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Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank.

The availability of protein measurements and whole exome sequence data in the UK Biobank enables investigation of potential observational and genetic protein-cancer risk associations. We investigated associations of 1463 plasma proteins with incidence of 19 cancers and 9 cancer subsites in UK Biobank participants (average 12 years follow-up). Emerging protein-cancer associations were further explored using two genetic approaches, cis-pQTL and exome-wide protein genetic scores (exGS). We identify 618 protein-cancer associations, of which 107 persist for cases diagnosed more than seven years after blood draw, 29 of 618 were associated in genetic analyses, and four had support from long time-to-diagnosis ( > 7 years) and both cis-pQTL and exGS analyses: CD74 and TNFRSF1B with NHL, ADAM8 with leukemia, and SFTPA2 with lung cancer. We present multiple blood protein-cancer risk associations, including many detectable more than seven years before cancer diagnosis and that had concordant evidence from genetic analyses, suggesting a possible role in cancer development.

Gastroschisis: A National Cohort Study to Describe Contemporary Surgical Strategies and Outcomes

This was a survey of all the cases of gastroschisis (n = 393) managed within the 28 neonatal surgical units in the UK and Ireland (18 months in 2006-2008) from a predicted birth cohort of 1.1 million. Results: Infants were divided into simple gastroschisis (n = 336, 85.5%) and complex gastroschisis (n = 45, 11.5%) - unknown category (n =12, 3%). Virtually all were detected antenatally (n = 385, 98%). Operative primary closure (n = 170, 51%) and staged closure after a preformed silo (n = 120, 36%) were the most commonly used techniques by intension for simple gastroschisis. There were 6 (2%) neonatal deaths (all in the simple group). Outcomes for infants in the complex group were significantly worse. They were more likely to be ventilated postoperatively (risk ratio [RR], 1.21; 95% CI, 1.09-1.33), more likely to require reoperation (RR, 6.53; 95% CI, 4.70-9.09), more likely to develop intestinal failure associated liver disease (RR, 8.21; 95% CI,3.70-18.2) and more likely to receive total parenteral nutrition for >28 days (RR, 2.07; 95% CI, 1.71-2.51). Conclusions: This study provided a comprehensive picture of current UK and Ireland practice for gastroschisis and a national benchmark.

Analysis of 3D pathology samples using weakly supervised AI.

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.

Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

High levels of patient satisfaction in joint uro-oncology clinics to assist patient choice in early prostate cancer and muscle-invasive bladder cancer

The impact of low-energy total diet replacement with behavioural support for remission of type 2 diabetes on disordered eating (ARIADNE): Protocol for a non-inferiority randomised controlled trial.

INTRODUCTION: The National Health Service (NHS) in England is currently piloting a weight loss programme for remission of newly diagnosed type 2 diabetes (T2D), where participants replace all food with low-energy nutritionally complete formula products for 12 weeks (total diet replacement, TDR) and receive behavioural support. In a clinical trial, this programme led to remission in nearly half the participants. However, this weight loss programme might also worsen disordered eating and prompt eating disorders in susceptible people. We aim to investigate if the TDR programme is non-inferior to standard care in terms of disordered eating in susceptible individuals. METHODS: Fifty six people with newly diagnosed T2D, BMI ≥ 27 kg/m2, and medium to high scores of disordered eating based on the Eating Disorders Examination questionnaire (EDE-Q) will be randomised 1:1 to TDR receiving remote weekly/bi-weekly dietetic support or standard care. Participants will be re-assessed remotely at 1, 3, 4, 6, and 12 months. The primary outcome will be the between-group difference in the score of the EDE-Q. If the sample size can be expanded to 150, we will reduce the non-inferiority boundary. Weight, glycated haemoglobin (HbA1c), impairment from disordered eating, and distress will be secondary outcomes. Using the recorded consultations, we will evaluate the process in observed changes in eating behaviour and disordered eating. CONCLUSIONS: If TDR for T2D remission is deemed non-inferior to standard care, more people may enrol and benefit from T2D remission. If TDR exacerbates disordered eating, screening may reduce unintended harm. TRIAL REGISTRATION: NCT05744232 (ClinicalTrials.gov, prospectively registered).

Characterising the immune response to combined skin and solid organ transplants

Transplantation offers a life-saving solution for patients with end-stage organ failure. Despite advances in recent years, managing acute rejection episodes remains challenging. This is partly due to difficulties in recognising when acute rejection is taking place. The concept of a sentinel skin flap for monitoring of organ transplantation has recently been introduced as a potential solution for this. The advent of abdominal wall transplants for the reconstruction of large defects in patients undergoing small bowel transplantation has further highlighted the usefulness of skin for monitoring, particularly in differentiating organ rejection from infections. Sentinel skin flaps also provide a site that is easy to biopsy, and which patients can be trained to review. There are limited data in the literature on the alloresponse to a combined skin and solid organ transplant. The aim of this thesis is to characterise in depth this immune response. In chapter 3 the systemic immune response is examined using a combination of flow cytometry and gene expression analysis to analyse blood samples. Chapters 4 and 5 investigate the local immune response in small bowel and skin samples respectively, using the multiplexed gene expression and spatial proteomic techniques. Finally in Chapter 6 a human transgenic mouse model is used to explore the role of Langerhans cell related pathways in skin transplant rejection. This is the first study to characterise both the systemic and local immune response in a combined skin and solid organ transplant, offering unique insights into the dynamic changes in immune phenotype post-transplantation and during rejection. The data provide support for the use of a sentinel skin flap for immune monitoring in solid organ transplantation and will be used to guide future clinical trials.

Reporting guideline for the early stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI.

A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico, evaluation, but few have yet demonstrated real benefit to patient care. Early stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use, and pave the way to further large scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multistakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two round, modified Delphi process to collect and analyse expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 predefined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. 123 experts participated in the first round of Delphi, 138 in the second, 16 in the consensus meeting, and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI specific reporting items (made of 28 subitems) and 10 generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we have developed a guideline comprising key items that should be reported in early stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings.

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.