Non-invasive Detection of Cortical Control Signals for Brain-Computer Interfaces

Thesis (Ph.D.)--University of Washington, 2016-05

Mollusca Non-Grata: The influence of top-down control and residence time on the abundance, distribution, and behavior of non-native marine snails in Washington State

Thesis (Ph.D.)--University of Washington, 2016-06

A national case-control study of Ewing's sarcoma family of tumours in Australia

Limited population-based epidemiologic information is available on Ewing's sarcoma family of tumours (ESFT), a rare group of neoplasms. Several associations have been noted on a few studies but results were not consistent, except for exposure to farming among cases and their parents. Here we present the non-farm findings of a nationwide case-control study of ESFT in children and young adults in Australia. The analysis included 106 persons with confirmed ESFT and 344 population-based controls selected randomly via telephone. Information was collected by interview (84% face to face). We found a strong and significant association of ESFT with hernias, in particular hernia repaired in hospital (OR = 5.6, 95% Cl 1.3-6.4). Among other factors, there was a near doubling of risk for males, and male cases had their pubertal signs earlier (started shaving earlier) than male controls. There was also an increased risk of ESFT at higher levels of self-assessed exercise, but no other factor really stood out. For pregnancy-related factors, there was a tripling of risk for glandular fever, a doubling of risk for urinary tract infection and a near doubling of risk for X-rays during or just before pregnancy, but these estimates were not significant. In addition, there was a large number of inverse associations with medical conditions (specifically bone disorders), case exposure to medications, vaccinations and X-rays, with ultrasound during the pregnancy having the most certain effects. We conclude that, although the aetiology of ESFT remains obscure, overall there is strong evidence of an association with inguinal hernia; this can now be added to the farm-associated risk reported by others and us. The other associations reported here await replication and refinement in future studies. (C) 2003 Wiley-Liss, Inc.

Mitochondrial control region diversity of the houbara bustard Chlamydotis undulata complex and genetic structure along the Atlantic seaboard of North Africa

The houbara bustard, Chlamydotis undulata, is a declining cryptic desert bird whose range extends from North Africa to Central Asia. Three subspecies are currently recognized by geographical distribution and morphology: C.u.fuertaventurae, C.u.undulata and C.u.macqueenii. We have sequenced 854 bp of mitochondrial control region from 73 birds to describe their population genetic structure with a particular sampling focus on the connectivity between C.u.fuertaventurae and C.u.undulata along the Atlantic seaboard of North Africa. Nucleotide and haplotypic diversity varied among the subspecies being highest in C.u.undulata, lowest in C.u.fuertaventurae and intermediate in C.u.macqueenii. C.u.fuertaventurae and C.u.undulata are paraphyletic and an average nucleotide divergence of 2.08% splits the later from C.u.macqueenii. We estimate that C.u.fuertaventurae and C.u.undulata split from C.u.macqueenii approximately 430 000 years ago. C.u.fuertaventurae and C.u.undulata are weakly differentiated (F-ST = 0.27, N-m = 1.3), indicative of a recent shared history. Archaeological evidence indicates that houbara bustards have been present on the Canary Islands for 130-170 000 years. However, our genetic data point to a more recent separation of C.u.fuertaventurae and C.u.undulata at around 20-25 000 years. Concordant archaeological, climatic opportunities for colonization and genetic data point to a scenario of: (i) initial colonization of the Canary Islands about 130 000 years ago; (ii) a period of secondary contact 19-30 000 years ago homogenizing any pre-existing genetic structure followed by; (iii) a period of relative isolation that persists today.

The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8x10(-6)) and genotype distributions (P=4x10(-5)). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.

Randomized control trial of a smoking cessation intervention directed at men whose partners are pregnant

Background. Although smoking cessation programs significantly reduce smoking rates in the general population, some sectors are poorly motivated by them, especially healthy men from lower socioeconomic classes. Methods. By using a significant life event (approaching birth of a child) we exploited a time of increased receptiveness to smoking cessation influences. A multicomponent intervention was conducted and evaluated using a stratified, randomised control trial, with an intention to treat analysis. Results. Five hundred and sixty-one men were enrolled and 505 (90%) followed to the end of their partners' pregnancy. At 6-month follow-up 16.5% of 291 smokers of the intervention group and 9.3% of 270 in the control group reported they had stopped smoking (P = 0.011, OR = 0.52, 95% CI 0.31 - 0.86). The strongest predictors of smoking cessation were being in a skilled occupation, having a higher number of quit attempts in the previous year and having the first cigarette of the day relatively later. Conclusions. The number of smoking men who had to be treated to achieve one stopping smoking (NNT) during their partner's pregnancy was 13 to 14. Innovative antismoking population health measures for the partners of antenatal patients are effective and perhaps should be more widely adopted. (C) 2003 American Health Foundation and Elsevier Inc. All rights reserved.

Population structure of the peridomestic mosquito Ochlerotatus notoscriptus in Australia

Ochlerotatus notoscriptus (Skuse) (Diptera: Culicidae) is the predominant peridomestic mosquito in Australia where it is the primary vector of dog heartworm, Dirofilaria immitis (Leidy), and a potentially important vector of arboviruses (Barmah Forest, Ross River) with geographical variation of vector competence. Although widespread, Oc. notoscriptus has low dispersal ability, so it may have isolated subpopulations. The identification of gene flow barriers may assist in understanding arbovirus epidemiology and disease risk, and for developing control strategies for this species. We investigated the population structure of Oc. notoscriptus from 17 sites around Australia, using up to 31 putative allozyme loci, 11 of which were polymorphic. We investigated the effect of larval environment and adult morphology on genetic variation. At least five subpopulations were found, four in New South Wales (NSW) and one unique to Darwin. Perth samples appear to be a product of recent colonization from the Australian east coast. For NSW sites, a Mantel test revealed an isolation by distance effect and spatial autocorrelation analysis revealed an area of effective gene flow of 67 km, which is high given the limited dispersal ability of this species. No consistent difference was observed between 'urban' and 'sylvan' habitats, which suggests frequent movement between these sites. However, a finer-scaled habitat study at Darwin revealed small but significant allele frequency differences, including for Gpi. No fixed allozyme differences were detected for sex, size, integument colour or the colour of species-diagnostic pale scales on the scutum. The domestic habit of Oc. notoscriptus and assisted dispersal have helped to homogenize this species geographically but population structure is still detectable on several levels associated with geographical variation of vector competence.

Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population

Background: Renal transplant recipients were noted to appear cushingoid while on low doses of steroid as part of a triple therapy immunosuppression of cyclosporin A (CsA), prednisolone, and azathioprine. Methods: The study group comprised adult renal transplant recipients with stable graft function who had received their renal allograft a minimum of 1 year previously (43 studies undertaken in 22 men and 20 women) with median daily prednisone dose of 7 mg (range 3-10). The control group was healthy nontransplant subjects [median dose 10 mg (10-30)]. Prednisolone bioavailability was measured using a limited 6-hour area under the curve (AUC), with prednisolone measured using specific HPLC assay. Results: The median prednisolone AUC/mg dose for all transplant recipients was significantly greater than the control group by approximately 50% (316 nmol(.)h/L/mg prednisolone versus 218). AUC was significantly higher in female recipients (median 415 versus 297 for men) and in recipients receiving cyclospotin (348 versus 285). The highest AUC was in women on estrogen supplements who were receiving cyclosporin (median 595). A significantly higher proportion of patients on triple therapy had steroid side effects compared with those on steroid and azathioprine (17/27 versus 4/15), more women than men had side effects (14/16 versus 7/22), and the AUC/mg prednisone was greater in those with side effects than without (median 377 versus 288 nmol-h/L/mg). Discussion: The results are consistent with the hypothesis that CsA increases the bioavailability of prednisolone, most likely through inhibition of beta-glycoprotein. The increased exposure to steroid increased the side-effect profile of steroids in the majority of patients. Because the major contributor to AUC is the maximum postdose concentration, it may be possible to use single-point monitoring (2 hours postdose) for routine clinical studies.

Diabetes mellitus and serum carotenoids: findings of a population-based study in Queensland, Australia

Background: Epidemiologic evidence suggests that serum carotenoids are potent antioxidants and may play a protective role in the development of chronic diseases including cancers, cardiovascular disease, and inflammatory diseases. The role of these antioxidants in the pathogenesis of diabetes mellitus remains unclear. Objective: This study examined data from a cross-sectional survey to investigate the association between serum carotenoids and type 2 diabetes. Design: Study participants were adults aged >= 25 y (n = 1597) from 6 randomly selected cities and towns in Queensland, Australia. Study examinations conducted between October and December 2000 included fasting plasma glucose, an oral-glucose-tolerance test, and measurement of the serum concentrations of 5 carotenoid compounds. Results: Mean 2-h postload plasma glucose and fasting insulin concentrations decreased significantly with increasing quintiles of the 5 serum carotenoids-alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene. Geometric mean concentrations for all serum carotenoids decreased (all decreases were significant except that of lycopene) with declining glucose tolerance status. beta-Carotene had the greatest decrease, to geometric means of 0.59, 0.50, and 0.42 mu mol/L in persons with normal glucose tolerance, impaired glucose metabolism, and type 2 diabetes, respectively (P < 0.01 for linear trend), after control for potential confounders. Conclusions: Serum carotenoids are inversely associated with type 2 diabetes and impaired glucose metabolism. Randomized trials of diets high in carotenoid-rich vegetables and fruit are needed to confirm these results and those from other observational studies. Such evidence would have very important implications for the prevention of diabetes.

Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis

Aims To investigate the concentration-effect relationship and pharmacokinetics of leflunomide in patients with rheumatoid arthritis (RA). Methods Data were collected from 23 RA patients on leflunomide therapy (as sole disease modifying antirheumatic drug (DMARD)) for at least 3 months. Main measures were A77 1726 (active metabolite of leflunomide) plasma concentrations and disease activity measures including pain, duration/intensity of morning stiffness, and SF-36 survey. A population estimate was sought for apparent clearance (CL/F ) and volume of distribution was fixed (0.155 l kg(-1)). Factors screened for influence on CL/F were weight, age, gender and estimated creatinine clearance. Results Significantly higher A77 1726 concentrations were seen in patients with less swollen joints and with higher SF-36 mental summary scores than in those with measures indicating more active disease (P < 0.05); concentration-effect trends were seen with five other disease activity measures. Statistical analysis of all disease activity measures showed that mean A77 1726 concentrations in groups with greater control of disease activity were significantly higher than those in whom the measures indicated less desirable control (P < 0.05). There was large between subject variability in the dose-concentration relationship. A steady-state infusion model best described the pharmacokinetic data. Inclusion of age as a covariate decreased interindividual variability (P < 0.01), but this would not be clinically important in terms of dosage changes. Final parameter estimate (% CV interindividual variability) for CL/F was 0.0184 l h(-1) (50%) (95% CI 0.0146, 0.0222). Residual (unexplained) variability (% CV) was 8.5%. Conclusions This study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. From our data, a plasma A77 1726 concentration of 50 mg l(-1) is more likely to indicate someone with less active disease than is a concentration around 30 mg l(-1). The marked variability in pharmacokinetics suggests a place for individualized dosing of leflunomide in RA therapy.

Assessing moth migration and population structuring in Helicoverpa annigera (Lepidoptera : Noctuidae) at the regional scale: Example from the Darling Downs, Australia

Analysis of gene flow and migration of Helicoverpa armigera (Hubner) in a major cropping region of Australia identified substantial genetic structuring, migration events, and significant population genotype changes over the 38-mo sample period from November 1999 to January 2003. Five highly variable microsatellite markers were used to analyze 916 individuals from 77 collections across 10 localities in the Darling Downs. The molecular data indicate that in some years (e.g., April 2002-March 2003), low levels of H. armigera migration and high differentiation between populations occurred, whereas in other years (e.g., April 2001-March 2002), there were higher levels of adult moth movement resulting in little local structuring of populations. Analysis of populations in other Australian cropping regions provided insight into the quantity and direction of immigration of H. armigera adults into the Darling Downs growing region of Australia. These data provide evidence adult moth movement differs from season to season, highlighting the importance of studies in groups such as the Lepidoptera extending over consecutive years, because short-term sampling may be misleading when population dynamics and migration change so significantly. This research demonstrates the importance of maintaining a coordinated insecticide resistance management strategy, because in some years H. armigera populations may be independent within a region and thus significantly influenced by local management practices; however, periods with high migration will occur and resistance may rapidly spread.

Cost-effectiveness analysis of a kidney and cardiovascular disease treatment program in an Australian aboriginal population

The objective of the study was to assess, from a health service perspective, whether a systematic program to modify kidney and cardiovascular disease reduced the costs of treating end-stage kidney failure. The participants in the study were 1,800 aboriginal adults with hypertension, diabetes with microalbuminuria or overt albuminuria, and overt albuminuria, living on two islands in the Northern Territory of Australia during 1995 to 2000. Perindopril was the primary treatment agent, and other medications were also used to control blood pressure. Control of glucose and lipid levels were attempted, and health education was offered. Evaluation of program resource use and costs for follow-up periods was done at 3 and 4.7 years. On an intention-to-treat basis, the number of dialysis starts and dialysis-years avoided were estimated by comparing the fate of the treatment group with that of historical control subjects, matched for disease severity, who were followed in the before the treatment program began. For the first three years, an estimated 11.6 person-years of dialysis were avoided, and over 4.7 years, 27.7 person-years of dialysis were avoided. The net cost of the program was $1,210 more per person per year than status quo care, and dialyses avoided gave net savings of $1.0 million at 3 years and $3.4 million at 4.6 years. The treatment program provided significant health benefit and impressive cost savings in dialysis avoided. (C) 2005 by the National Kidney Foundation, Inc.

Optimal control and operation of drum granulation processes

Process optimisation and optimal control of batch and continuous drum granulation processes are studied in this paper. The main focus of the current research has been: (i) construction of optimisation and control relevant, population balance models through the incorporation of moisture content, drum rotation rate and bed depth into the coalescence kernels; (ii) investigation of optimal operational conditions using constrained optimisation techniques; (iii) development of optimal control algorithms based on discretized population balance equations; and (iv) comprehensive simulation studies on optimal control of both batch and continuous granulation processes. The objective of steady state optimisation is to minimise the recycle rate with minimum cost for continuous processes. It has been identified that the drum rotation-rate, bed depth (material charge), and moisture content of solids are practical decision (design) parameters for system optimisation. The objective for the optimal control of batch granulation processes is to maximize the mass of product-sized particles with minimum time and binder consumption. The objective for the optimal control of the continuous process is to drive the process from one steady state to another in a minimum time with minimum binder consumption, which is also known as the state-driving problem. It has been known for some time that the binder spray-rate is the most effective control (manipulative) variable. Although other possible manipulative variables, such as feed flow-rate and additional powder flow-rate have been investigated in the complete research project, only the single input problem with the binder spray rate as the manipulative variable is addressed in the paper to demonstrate the methodology. It can be shown from simulation results that the proposed models are suitable for control and optimisation studies, and the optimisation algorithms connected with either steady state or dynamic models are successful for the determination of optimal operational conditions and dynamic trajectories with good convergence properties. (c) 2005 Elsevier Ltd. All rights reserved.

A modelling approach to estimate the effect of exotic pollinators on exotic weed population dynamics: bumblebees and broom in Australia

The role of mutualisms in contributing to species invasions is rarely considered, inhibiting effective risk analysis and management options. Potential ecological consequences of invasion of non-native pollinators include increased pollination and seed set of invasive plants, with subsequent impacts on population growth rates and rates of spread. We outline a quantitative approach for evaluating the impact of a proposed introduction of an invasive pollinator on existing weed population dynamics and demonstrate the use of this approach on a relatively data-rich case study: the impacts on Cytisus scoparius (Scotch broom) from proposed introduction of Bombus terrestris. Three models have been used to assess population growth (matrix model), spread speed (integrodifference equation), and equilibrium occupancy (lattice model) for C. scoparius. We use available demographic data for an Australian population to parameterize two of these models. Increased seed set due to more efficient pollination resulted in a higher population growth rate in the density-independent matrix model, whereas simulations of enhanced pollination scenarios had a negligible effect on equilibrium weed occupancy in the lattice model. This is attributed to strong microsite limitation of recruitment in invasive C. scoparius populations observed in Australia and incorporated in the lattice model. A lack of information regarding secondary ant dispersal of C. scoparius prevents us from parameterizing the integrodifference equation model for Australia, but studies of invasive populations in California suggest that spread speed will also increase with higher seed set. For microsite-limited C. scoparius populations, increased seed set has minimal effects on equilibrium site occupancy. However, for density-independent rapidly invading populations, increased seed set is likely to lead to higher growth rates and spread speeds. The impacts of introduced pollinators on native flora and fauna and the potential for promoting range expansion in pollinator-limited 'sleeper weeds' also remain substantial risks.

Control of structured populations by harvest

It has long been recognized that demographic structure within a population can significantly affect the likely outcomes of harvest. Many studies have focussed on equilibrium dynamics and maximization of the value of the harvest taken. However, in some cases the management objective is to maintain the population at a abundance that is significantly below the carrying capacity. Achieving such an objective by harvest can be complicated by the presence of significant structure (age or stage) in the target population. in such cases, optimal harvest strategies must account for differences among age- or stage-classes of individuals in their relative contribution to the demography of the population. In addition, structured populations are also characterized by transient non-linear dynamics following perturbation, such that even under an equilibrium harvest, the population may exhibit significant momentum, increasing or decreasing before cessation of growth. Using simple linear time-invariant models, we show that if harvest levels are set dynamically (e.g., annually) then transient effects can be as or more important than equilibrium outcomes. We show that appropriate harvest rates can be complicated by uncertainty about the demographic structure of the population, or limited control over the structure of the harvest taken. (c) 2006 Elsevier B.V. All rights reserved.