards to allow use of the products in humans. GMP compliance is costly, with the equipment and reagents providing a significant cost barrier and requiring specialized facilities and personnel. Conforming to the regulations set centrally by the EMA is difficult, and the different interpretations of the regulations across the various member states further complicates the regulatory approval process. The end products then require a complex and robust distribution network to ensure timely delivery of potentially life saving treatments to patients. In a European market whose logistics networks have been hammered by COVID and Brexit, ensuring rapid and reliable delivery systems is a more complex task than ever. In this article we will examine the impact of these barriers on the development and adoption of Tregs in Europe, and potential approaches which could facilitate more widespread use of Tregs, instead of its current concentration in a few very specialized centers.
Patients’ priorities in kidney stone disease
Engaging with patients and the public is essential to design and deliver impactful research. Enhancing the relevance of research and tailoring treatments to align with patients’ preferences can facilitate improved clinical care. We aimed to identify the research, support, and treatment priorities of individuals with kidney stone disease (KSD) using a 25-question survey in inpatient and outpatient urology departments. Forty-four individuals with KSD responded to our survey; 28 (64%) had experienced multiple KSD episodes and 11 reported five or more episodes. Median self-rated quality-of-life (QoL) impact (0=negligible, 10=severe) was 7.00/10.00 [IQR:5.00–9.00],equivalent in individuals with single and recurrent stone episodes. Pain (N=34), haematuria (N=28), and anxiety (N=22) were the primary factors contributing to QoL impact. Participants prioritised research into preventing recurrence, alleviating pain, and slowing stone growth. Over one third desired more information about KSD. Most (N=36) felt “likely” or “very likely” to take medication to reduce their risk of KSD and 25 would commit to life-long therapy. Daily dosing was acceptable to 13 participants if risk of KSD recurrence was reduced by 50%, rising to 34 respondents if risk of recurrence was reduced by 75%. Most respondents (N=44) expressed willingness to have genetic testing to facilitate personalised medicine research. Our findings emphasise symptoms contributing to reduced physical and psychological wellbeing in patients with KSD. We highlight the need for research into developing therapies to prevent stone recurrence, alleviate pain, and slow stone growth, and for educational materials. Responses indicate an appetite for personalised medicine and oral medications in KSD.
Characterisation of HBV and co-infection with HDV and HIV through spatial transcriptomics.
BACKGROUND AND AIMS: The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection. METHOD: The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions. RESULTS: Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including 'cytotoxicity' and 'B cell receptor signalling' were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression. CONCLUSION: This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.
Trends in Investigations for Suspected Head and Neck Carcinoma of the Unknown Primary: A HNCIG and IFHNOS International Survey of Practice
Background: The aim of this clinical survey was to assess variations in head and neck squamous cell carcinoma from an unknown primary (HNSCCUP) diagnostic practices across international centers. Methods: Clinical practice survey of experts nominated by Head and Neck Cancer International Group (HNCIG) and International Federation of Head and Neck Oncologic Societies (IFHNOS). Results: Responses were received from 48/49 (97.9%) participants. Outpatient laryngoscopy, CT, and 18-FDG-PETCT were used always or most of the time by 81.3%, 77.1%, and 79.2%, but only 50% regularly used MRI. Unilateral and bilateral tonsillectomy were frequently performed in 41.6% and 27.1% of unilateral nodal disease, and in 18.8% and 52.1% for bilateral disease. Ipsilateral Tongue Base Mucosectomy (TBM) was used always or most of the time in 12.5% of unilateral and 6.3% of bilateral HNSCCUP. Bilateral TBM was used in 10.4% for unilateral and 22.9% for bilateral cancers. Conclusions: While there is broad agreement regarding examination and cross-sectional imaging, there are considerable differences in the surgical strategies used to identify occult primaries.