Quasi-diffusion magnetic resonance imaging (QDI): A fast, high b-value diffusion imaging technique.

To enable application of non-Gaussian diffusion magnetic resonance imaging (dMRI) techniques in large-scale clinical trials and facilitate translation to clinical practice there is a requirement for fast, high contrast, techniques that are sensitive to changes in tissue structure which provide diagnostic signatures at the early stages of disease. Here we describe a new way to compress the acquisition of multi-shell b-value diffusion data, Quasi-Diffusion MRI (QDI), which provides a probe of subvoxel tissue complexity using short acquisition times (1-4 min). We also describe a coherent framework for multi-directional diffusion gradient acquisition and data processing that allows computation of rotationally invariant quasi-diffusion tensor imaging (QDTI) maps. QDI is a quantitative technique that is based on a special case of the Continuous Time Random Walk model of diffusion dynamics and assumes the presence of non-Gaussian diffusion properties within tissue microstructure. QDI parameterises the diffusion signal attenuation according to the rate of decay (i.e. diffusion coefficient, D in mm2 s-1) and the shape of the power law tail (i.e. the fractional exponent, α). QDI provides analogous tissue contrast to Diffusional Kurtosis Imaging (DKI) by calculation of normalised entropy of the parameterised diffusion signal decay curve, Hn, but does so without the limitations of a maximum b-value. We show that QDI generates images with superior tissue contrast to conventional diffusion imaging within clinically acceptable acquisition times of between 84 and 228 s. We show that QDI provides clinically meaningful images in cerebral small vessel disease and brain tumour case studies. Our initial findings suggest that QDI may be added to routine conventional dMRI acquisitions allowing simple application in clinical trials and translation to the clinical arena

Optimization of quasi-diffusion magnetic resonance imaging for quantitative accuracy and time-efficient acquisition.

Purpose Quasi-diffusion MRI (QDI) is a novel quantitative technique based on the continuous time random walk model of diffusion dynamics. QDI provides estimates of the diffusion coefficient D1,2, in mm2 s−1 and a fractional exponent, α, defining the non-Gaussianity of the diffusion signal decay. Here, the b-value selection for rapid clinical acquisition of QDI tensor imaging (QDTI) data is optimized. Methods Clinically appropriate QDTI acquisitions were optimized in healthy volunteers with respect to a multi-b-value reference (MbR) dataset comprising 29 diffusion-sensitized images arrayed between b = 0 and 5000 s mm−2. The effects of varying maximum b-value (bmax), number of b-value shells, and the effects of Rician noise were investigated. Results QDTI measures showed bmax dependence, most significantly for α in white matter, which monotonically decreased with higher bmax leading to improved tissue contrast. Optimized 2 b-value shell acquisitions showed small systematic differences in QDTI measures relative to MbR values, with overestimation of D1,2 and underestimation of α in white matter, and overestimation of D1,2 and α anisotropies in gray and white matter. Additional shells improved the accuracy, precision, and reliability of QDTI estimates with 3 and 4 shells at bmax = 5000 s mm−2, and 4 b-value shells at bmax = 3960 s mm−2, providing minimal bias in D1,2 and α compared to the MbR. Conclusion A highly detailed optimization of non-Gaussian dMRI for in vivo brain imaging was performed. QDI provided robust parameterization of non-Gaussian diffusion signal decay in clinically feasible imaging times with high reliability, accuracy, and precision of QDTI measures

The Mathematics of Quasi-Diffusion Magnetic Resonance Imaging

Quasi-diffusion imaging (QDI) is a novel quantitative diffusion magnetic resonance imaging (dMRI) technique that enables high quality tissue microstructural imaging in a clinically feasible acquisition time. QDI is derived from a special case of the continuous time random walk (CTRW) model of diffusion dynamics and assumes water diffusion is locally Gaussian within tissue microstructure. By assuming a Gaussian scaling relationship between temporal (α) and spatial (β) fractional exponents, the dMRI signal attenuation is expressed according to a diffusion coefficient, D (in mm2 s−1), and a fractional exponent, α. Here we investigate the mathematical properties of the QDI signal and its interpretation within the quasi-diffusion model. Firstly, the QDI equation is derived and its power law behaviour described. Secondly, we derive a probability distribution of underlying Fickian diffusion coefficients via the inverse Laplace transform. We then describe the functional form of the quasi-diffusion propagator, and apply this to dMRI of the human brain to perform mean apparent propagator imaging. QDI is currently unique in tissue microstructural imaging as it provides a simple form for the inverse Laplace transform and diffusion propagator directly from its representation of the dMRI signal. This study shows the potential of QDI as a promising new model-based dMRI technique with significant scope for further development

UBC-Nepal Expedition: Acute alterations in sympathetic nervous activity do not influence brachial artery endothelial function at sea-level and high-altitude.

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high-altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g. shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that: 1) at rest, SNA would be elevated and FMD would be reduced at HA compared to sea-level (SL); and 2) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344m) and HA (5050m) in 14 participants during mild lower-body negative pressure (LBNP; -10 mmHg) and lower-body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrodcardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants (n=5). Our findings were: 1) at rest, SNA was elevated (P<0.01), and absolute FMD was reduced (P=0.024), but relative FMD remained unaltered (P=0.061), at HA compared to SL, and 2) despite significantly altering SNA with LBNP (+60.3±25.5%) and LBPP (-37.2±12.7%) (P<0.01), FMD was unaltered at SL (P=0.448), and HA (P=0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA

UBC-Nepal Expedition: Acute alterations in sympathetic nervous activity do not influence brachial artery endothelial function at sea-level and high-altitude.

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high-altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g. shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that: 1) at rest, SNA would be elevated and FMD would be reduced at HA compared to sea-level (SL); and 2) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344m) and HA (5050m) in 14 participants during mild lower-body negative pressure (LBNP; -10 mmHg) and lower-body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrodcardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants (n=5). Our findings were: 1) at rest, SNA was elevated (P<0.01), and absolute FMD was reduced (P=0.024), but relative FMD remained unaltered (P=0.061), at HA compared to SL, and 2) despite significantly altering SNA with LBNP (+60.3±25.5%) and LBPP (-37.2±12.7%) (P<0.01), FMD was unaltered at SL (P=0.448), and HA (P=0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA

Modifiable healthcare factors affecting 28-day survival in bloodstream infection: a prospective cohort study

Background: Bloodstream infection is common in the UK and has significant mortality depending on the pathogen involved, site of infection and other patient factors. Healthcare staffing and ward activity may also impact on outcomes in a range of conditions, however there is little specific National Health Service (NHS) data on the impact for patients with bloodstream infection. Bloodstream Infections – Focus on Outcomes is a multicentre cohort study with the primary aim of identifying modifiable risk factors for 28-day mortality in patients with bloodstream infection due to one of six key pathogens. Methods: Adults under the care of five NHS Trusts in England and Wales between November 2010 and May 2012 were included. Multivariable Cox regression was used to quantify the association between modifiable risk factors, including staffing levels and timing of appropriate therapy, and 28-day mortality, after adjusting for non-modifiable risk factors such as patient demographics and long-term comorbidities. Results: A total of 1676 patients were included in the analysis population. Overall, 348/1676 (20.8%) died within 28 days. Modifiable factors associated with 28-day mortality were ward speciality, ward activity (admissions and discharges), movement within ward speciality, movement from critical care, and time to receipt of appropriate antimicrobial therapy in the first 7 days. For each additional admission or discharge per 10 beds, the hazard increased by 4% (95% CI 1 to 6%) in medical wards and 11% (95% CI 4 to 19%) in critical care. Patients who had moved wards within speciality or who had moved out of a critical care ward had a reduction in hazard of mortality. In the first 7 days, hazard of death increased with increasing time to receipt of appropriate antimicrobial therapy. Conclusion: This study underlines the importance of appropriate antimicrobials within the first 7 days, and the potential for ward activity and ward movements to impact on survival in bloodstream infection

Lentiviral vectors can be used for full-length dystrophin gene therapy

Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. In our work, we have demonstrated that lentiviral vectors can package and deliver inserts of a similar size to dystrophin. We report a novel approach for delivering large transgenes in lentiviruses, in which we demonstrate proof-of-concept for a 'template-switching' lentiviral vector that harnesses recombination events during reverse-transcription. During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD

Contribution of cyanobacterial alkane production to the ocean hydrocarbon cycle.

Hydrocarbons are ubiquitous in the ocean, where alkanes such as pentadecane and heptadecane can be found even in waters minimally polluted with crude oil. Populations of hydrocarbon-degrading bacteria, which are responsible for the turnover of these compounds, are also found throughout marine systems, including in unpolluted waters. These observations suggest the existence of an unknown and widespread source of hydrocarbons in the oceans. Here, we report that strains of the two most abundant marine cyanobacteria, Prochlorococcus and Synechococcus, produce and accumulate hydrocarbons, predominantly C15 and C17 alkanes, between 0.022 and 0.368% of dry cell weight. Based on global population sizes and turnover rates, we estimate that these species have the capacity to produce 2-540 pg alkanes per mL per day, which translates into a global ocean yield of ∼ 308-771 million tons of hydrocarbons annually. We also demonstrate that both obligate and facultative marine hydrocarbon-degrading bacteria can consume cyanobacterial alkanes, which likely prevents these hydrocarbons from accumulating in the environment. Our findings implicate cyanobacteria and hydrocarbon degraders as key players in a notable internal hydrocarbon cycle within the upper ocean, where alkanes are continually produced and subsequently consumed within days. Furthermore we show that cyanobacterial alkane production is likely sufficient to sustain populations of hydrocarbon-degrading bacteria, whose abundances can rapidly expand upon localized release of crude oil from natural seepage and human activities

Argumentation in school science : Breaking the tradition of authoritative exposition through a pedagogy that promotes discussion and reasoning

The value of argumentation in science education has become internationally recognised and has been the subject of many research studies in recent years. Successful introduction of argumentation activities in learning contexts involves extending teaching goals beyond the understanding of facts and concepts, to include an emphasis on cognitive and metacognitive processes, epistemic criteria and reasoning. The authors focus on the difficulties inherent in shifting a tradition of teaching from one dominated by authoritative exposition to one that is more dialogic, involving small-group discussion based on tasks that stimulate argumentation. The paper builds on previous research on enhancing the quality of argument in school science, to focus on how argumentation activities have been designed, with appropriate strategies, resources and modelling, for pedagogical purposes. The paper analyses design frameworks, their contexts and lesson plans, to evaluate their potential for enhancing reasoning through foregrounding the processes of argumentation. Examples of classroom dialogue where teachers adopt the frameworks/plans are analysed to show how argumentation processes are scaffolded. The analysis shows that several layers of interpretation are needed and these layers need to be aligned for successful implementation. The analysis serves to highlight the potential and limitations of the design frameworks

UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level

Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia