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Ken had been Director of the Tissue Typing Laboratories as a Principal Scientist for some 10 years
Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review.
Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI.
Developing Trustworthy Artificial Intelligence Models to Predict Vascular Disease Progression: the VASCUL-AID-RETRO Study Protocol.
INTRODUCTION: Abdominal aortic aneurysms (AAAs) and peripheral artery disease (PAD) are two vascular diseases with a significant risk of major adverse cardiovascular events and mortality. A challenge in current disease management is the unpredictable disease progression in individual patients. The VASCUL-AID-RETRO study aims to develop trustworthy multimodal predictive artificial intelligence (AI) models for multiple tasks including risk stratification of disease progression and cardiovascular events in patients with AAA and PAD. METHODS: The VASCUL-AID-RETRO study will collect data from 5000 AAA and 6000 PAD patients across multiple European centers of the VASCUL-AID consortium using electronic health records from 2015 to 2024. This retrospectively-collected data will be enriched with additional data from existing biobanks and registries. Multimodal data, including clinical records, radiological imaging, proteomics, and genomics, will be collected to develop AI models predicting disease progression and cardiovascular risks. This will be done while integrating the international ethics guidelines and legal standards for trustworthy AI, to ensure a socially-responsible data integration and analysis. PROPOSED ANALYSES: A consensus-based variable list of clinical parameters and core outcome set for both diseases will be developed through meetings with key opinion leaders. Blood, plasma, and tissue samples from existing biobanks will be analyzed for proteomic and genomic variations. AI models will be trained on segmented AAA and PAD artery geometries for estimation of hemodynamic parameters to quantify disease progression. Initially, risk prediction models will be developed for each modality separately, and subsequently, all data will be combined to be used as input to multimodal prediction models. During all processes, data security, data quality, and ethical guidelines and legal standards will be carefully considered. As a next step, the developed models will be further adjusted with prospective data and internally validated in a prospective cohort (VASCUL-AID-PRO study). CONCLUSION: The VASCUL-AID-RETRO study will utilize advanced AI techniques and integrate clinical, imaging, and multi-omics data to predict AAA and PAD progression and cardiovascular events. CLINICAL TRIAL REGISTRATION: The VASCUL-AID-RETRO study is registered at www.clinicaltrials.gov under the identification number NCT06206369. CLINICAL IMPACT: The VASCUL-AID-RETRO study aims to improve clinical practice of vascular surgery by developing artificial intelligence-driven multimodal predictive models for patients with abdominal aortic aneurysms or peripheral artery disease, enhancing personalized medicine. By integrating comprehensive data sets including clinical, imaging, and multi-omics data, these models have the potential to provide accurate risk stratification for disease progression and cardiovascular events. An innovation lies in the extensive European data set in combination with multimodal analyses approaches, which enables the development of advanced models to facilitate better understanding of disease mechanisms and progression. For clinicians, this means that more precise, individualized treatment plans can be established, ultimately aiming to improve patient outcomes.
Burns in Malawi.
OBJECTIVE: To describe burns seen at the largest hospital in Malawi. METHODS: In a prospective study conducted at Queen Elizabeth Central Hospital, Blantyre, Malawi, a series of twelve accidental burns was analysed over a four-week period. RESULTS: Hot water was the commonest source of burns (6 out of 12). Open-fire and petroleum lamp accidents were the commonest cause of burns among epileptic patients. Males were affected more than females (male:female ratio = 8:4). Most burns were superficial (11 out of 12). One patient had deep burns requiring grafting. All patients were treated with topical silver sulphadiazine and a combination antibiotic regime. Children aged six yr or under were a major subgroup at risk of suffering burns (7 out of 12) and only one patient was aged over 30 yr. Lack of anti-epileptic medication resulted in potentially avoidable burns in four epileptic patients. CONCLUSIONS: There is a need for cheap preventive health promotion measures as well as the provision of simple resources as most burns encountered can be managed effectively by simple measures.
Current management of fractures of distal radius and ulna.
Distal radial and ulnar fractures are very common and their morbidity is greatly underestimated. This article reviews the current management of these injuries and that of their associated complications.
Impact and outcomes of the Emerging Leaders Programme: a mixed-methods evaluation of a leadership development programme for healthcare professionals.
BACKGROUND: The significance of effective medical leadership in enhancing healthcare outcomes has been widely acknowledged. This study evaluates the Emerging Leaders Programme, a multidisciplinary leadership development initiative for healthcare professionals at a UK Hospital Trust. METHODS: The evaluation spanned three cohorts (2017-2019) and a total of 54 participants, employing mixed methods to assess participant reactions, learning, behaviour changes and organisational impact. Quantitative pre-/post-measures included the Primary Colours Questionnaire (PCQ), Medical Leadership Competency Framework Questionnaire (MLCFQ) and Brief Resilience Scale (BRS), while qualitative data were gathered via free-text comments and long-term follow-up interviews. RESULTS: The programme had high satisfaction ratings, with particularly positive feedback relating to the multidisciplinary cohort and experiential learning via Quality Improvement projects. Findings indicated improvements in participants' leadership skills, knowledge, confidence and job satisfaction. Organisational outcomes included increased organisational interest in quality improvement and individual career progression. CONCLUSION: The results highlight the value of a structured leadership programme in developing healthcare leaders and driving organisational improvements, with long-term effects. Recommendations for future programmes include multidisciplinary involvement, experiential learning, inspiring speakers and embedded mixed-methods evaluation.
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P
Ten-year outcomes after off-pump versus on-pump coronary artery bypass grafting: Insights from the Arterial Revascularization Trial.
OBJECTIVE: We performed a post hoc analysis of the Arterial Revascularization Trial to compare 10-year outcomes after off-pump versus on-pump surgery. METHODS: Among 3102 patients enrolled, 1252 (40% of total) and 1699 patients received off-pump and on-pump surgery (151 patients were excluded because of other reasons); 2792 patients (95%) completed 10-year follow-up. Propensity matching and mixed-effect Cox model were used to compare long-term outcomes. Interaction term analysis was used to determine whether bilateral internal thoracic artery grafting was a significant effect modifier. RESULTS: One thousand seventy-eight matched pairs were selected for comparison. A total of 27 patients (2.5%) in the off-pump group required conversion to on-pump surgery. The off-pump and on-pump groups received a similar number of grafts (3.2 ± 0.89 vs 3.1 ± 0.8; P = .88). At 10 years, when compared with on-pump, there was no significant difference in death (adjusted hazard ratio for off-pump, 1.1; 95% confidence interval, 0.84-1.4; P = .54) or the composite of death, myocardial infarction, stroke, and repeat revascularization (adjusted hazard ratio, 0.92; 95% confidence interval, 0.72-1.2; P = .47). However, off-pump surgery performed by low volume off-pump surgeons was associated with a significantly lower number of grafts, increased conversion rates, and increased cardiovascular death (hazard ratio, 2.39; 95% confidence interval, 1.28-4.47; P = .006) when compared with on-pump surgery performed by on-pump-only surgeons. CONCLUSIONS: The findings showed that in the Arterial Revascularization Trial, off-pump and on-pump techniques achieved comparable long-term outcomes. However, when off-pump surgery was performed by low-volume surgeons, it was associated with a lower number of grafts, increased conversion, and a higher risk of cardiovascular death.
High-intensity focused ultrasound treatment of unresectable soft tissue sarcoma and desmoid tumours - a systematic review.
AIM: We review the evidence for high-intensity focused ultrasound (HIFU) in the treatment of soft tissue sarcoma (STS) and desmoid tumour (DT). MATERIALS AND METHODS: We searched Embase, Medline, PubMed, and Google Scholar for relevant studies between 2000-2024 using search terms 'high intensity focused ultrasound' and 'sarcoma' or 'chordoma' or 'desmoid'. We extracted data on patient demographics and treatment outcomes. RESULTS: We identified 12 studies pertaining to STS (n=178) and 15 studies pertaining to DT (n=417). These were prospective phase I/II open-label trials and retrospective case series or reports. The commonest adverse effects were skin burns, transient pain, and fever. Less common adverse effects of nerve injury and bowel perforation were depended on anatomic relations of the tumour. The majority of patients treated had unresectable disease that was partially ablated with HIFU for the purpose of local control. There was a high degree of variability in the reporting of outcomes making quantitative analysis challenging. CONCLUSION: The studied papers show that HIFU has a favourable safety profile with a potential role in patients with unresectable STS and DT. HIFU may confer advantages in cases of oligometastatic progression for disease control, complex anatomy including proximity to vital structures, recurrent cases in previously radiotherapy-exposed and/or operated locations with limited other locally-directed treatment options. However, there is limited reporting of the clinically important outcomes of recurrence and survival and further research is required, and this may represent an opportunity for later-phase trials in the UK and worldwide.
Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer.
Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
Imaging and intervention for soft tissue tumours in the era of locoregional therapies and immunotherapy.
As part of a multidisciplinary team, clinical radiology plays key roles in the diagnosis, staging and treatment response assessment for soft tissue sarcoma (STS) and desmoid tumours (DTs), typically using a combination of ultrasound and magnetic resonance imaging (MRI) modalities. There is an increasing role for interventional radiology in the treatment of recurrent and oligometastatic disease in these tumour types. This clinical radiology review is aimed primarily at non-specialist cross-sectional consultant radiologists and more junior radiology consultants/specialist trainees with a special interest in musculoskeletal oncology. The existing role of F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and MRI for assessment of treatment response in STS and DT, including the emerging role of whole-body MRI is outlined. Response metrics including Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), modified RECIST, Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST), immune Response Evaluation Criteria in Solid Tumors, iPERCIST and non-perfused volume ratio are also discussed in context. We introduce the potential role for locoregional therapies (LRTs), including microwave, cryotherapy and therapeutic ultrasound-based treatments as adjunctive treatments for selected cases within the current UK guidelines. We discuss the potential of high intensity focused ultrasound and other LRTs to release sarcoma tumour antigens systemically with the potential to enhance anti-tumour immunity (the 'abscopal' effect). With increasing indications and availability of locoregional therapies (LRTs) and the first indications of immunotherapy for selected subtypes of STS, potential future directions in functional imaging capability for STS and DT are also discussed.
Multidisciplinary evidence-based consensus statements on salvage surgery for recurrent head and neck cancer (International Centre for Recurrent head and neck Cancer).
BACKGROUND: Recurrent head and neck squamous cell carcinomas (rHNSCC) are an understudied subgroup, lacking high quality evidence and thus gold standard management recommendations, resulting in significant variations in practice. The aim of this project was to deliver a national multi-disciplinary expert consensus on patients with rHNSCC managed by curative salvage surgery. METHODS: The AGREEII protocol guided the Delphi process. Best practice statements were developed after literature review on the perioperative management and surgical salvage of major rHNSCC subsites. Members of the International centre for Recurrent head and neck cancer (IREC) network, and other UK based professional stakeholder organisations were invited into an online Delphi study. Participants voted upon statements over three rounds, with items modified in response to vote thresholds and comments. RESULTS: Twenty-eight experts participated including 11 otolaryngologists, 7 oncologists, 9 oral and maxillofacial surgeons, and 1 speech and language therapist. Consensus was achieved on 73 statements, with 29 (39.7%) achieving unanimous (threshold: 100%) and 25 (34.2%) (threshold >90%) agreement. CONCLUSIONS: Salvage surgery for rHNSCC are challenging cases that require intensive multidisciplinary input to achieve cure while balancing impact on function and quality-of-life. In this article, we provide a large series of statements based on UK-wide expert consensus, that will guide clinicians through the complex intra- and perioperative management of patients undergoing surgical salvage.
An intensive weight loss programme with behavioural support for people with type 2 diabetes at risk of eating disorders in England (ARIADNE): a randomised, controlled, non-inferiority trial
Background: There are concerns that low-energy total diet replacement (TDR) programmes could trigger eating disorders, given their focus on weight and rigid dietary rules. We aimed to assess the effect of a TDR programme on eating disorder symptoms in people living with overweight or obesity and type 2 diabetes at high risk of developing an eating disorder. Methods: In this randomised, controlled, non-inferiority trial, participants with type 2 diabetes, overweight, and eating disorder symptoms across England were randomly assigned (1:1) to a low-energy TDR programme with formula products and behavioural support delivered remotely, or usual care. In brief, the intervention comprised 12 weeks of low-energy TDR in a nutritionally complete package of soups, shakes, and bars. After the 12 weeks, the intervention continued with stepped food reintroduction (around 8 weeks) based on a low-energy, nutrient-rich diet, followed by weight maintenance advice (around 4 weeks), personalised to an individual participant's circumstances and preferences. Participants allocated to the control group received usual care for their diabetes. The primary outcome was the change in eating disorder symptoms using the Eating Disorders Examination Questionnaire (EDE-Q) global score at 6 months (programme end). Safety was determined by the incidence of cases with high suspicion of a new eating disorder. The primary outcome analysis had an upper non-inferiority margin for EDE-Q of +1 SD (0·72). People with lived experience were involved throughout the trial and provided input on study conceptualisation, protocol development, delivery of the intervention, and intervention materials. The study was registered with ClinicalTrials.gov, NCT05744232. Findings: Between March 8, 2023, and Sept 12, 2023, 56 participants were randomly assigned to the intervention group (28 participants) or control group (28 participants). Participants had a mean age of 49·9 years (SD 8·1). 35 (63%) of 56 participants were women, 20 (36%) were men, and one (2%) was non-binary. 54 (96%) of participants were White and two (4%) were Asian. Participants had a mean BMI of 39·6 kg/m2 (SD 7·8) and a mean EDE-Q global score of 3·3 (0·4). 49 (88%) of 56 participants provided outcome data at 6 months and 45 (80%) at 1 year. At completion of the programme at 6 months, the mean weight loss was –13·9 kg (SD 11·2) in the intervention group and –3·7 kg (7·9) in the control group, with a between-group difference of –10·2 kg (95% CI –14·2 to –6·2). The between-group difference in the EDE-Q score was –0·8 points (–1·4 to –0·3) at 6 months, indicating non-inferiority. At 12 months, weight change was not different between groups, but non-inferiority and superiority in EDE-Q remained. No participants were suspected of having developed an eating disorder. 13 adverse events were documented, of which one, a cholecystectomy, was serious. Interpretation: Participation in a supported TDR programme did not worsen eating disorder symptoms in people with overweight or obesity and type 2 diabetes at high risk of developing an eating disorder. We found no evidence these programmes cause harm and a suggestion of benefit on eating disorder symptoms, independent of weight loss. Funding: Novo Nordisk UK Research Foundation.
A novel synergistic drug combination of a mitogen-activated extracellular signal-regulated kinase inhibitor with [177Lu]Lu-rhPSMA-10.1 for prostate cancer treatment: Results of a preclinical evaluation.
PURPOSE: The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [177Lu]Lu-rhPSMA-10.1 is a promising next-generation radiopharmaceutical therapy in prostate cancer. This preclinical evaluation comprised an in vitro screen of potential novel synergistic drug combinations with [177Lu]Lu-rhPSMA-10.1, and an in vivo efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts. METHODS: In total, 177 anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells which used 5-fold serial dilutions of the test drug (≤ 20 μM) to determine the half-maximal inhibitory concentration (IC50), compared to incubations of the test drug plus [177Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [177Lu]Lu-rhPSMA-10.1 (0-25 MBq/mL) on drug IC50. Synergy scores were determined using the zero interaction potency (ZIP) reference model (ZIP scores >5 % indicate high synergistic potency) and the multidimensional synergy of combinations (MuSyC) platform (log α >0 indicates synergistic potency). Therapeutic efficacy of the lead drug combination was evaluated in vivo: intravenous [177Lu]Lu-rhPSMA-10.1 (30 MBq, single dose) and oral cobimetinib (0.25 mg/day for 21 days) (alone/in combination) were administered to 22Rv1 tumor-bearing NMRI nude mice (eight mice/group plus untreated controls). Tumor volume was measured twice weekly for 69 days (two-way ANOVA and Tukey's multiple comparisons test: data analyzed until three mice/group remained). KaplanMeier Log-rank survival analyses were performed. RESULTS: In vitro screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [177Lu]Lu-rhPSMA-10.1 across a wide concentration range (ZIP score=13 %). MuSyC analysis suggested synergistic efficacy from enhanced potency of both drugs in the combination (both log α>3). Combination treatment significantly suppressed tumor growth in vivo versus untreated controls (from Day 13-30; p<0.01) and [177Lu]Lu-rhPSMA-10.1 (from Day 17-30; p<0.001). Median survival was significantly longer with combination treatment (49 days) versus untreated controls (23 days; p=0.001) and [177Lu]Lu-rhPSMA-10.1 monotherapy (36 days; p=0.002). No major compound-related toxicity for cobimetinib ± [177Lu]Lu-rhPSMA-10.1 was observed. CONCLUSIONS: The combination of cobimetinib and [177Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy versus single agents, supporting clinical investigation of this novel drug combination in prostate cancer.