Search results

Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells

Molecular analysis of archival diagnostic prostate cancer biopsies identifies genomic similarities in cases with progression post-radiotherapy, and those with de novo metastatic disease.

BACKGROUND: It is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin-fixed paraffin-embedded (FFPE) prostate biopsies from cohorts with post-radiotherapy (RT) long-term clinical follow-up has been limited. Utilizing parallel sequencing modalities, we performed a proof-of-principle sequencing analysis of historical diagnostic FFPE prostate biopsies. We compared patients with (i) stable PCa (sPCa) postprimary or salvage RT, (ii) progressing PCa (pPCa) post-RT, and (iii) de novo metastatic PCa (mPCa). METHODS: A cohort of 19 patients with diagnostic prostate biopsies (n = 6 sPCa, n = 5 pPCa, n = 8 mPCa) and mean 4 years 10 months follow-up (diagnosed 2009-2016) underwent nucleic acid extraction from demarcated malignancy. Samples underwent 3'RNA sequencing (3'RNAseq) (n = 19), nanoString analysis (n = 12), and Illumina 850k methylation (n = 8) sequencing. Bioinformatic analysis was performed to coherently identify differentially expressed genes and methylated genomic regions (MGRs). RESULTS: Eighteen of 19 samples provided useable 3'RNAseq data. Principal component analysis (PCA) demonstrated similar expression profiles between pPCa and mPCa cases, versus sPCa. Coherently differentially methylated probes between these groups identified ~600 differentially MGRs. The top 50 genes with increased expression in pPCa patients were associated with reduced progression-free survival post-RT (p 

Recognising contributions to work in research collaboratives: Guidelines for standardising reporting of authorship in collaborative research.

BACKGROUND: Trainee research collaboratives (TRCs) have been revolutionary changes to the delivery of high-quality, multicentre research. The aim of this study was to define common roles in the conduct of collaborative research, and map these to academic competencies as set out by General Medical Council (GMC) in the United Kingdom. This will support trainers and assessors when judging academic achievements of those involved in TRC projects, and supports trainees by providing guidance on how to fulfil their role in these studies. METHODS: A modified Delphi process was followed. Electronic discussion with key stakeholders was undertaken to identify and describe common roles. These were refined and mapped to GMC educational domains and International Committee of Medical Journal Editors authorship (ICJME) guidelines. The resulting roles and descriptions were presented to a face-to-face consensus meeting for voting. The agreed roles were then presented back to the electronic discussion group for approval. RESULTS: Electronic discussion generated six common roles. All of these were agreed in face-to-face meetings, where two further roles identified and described. All eight roles required skills that map to part of the academic requirements for surgical training in the UK. DISCUSSION: This paper presents a standardised framework for reporting authorship in collaborative group authored research publications. Linkage of collaborator roles to the ICMJE guidelines and GMC academic competency guidelines will facilitate incorporation into relevant training curricular and journal publication policies.

Impact of reduced working time on surgical training in the United Kingdom and Ireland

The European Working Time Directive (EWTD) 48 h working week has been law in European countries since 1998. A phased approach to implementation was agreed for doctors in training, which steadily brought down working hours to 58 in 2004, 56 in 2007 and 48 in 2009. Medical trainees can " opt out" to a 54 h working week but this has to be voluntary and rotas cannot be constructed that assume an opt out is taking place. A key component of the working week arrangements is that the maximum period of work for a resident doctor without rest is 13 h. Shorter sessions of work have led to complex rotas, frequent handovers with difficulties maintaining continuity of care with implications for patient safety. Although there has been over 10 years notice of the changes to the working week and progress has up to now been reasonable (helped, in part by a steady increase in consultant numbers) this latest reduction from 56 h to 48 h seems to have been the most difficult to manage. © 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.

What do surgical trainees think about patient safety culture, and is this different from their consultants?

Introduction Little is known about the patient safety culture within surgical departments in UK hospitals. What has been done to date is to survey only permanent senior staff opinion of the safety culture in their institution. This study surveyed both consultant and trainee views on perceived patient safety and compared the results between these two groups. Material and methods The previously validated Team Work and Safety Climate Questionnaire was configured in Survey Monkey format and sent to all surgical trainees and consultant surgeons in the South West Strategic Health Authority. Two reminders were sent to achieve as high a return rate as possible. Results Two hundred and ninety-six replies were received. Forty-four percent of trainees and 30% of consultants responded to the survey. Consultants consistently rated a higher safety culture than surgical trainees. Only 2.9% of trainees believe their patient safety concerns would be acted upon by hospital management. There is notable variation in perceived patient safety culture between hospitals. Conclusion This study has suggested that the patient safety culture in hospitals, within a Strategic Health Authority, is variable and sub-optimal when viewed by surgical trainees and their consultants. This study also provides some evidence that the perception of patient safety in an organization varies according to clinical experience. As trainees deliver a great deal of clinical care, surveys of safety culture should include this group. As perceived patient safety culture is correlated to clinical outcomes, validated safety surveys might form part of the assessment of a hospital's performance, along with outcome and patient satisfaction.

A New Curriculum for Surgical Training within the United Kingdom: The First Stages of Implementation

This is the second of 2 articles on the UK's new surgical curriculum. The first article described the UK curriculum initiative first in terms of the political and professional context for curriculum reform, and second in terms of the development of the curriculum model itself. This article concerns the implementation stage, focusing on evaluation and the implications for organizational change. The article concludes with some lessons that have been learned en route.

A New Curriculum for Surgical Training within the United Kingdom: Context and Model

This is the first of 2 articles on the United Kingdom's new surgical curriculum. In this article, the UK curriculum initiative is described first in terms of the political and the professional context for curriculum reform, and second in terms of the development of the curriculum model itself. The second article concerns the implementation stage, focusing on evaluation and the implications for organizational change. The article concludes with some lessons that have been learned en route.

CDK9 inhibition activates innate immune response through viral mimicry.

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition-induced cancer cell-selective anti-proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition activates the innate immune response through viral mimicry in cancer cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to the gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics, and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of cytokines related to the innate immune response. In particular, CDK9 inhibition activates NFκB-driven cytokine signaling at the transcriptional and secretome levels. The transcriptional signature induced by CDK9 inhibition identifies prostate cancers with a high level of genome instability. We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage in vitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late-stage prostate cancer, a currently lethal disease.

Changing estimates of leadership ability before a programme: retrospective self-assessments and response-shift bias.

BACKGROUND: Most evaluations of clinical leadership development programmes rely on self-assessments. Self-assessments are vulnerable to response-shift bias. Using retrospective then-tests may help to avoid this bias.In this study, we investigate whether post-programme then-tests (retrospective self-assessments) are more sensitive to change in clinical leadership development programme participants than traditional pre-programme pre-tests when paired with post-test self-assessments. METHODS: 17 healthcare professionals participated in an 8-month single-centre multidisciplinary leadership development programme. Participants completed prospective pre-test, retrospective then-test and traditional post-test self-assessments using the Primary Colours Questionnaire (PCQ) and Medical Leadership Competency Framework Self-Assessment Tool (MLCFQ). Pre-post pairs and then-post pairs were analysed for changes using Wilcoxon signed-rank tests and compared with a parallel multimethod evaluation organised by Kirkpatrick levels. RESULTS: A greater number of significant changes were detected using then-test pairs than pre-test pairs for both the PCQ (11 of 12 vs 4 of 12 items) and MLCFQ (7 of 7 vs 3 of 7 domains). The multimethods data showed positive outcomes at all Kirkpatrick levels. CONCLUSIONS: In ideal circumstances, both pre-test and then-test evaluations should be conducted. We cautiously suggest that if only one post-programme evaluation can be conducted, then-tests may be appropriate means of detecting change.

Transient time flow measurement in arterial grafts.

Coronary artery bypass grafting (CABG) is one of the foundations of treatment for coronary artery disease. While it has improved substantially since its inception more than 50 years ago, including a rising use of multiple arterial grafting, intraoperative quality assessment is yet to be disseminated as an integral part of the procedure. Herein we review the fundamentals of intraoperative quality assessment in CABG using transient time flow measurement (TTFM) with a focus on its use in arterial grafting.

A National audit of the care of patients with acute kidney injury in England and Wales in 2019 and the association with patient outcomes.

BACKGROUND: Acute kidney injury (AKI) is a common complication of hospitalisations. This national audit assessed the care received by patients with AKI in hospital Trusts in England and Wales. METHODS: Twenty four hospital Trusts across England and Wales took part. Patients with AKI stage2/3 were identified using the UK Renal Registry AKI master patient index. Data was returned through a secure portal with linkage to hospital episode statistic mortality and hospitalisation data. Completion rates of AKI care standards and regional variations in care were established. RESULTS: 989 AKI episodes were included in the analyses. In-hospital 30-day mortality was 31-33.1% (AKI 2/3). Standard AKI interventions were completed in >80% of episodes. Significant inter-hospital variation remained in attainment of AKI care standards after adjustment for age and sex. Recording of urinalysis (41.9%) and timely imaging (37.2%) were low. Information on discharge summaries relating to medication changes/re-commencement and follow-up blood tests associated with reduced mortality. No quality indicators relating to clinical management associated with mortality. Better communication on discharge summaries associated with reduced mortality. CONCLUSIONS: Outcomes for patients with AKI in hospital remain poor. Regional variation in care exists. Work is needed to assess whether improving and standardising care improves patient outcomes.

Bariatric surgery improves access to renal transplantation and is safe in renal failure as well as after transplantation: A systematic review and meta-analysis.

INTRODUCTION: Effective workup and listing of end-stage renal disease (ESRD) patients for renal transplantation, often with multiple co-morbidities, poses a challenge for transplant teams. Obesity is a common co-morbidity associated with adverse outcomes in ESRD and kidney transplant (KT) recipients. Bariatric and metabolic surgery (BMS) has long been established as a safe and effective treatment for morbid obesity. In this study, the authors aimed to evaluate the strength of evidence for both the efficacy and safety of bariatric surgery in patients with ESRD or kidney transplantation. METHODS: A literature search was performed using key terms including "transplantation", "kidney", "renal", "obesity", and "bariatric". Databases searched include MEDLINE, EMBASE and Web of Science from inception to date (April 2021). Methodological quality was assessed using the Newcastle-Ottawa tool. Selected articles were then categorised into patients awaiting waiting list acceptance, patients awaiting transplantation, patients undergoing simultaneous BMS + KT and patients undergoing BMS following a previous renal transplant. Summary effects are presented with a level of statistical significance and 95% Confidence Intervals. RESULTS: A total of 28 articles were selected following the literature search. Fourteen studies on patients awaiting listing (n = 1903), nine on patients on the KT waiting list (n = 196), a single study on simultaneous BMS and KT and ten studies on patients undergoing BMS following KT (n = 198). Mean change in BMI for patients awaiting listing was -11.3 kg/m2 (95%CI: -15.3 to -7.3, p 

Abstract 1369: Predicting clinical pharmacokinetics and toxicity of current and emerging oncology therapeutics by normothermic perfusion of isolated human-sized organs

Abstract Novel cancer therapeutics have less than a 12% probability of translating from bench to bedside. Unwarranted toxicity and inadequate therapeutic delivery due to uptake by clearance organs, not predicted by current preclinical methods, have contributed towards this high rate of attrition. In the present work, we propose normothermic machine perfusion of human or human-sized organs as a more predictive, closer-to-human model to investigate drug pharmacokinetics and toxicity. Over the past decade, developments in the field of organ preservation for transplantation have enabled prolonged (>12 hours) normothermic machine perfusion (NMP) of isolated porcine or human organs ex vivo, maintaining quasi-physiological haemodynamic, synthetic and metabolic function using a packed red cell perfusate with physiological oxygenation and nutrient levels at normal body temperature. This preserves physiological processes such as metabolism and drug elimination, and enables easy access to tissue, blood and excreted biological fluids, with NMP livers producing bile and NMP kidneys producing urine. We hypothesise that this will provide a physiologically relevant platform to investigate drug pharmacokinetics and toxicity. We selected a widely used small-molecule chemotherapeutic (Irinotecan hydrochloride 2mg/ml, Medac, UK) which has seen decades of clinical use and benefits from extensive clinical pharmacokinetic data. The small-molecule drug was infused into isolated porcine and human livers and kidneys, with quantification of concentration time profiles of the prodrug and its main metabolites in plasma, bile and urine over 16-24 hours of NMP. In addition to irinotecan (CPT11), three of its metabolites (APC, SN38G, SN38) were successfully detected and quantified, demonstrating peak plasma concentrations (Cmax ~ 10,000 ng/mL, 1000 ng/mL, 100 ng/g, 30 ng/g), plasma decay rates and percentages of injected dose in bile (%ID ~20%, 8%, 25%, 1%) and urine (%ID ~20%, 0.06%, 0.5%,0.1%) that are comparable to clinical data. Drug-tissue toxicity could also be adequately replicated in the NMP model. In conclusion, we have demonstrated that human-sized isolated, normothermically perfused livers and kidneys accurately represent the clinically observed pharmacokinetic and toxicity profiles of an established small-molecule therapeutic. Further model validation is ongoing for biologics and other nanomedicines which are susceptible to clearance by the mononuclear phagocytic system or are hepato- or nephrotoxic. If this proves successful, normothermic machine perfusion of isolated porcine and human organs could greatly aid the early screening of candidate therapeutics and significantly enhance the pace and success rate with which they are translated into patients. Citation Format: Tamsyn Clark, Luca Bau, Fungai Dengu, Daniel Voyce, Robert Carlisle, Peter Friend, Constantin Coussios. Predicting clinical pharmacokinetics and toxicity of current and emerging oncology therapeutics by normothermic perfusion of isolated human-sized organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1369.

SARS-CoV-2-Specific T Cell Responses Are Not Associated with Protection against Reinfection in Hemodialysis Patients.

Patients on hemodialysis (HD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mount poor neutralizing antibody responses after two-dose vaccination. Although serological responses have been associated with reduced rates of reinfection, the relationship between cellular immunogenicity and protection has not been established. We report, for the first time, high incidence of reinfection in patients on HD who are vaccine naive (25%), which identifies that T cell responses do not predict protection against reinfection. Instead, patients on HD who went on to become reinfected had mounted highly variable and sometimes robust proliferative T cell responses to a broad array of SARS-CoV-2 peptide pools during the primary infection. The understanding that SARS-CoV-2–specific T cell responses are not predictive of protection against future infection will be a critical issue when measuring clinical efficacy of vaccination in these vulnerable cohorts, particularly when facing rapidly emerging variants of concern.

Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation.

Static cold storage (SCS) is the standard method for pancreas preservation prior to transplantation; however, it does not permit organ assessment. Normothermic reperfusion (NR) is utilized clinically for other organs to assess viability. Our aim was to develop NR using normothermic machine perfusion technique to simulate reperfusion at the time of transplantation, enabling evaluation of oxygenated hypothermic machine perfusion (HMPO2) as a newer strategy to optimize pancreas preservation. 13 porcine pancreases procured after circulatory death were divided into 3 groups: 4 pancreases preserved using SCS, and 2 groups preserved by HMPO2 (n = 4 and n = 5, differing by type of preservation solution). Duration of perfusion or cold storage was 6 hours before the 1-hour assessment using NR. Outcome measures were perfusion characteristics, biochemistry and change in tissue water mass as oedema assessment. During NR, the HMPO2 groups demonstrated better perfusion characteristics, normal macroscopic appearances, decreased water mass and one HMPO2 group demonstrated a response to glucose stimulation. Conversely, the SCS group showed an increased water mass and developed early macroscopic appearances of oedema, interstitial haemorrhage and minimal portal outflow. This study suggests that ex situ assessment of pancreases by NR is promising, and that HMPO2 may be better than SCS.

Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation.

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment.

Assessment of Mitochondrial Function and Oxygen Consumption Measured During Ex Vivo Normothermic Machine Perfusion of Injured Pig Kidneys Helps to Monitor Organ Viability.

Donor kidney assessment may improve organ utilisation. Normothermic Machine Perfusion (NMP) has the potential to facilitate this advance. The mechanism of action is not yet determined and we aimed to assess mitochondrial function during NMP. Anaesthetised pigs (n = 6) had one kidney clamped for 60 min. The healthy contralateral kidney was removed and underwent NMP for 8 h (healthy control (HC), n = 6). Following 60 min warm ischaemia the injured kidney underwent HMP for 24 h, followed by NMP for 8 h (n = 6). Mitochondria were extracted from fresh tissue for analysis. Injured kidneys were analysed as two separate groups (IMa, n = 3 and IMb, n = 3). Renal resistance was higher (0.39ï, ± 0.29 vs. 1.65ï, ± 0.85; p = 0.01) and flow was lower (55ï, ± 28 vs. 7ï, ± 4; p = 0.03) during HMP in IMb than IMa. NMP blood flow was higher in IMa versus IMb (2-way ANOVA; p < 0.001) After 60 min NMP, O2 consumption was significantly lower in IMb versus IMa (p ≤ 0.002). State-3 respiration was significantly different between the groups (37ï, ± 19 vs. 24ï, ± 14 vs. 10ï, ± 8; nmolO2/min/mg; p = 0.049). Lactate levels were significantly lower in IMa versus IMb (p = 0.028). Mitochondrial respiration levels during NMP may be suggestive of kidney viability. Oxygen consumption, renal blood flow and lactate can differentiate severity of kidney injury during NMP.

Abdominal multiorgan procurement from slaughterhouse pigs: a bespoke model in organ donation after circulatory death for ex vivo organ perfusion compliant with the 3 Rs (Reduction, Replacement & Refinement).

BACKGROUND: Advances in organ preservation, reconditioning and assessment have been driven by the increasing necessity to utilise organs from extended criteria donors, particularly donors after circulatory death. Research efforts in this area have aided translation of machine perfusion technology into clinical practice. Pigs are anatomically and physiologically similar to humans and are an excellent model. However, conducting large animal experimental research is challenging and typically limited by ethical and economic constraints. Here we describe a reproducible, cost-effective multi-organ abdominal procurement model of porcine organs from the slaughterhouse. METHODS: Domestic pigs are electrically stunned and exsanguinated following the standard abattoir process. Via a longitudinal midline incision, the thoracoabdominal viscera are removed en bloc by incising along the anterior vertebral plane. The abdominal organs are isolated, perfused and separated preserving their respective vasculature, allowing individual organ use for specific experiments. RESULTS: The warm ischaemic time is kept between 15-30 minutes. Using this highly protocolized procurement technique we have procured 12 livers, 162 kidneys and 12 pancreata for research, the majority of which have been utilized for ex situ perfusion experiments. CONCLUSIONS: We have described a reliable and reproducible procedure for abdominal multi-organ procurement from slaughterhouse pigs.

Auditory cues modulate the short timescale dynamics of STN activity during stepping in Parkinson's disease.

BACKGROUND: Gait impairment has a major impact on quality of life in patients with Parkinson's disease (PD). It is believed that basal ganglia oscillatory activity at β frequencies (15-30 Hz) may contribute to gait impairment, but the precise dynamics of this oscillatory activity during gait remain unclear. Additionally, auditory cues are known to lead to improvements in gait kinematics in PD. If the neurophysiological mechanisms of this cueing effect were better understood they could be leveraged to treat gait impairments using adaptive Deep Brain Stimulation (aDBS) technologies. OBJECTIVE: We aimed to characterize the dynamics of subthalamic nucleus (STN) oscillatory activity during stepping movements in PD and to establish the neurophysiological mechanisms by which auditory cues modulate gait. METHODS: We studied STN local field potentials (LFPs) in eight PD patients while they performed stepping movements. Hidden Markov Models (HMMs) were used to discover transient states of spectral activity that occurred during stepping with and without auditory cues. RESULTS: The occurrence of low and high β bursts was suppressed during and after auditory cues. This manifested as a decrease in their fractional occupancy and state lifetimes. Interestingly, α transients showed the opposite effect, with fractional occupancy and state lifetimes increasing during and after auditory cues. CONCLUSIONS: We show that STN oscillatory activity in the α and β frequency bands are differentially modulated by gait-promoting oscillatory cues. These findings suggest that the enhancement of α rhythms may be an approach for ameliorating gait impairments in PD.