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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.
To keep the transplantation community informed about recently published level 1 evidence in organ transplantation, ESOT (https://esot.org/) and the Centre for Evidence in Transplantation (https://www.transplantevidence.com/) have developed the Transplant Trial Watch. The Transplant Trial Watch is a monthly overview of 10 new randomized controlled trials (RCTs) and systematic reviews. This page of Transplant International offers commentaries on methodological issues and clinical implications on two articles of particular interest from the CET Transplant Trial Watch monthly selection. For all high-quality evidence in solid organ transplantation, visit the Transplant Library (www.transplantlibrary.com).
Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation
The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability—and ambiguity—in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.
Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation
Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.
Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient’s circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non–HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.
Objective: To implement and evaluate the use of the conflict management framework (CMF) in four tertiary UK paediatric services. Design: Mixed methods multisite evaluation including prospective pre and post intervention collection of conflict data alongside semistructured interviews. Setting: Eight inpatient or day care wards across four tertiary UK paediatric services. Interventions: The two-stage CMF was used in daily huddles to prompt the recognition and management of conflict. Results: Conflicts were recorded for a total of 67 weeks before and 141 weeks after implementation of the CMF across the four sites. 1000 episodes of conflict involving 324 patients/families across the four sites were recorded. After implementation of the CMF, time spent managing episodes of conflict around the care of a patient was decreased by 24% (p<0.001) (from 73 min to 55 min) and the estimated cost of this staff time decreased by 20% (p<0.02) (from £26 to £21 sterling per episode of conflict). This reduction occurred despite conflict episodes after implementation of the CMF having similar severity to those before implementation. Semistructured interviews highlighted the importance of broad multidisciplinary leadership and training to embed a culture of proactive and collaborative conflict management. Conclusions: The CMF offers an effective adjunct to conflict management training, reducing time spent managing conflict and the associated staff costs.
BACKGROUND: Leadership is increasingly being recognised as an essential requirement for doctors. Many medical schools are in the process of developing formal leadership training programmes, but it remains to be elucidated what characteristics make such programmes effective, and to what extent current programmes are effective, beyond merely positive learner reactions. This review's objective was to investigate the effectiveness of undergraduate medical leadership curricula and to explore common features of effective curricula. METHODS: A systematic literature search was conducted. Articles describing and evaluating undergraduate medical leadership curricula were included. Outcomes were stratified and analysed according to a modified Kirkpatrick's model for evaluating educational outcomes. RESULTS: Eleven studies met inclusion criteria. Leadership curricula evaluated were markedly heterogeneous in their duration and composition. The majority of studies utilised pre- and post- intervention questionnaires for evaluation. Two studies described randomised controlled trials with objective measures. Outcomes were broadly positive. Only one study reported neutral outcomes. CONCLUSIONS: A wide range of leadership curricula have shown subjective effectiveness, including short interventions. There is limited objective evidence however, and few studies have measured effectiveness at the system and patient levels. Further research is needed investigating objective and downstream outcomes, and use of standard frameworks for evaluation will facilitate effective comparison of initiatives.
Guidance for Health Care Leaders During the Recovery Stage of the COVID-19 Pandemic: A Consensus Statement.
Importance: The COVID-19 pandemic is the greatest global test of health leadership of our generation. There is an urgent need to provide guidance for leaders at all levels during the unprecedented preresolution recovery stage. Objective: To create an evidence- and expertise-informed framework of leadership imperatives to serve as a resource to guide health and public health leaders during the postemergency stage of the pandemic. Evidence Review: A literature search in PubMed, MEDLINE, and Embase revealed 10 910 articles published between 2000 and 2021 that included the terms leadership and variations of emergency, crisis, disaster, pandemic, COVID-19, or public health. Using the Standards for Quality Improvement Reporting Excellence reporting guideline for consensus statement development, this assessment adopted a 6-round modified Delphi approach involving 32 expert coauthors from 17 countries who participated in creating and validating a framework outlining essential leadership imperatives. Findings: The 10 imperatives in the framework are: (1) acknowledge staff and celebrate successes; (2) provide support for staff well-being; (3) develop a clear understanding of the current local and global context, along with informed projections; (4) prepare for future emergencies (personnel, resources, protocols, contingency plans, coalitions, and training); (5) reassess priorities explicitly and regularly and provide purpose, meaning, and direction; (6) maximize team, organizational, and system performance and discuss enhancements; (7) manage the backlog of paused services and consider improvements while avoiding burnout and moral distress; (8) sustain learning, innovations, and collaborations, and imagine future possibilities; (9) provide regular communication and engender trust; and (10) in consultation with public health and fellow leaders, provide safety information and recommendations to government, other organizations, staff, and the community to improve equitable and integrated care and emergency preparedness systemwide. Conclusions and Relevance: Leaders who most effectively implement these imperatives are ideally positioned to address urgent needs and inequalities in health systems and to cocreate with their organizations a future that best serves stakeholders and communities.
Heterogeneous indications and the need for viability assessment: An international survey on the use of machine perfusion in liver transplantation
Although machine perfusion (MP) is being increasingly adopted in liver transplantation, indications, timing, and modality are debated. To investigate current indications for MP a web-based Google Forms survey was launched in January 2021 and addressed to 127 experts in the field, identified among first and corresponding Authors of MP literature in the last 10 years. The survey presented 10 real-life cases of donor–recipient matching, asking whether the liver would be accepted (Q1), whether MP would be used in that particular setting (Q2) and, if so, by which MP modality (Q3) and at what timing during preservation (Q4). Respondents could also comment on each case. The agreement was evaluated using Krippendorff's alpha coefficient. Answers from 39 (30.1%) participants disclosed significant heterogeneity in graft acceptance, MP indications, technique, and timing. Agreement between respondents was generally poor (Q1, α = 0.11; Q2, α = 0.14; Q3, α = 0.12, Q4, α = 0.11). Overall, respondents preferred hypothermic MP and an end-ischemic approach in 56.3% and 81.1% of cases, respectively. A total of 18 (46.2%) participants considered only one MP approach, whereas 17 (43.6%) and 3 (7.7%) considered using alternatively 2 or 3 different techniques. Of 38 comments, 17 (44.7%) were about the use of MP for graft viability assessment before implantation. This survey shows considerable variability in MP indications, emphasizing the need to identify scenarios of optimal utilization for each technique. Viability assessment emerges as a fundamental need of transplant professionals when considering the use of MP.
Patient safety associated with the surgical treatment of bone and soft tissue tumours during the COVID-19 pandemic-results from an observational study at the Oxford Sarcoma Service.
PURPOSE: Deferring cancer surgery can have profound adverse effects including patient mortality. During the COVID-19 pandemic, departmental reorganisation and adherence to evolving guidelines enabled provision of uninterrupted surgical care to patients with bone and soft tissue tumours (BST) in need of surgery. We reviewed the outcomes of surgeries on BST during the first two months of the pandemic at one of the tertiary BST centres in the UK. MATERIALS AND METHODS: Between 12 March 2020 and 12 May 2020, 56 patients of a median age of 57 years (18-87) underwent surgery across two sites: index hospital (n = 27) and COVID-free facility (n = 29). Twenty-five (44.6%) patients were above the age of 60 years and 20 (35.7%) patients were in ASA III and ASA IV category. The decision to offer surgery was made in adherence with the guidelines issued by the NHS, BOOS and BSG. RESULTS: At a minimum follow-up of 30 days post-surgery, 54 (96.4%) patients were recovering well. Thirteen patients (23.2%) had post-operative complications which included four (7.1%) patients developing pulmonary embolism. The majority of complications (12/13 = 92.7%) occurred in ASA III and IV category patients. Four (7.1%) patients contracted COVID-19, of which three required escalation of care due to pulmonary complications and two (3.6%) died. Patients 60 years (p
Service delivery during the COVID-19 pandemic: Experience from The Oxford Bone Tumour and Soft Tissue Sarcoma service.
The COVID-19 (Coronavirus disease 2019) pandemic has caused an unprecedented strain on healthcare systems across the globe. Apart from being a major hurdle to delivery of basic healthcare services, this may be associated with potential harm for cancer patients. Usually being immunocompromised, cancer patients are at a higher risk of contracting the disease and with hospitals being a potential source of the infection, an urgent need to reorganise the structure of delivery of cancer care is essential. Cancer departments must balance patient care whilst also minimising transmission among patients and healthcare professionals. The Oxford Sarcoma Service was re-structured based on the guidelines issued by the National Health Service (NHS) and the British Orthopaedic Oncology Society (BOOS) to deliver unhindered care to patients. Prioritising patients who needed urgent surgery, weighing the risk-benefit ratio while delivering adjuvant treatments and conducting regular virtual multi-disciplinary team (MDT) meetings combined with personal protection equipment (PPE) usage by all involved healthcare workers were salient features in terms of ensuring the delivery of effective care during the COVID-19 pandemic. Our new model of modus operandi during this global crisis was effective in delivering high standard of care to patients and might serve as a guide to similar units managing bone and soft tissue tumours.
Abstract Co-targeting of O-GlcNAc transferase (OGT) and the transcriptional kinase CDK9 is toxic to prostate cancer cells. As OGT is an essential glycosyltransferase, identifying an alternative target showing similar effects is of great interest. Here, we used a multiomics approach (transcriptomics, metabolomics and proteomics) to better understand the mechanistic basis of the combinatorial lethality between OGT and CDK9 inhibition. CDK9 inhibition preferentially affected transcription. In contrast, depletion of OGT activity predominantly remodeled the metabolome. Using an unbiased systems biology approach (weighted gene correlation network analysis), we discovered that CDK9 inhibition alters mitochondrial activity / flux, and high OGT activity is essential to maintain mitochondrial respiration when CDK9 activity is depleted. Our metabolite profiling data revealed that pantothenic acid (vitamin B5) is the metabolite that is most robustly induced by both OGT and OGT+CDK9 inhibitor treatments, but not by CDK9 inhibition alone. Finally, supplementing prostate cancer cell lines with vitamin B5 in the presence of CDK9 inhibitor mimics the effects of co-targeting OGT and CDK9.
Introduction: A reproducible, standardised model for cutaneous scar tissue to assess therapeutics is crucial to the progress of the field. A systematic review was performed to critically evaluate scarring models in both animal and human research. Method: All studies in which cutaneous scars are modelling in animals or humans were included. Models that were focused on the wound healing process or those in humans with scars from an existing injury were excluded. Ovid Medline® was searched on 25 February 2019 to perform two near identical searches; one aimed at animals and the other aimed at humans. Two reviewers independently screened the titles and abstracts for study selection. Full texts of potentially suitable studies were then obtained for analysis. Results: The animal kingdom search yielded 818 results, of which 71 were included in the review. Animals utilised included rabbits, mice, pigs, dogs and primates. Methods used for creating scar tissue included sharp excision, dermatome injury, thermal injury and injection of fibrotic substances. The search for scar assessment in humans yielded 287 results, of which 9 met the inclusion criteria. In all human studies, sharp incision was used to create scar tissue. Some studies focused on patients before or after elective surgery, including bilateral breast reduction, knee replacement or midline sternotomy. Discussion: The rabbit ear scar model was the most popular tool for scar research, although pigs produce scar tissue which most closely resembles that of humans. Immunodeficient mouse models allow for in vivo engraftment and study of human scar tissue, however, there are limitations relating to the systemic response to these xenografts. Factors that determine the use of animals include cost of housing requirements, genetic traceability, and ethical concerns. In humans, surgical patients are often studied for scarring responses and outcomes, but reproducibility and patient factors that impact healing can limit interpretation. Human tissue use in vitro may serve as a good basis to rapidly screen and assess treatments prior to clinical use, with the advantage of reduced cost and setup requirements.
Single versus multiple arterial grafting in diabetic patients at 10 years: the Arterial Revascularization Trial.
AIMS: To evaluate the impact of multiple arterial grafting (MAG) vs. single arterial grafting (SAG) in a post hoc analysis of 10-year outcomes in patients with diabetes mellitus (DM) from the Arterial Revascularization Trial (ART). METHODS AND RESULTS: The primary endpoint was all-cause mortality and the secondary endpoint was a composite of major adverse cardiac events (MACE) at 10-year follow-up. Patients were stratified by diabetes status (non-DM and DM) and grafting strategy (MAG vs. SAG). A total of 3020 patients were included in the analysis; 716 (23.7%) had DM. Overall, 55.8% non-DM patients received MAG and 44.2% received SAG, while 56.6% DM patients received MAG and 43.4% received SAG. The use of MAG compared with SAG was associated with lower 10-year mortality for both non-DM [17.7 vs. 21.0%, adjusted hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.72-1.06] and DM patients (21.5 vs. 29.9%, adjusted HR 0.65, 95% CI 0.48-0.89; P for interaction = 0.12). For both groups, the rate of 10-year MACE was also lower for MAG vs. SAG. Overall, deep sternal wound infections (DSWIs) were uncommon but more frequent in the MAG vs. SAG group in both non-DM (3.3 vs. 2.1%) and DM patients (7.9 vs. 4.8%). The highest rates of DSWI were in insulin-treated patients receiving MAG (9.6 vs. 6.3%, when compared with SAG). CONCLUSION: In this post hoc analysis of the ART, MAG was associated with substantially lower mortality rates at 10 years after coronary artery bypass grafting in patients with DM. Patients with DM receiving MAG had a higher incidence of DSWI, especially if insulin dependent.
Prognostic factors of 10-year mortality after coronary artery bypass graft surgery: a secondary analysis of the arterial revascularization trial.
OBJECTIVES: The objective of this investigation was to determine the preoperative prognostic factors of long-term (10-year) mortality in patients treated with isolated coronary artery bypass graft surgery in the arterial revascularization trial (ART). METHODS: A post hoc analysis of the ART was conducted. Cumulative 10-year mortality was estimated using the Kaplan-Meier method. Prospectively collected preoperative data were used to determine the prognostic factors of 10-year all-cause mortality in patients who participated in the ART (Cox proportional hazards model). RESULTS: A total of 3102 patients who participated in the ART were included in the analysis. Ten-year follow-up was completed in 3040 patients (98%). A total of 644 patients (20.8%) had died by 10 years. Preoperative factors that were identified as statistically significant predictors of 10-year mortality in the multivariable analysis (all P ≤ 0.01) were: left ventricular ejection fraction, atrial fibrillation, age, diabetes, prior cerebrovascular event (stroke or transient ischaemic attack), serum creatinine and smoking status. The following variables were significantly associated in univariable models but did not retain significance in the multivariable model for mortality: non-Caucasian ethnicity, hypertension, peripheral vascular disease, chronic obstructive pulmonary disease and prior myocardial infarction. CONCLUSIONS: Independent predictors of 10-year mortality in the ART were multifactorial. Several key independent predictors of 10-year mortality in the ART were identified including: heart function, renal function, cerebrovascular disease, age, atrial fibrillation, smoking status and diabetes. Understanding which preoperative variables influence long-term outcome after coronary artery bypass grafting may help to target treatments to those at higher risk to reduce mortality.