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  1. Article ; Online: Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury

    Frederick A. Zeiler / Yasser Iturria-Medina / Eric P. Thelin / Alwyn Gomez / Jai J. Shankar / Ji Hyun Ko / Chase R. Figley / Galen E. B. Wright / Chris M. Anderson

    Frontiers in Neurology, Vol

    2021  Volume 12

    Abstract: Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the “one-treatment fits all” approach to such ... ...

    Abstract Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the “one-treatment fits all” approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex “-omics” data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can be a daunting task for the treating clinician. Within this review, we highlight the current status of such multi-modal omics data sets in moderate/severe TBI, current limitations to the utilization of such data, and a potential path forward through employing integrative neuroinformatic approaches, which are applied in other neuropathologies. Such advances are positioned to facilitate the transition to precision prognostication and inform a top-down approach to the development of personalized therapeutics in moderate/severe TBI.
    Keywords multi-modal data ; neuroinformatics ; precision medicine ; traumatic brain injury ; big data ; Neurology. Diseases of the nervous system ; RC346-429
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Dynamics of cerebrospinal fluid levels of matrix metalloproteinases in human traumatic brain injury

    Karolina Minta / Gunnar Brinkmalm / Faiez Al Nimer / Eric P. Thelin / Fredrik Piehl / Mats Tullberg / Anna Jeppsson / Erik Portelius / Henrik Zetterberg / Kaj Blennow / Ulf Andreasson

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 11

    Abstract: Abstract Matrix metalloproteinases (MMPs) are extracellular enzymes involved in the degradation of extracellular matrix (ECM) proteins. Increased expression of MMPs have been described in traumatic brain injury (TBI) and may contribute to additional ... ...

    Abstract Abstract Matrix metalloproteinases (MMPs) are extracellular enzymes involved in the degradation of extracellular matrix (ECM) proteins. Increased expression of MMPs have been described in traumatic brain injury (TBI) and may contribute to additional tissue injury and blood–brain barrier damage. The objectives of this study were to determine longitudinal changes in cerebrospinal fluid (CSF) concentrations of MMPs after acute TBI and in relation to clinical outcomes, with patients with idiopathic normal pressure hydrocephalus (iNPH) serving as a contrast group. The study included 33 TBI patients with ventricular CSF serially sampled, and 38 iNPH patients in the contrast group. Magnetic bead-based immunoassays were utilized to measure the concentrations of eight MMPs in ventricular human CSF. CSF concentrations of MMP-1, MMP-3 and MMP-10 were increased in TBI patients (at baseline) compared with the iNPH group (p < 0.001), while MMP-2, MMP-9 and MMP-12 did not differ between the groups. MMP-1, MMP-3 and MMP-10 concentrations decreased with time after trauma (p = 0.001–0.04). Increased concentrations of MMP-2 and MMP-10 in CSF at baseline were associated with an unfavourable TBI outcome (p = 0.002–0.02). Observed variable pattern of changes in MMP concentrations indicates that specific MMPs serve different roles in the pathophysiology following TBI, and are in turn associated with clinical outcomes.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610 ; 616
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Statistical analysis plan for the Dex-CSDH trial

    Annabel Allison / Ellie Edlmann / Angelos G. Kolias / Carol Davis-Wilkie / Harry Mee / Eric P. Thelin / Carole Turner / Peter J. Hutchinson / Simon Bond

    Trials, Vol 20, Iss 1, Pp 1-

    a randomised, double-blind, placebo-controlled trial of a 2-week course of dexamethasone for adult patients with a symptomatic chronic subdural haematoma

    2019  Volume 5

    Abstract: Abstract Background The incidence of chronic subdural haematoma (CSDH) is increasing. Although surgery remains the mainstay of management for symptomatic patients, uncertainty remains regarding the role of steroids. Hence, the Dex-CSDH trial was launched ...

    Abstract Abstract Background The incidence of chronic subdural haematoma (CSDH) is increasing. Although surgery remains the mainstay of management for symptomatic patients, uncertainty remains regarding the role of steroids. Hence, the Dex-CSDH trial was launched in the UK in 2015 aiming to determine whether, compared to placebo, dexamethasone can improve the 6-month functional outcome of patients with symptomatic CSDH by reducing the rate of surgical intervention and recurrence rate. Methods and design Dex-CSDH is a multi-centre, pragmatic, parallel group, double-blind, randomised trial assessing the clinical utility of a 2-week course of dexamethasone following a CSDH. Seven hundred fifty patients were randomised to either dexamethasone or placebo. The primary outcome is the modified Rankin Scale at 6 months which is dichotomised to favourable (a score of 0–3) versus unfavourable (a score of 4–6). Conclusions This paper and the accompanying additional material describe the statistical analysis plan for the trial. Trial registration ISRCTN, ISRCTN80782810. Registered on 7 November 2014. http://www.isrctn.com/ISRCTN80782810. EudraCT, 2014-004948-35. Registered on 20 March 2015.
    Keywords Dexamethasone ; Chronic subdural haematoma ; Randomised trial ; Steroid ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury

    Matthew G. Stovell / Marius O. Mada / Adel Helmy / T. Adrian Carpenter / Eric P. Thelin / Jiun-Lin Yan / Mathew R. Guilfoyle / Ibrahim Jalloh / Duncan J. Howe / Peter Grice / Andrew Mason / Susan Giorgi-Coll / Clare N. Gallagher / Michael P. Murphy / David K. Menon / Peter J. Hutchinson / Keri L. H. Carpenter

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: Abstract A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence ... ...

    Abstract Abstract A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (−13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = −0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610 ; 616
    Language English
    Publishing date 2018-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Correction to

    Angelos G. Kolias / Ellie Edlmann / Eric P. Thelin / Diederik Bulters / Patrick Holton / Nigel Suttner / Kevin Owusu-Agyemang / Yahia Z. Al-Tamimi / Daniel Gatt / Simon Thomson / Ian A. Anderson / Oliver Richards / Peter Whitfield / Monica Gherle / Karen Caldwell / Carol Davis-Wilkie / Silvia Tarantino / Garry Barton / Hani J. Marcus /
    Aswin Chari / Paul Brennan / Antonio Belli / Simon Bond / Carole Turner / Lynne Whitehead / Ian Wilkinson / Peter J. Hutchinson / British Neurosurgical Trainee Research Collaborative (BNTRC) and Dex-CSDH Trial Collaborators

    Trials, Vol 20, Iss 1, Pp 1-

    Dexamethasone for adult patients with a symptomatic chronic subdural haematoma (Dex-CSDH) trial: study protocol for a randomised controlled trial

    2019  Volume 1

    Abstract: After publication of the original article [1], the authors notified that that one of the BNTRC institutional collaborator names was misspelled. ...

    Abstract After publication of the original article [1], the authors notified that that one of the BNTRC institutional collaborator names was misspelled.
    Keywords Medicine (General) ; R5-920
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Dexamethasone for adult patients with a symptomatic chronic subdural haematoma (Dex-CSDH) trial

    Angelos G. Kolias / Ellie Edlmann / Eric P. Thelin / Diederik Bulters / Patrick Holton / Nigel Suttner / Kevin Owusu-Agyemang / Yahia Z. Al-Tamimi / Daniel Gatt / Simon Thomson / Ian A. Anderson / Oliver Richards / Peter Whitfield / Monica Gherle / Karen Caldwell / Carol Davis-Wilkie / Silvia Tarantino / Garry Barton / Hani J. Marcus /
    Aswin Chari / Paul Brennan / Antonio Belli / Simon Bond / Carole Turner / Lynne Whitehead / Ian Wilkinson / Peter J. Hutchinson / British Neurosurgical Trainee Research Collaborative (BNTRC) and Dex-CSDH Trial Collaborators

    Trials, Vol 19, Iss 1, Pp 1-

    study protocol for a randomised controlled trial

    2018  Volume 14

    Abstract: Abstract Background Chronic subdural haematoma (CSDH) is a common neurosurgical condition, typically treated with surgical drainage of the haematoma. However, surgery is associated with mortality and morbidity, including up to 20% recurrence of the CSDH. ...

    Abstract Abstract Background Chronic subdural haematoma (CSDH) is a common neurosurgical condition, typically treated with surgical drainage of the haematoma. However, surgery is associated with mortality and morbidity, including up to 20% recurrence of the CSDH. Steroids, such as dexamethasone, have been identified as a potential therapy for reducing recurrence risk in surgically treated CSDHs. They have also been used as a conservative treatment option, thereby avoiding surgery altogether. The hypothesis of the Dex-CSDH trial is that a two-week course of dexamethasone in symptomatic patients with CSDH will lead to better functional outcome at six months. This is anticipated to occur through reduced number of hospital admissions and surgical interventions. Methods Dex-CSDH is a UK multi-centre, double-blind randomised controlled trial of dexamethasone versus placebo for symptomatic adult patients diagnosed with CSDH. A sample size of 750 patients has been determined, including an initial internal pilot phase of 100 patients to confirm recruitment feasibility. Patients must be recruited within 72 h of admission to a neurosurgical unit and exclusions include patients already on steroids or with steroid contraindications, patients who have a cerebrospinal fluid shunt and those with a history of psychosis. The decision regarding surgical intervention will be made by the clinical team and patients can be included in the trial regardless of whether operative treatment is planned or has been performed. The primary outcome measure is the modified Rankin Scale (mRS) at six months. Secondary outcomes include the number of CSDH-related surgical interventions during follow-up, length of hospital stay, mRS at three months, EQ-5D at three and six months, adverse events, mortality and a health-economic analysis. Discussion This multi-centre trial will provide high-quality evidence as to the effectiveness of dexamethasone in the treatment of CSDH. This has implications for patient morbidity and mortality as well as a potential economic impact on the overall health service burden from this condition. Trial registration ISRCTN, ISRCTN80782810. Registered on 7 November 2014. EudraCT, 2014-004948-35. Registered on 20 March 2015. Dex-CSDH trial protocol version 3, 27 Apr 2017. This protocol was developed in accordance with the SPIRIT checklist. Available as a separate document on request.
    Keywords Chronic subdural haematoma ; Dexamethasone ; Neurosurgery ; Neurology ; Randomised control trial ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2018-12-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Dex-CSDH randomised, placebo-controlled trial of dexamethasone for chronic subdural haematoma

    Ellie Edlmann / Eric P. Thelin / Karen Caldwell / Carole Turner / Peter Whitfield / Diederik Bulters / Patrick Holton / Nigel Suttner / Kevin Owusu-Agyemang / Yahia Z. Al-Tamimi / Daniel Gatt / Simon Thomson / Ian A. Anderson / Oliver Richards / Monica Gherle / Emma Toman / Dipankar Nandi / Phillip Kane / Beatrice Pantaleo /
    Carol Davis-Wilkie / Silvia Tarantino / Garry Barton / Hani J. Marcus / Aswin Chari / Antonio Belli / Simon Bond / Rafael Gafoor / Sarah Dawson / Lynne Whitehead / Paul Brennan / Ian Wilkinson / Angelos G Kolias / Peter J. A. Hutchinson / Dex-CSDH trial collaborative and BNTRC collaborative.

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    report of the internal pilot phase

    2019  Volume 13

    Abstract: Abstract The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the ... ...

    Abstract Abstract The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the feasibility of multi-centre recruitment. Primary outcome data collection and safety were also assessed, whilst maintaining blinding. We aimed to recruit 100 patients from United Kingdom Neurosurgical Units within 12 months. Trial participants were randomised to a 2-week course of dexamethasone or placebo in addition to receiving standard care (which could include surgery). The primary outcome measure of the trial is the modified Rankin Scale at 6 months. This pilot recruited ahead of target; 100 patients were recruited within nine months of commencement. 47% of screened patients consented to recruitment. The primary outcome measure was collected in 98% of patients. No safety concerns were raised by the independent data monitoring and ethics committee and only five patients were withdrawn from drug treatment. Pilot trial data can inform on the design and resource provision for substantive trials. This internal pilot was successful in determining recruitment feasibility. Excellent follow-up rates were achieved and exploratory outcome measures were added to increase the scientific value of the trial.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2019-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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