Proximity-based systems : incorporating mobility and scalability through proximity sensing

This thesis argues that the concept of spatial proximity offers a viable and practical option for the development of context-aware systems for highly mobile and dynamic environments. Such systems would overcome the shortcomings experienced by today’s location-based and infrastructure dependent systems whose ability to deliver context-awareness is prescribed by their infrastructure. The proposed architecture will also allow for scalable interaction as against the single level of interaction in existing systems which limits services to a particular sized area. The thesis examines the concept of spatial proximity and demonstrates how this concept can be exploited to take advantage of technological convergence to offer mobility and scalability to systems. It discusses the design of a proximity-based system that can deliver scalable context-aware services in highly mobile and dynamic environments. It explores the practical application of this novel design in a proximity-sensitive messaging application by creating a proof-of-concept prototype. The proof-of-concept prototype is used to evaluate the design as well as to elicit user views and expectations about a proximity-based approach. Together these provide a valuable insight into the applicability of the proximity-based approach for designing context-aware systems. The design and development work discussed in the thesis presents a Proximity-Sensitive System Architecture that can be adapted for a variety of proximity-sensitive services. This is illustrated by means of examples, including a variety of context-aware messaging applications. The thesis also raises issues for information delivery, resource sharing, and human-computer interaction. While the technological solution (proximity-based messaging) offered is only one among several that can be developed using this architecture, it offers the opportunity to stimulate ideas in the relatively new field of proximity and technological convergence research, and contributes to a better understanding of their potential role in offering context-aware services.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Proximity-based systems : incorporating mobility and scalability through proximity sensing

This thesis argues that the concept of spatial proximity offers a viable and practical option for the development of context-aware systems for highly mobile and dynamic environments. Such systems would overcome the shortcomings experienced by today’s location-based and infrastructure dependent systems whose ability to deliver context-awareness is prescribed by their infrastructure. The proposed architecture will also allow for scalable interaction as against the single level of interaction in existing systems which limits services to a particular sized area. The thesis examines the concept of spatial proximity and demonstrates how this concept can be exploited to take advantage of technological convergence to offer mobility and scalability to systems. It discusses the design of a proximity-based system that can deliver scalable context-aware services in highly mobile and dynamic environments. It explores the practical application of this novel design in a proximity-sensitive messaging application by creating a proof-of-concept prototype. The proof-of-concept prototype is used to evaluate the design as well as to elicit user views and expectations about a proximity-based approach. Together these provide a valuable insight into the applicability of the proximity-based approach for designing context-aware systems. The design and development work discussed in the thesis presents a Proximity-Sensitive System Architecture that can be adapted for a variety of proximity-sensitive services. This is illustrated by means of examples, including a variety of context-aware messaging applications. The thesis also raises issues for information delivery, resource sharing, and human-computer interaction. While the technological solution (proximity-based messaging) offered is only one among several that can be developed using this architecture, it offers the opportunity to stimulate ideas in the relatively new field of proximity and technological convergence research, and contributes to a better understanding of their potential role in offering context-aware services.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with anderson-fabry disease

Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT-proBNP was measured under at rest conditions in 117 patients with AFD (age 48 ± 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range <5 to 6,059). Of the 117 patients, 67 (57%) had elevated, age-corrected, NT-proBNP levels. In the 56 patients (48%) with normal echocardiographic findings, the NT-proBNP levels were greater than the age-predicted cutoffs in 10 of 25 patients with abnormal electrocardiographic findings and 3 of 31 patients with normal electrocardiographic findings (p <0.05). On multiple regression analysis, age, creatinine, left atrial volume index, E/Ea, and the presence of abnormal electrocardiographic findings were independently associated with log NT-proBNP (R(2) = 0.67, p <0.05). In conclusion, NT-proBNP concentrations were elevated in patients with AFD and early cardiac involvement, suggesting its measurement could assist in decisions regarding the timing of enzyme replacement therapy

Effect of trimetazidine dihydrochloride therapy on exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy: A randomized clinical trial

Importance: Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective: To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants: This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions: Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures: The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level. Results: Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months. Conclusions and Relevance: In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration: ClinicalTrials.gov identifier: NCT01696370

Effects of Allergen Sensitization on Response to Therapy in Children with Eosinophilic Esophagitis

Background: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. Objective: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. Methods: Patients 2 to 18 years old who were referred to the Arkansas Children’s Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count \u3c 15 per high-power field [HPF]) and nonresponders (\u3e 25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. Results: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with none-PPI-responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (≥ 1 but ≤ 25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). Conclusion: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE

Using rapid point-of-care tests to inform antibiotic choice to mitigate drug resistance in gonorrhoea

Background: The first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the ‘stepping-stone’ mutation to gepotidacin resistance. Aim: To investigate how POCTs detecting Neisseria gonorrhoeae resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin. Methods: We use individual-based stochastic simulations to formally investigate the aim. Results: The level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1–13%. Conclusion: Mutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship

Population neuroimaging:generation of a comprehensive data resource within the ALSPAC pregnancy and birth cohort

Neuroimaging offers a valuable insight into human brain development by allowing in vivo assessment of structure, connectivity and function. Multimodal neuroimaging data have been obtained as part of three sub-studies within the Avon Longitudinal Study of Parents and Children, a prospective multigenerational pregnancy and birth cohort based in the United Kingdom. Brain imaging data were acquired when offspring were between 18 and 24 years of age, and included acquisition of structural, functional and magnetization transfer magnetic resonance, diffusion tensor, and magnetoencephalography imaging. This resource provides a unique opportunity to combine neuroimaging data with extensive phenotypic and genotypic measures from participants, their mothers, and fathers

Loss associated with subtractive health service change: The case of specialist cancer centralization in England

OBJECTIVE: Major system change can be stressful for staff involved and can result in 'subtractive change' - that is, when a part of the work environment is removed or ceases to exist. Little is known about the response to loss of activity resulting from such changes. Our aim was to understand perceptions of loss in response to centralization of cancer services in England, where 12 sites offering specialist surgery were reduced to four, and to understand the impact of leadership and management on enabling or hampering coping strategies associated with that loss. METHODS: We analysed 115 interviews with clinical, nursing and managerial staff from oesophago-gastric, prostate/bladder and renal cancer services in London and West Essex. In addition, we used 134 hours of observational data and analysis from over 100 documents to contextualize and to interpret the interview data. We performed a thematic analysis drawing on stress-coping theory and organizational change. RESULTS: Staff perceived that, during centralization, sites were devalued as the sites lost surgical activity, skills and experienced teams. Staff members believed that there were long-term implications for this loss, such as in retaining high-calibre staff, attracting trainees and maintaining autonomy. Emotional repercussions for staff included perceived loss of status and motivation. To mitigate these losses, leaders in the centralization process put in place some instrumental measures, such as joint contracting, surgical skill development opportunities and trainee rotation. However, these measures were undermined by patchy implementation and negative impacts on some individuals (e.g. increased workload or travel time). Relatively little emotional support was perceived to be offered. Leaders sometimes characterized adverse emotional reactions to the centralization as resistance, to be overcome through persuasion and appeals to the success of the new system. CONCLUSIONS: Large-scale reorganizations are likely to provoke a high degree of emotion and perceptions of loss. Resources to foster coping and resilience should be made available to all organizations within the system as they go through major change

SLC25A51 is a mammalian mitochondrial NAD+ transporter

Mitochondria require nicotinamide adenine dinucleotide (NAD+) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2, but their existence in mammals remains controversial3,4,5. Here we demonstrate that mammalian mitochondria can take up intact NAD+, and identify SLC25A51 (also known as MCART1)—an essential6,7 mitochondrial protein of previously unknown function—as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial—but not whole-cell—NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD+ into mitochondria.acceptedVersio