Phase-Controlled Synthesis of Ruthenium and Palladium Nanocrystals

The utility of noble-metal nanocrystals in applications ranging from catalysis to biomedical applications has increased with the ability to finely tune their shapes and sizes. In particular, the catalytic activity of the nanocrystals is strongly affected by their shape, as this parameter is directly related to the atomic arrangement on the surface. Another way to alter the surface atomic arrangement is through changing the crystal structure (or phase) of the nanocrystal, a property known as polymorphism. A powerful method to achieve such control over the crystal structure is through template-directed growth to obtain metastable core-shell nanocrystals. In this dissertation, I present a number of studies delving into the mechanistic details behind template-directed phase control for Pd and Ru, alongside an evaluation of their catalytic properties. First, the importance of particle size on successful template-directed deposition was demonstrated through deposition of Ru on 12-, 18-, 22-, and 26-nm Pd nanoplates, where small nanoplates resulted in fcc-Ru shells, while the larger ones gave hcp-Ru overgrowth. The size dependence was ascribed to a trade-off between the bulk and surface energies that changed with particle size. On small nanoplates, the high proportion of total surface area coming from the side faces makes it favorable to grow fcc-Ru, which deposits smoothly on the side facets (low surface energy) at the expense of forming a metastable phase (high bulk energy). For large nanoplates, only a small proportion of the surface area comes from the side, promoting the growth of hcp-Ru as the resulting jagged side faces (high surface energy) could be compensated by the formation of a thermodynamically stable phase (low bulk energy). To further elucidate the mechanistic details involved in phase-controlled synthesis, the influence of the template’s shape was investigated next. When Ru was deposited on 8-25 nm Pd cubic nanocrystals, the Ru shell took an fcc phase, but on 14-26 nm Pd octahedral nanocrystals, the Ru was deposited as fcc on the small templates before reverting to hcp on the larger ones. The {100} facets displayed on cubic templates forced the Ru to take the fcc phase due to a symmetry mismatch between the facets of the fcc¬-Pd template and hcp-Ru, while on octahedral templates, the displayed {111} facets could be symmetrically aligned with either hcp- or fcc-Ru, allowing for the overgrowth of either crystal structure. Thus, on octahedral templates, the crystal structure depends on particle size and it is determined by the balance of surface and bulk energies. With an improved understanding of template-directed phase control, this method could be extended to obtain hcp-Pd deposition on an hcp¬-Ru template. Under careful control of the reaction conditions, Pd could be deposited on an hcp-Ru template in either the standard fcc phase, or in a novel, metastable hcp phase. It was essential to slow down the reduction rate of the Pd precursor in order to obtain phase-controlled Pd. The ability to control the crystal structure of noble-metal nanocrystals, coupled with a mechanistic understanding of this process, will enable the development of nanostructured materials with unique properties through rational and deterministic syntheses.Ph.D

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation. Methods: The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a) that recognizes the Nterminus of micro-dystrophin. The degree of physiologic correction was assessed by measuring tetanic force and protection from eccentric contraction in the extensor digitorum longus muscle (EDL). The vascular delivery paradigm found successful in the mouse was carried to the non-human primate to test its potential translation to boys with DMD. Results: Regional vascular delivery resulted in transduction by rAAV8.micro-dystrophin reaching 94.5 ± 0.9 (1 month), 91.3 ± 3.1 (2 months), and 89.6 ± 1.6% (3 months). rAAV6.micro-dystrophin treated animals demonstrated 87.7 ± 6.8 (1 month), 78.9 ± 7.4 (2 months), and 81.2 ± 6.2% (3 months) transduction. In striking contrast, rAAV1 demonstrated very low transduction efficiency [0.9 ± 0.3 (1 month), 2.1 ± 0.8 (2 months), and 2.1 ± 0.7% (3 months)] by vascular delivery. Micro-dystrophin delivered by rAAV8 and rAAV6 through the femoral artery significantly improved tetanic force and protected against eccentric contraction. Mouse studies translated to the hindlimb of cynamologous macaques using a similar vascular delivery paradigm. rAAV8 carrying eGFP in doses proportional to the mouse (5 × 1012 vg/kg in mouse vs 2 × 1012 vg/kg in monkey) demonstrated widespread gene expression [medial gastrocnemius – 63.8 ± 4.9%, lateral gastrocnemius – 66.0 ± 4.5%, EDL – 80.2 ± 3.1%, soleus – 86.4 ± 1.9%, TA – 72.2 ± 4.0%. Conclusion: These studies demonstrate regional vascular gene delivery with AAV serotype(s) in mouse and non-human primate at doses, pressures and volumes applicable for clinical trials in children with DMD

Factors Influencing the Delivery of Intensive Rehabilitation in Stroke: Patient Perceptions Versus Rehabilitation Therapist Perceptions

Background Despite increasing evidence on intensive task-specific practice and aerobic exercise in stroke rehabilitation, implementation remains difficult. The factors influencing implementation have been explored from therapists’ perspectives; however, despite an increased emphasis on patient involvement in research, patients’ perceptions have not yet been investigated. Objective The study aimed to investigate factors influencing implementation of higher intensity activity in people with stroke and to compare this with therapists’ perspectives. Design The design was a cross-sectional qualitative study. Methods The study used semi-structured interviews with people with stroke who were part of a randomized clinical trial, the Determining Optimal post-Stroke Exercise (DOSE) study, which delivered a higher intensity intervention. An interview guide was developed and data analyzed using implementation frameworks. Factors emerging from people with stroke were compared and contrasted to factors perceived by rehabilitation therapists. Results Ten people with stroke were interviewed before data saturation was reached. Participants had a positive attitude regarding working hard, and were satisfied with the graded exercise test, high intensity intervention, and the feedback monitoring devices. Therapists and patients had contrasting perceptions about their beliefs of intensive exercise and the content of the intervention, with therapists more focused on the methods and patients more focused on the personal interactions stemming from the therapeutic relationship. Conclusions People with stroke perceived no barriers regarding the implementation of higher intensity rehabilitation in practice and were positive towards working at more intense levels. Contrastingly, from the therapists’ perspective, therapists’ beliefs about quality of movement and issues around staffing and resources were perceived to be barriers. In addition, therapists and people with stroke perceived the contents of the intervention differently, highlighting the importance of involving patients and clinicians in the development and evaluation of rehabilitation interventions

Delivering intensive rehabilitation in stroke: factors influencing implementation

Background The evidence-base for stroke rehabilitation recommends intensive and repetitive task-specific practice, as well as aerobic exercise. However, translating these evidence-based interventions from research into clinical practice remains a major challenge. Objective To investigate factors influencing implementation of higher intensity activity in stroke rehabilitation settings Design A cross-sectional qualitative study. Methods Semi-structured interviews with rehabilitation therapists who had experience of delivering a higher intensity intervention as part of a clinical trial (DOSE), from four sites, across two provinces, in Canada. An interview guide was developed and data analysed using implementation frameworks. Results Fifteen therapists were interviewed before data saturation was reached. Therapists and patients generally had positive experiences regarding high intensity interventions. However, therapists felt they would adapt the protocol to accommodate their beliefs about ensuring movement quality. The requirement for all patients to have a graded exercise test, and the use of sensors, e.g. heart rate monitors, gave therapists confidence to push patients harder than they normally would. Paradoxically, a system that enables routine graded exercise testing, and the availability of staff and equipment contribute challenges for implementation in everyday practice. Conclusions Even therapists involved in delivering a high intensity intervention as part of a trial wanted to adapt it for clinical practice. Hence it is imperative that researchers are explicit regarding key intervention components and what can be adapted to help ensure implementation fidelity. Changes in therapist’s beliefs and system level changes (staffing and resources) are likely to be required to facilitate higher intensity rehabilitation in practice

Can stroke survivors use e-bikes as a form of outdoor physical activity?

This research is adapted from Exploring the factors influencing the use of electrically assisted bikes (e-bikes) by stroke survivors: a mixed methods multiple case study published by Taylor & Francis in Disability and Rehabilitatio

Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment

INTRODUCTION: Recent data about radiographic progression during treatment with tumor necrosis factor-alpha (TNF-α) blocker agents in patients with ankylosing spondylitis (AS) have prompted an intensive discussion about the link between inflammation/bone destruction and new bone formation and the order of events. Therefore, we analysed parameters of cartilage degradation, neoangiogenesis, and new bone formation in different cohorts of patients with axial spondyloarthritis with and without treatment with TNF-α blocker agents. METHOD: TNF-α blocker-naïve AS patients were investigated for serum levels of metalloproteinase-3 (MMP-3) (n = 71), vasoendothelial growth factor (VEGF) (n = 50), and bone-specific alkaline phosphatase (BALP) (n = 71) at baseline and after 1 and 2 years. This was compared with 34 adalimumab-treated patients with axial spondyloarthritis (22 AS and 12 non-radiographic axial spondyloarthritis patients) before and after 36 to 52 weeks of treatment. RESULTS: There were no significant changes in serum levels of MMP-3 (P > 0.05), VEGF (P > 0.05), and BALP (P > 0.05) in a large cohort of TNF-α blocker-naïve AS patients followed for 2 years. In contrast, adalimumab-treated spondyloarthritis (AS and non-radiographic axial spondyloarthritis) patients had a significant decrease of VEGF (P < 0.001) and MMP-3 (P = 0.022) after 36 to 52 weeks of therapy. Most interestingly, the level of BALP increased significantly after 36 to 52 weeks of therapy (P < 0.001). A decrease in MMP-3 serum levels correlated significantly to an increase of BALP (r = -0.398, P = 0.02). In the case of VEGF, there was a negative correlation without significance (r = -0.214, P > 0.05). CONCLUSIONS: Rising levels of BALP and the negative correlation between MMP-3 and BALP in spondyloarthritis patients with TNF-α blocker treatment indicate that new bone formation in AS occurs if inflammation is successfully treated and might be part of a healing process

Effects of air pollution and the introduction of the London Low Emission Zone on the prevalence of respiratory and allergic symptoms in schoolchildren in East London: a sequential cross-sectional study

The adverse effects of traffic-related air pollution on children’s respiratory health have been widely reported, but few studies have evaluated the impact of traffic-control policies designed to reduce urban air pollution. We assessed associations between traffic-related air pollutants and respiratory/allergic symptoms amongst 8–9 year-old schoolchildren living within the London Low Emission Zone (LEZ). Information on respiratory/allergic symptoms was obtained using a parent-completed questionnaire and linked to modelled annual air pollutant concentrations based on the residential address of each child, using a multivariable mixed effects logistic regression analysis. Exposure to traffic-related air pollutants was associated with current rhinitis: NOx (OR 1.01, 95% CI 1.00–1.02), NO2 (1.03, 1.00–1.06), PM10 (1.16, 1.04–1.28) and PM2.5 (1.38, 1.08–1.78), all per μg/m3 of pollutant, but not with other respiratory/allergic symptoms. The LEZ did not reduce ambient air pollution levels, or affect the prevalence of respiratory/allergic symptoms over the period studied. These data confirm the previous association between traffic-related air pollutant exposures and symptoms of current rhinitis. Importantly, the London LEZ has not significantly improved air quality within the city, or the respiratory health of the resident population in its first three years of operation. This highlights the need for more robust measures to reduce traffic emissions

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

Cardiorespiratory fitness is associated with hard and light intensity physical activity but not time spent sedentary in 10–14 year old schoolchildren: the HAPPY study

Sedentary behaviour is a major risk factor for developing chronic diseases and is associated with low cardiorespiratory fitness in adults. It remains unclear how sedentary behaviour and different physical activity subcomponents are related to cardiorespiratory fitness in children. The purpose of this study was to assess how sedentary behaviour and different physical activity subcomponents are associated with 10–14 year-old schoolchildren's cardiorespiratory fitness