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  • Open Access English
    Authors: 
    Madiha Salman; Jason I. Gerhard; David W. Major; Paolo Pironi; Rory Hadden;
    Countries: United Kingdom, Canada

    Self-sustaining treatment for active remediation (STAR) is an innovative soil remediation approach based on smoldering combustion that has been demonstrated to effectively destroy complex hydrocarbon nonaqueous phase liquids (NAPLs) with minimal energy input. This is the first study to explore the smoldering remediation of sand contaminated by a volatile NAPL (trichloroethylene, TCE) and the first to consider utilizing vegetable oil as supplemental fuel for STAR. Thirty laboratory-scale experiments were conducted to evaluate the relationship between key outcomes (TCE destruction, rate of remediation) to initial conditions (vegetable oil type, oil: TCE mass ratio, neat versus emulsified oils). Several vegetable oils and emulsified vegetable oil formulations were shown to support remediation of TCE via self-sustaining smoldering. A minimum concentration of 14,000 mg/kg canola oil was found to treat sand exhibiting up to 80,000 mg/kg TCE. On average, 75% of the ICE mass was removed due to volatilization. This proof-of-concept study suggests that injection and smoldering of vegetable oil may provide a new alternative for driving volatile contaminants to traditional vapour extraction systems without supplying substantial external energy. (C) 2014 Elsevier B.V. All rights reserved.

  • Open Access English
    Authors: 
    David A. Palma; Robert Olson; Stephen Harrow; Rohann J. M. Correa; Famke Schneiders; Cornelis J. A. Haasbeek; George B. Rodrigues; Michael Lock; Brian P. Yaremko; Glenn S. Bauman; +15 more
    Countries: Canada, Netherlands, United Kingdom

    Background Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1–3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4–10 metastatic cancer lesions. Methods One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4–10 oligometastatic lesions. Trial registration Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018. Electronic supplementary material The online version of this article (10.1186/s12885-019-5977-6) contains supplementary material, which is available to authorized users.

  • Open Access English
    Authors: 
    Andrew S Moriarty; Nicholas Meader; Kym I E Snell; Richard D Riley; Lewis William Paton; Carolyn Chew-Graham; Simon Gilbody; Rachel Churchill; Robert S. Phillips; Shehzad Ali; +1 more
    Publisher: Wiley
    Countries: United Kingdom, Canada, United Kingdom

    BACKGROUND: Relapse (the re-emergence of depressive symptoms after some level of improvement but preceding recovery) and recurrence (onset of a new depressive episode after recovery) are common in depression, lead to worse outcomes and quality of life for patients and exert a high economic cost on society. Outcomes can be predicted by using multivariable prognostic models, which use information about several predictors to produce an individualised risk estimate. The ability to accurately predict relapse or recurrence while patients are well (in remission) would allow the identification of high-risk individuals and may improve overall treatment outcomes for patients by enabling more efficient allocation of interventions to prevent relapse and recurrence. \ud \ud OBJECTIVES: To summarise the predictive performance of prognostic models developed to predict the risk of relapse, recurrence, sustained remission or recovery in adults with major depressive disorder who meet criteria for remission or recovery. \ud \ud SEARCH METHODS: We searched the Cochrane Library (current issue); Ovid MEDLINE (1946 onwards); Ovid Embase (1980 onwards); Ovid PsycINFO (1806 onwards); and Web of Science (1900 onwards) up to May 2020. We also searched sources of grey literature, screened the reference lists of included studies and performed a forward citation search. There were no restrictions applied to the searches by date, language or publication status . \ud \ud SELECTION CRITERIA: We included development and external validation (testing model performance in data separate from the development data) studies of any multivariable prognostic models (including two or more predictors) to predict relapse, recurrence, sustained remission, or recovery in adults (aged 18 years and over) with remitted depression, in any clinical setting. We included all study designs and accepted all definitions of relapse, recurrence and other related outcomes. We did not specify a comparator prognostic model. \ud \ud DATA COLLECTION AND ANALYSIS: Two review authors independently screened references; extracted data (using a template based on the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS)); and assessed risks of bias of included studies (using the Prediction model Risk Of Bias ASsessment Tool (PROBAST)). We referred any disagreements to a third independent review author. Where we found sufficient (10 or more) external validation studies of an individual model, we planned to perform a meta-analysis of its predictive performance, specifically with respect to its calibration (how well the predicted probabilities match the observed proportions of individuals that experience the outcome) and discrimination (the ability of the model to differentiate between those with and without the outcome). Recommendations could not be qualified using the GRADE system, as guidance is not yet available for prognostic model reviews. \ud \ud MAIN RESULTS: We identified 11 eligible prognostic model studies (10 unique prognostic models). Seven were model development studies; three were model development and external validation studies; and one was an external validation-only study. Multiple estimates of performance measures were not available for any of the models and, meta-analysis was therefore not possible. Ten out of the 11 included studies were assessed as being at high overall risk of bias. Common weaknesses included insufficient sample size, inappropriate handling of missing data and lack of information about discrimination and calibration. One paper (Klein 2018) was at low overall risk of bias and presented a prognostic model including the following predictors: number of previous depressive episodes, residual depressive symptoms and severity of the last depressive episode. The external predictive performance of this model was poor (C-statistic 0.59; calibration slope 0.56; confidence intervals not reported). None of the identified studies examined the clinical utility (net benefit) of the developed model.\ud \ud AUTHORS' CONCLUSIONS: Of the 10 prognostic models identified (across 11 studies), only four underwent external validation. Most of the studies (n = 10) were assessed as being at high overall risk of bias, and the one study that was at low risk of bias presented a model with poor predictive performance. There is a need for improved prognostic research in this clinical area, with future studies conforming to current best practice recommendations for prognostic model development/validation and reporting findings in line with the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement.

  • Open Access English
    Authors: 
    Rieder, Michael; Hawcutt, Daniel;
    Publisher: John Wiley and Sons Inc.
    Countries: Canada, United Kingdom

    It has historically been very difficult to conduct early phase drug studies in children for a number of reasons related to ethics, acceptability, rarity, standardization, end points, safety, dosing and feasibility. Over the past decade there have been a number of developments including novel clinical trial design, in silico pharmacology and microdosing that have significantly enhanced the ability of investigators to conduct early phase drug studies in children. While the evolution of drug therapy is creating a series of new challenges, there has never been a better time for conducting drug studies in children.

  • Publication . Other literature type . Article . 2017
    Open Access English
    Authors: 
    Jing Xu; Naveed Ejaz; Benjamin Hertler; Meret Branscheidt; Mario Widmer; Andreia V. Faria; Michelle D. Harran; Juan C. Cortes; Nathan Kim; Pablo Celnik; +4 more
    Countries: Switzerland, Canada
    Project: WT

    Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation. NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity.

  • Open Access English
    Authors: 
    Joo Ho Tai; Jean J. Tessier; Anderson J. Ryan; Lisa M. Hoffman; Xiaogang Chen; Ting-Yim Lee;
    Countries: United Kingdom, Canada

    Tumor size is not a reliable marker for the assessment of early antivascular effects of antiangiogenics. In the present study, we used 200-μm in-plane high-resolution dynamic contrast-enhanced computed tomography (DCE-CT) to noninvasively assess the immediate antivascular effects of vandetanib in a subcutaneous human colon cancer (LoVo) xenograft model in nude rats and to investigate correlation between changes in CT perfusion parameters and tumor volume or immunohistochemical end points. At 3 to 4 weeks after LoVo cell implantation, the animal was gavaged with either vandetanib (50 mg/kg) or vehicle twice (22 hours apart) and scanned with a preclinical DCE-CT scanner before (0 hour) and after treatment (24 hours). Quantitative maps of blood flow (BF) and volume (BV) of the tumor were calculated from the acquired DCE-CT images. The rats were divided into nonhypovascular, hypovascular, and combined (regardless of vascularity) groups. In the nonhypovascular group, significant decreases in both tumor BF and BV were observed in the vandetanib-treated rats compared with increases in the vehicle-treated rats. A significant decrease in BV was detected in the vandetanib-treated rats in the combined group as well. No differences in tumor growth, vascular endothelial growth factor expression, microvessel density, or apoptosis were observed between vandetanib- and vehicle-treated rats in all three groups. These results demonstrate that BF and BV imaging biomarkers from DCE-CT imaging can be used for rapid monitoring of immediate (24 hours after) antimicrovascular effects of vandetanib on tumors, even in the absence of significant changes of tumor volume or clinically relevant immunohistochemical end points. © 2010 Neoplasia Press, Inc.

  • Publication . Article . Other literature type . 2018
    Open Access English
    Authors: 
    Karen Horsburgh; Joanna M. Wardlaw; Tom van Agtmael; Stuart M. Allan; Mike L.J. Ashford; Philip M. Bath; Rosalind Brown; Jason Berwick; M. Zameel Cader; Roxana O. Carare; +36 more
    Countries: Canada, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom

    Cerebral small vessel disease (SVD) is a major health challenge. Therapeutic approaches remain limited, hampered by the lack of mechanistic understanding and identification of therapeutic targets. Relevant animal models could provide a cornerstone to basic scientific studies of disease mechanisms and pre-clinical studies of potential therapies, but there is a critical need to improve the current translational gap that exists between pre-clinical research and treatments in patients. The Medical Research Council Dementias Platform UK (MRC DPUK) Vascular Experimental Medicine Theme identified that a comprehensive assessment of the latest developments in animal models and of their contribution to understanding of cerebral microvascular disease would reduce the translational gap. In response to this, a two day workshop took place in late January 2017 at the British Heart Foundation Centre of Research Excellence in Glasgow, Scotland in conjunction with MRC DPUK and brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. There were presentations from UK and international researchers and a specific focus on animal models of cerebral microvascular disease and dementia, considering vascular biology, neurogliovascular coupling, blood-brain barrier function, neuroinflammation, cerebral drainage pathways, and methodological and translational challenges (see Figure 1 for the general organisation of the meeting including the key topics and themes discussed). This overview provides a summary of the key talks, with a particular focus on mechanisms of cerebral vascular disease (see Figure 2) and improving translation. These talks were followed by related themed discussion groups on the gaps in knowledge and requirements to advance knowledge, the outcomes of which are highlighted in Table 1. Additional related articles are published in the Special Edition of Clinical Science (http://www.portlandpresspublishing.com/cc/small-vessels).

  • Open Access English
    Authors: 
    Kelly Shen; Gleb Bezgin; Michael Schirner; Petra Ritter; Stefan Everling; Anthony R. McIntosh;
    Publisher: Nature Publishing Group UK
    Country: Canada
    Project: EC | BrainModes (683049), EC | HBP SGA2 (785907), EC | VirtualBrainCloud (826421), CIHR

    Models of large-scale brain networks that are informed by the underlying anatomical connectivity contribute to our understanding of the mapping between the structure of the brain and its dynamical function. Connectome-based modelling is a promising approach to a more comprehensive understanding of brain function across spatial and temporal scales, but it must be constrained by multi-scale empirical data from animal models. Here we describe the construction of a macaque (Macaca mulatta and Macaca fascicularis) connectome for whole-cortex simulations in TheVirtualBrain, an open-source simulation platform. We take advantage of available axonal tract-tracing datasets and enhance the existing connectome data using diffusion-based tractography in macaques. We illustrate the utility of the connectome as an extension of TheVirtualBrain by simulating resting-state BOLD-fMRI data and fitting it to empirical resting-state data. Design Type(s)data integration objective • source-based data transformation objective • modeling and simulation objectiveMeasurement Type(s)brain measurementTechnology Type(s)functional magnetic resonance imaging • Diffusion Weighted ImagingFactor Type(s)Sample Characteristic(s)Macaca • brain Machine-accessible metadata file describing the reported data (ISA-Tab format)

  • Open Access English
    Authors: 
    Winder-Rhodes, Sophie E.; Hampshire, Adam; Rowe, James B.; Peelle, Jonathan E.; Robbins, Trevor W.; Owen, Adrian M.; Barker, Roger A.;
    Publisher: Elsevier
    Countries: Canada, United Kingdom
    Project: WT | Optimisation of cognitive... (088324)

    Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging. This work was funded by Parkinson's UK, the Medical Research Council, the Wellcome Trust (088324), and the NIHR Comprehensive Biomedical Research Centre (RG64473). The BCNI is co-funded by the MRC and Wellcome Trust. Sophie E. Winder-Rhodes received PhD funding from a Merck Sharp and Dohme studentship. This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.006)

  • Open Access English
    Authors: 
    Rebecca M. Todd; Taylor W. Schmitz; Josh Susskind; Adam K. Anderson;
    Publisher: Frontiers Media S.A.
    Country: Canada

    It is well known that emotionally salient events are remembered more vividly than mundane ones. Our recent research has demonstrated that such memory vividness is due in part to the subjective experience of emotional events as more perceptually vivid, an effect we call emotion-enhanced vividness, or EEV. The present study built on previously reported research in which fMRI data were collected while participants rated relative levels of visual noise overlaid on emotionally salient and neutral images. Ratings of greater EEV were associated with greater activation in the amygdala, visual cortex, and posterior insula. In the present study, we measured BOLD activation that predicted recognition memory vividness for these same images one week later. Results showed that, after controlling for differences between scenes in low-level objective features, hippocampus activation uniquely predicted subsequent memory vividness. In contrast, amygdala and visual cortex regions that were sensitive to EEV were also modulated by subsequent ratings of memory vividness. These findings suggest shared neural substrates for the influence of emotional salience on perceptual and mnemonic vividness, with amygdala and visual cortex activation at encoding contributing to the experience of both perception and subsequent memory. © 2013 Todd, Schmitz, Susskind and Anderson.

search
Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
233 Research products, page 1 of 24
  • Open Access English
    Authors: 
    Madiha Salman; Jason I. Gerhard; David W. Major; Paolo Pironi; Rory Hadden;
    Countries: United Kingdom, Canada

    Self-sustaining treatment for active remediation (STAR) is an innovative soil remediation approach based on smoldering combustion that has been demonstrated to effectively destroy complex hydrocarbon nonaqueous phase liquids (NAPLs) with minimal energy input. This is the first study to explore the smoldering remediation of sand contaminated by a volatile NAPL (trichloroethylene, TCE) and the first to consider utilizing vegetable oil as supplemental fuel for STAR. Thirty laboratory-scale experiments were conducted to evaluate the relationship between key outcomes (TCE destruction, rate of remediation) to initial conditions (vegetable oil type, oil: TCE mass ratio, neat versus emulsified oils). Several vegetable oils and emulsified vegetable oil formulations were shown to support remediation of TCE via self-sustaining smoldering. A minimum concentration of 14,000 mg/kg canola oil was found to treat sand exhibiting up to 80,000 mg/kg TCE. On average, 75% of the ICE mass was removed due to volatilization. This proof-of-concept study suggests that injection and smoldering of vegetable oil may provide a new alternative for driving volatile contaminants to traditional vapour extraction systems without supplying substantial external energy. (C) 2014 Elsevier B.V. All rights reserved.

  • Open Access English
    Authors: 
    David A. Palma; Robert Olson; Stephen Harrow; Rohann J. M. Correa; Famke Schneiders; Cornelis J. A. Haasbeek; George B. Rodrigues; Michael Lock; Brian P. Yaremko; Glenn S. Bauman; +15 more
    Countries: Canada, Netherlands, United Kingdom

    Background Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1–3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4–10 metastatic cancer lesions. Methods One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4–10 oligometastatic lesions. Trial registration Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018. Electronic supplementary material The online version of this article (10.1186/s12885-019-5977-6) contains supplementary material, which is available to authorized users.

  • Open Access English
    Authors: 
    Andrew S Moriarty; Nicholas Meader; Kym I E Snell; Richard D Riley; Lewis William Paton; Carolyn Chew-Graham; Simon Gilbody; Rachel Churchill; Robert S. Phillips; Shehzad Ali; +1 more
    Publisher: Wiley
    Countries: United Kingdom, Canada, United Kingdom

    BACKGROUND: Relapse (the re-emergence of depressive symptoms after some level of improvement but preceding recovery) and recurrence (onset of a new depressive episode after recovery) are common in depression, lead to worse outcomes and quality of life for patients and exert a high economic cost on society. Outcomes can be predicted by using multivariable prognostic models, which use information about several predictors to produce an individualised risk estimate. The ability to accurately predict relapse or recurrence while patients are well (in remission) would allow the identification of high-risk individuals and may improve overall treatment outcomes for patients by enabling more efficient allocation of interventions to prevent relapse and recurrence. \ud \ud OBJECTIVES: To summarise the predictive performance of prognostic models developed to predict the risk of relapse, recurrence, sustained remission or recovery in adults with major depressive disorder who meet criteria for remission or recovery. \ud \ud SEARCH METHODS: We searched the Cochrane Library (current issue); Ovid MEDLINE (1946 onwards); Ovid Embase (1980 onwards); Ovid PsycINFO (1806 onwards); and Web of Science (1900 onwards) up to May 2020. We also searched sources of grey literature, screened the reference lists of included studies and performed a forward citation search. There were no restrictions applied to the searches by date, language or publication status . \ud \ud SELECTION CRITERIA: We included development and external validation (testing model performance in data separate from the development data) studies of any multivariable prognostic models (including two or more predictors) to predict relapse, recurrence, sustained remission, or recovery in adults (aged 18 years and over) with remitted depression, in any clinical setting. We included all study designs and accepted all definitions of relapse, recurrence and other related outcomes. We did not specify a comparator prognostic model. \ud \ud DATA COLLECTION AND ANALYSIS: Two review authors independently screened references; extracted data (using a template based on the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS)); and assessed risks of bias of included studies (using the Prediction model Risk Of Bias ASsessment Tool (PROBAST)). We referred any disagreements to a third independent review author. Where we found sufficient (10 or more) external validation studies of an individual model, we planned to perform a meta-analysis of its predictive performance, specifically with respect to its calibration (how well the predicted probabilities match the observed proportions of individuals that experience the outcome) and discrimination (the ability of the model to differentiate between those with and without the outcome). Recommendations could not be qualified using the GRADE system, as guidance is not yet available for prognostic model reviews. \ud \ud MAIN RESULTS: We identified 11 eligible prognostic model studies (10 unique prognostic models). Seven were model development studies; three were model development and external validation studies; and one was an external validation-only study. Multiple estimates of performance measures were not available for any of the models and, meta-analysis was therefore not possible. Ten out of the 11 included studies were assessed as being at high overall risk of bias. Common weaknesses included insufficient sample size, inappropriate handling of missing data and lack of information about discrimination and calibration. One paper (Klein 2018) was at low overall risk of bias and presented a prognostic model including the following predictors: number of previous depressive episodes, residual depressive symptoms and severity of the last depressive episode. The external predictive performance of this model was poor (C-statistic 0.59; calibration slope 0.56; confidence intervals not reported). None of the identified studies examined the clinical utility (net benefit) of the developed model.\ud \ud AUTHORS' CONCLUSIONS: Of the 10 prognostic models identified (across 11 studies), only four underwent external validation. Most of the studies (n = 10) were assessed as being at high overall risk of bias, and the one study that was at low risk of bias presented a model with poor predictive performance. There is a need for improved prognostic research in this clinical area, with future studies conforming to current best practice recommendations for prognostic model development/validation and reporting findings in line with the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement.

  • Open Access English
    Authors: 
    Rieder, Michael; Hawcutt, Daniel;
    Publisher: John Wiley and Sons Inc.
    Countries: Canada, United Kingdom

    It has historically been very difficult to conduct early phase drug studies in children for a number of reasons related to ethics, acceptability, rarity, standardization, end points, safety, dosing and feasibility. Over the past decade there have been a number of developments including novel clinical trial design, in silico pharmacology and microdosing that have significantly enhanced the ability of investigators to conduct early phase drug studies in children. While the evolution of drug therapy is creating a series of new challenges, there has never been a better time for conducting drug studies in children.

  • Publication . Other literature type . Article . 2017
    Open Access English
    Authors: 
    Jing Xu; Naveed Ejaz; Benjamin Hertler; Meret Branscheidt; Mario Widmer; Andreia V. Faria; Michelle D. Harran; Juan C. Cortes; Nathan Kim; Pablo Celnik; +4 more
    Countries: Switzerland, Canada
    Project: WT

    Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation. NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity.

  • Open Access English
    Authors: 
    Joo Ho Tai; Jean J. Tessier; Anderson J. Ryan; Lisa M. Hoffman; Xiaogang Chen; Ting-Yim Lee;
    Countries: United Kingdom, Canada

    Tumor size is not a reliable marker for the assessment of early antivascular effects of antiangiogenics. In the present study, we used 200-μm in-plane high-resolution dynamic contrast-enhanced computed tomography (DCE-CT) to noninvasively assess the immediate antivascular effects of vandetanib in a subcutaneous human colon cancer (LoVo) xenograft model in nude rats and to investigate correlation between changes in CT perfusion parameters and tumor volume or immunohistochemical end points. At 3 to 4 weeks after LoVo cell implantation, the animal was gavaged with either vandetanib (50 mg/kg) or vehicle twice (22 hours apart) and scanned with a preclinical DCE-CT scanner before (0 hour) and after treatment (24 hours). Quantitative maps of blood flow (BF) and volume (BV) of the tumor were calculated from the acquired DCE-CT images. The rats were divided into nonhypovascular, hypovascular, and combined (regardless of vascularity) groups. In the nonhypovascular group, significant decreases in both tumor BF and BV were observed in the vandetanib-treated rats compared with increases in the vehicle-treated rats. A significant decrease in BV was detected in the vandetanib-treated rats in the combined group as well. No differences in tumor growth, vascular endothelial growth factor expression, microvessel density, or apoptosis were observed between vandetanib- and vehicle-treated rats in all three groups. These results demonstrate that BF and BV imaging biomarkers from DCE-CT imaging can be used for rapid monitoring of immediate (24 hours after) antimicrovascular effects of vandetanib on tumors, even in the absence of significant changes of tumor volume or clinically relevant immunohistochemical end points. © 2010 Neoplasia Press, Inc.

  • Publication . Article . Other literature type . 2018
    Open Access English
    Authors: 
    Karen Horsburgh; Joanna M. Wardlaw; Tom van Agtmael; Stuart M. Allan; Mike L.J. Ashford; Philip M. Bath; Rosalind Brown; Jason Berwick; M. Zameel Cader; Roxana O. Carare; +36 more
    Countries: Canada, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom, United Kingdom

    Cerebral small vessel disease (SVD) is a major health challenge. Therapeutic approaches remain limited, hampered by the lack of mechanistic understanding and identification of therapeutic targets. Relevant animal models could provide a cornerstone to basic scientific studies of disease mechanisms and pre-clinical studies of potential therapies, but there is a critical need to improve the current translational gap that exists between pre-clinical research and treatments in patients. The Medical Research Council Dementias Platform UK (MRC DPUK) Vascular Experimental Medicine Theme identified that a comprehensive assessment of the latest developments in animal models and of their contribution to understanding of cerebral microvascular disease would reduce the translational gap. In response to this, a two day workshop took place in late January 2017 at the British Heart Foundation Centre of Research Excellence in Glasgow, Scotland in conjunction with MRC DPUK and brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. There were presentations from UK and international researchers and a specific focus on animal models of cerebral microvascular disease and dementia, considering vascular biology, neurogliovascular coupling, blood-brain barrier function, neuroinflammation, cerebral drainage pathways, and methodological and translational challenges (see Figure 1 for the general organisation of the meeting including the key topics and themes discussed). This overview provides a summary of the key talks, with a particular focus on mechanisms of cerebral vascular disease (see Figure 2) and improving translation. These talks were followed by related themed discussion groups on the gaps in knowledge and requirements to advance knowledge, the outcomes of which are highlighted in Table 1. Additional related articles are published in the Special Edition of Clinical Science (http://www.portlandpresspublishing.com/cc/small-vessels).

  • Open Access English
    Authors: 
    Kelly Shen; Gleb Bezgin; Michael Schirner; Petra Ritter; Stefan Everling; Anthony R. McIntosh;
    Publisher: Nature Publishing Group UK
    Country: Canada
    Project: EC | BrainModes (683049), EC | HBP SGA2 (785907), EC | VirtualBrainCloud (826421), CIHR

    Models of large-scale brain networks that are informed by the underlying anatomical connectivity contribute to our understanding of the mapping between the structure of the brain and its dynamical function. Connectome-based modelling is a promising approach to a more comprehensive understanding of brain function across spatial and temporal scales, but it must be constrained by multi-scale empirical data from animal models. Here we describe the construction of a macaque (Macaca mulatta and Macaca fascicularis) connectome for whole-cortex simulations in TheVirtualBrain, an open-source simulation platform. We take advantage of available axonal tract-tracing datasets and enhance the existing connectome data using diffusion-based tractography in macaques. We illustrate the utility of the connectome as an extension of TheVirtualBrain by simulating resting-state BOLD-fMRI data and fitting it to empirical resting-state data. Design Type(s)data integration objective • source-based data transformation objective • modeling and simulation objectiveMeasurement Type(s)brain measurementTechnology Type(s)functional magnetic resonance imaging • Diffusion Weighted ImagingFactor Type(s)Sample Characteristic(s)Macaca • brain Machine-accessible metadata file describing the reported data (ISA-Tab format)

  • Open Access English
    Authors: 
    Winder-Rhodes, Sophie E.; Hampshire, Adam; Rowe, James B.; Peelle, Jonathan E.; Robbins, Trevor W.; Owen, Adrian M.; Barker, Roger A.;
    Publisher: Elsevier
    Countries: Canada, United Kingdom
    Project: WT | Optimisation of cognitive... (088324)

    Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging. This work was funded by Parkinson's UK, the Medical Research Council, the Wellcome Trust (088324), and the NIHR Comprehensive Biomedical Research Centre (RG64473). The BCNI is co-funded by the MRC and Wellcome Trust. Sophie E. Winder-Rhodes received PhD funding from a Merck Sharp and Dohme studentship. This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.006)

  • Open Access English
    Authors: 
    Rebecca M. Todd; Taylor W. Schmitz; Josh Susskind; Adam K. Anderson;
    Publisher: Frontiers Media S.A.
    Country: Canada

    It is well known that emotionally salient events are remembered more vividly than mundane ones. Our recent research has demonstrated that such memory vividness is due in part to the subjective experience of emotional events as more perceptually vivid, an effect we call emotion-enhanced vividness, or EEV. The present study built on previously reported research in which fMRI data were collected while participants rated relative levels of visual noise overlaid on emotionally salient and neutral images. Ratings of greater EEV were associated with greater activation in the amygdala, visual cortex, and posterior insula. In the present study, we measured BOLD activation that predicted recognition memory vividness for these same images one week later. Results showed that, after controlling for differences between scenes in low-level objective features, hippocampus activation uniquely predicted subsequent memory vividness. In contrast, amygdala and visual cortex regions that were sensitive to EEV were also modulated by subsequent ratings of memory vividness. These findings suggest shared neural substrates for the influence of emotional salience on perceptual and mnemonic vividness, with amygdala and visual cortex activation at encoding contributing to the experience of both perception and subsequent memory. © 2013 Todd, Schmitz, Susskind and Anderson.