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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.
BACKGROUND: Medical students' preparedness for clinical practice is well researched, yet little is known on the extent to which students are being prepared for a medical career. This paper reports the construction of a short medical inventory titled eXploring medical sTudents' caReer reAdiness (XTRA) to measure students' career readiness based on Super's theory of career maturity. APPROACH: We designed an instrument consisting of a series of 5-point Likert-scale to identify participants competencies regarding career exploration and planning during their undergraduate studies. The instrument was completed by 348 medical students from 41 universities in the United Kingdom. We examined the validity and reliability of the instrument through Exploratory Factor Analysis, Cronbach's coefficient α and Pearson correlation. EVALUATION: Exploratory Factor Analysis revealed that 16 of the 20-items survey were aligned with the exploration stage of Super's theory: Crystallisation (Career goals), Specification (Career pathways) and Implementation (Career accomplishments). The four items that formed two separate statistical factors were specific to a current medical career in the UK. Internal reliability for Super's factor subscales were acceptable (α = 0.71 to α = 0.81). A significant positive relationship was found between students' overall rating of career readiness and the three factors, indicating construct validity. IMPLICATIONS: The XTRA Inventory is a short instrument with construct and content validity specifically designed to measure career readiness of medical students. Further work on its psychometric properties will help establish this inventory to be used as a guidance and career counselling tool by medical educators and educational institutions in developing career development programmes.
Equity, Diversity and Inclusion (EDI) in Organ Transplantation: An ESOT Survey About EDI Within ESOT as an Organization and its Educational Activities, and Transplantation Research and Science.
The European Society of Organ Transplantation (ESOT) strives to promote equity, diversity, and inclusion (EDI) across all its activities. We surveyed the transplant community's experiences and perspectives regarding EDI within ESOT as an organization and its educational activities, and research in general. A total of 299 respondents completed the questionnaire. About half agreed that ESOT's Executive Committee, Council, and Sections/Committees are diverse and inclusive (51%) and that ESOT promotes EDI in its live and digital educational activities (54%). Forty percent of respondents agreed that scientific and clinical trials in the field of transplantation are diverse and inclusive. Despite the wide distribution of the survey, most of the respondents self-identified as White and were either physician or surgeon. However, the results contribute a unique insight into the experiences and perspectives of the transplantation community regarding EDI. Whilst ESOT is committed to the principles of EDI, perceptions and the high number of proposals show the apparent need to prioritize efforts to embed EDI across ESOT and transplantation science. These data should constitute a starting point for change and provide guidance for future efforts to promote EDI within the transplantation community.
Red blood cells as oxygen carrier during normothermic machine perfusion of kidney grafts: Friend or foe?
Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP.
Banff 2022 Vascularized Composite Allotransplantation Meeting Report: Diagnostic Criteria for Vascular Changes.
As more data becomes available, the Banff 2007 working classification of skin-containing vascularized composite allograft (VCA) pathology is expected to evolve and develop. This report represents the Banff VCA Working Group's consensus on the first revision of the 2007 scoring system. Prior to the 2022 Banff-CST Joint Meeting, eighty-three clinicians and/or researchers were invited to a virtual meeting to discuss whether the 2007 Banff VCA system called for a revision. Unanimously, it was determined that the vascular changes were to be included in the first revision. Subsequently, two international online surveys, each followed by virtual discussions, were launched. The goals were: 1) to identify which changes define severe rejection, 2) to grade their importance in the evaluation of severe rejection, 3) to identify emerging criteria to diagnose rejection. A final hybrid (in person and virtual) discussion at the Banff/CST join meeting finalized the terminology, the definition, a scoring system, and a reporting system of the vascular changes. This proposal represents an international consensus on this topic and establishes the first revision of the Banff 2007 working classification of skin-containing vascularized composite allograft pathology.
Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis, increasing the risk of cerebrovascular complications
The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease, is conceptualized as lipid-driven inflammation in which macrophages play a nonredundant role. However, evidence emerging so far from single-cell atlases suggests a dichotomy between lipid-associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining single-cell RNA sequencing (scRNA-seq) of human surgical carotid endarterectomies in a discovery cohort with bulk RNA-seq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project), we reveal the existence of PLIN2hi/TREM1hi macrophages as a Toll-like receptor (TLR)-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for cardiovascular disease.
Invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ from 1990 to 2018 in England: population based cohort study.
OBJECTIVES: To evaluate the long term risks of invasive breast cancer and death related to breast cancer after non-screen detected ductal carcinoma in situ. Risks for women in the general population and for women diagnosed with ductal carcinoma in situ via the screening programme were compared. DESIGN: Population based cohort study. SETTING: Data from the National Disease Registration Service. PARTICIPANTS: All 27 543 women in England who were diagnosed with ductal carcinoma in situ, outside the NHS breast screening programme, during 1990 to 2018. MAIN OUTCOME MEASURES: Incident invasive breast cancer and death caused by breast cancer. RESULTS: By 31 December 2018, 3651 women with non-screen detected ductal carcinoma in situ had developed invasive breast cancer, more than four times higher than expected from national cancer incidence rates (ratio of observed to expected rate was 4.21 (95% conference interval 4.07 to 4.35)). The ratio of observed to expected rate of developing invasive breast cancer remained increased throughout follow-up among women aged <45-70 years. The 25 year cumulative risks of invasive breast cancer by age at diagnosis of ductal carcinoma in situ were 27.3% for <45 years, 25.2% for 45-49 years, 21.7% for 50-59 years, and 20.8% for 60-70 years. 908 women died of breast cancer, almost four times higher than that expected from breast cancer death rates in the general population (ratio of observed to expected rate 3.83 (3.59 to 4.09)). The ratio of observed to expected rate of mortality attributed to breast cancer remained increased throughout follow-up. The 25 year cumulative risks of breast cancer death by age at ductal carcinoma in situ diagnosis were 7.6% for <45 years, 5.8% for 45-49 years, 5.9% for 50-59 years, and 6.2% for 60-70 years. Among women aged 50-64 years, and therefore eligible for breast screening by the NHS, the ratio of observed to expected rate of invasive breast cancer in women with non-screen detected compared with screen detected ductal carcinoma in situ was 1.26 (95% conference interval 1.17 to 1.35), while the ratio for mortality from breast cancer was 1.37 (1.17 to 1.60). Among 22 753 women with unilateral ductal carcinoma in situ undergoing surgery, those who had mastectomy rather than breast conserving surgery had a lower 25 year cumulative rate of ipsilateral invasive breast cancer (mastectomy 8.2% (95% conference interval 7.0% to 9.4%), breast conserving surgery with radiotherapy 19.8% (16.2% to 23.4%), and breast conserving surgery with no radiotherapy recorded 20.6% (18.7% to 22.4%)). However, reductions did not translate into a lower 25 year cumulative rate of deaths attributable to breast cancer (mastectomy 6.5% (4.9% to 10.9%), breast conserving surgery with radiotherapy 8.6% (5.9% to 15.5%), breast conserving surgery with no radiotherapy recorded 7.8% (6.3% to 11.5%)). CONCLUSIONS: For at least 25 years after their diagnosis, women with non-screen detected ductal carcinoma in situ had higher long term risks of invasive breast cancer and breast cancer death than women in the general population. Additionally, they had higher long term risks than women with screen detected ductal carcinoma in situ. Mastectomy was associated with lower risks of invasive breast cancer than breast conserving surgery, even when accompanied by radiotherapy. However, risks of breast cancer death appeared similar for mastectomy, breast conserving surgery with radiotherapy, and breast conserving surgery with no radiotherapy recorded.
Aim: Despite its abundance in pancreatic islets of Langerhans and proven antihyperglycemic effects, the impact of the essential amino acid, taurine, on islet β-cell biology has not yet received due consideration, which prompted the current studies exploring the molecular selectivity of taurine import into β-cells and its acute and chronic intracellular interactions. Methods: The molecular aspects of taurine transport were probed by exposing the clonal pancreatic BRIN BD11 β-cells and primary mouse and human islets to a range of the homologs of the amino acid (assayed at 2–20 mM), using the hormone release and imaging of intracellular signals as surrogate read-outs. Known secretagogues were employed to profile the interaction of taurine with acute and chronic intracellular signals. Results: Taurine transporter TauT was expressed in the islet β-cells, with the transport of taurine and homologs having a weak sulfonate specificity but significant sensitivity to the molecular weight of the transporter. Taurine, hypotaurine, homotaurine, and β-alanine enhanced insulin secretion in a glucose-dependent manner, an action potentiated by cytosolic Ca2+ and cAMP. Acute and chronic β-cell insulinotropic effects of taurine were highly sensitive to co-agonism with GLP-1, forskolin, tolbutamide, and membrane depolarization, with an unanticipated indifference to the activation of PKC and CCK8 receptors. Pre-culturing with GLP-1 or KATP channel inhibitors sensitized or, respectively, desensitized β-cells to the acute taurine stimulus. Conclusion: Together, these data demonstrate the pathways whereby taurine exhibits a range of beneficial effects on insulin secretion and β-cell function, consistent with the antidiabetic potential of its dietary low-dose supplementation.
Molecular Anatomy of Prostate Cancer and Its Implications in Active Surveillance and Early Intervention Strategies
Understanding prostate carcinogenesis is crucial not only for identifying new treatment targets but also for developing effective strategies to manage the asymptomatic form of the disease. There is a lack of consensus about predicting the indolent form of the disease prostate cancer, leading to uncertainties regarding treatment initiation. This review aims to enhance the assessment and management of early prostate cancer by providing a comprehensive picture of the molecular anatomy of the prostate, synthesising current evidence, highlighting knowledge gaps, and identifying future directions. It presents evidence for the efficacy of active surveillance as an alternative treatment strategy and its potential benefits in specific patient groups through androgen receptor disruption. Overall, an improved understanding of prostate carcinogenesis and its molecular underpinnings can pave the way for tailored and precise management approaches for this common cancer. Further development and validation of molecule-based assessment tools are needed. Integrating genomic, proteomic, and phenotypic models, as well as functional approaches, can help predict outcomes. This facilitates selecting candidates for active surveillance and targeting interventions for higher-risk cases, contributing to more precise management strategies.
Effect of planned pauses versus continuous energy restriction on weight loss and attrition: a systematic review.
OBJECTIVE: The objective of this study was to investigate whether pausing a weight loss program for a defined period of time could enhance weight loss and reduce attrition. METHODS: Five databases and two trial registries were searched from inception to July 2023. Randomized-controlled trials of adults with overweight and/or obesity were included if they compared planned-pause interventions with continuous energy restriction (CER), usual care, or a minimal intervention. To be included, the weight loss intervention must have incorporated a pause of at least 1 week. Pooled mean differences for weight change and risk ratios for attrition were calculated using random-effects meta-analyses. RESULTS: Nine intervention arms (N = 796 participants, 77% female) were included. Pooled results did not detect a significant difference in weight change between planned pauses and CER interventions at the end of the active intervention at a median 26 weeks (planned pauses vs. CER mean: -7.09 vs. -7.0 kg; mean difference: -0.09 kg; 95% CI: -1.10 to 0.93) or at final follow-up at a median 52 weeks (planned pauses vs. CER mean: -6.91 vs. -6.19 kg; mean difference: -0.72 kg; 95% CI: -2.92 to 1.48). There was no difference in attrition between planned pauses and CER interventions at the end of the active intervention (risk ratio: 1.20, 95% CI: 0.82 to 1.75) or at final follow-up (risk ratio: 1.04, 95% CI: 0.89 to 1.22). CONCLUSIONS: Planned pauses were consistently found to be no more or less effective than CER for weight loss or attrition.
Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.
Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden1,2 with a heritability of ~45-60%3. To identify genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations, including 12,123 nephrolithiasis cases and 416,928 controls. Twenty loci associated with nephrolithiasis were identified, ten of which are novel. A novel CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of nephrolithiasis patients the CYP24A1-associated locus correlated with serum calcium concentration and number of kidney stone episodes, and the DGKD-associated locus correlated with urinary calcium excretion. Moreover, DGKD knockdown impaired CaSR-signal transduction in vitro, an effect that was rectifiable with the calcimimetic cinacalcet. Our findings indicate that genotyping may inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR-signaling or vitamin D activation pathways in patients with recurrent kidney stones.
The IDEAL framework for surgical robotics: development, comparative evaluation and long-term monitoring.
The next generation of surgical robotics is poised to disrupt healthcare systems worldwide, requiring new frameworks for evaluation. However, evaluation during a surgical robot's development is challenging due to their complex evolving nature, potential for wider system disruption and integration with complementary technologies like artificial intelligence. Comparative clinical studies require attention to intervention context, learning curves and standardized outcomes. Long-term monitoring needs to transition toward collaborative, transparent and inclusive consortiums for real-world data collection. Here, the Idea, Development, Exploration, Assessment and Long-term monitoring (IDEAL) Robotics Colloquium proposes recommendations for evaluation during development, comparative study and clinical monitoring of surgical robots-providing practical recommendations for developers, clinicians, patients and healthcare systems. Multiple perspectives are considered, including economics, surgical training, human factors, ethics, patient perspectives and sustainability. Further work is needed on standardized metrics, health economic assessment models and global applicability of recommendations.
Background There is debate whether the use of more arterial grafts during coronary artery bypass graft surgery provides advantages to the standard operation using the left internal thoracic artery plus vein grafts. We review data from the Arterial Revascularisation Trial to determine whether there is support for the multiple arterial graft hypothesis. Methods Patients undergoing coronary artery bypass graft for clinical reasons and who provided written informed consent were randomised to standard coronary artery bypass graft using the single internal thoracic artery or use of bilateral internal thoracic arteries. Additional vein grafts could be used. The primary outcome was all-cause mortality at 10 years and exploratory analyses were carried out to test the multiple arterial graft hypothesis. Results A total of 3102 patients were enrolled (1548 bilateral internal thoracic artery and 1554 single internal thoracic artery). Follow-up to 10 years for vital status was 98% complete. In the bilateral group, 14% of patients received a single internal thoracic artery only and use of radial artery grafts occurred in about 20% of patients in both groups. Aspirin was used in 81% of the patients, beta-blockers in 74%, statins in 90% and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 73%. At 10 years, death rates were 20.3% and 21.2% in the bilateral internal thoracic artery and single internal thoracic artery groups, respectively (hazard ratio 0.96, 95% confidence intervals 0.82 to 1.12; p = 0.62) and composite of all-cause mortality, myocardial infarction or stroke 24.9% and 27.3%, respectively (hazard ratio 0.90, 95% confidence interval 0.79 to 1.03; p = 0.12). Exploratory analyses using the ‘as-treated’ approach indicate that outcomes were better in patients who received multiple arterial grafts (adding the right internal thoracic and/or radial arteries) compared with a single arterial graft. This effect appeared to be greater in patients with diabetes and those aged 70 years or less. Use of total arterial grafting without vein grafts may provide the best outcomes. Limitations The elevated cross-over rate between bilateral internal thoracic artery and single internal thoracic artery and the non-randomised use of radial artery grafts may have contributed to a loss of power to detect a difference in mortality between the two groups. Moreover, secondary analyses are prone to bias as they compare non-randomised groups. Conclusions The Arterial Revascularisation Trial is one of the largest long-term studies in cardiac surgery. The primary analysis did not show a mortality benefit for bilateral internal thoracic artery at 10 years, perhaps due to high crossover rates in the bilateral internal thoracic artery group and concomitant use of the radial artery. Secondary analyses suggest a mortality benefit for patients receiving multiple arterial grafts compared with single arterial graft with possible greater effects in patients with diabetes and separately in patients aged 70 years or above. The trial will follow patients to 15 years and the continuing Randomized Comparison of the Clinical Outcome of Single versus Multiple Arterial Grafts trial will further test the multiple arterial graft hypothesis. Trial registration This trial is registered as ISRCTN46552265. Funding This project was funded by the British Heart Foundation, the UK. Medical Research Council and the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 7. See the NIHR Journals Library website for further project information.