ORCID Profile
0000-0002-7347-830X
Current Organisation
The University of Edinburgh
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Publisher: MDPI AG
Date: 30-07-2021
Abstract: Background: To support the early detection and diagnosis of brain tumours we have developed a rapid, cost-effective and easy to use spectroscopic liquid biopsy based on the absorbance of infrared radiation. We have previously reported highly sensitive results of our approach which can discriminate patients with a recent brain tumour diagnosis and asymptomatic controls. Other liquid biopsy approaches (e.g., based on tumour genetic material) report a lower classification accuracy for early-stage tumours. In this manuscript we present an investigation into the link between brain tumour volume and liquid biopsy test performance. Methods: In a cohort of 177 patients (90 patients with high-grade glioma (glioblastoma (GBM) or anaplastic astrocytoma), or low-grade glioma (astrocytoma, oligoastrocytoma and oligodendroglioma)) tumour volumes were calculated from magnetic resonance imaging (MRI) investigations and patients were split into two groups depending on MRI parameters (T1 with contrast enhancement or T2/FLAIR (fluid-attenuated inversion recovery)). Using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with supervised learning methods and machine learning algorithms, 90 tumour patients were stratified against 87 control patients who displayed no symptomatic indications of cancer, and were classified as either glioma or non-glioma. Results: Sensitivities, specificities and balanced accuracies were all greater than 88%, the area under the curve (AUC) was 0.98, and cancer patients with tumour volumes as small as 0.2 cm3 were correctly identified. Conclusions: Our spectroscopic liquid biopsy approach can identify gliomas that are both small and low-grade showing great promise for deployment of this technique for early detection and diagnosis.
Publisher: Cold Spring Harbor Laboratory
Date: 20-11-2020
DOI: 10.1101/2020.11.13.20225839
Abstract: The transfer validity of portable laparoscopy simulation is well established. However, attempts to integrate take-home simulation into surgical training have met with inconsistent engagement, as reported in our 2014-15 study of an Incentivised Laparoscopy Practice (ILP) programme. Our subsequent multi-centre study examined barriers and facilitators, informing revisions of the programme for 2018-20. We now report engagement with the revised versions. In ILP v2.1 and 2.2, two consecutive year-groups of new CSTs (n= 48 and 46) were loaned portable simulators. The 6-month programme included induction, technical support, and intermittent feedback. Six tasks were prescribed, with video instruction and charting of metric scores. Video uploads were required and scored by faculty. A pass resulted in an eCertificate, expected at Annual Review. ILP was set within a wider reform, “Improving Surgical Training”. ILP v2.1 and 2.2 saw pass rates of 94% and 76% (45/48 and 35/46 trainees respectively), compared with only 26% (7/27) in v1, despite the v2.1 and v2.2 groups having less electronic gaming experience. In the ILP v2.2 group, 73% reported their engagement was adversely affected by COVID19 redeployments. Simply providing kit, no matter how good, is not enough. To achieve trainee engagement with take- home simulators, as in ILP v2, a whole programme is required, with motivated learning, in idual and group practice, intermittent feedback, and clear goals and assessments. ILP is a complex intervention, best understood as a “reform within a reform, within a context.” This may explain why trainee engagement fell away during early pandemic conditions. Attaining automation of motor skills is essential to free up operating surgeons’ attention for higher cognitive functions. Laparoscopic operating skills can transfer from simulation to the operating room, and deliberate practice is the most important variable in the development of expertise. Simply providing take-home portable simulators to surgical trainees, even with online training programmes, is insufficient to facilitate consistent deliberate practice by more than a minority of trainees. A package of evidence-based reforms transformed participation of Core Surgical trainees in a 6-month programme of practice using take-home portable simulators, resulting in near- 100% engagement. Such reforms are complex, including motivators for learning, in idual and group practice, intermittent feedback, clear goals and assessments, and adoption into a wider curriculum reform called “Improving Surgical Training”. The improved engagement with this form of remote simulation-based training did not continue in the face of a national “lockdown” for the COVID19 pandemic, where there was widespread redeployment of trainees.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2011
DOI: 10.1038/NATURE10531
Publisher: Springer Science and Business Media LLC
Date: 11-11-2016
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JBIOR.2019.100658
Abstract: Three dimensional (3D) bioprinting of multiple cell types within optimised extracellular matrices has the potential to more closely model the 3D environment of human physiology and disease than current alternatives. In this study, we used a multi-nozzle extrusion bioprinter to establish models of glioblastoma made up of cancer and stromal cells printed within matrices comprised of alginate modified with RGDS cell adhesion peptides, hyaluronic acid and collagen-1. Methods were developed using U87MG glioblastoma cells and MM6 monocyte/macrophages, whilst more disease relevant constructs contained glioblastoma stem cells (GSCs), co-printed with glioma associated stromal cells (GASCs) and microglia. Printing parameters were optimised to promote cell-cell interaction, avoiding the 'caging in' of cells due to overly dense cross-linking. Such printing had a negligible effect on cell viability, and cells retained robust metabolic activity and proliferation. Alginate gels allowed the rapid recovery of printed cell protein and RNA, and fluorescent reporters provided analysis of protein kinase activation at the single cell level within printed constructs. GSCs showed more resistance to chemotherapeutic drugs in 3D printed tumour constructs compared to 2D monolayer cultures, reflecting the clinical situation. In summary, a novel 3D bioprinting strategy is developed which allows control over the spatial organisation of tumour constructs for pre-clinical drug sensitivity testing and studies of the tumour microenvironment.
Publisher: Wiley
Date: 20-11-2020
DOI: 10.1002/ANA.25949
Abstract: A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long‐term outcome after intracerebral hemorrhage. We performed a prospective, community‐based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May 31, 2013. A neuroradiologist rated the diagnostic brain CT for acute intracerebral hemorrhage features and SVD biomarkers. We used severity of white matter lucencies and cerebral atrophy, and the number of lacunes to calculate the CT SVD score. We assessed the association between CT SVD biomarkers and either death, or death or dependence (modified Rankin Scale scores = 4–6) 1 year after first‐ever intracerebral hemorrhage using logistic regression, adjusting for known predictors of outcome. Within 1 year of intracerebral hemorrhage, 224 (56%) of 402 patients died. In separate models, 1‐year death was associated with severe atrophy (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.44–4.49, p = 0.001) but not lacunes or severe white matter lucencies, and CT SVD sum score ≥ 1 (aOR = 2.50, 95% CI = 1.40–4.45, p = 0.002). Two hundred seventy‐seven (73%) of 378 patients with modified Rankin Scale data were dead or dependent at 1 year. In separate models, 1‐year death or dependence was associated with severe atrophy (aOR = 3.67, 95% CI = 1.71–7.89, p = 0.001) and severe white matter lucencies (aOR = 2.18, 95% CI = 1.06–4.51, p = 0.035) but not lacunes, and CT SVD sum score ≥ 1 (aOR = 2.81, 95% CI = 1.45–5.46, p = 0.002). SVD biomarkers on the diagnostic brain CT are associated with 1‐year death and dependence after intracerebral hemorrhage, independent of known predictors of outcome. ANN NEUROL 2021 :266–279
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.MOLCEL.2019.05.024
Abstract: Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippoc al neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3' transduction. The source (donor) L1 for this insertion was slightly 5' truncated, lacked the YY1 binding site, and was highly mobile when tested in vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.
Publisher: Elsevier BV
Date: 12-2020
Publisher: BMJ
Date: 03-2023
DOI: 10.1136/BMJOPEN-2022-070504
Abstract: Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates. The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target s le size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study’s aims. Ethical approval has been given by South Central H shire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals. ISRCTN17658526 .
Publisher: SAGE Publications
Date: 25-11-2020
Abstract: Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R 2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87) p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45) p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42) p = 0.0004). Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Anonymized summary data may be requested from the corresponding author.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Wiley
Date: 12-2014
DOI: 10.1002/EBM2.6
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9AN01731C
Abstract: There are currently no methods in place for the early detection of brain cancer. A reliable serum triage test could avoid the need for surgery, and speed up time to definitive treatment. Could high-throughput infrared spectroscopy fill the void?
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Paul Brennan.