Mathematical modelling of controlled drug release from polymer micro-spheres : incorporating the effects of swelling, diffusion and dissolution via moving boundary problems

Controlled drug delivery is a key topic in modern pharmacotherapy, where controlled drug delivery devices are required to prolong the period of release, maintain a constant release rate, or release the drug with a predetermined release profile. In the pharmaceutical industry, the development process of a controlled drug delivery device may be facilitated enormously by the mathematical modelling of drug release mechanisms, directly decreasing the number of necessary experiments. Such mathematical modelling is difficult because several mechanisms are involved during the drug release process. The main drug release mechanisms of a controlled release device are based on the device’s physiochemical properties, and include diffusion, swelling and erosion. In this thesis, four controlled drug delivery models are investigated. These four models selectively involve the solvent penetration into the polymeric device, the swelling of the polymer, the polymer erosion and the drug diffusion out of the device but all share two common key features. The first is that the solvent penetration into the polymer causes the transition of the polymer from a glassy state into a rubbery state. The interface between the two states of the polymer is modelled as a moving boundary and the speed of this interface is governed by a kinetic law. The second feature is that drug diffusion only happens in the rubbery region of the polymer, with a nonlinear diffusion coefficient which is dependent on the concentration of solvent. These models are analysed by using both formal asymptotics and numerical computation, where front-fixing methods and the method of lines with finite difference approximations are used to solve these models numerically. This numerical scheme is conservative, accurate and easily implemented to the moving boundary problems and is thoroughly explained in Section 3.2. From the small time asymptotic analysis in Sections 5.3.1, 6.3.1 and 7.2.1, these models exhibit the non-Fickian behaviour referred to as Case II diffusion, and an initial constant rate of drug release which is appealing to the pharmaceutical industry because this indicates zeroorder release. The numerical results of the models qualitatively confirms the experimental behaviour identified in the literature. The knowledge obtained from investigating these models can help to develop more complex multi-layered drug delivery devices in order to achieve sophisticated drug release profiles. A multi-layer matrix tablet, which consists of a number of polymer layers designed to provide sustainable and constant drug release or bimodal drug release, is also discussed in this research. The moving boundary problem describing the solvent penetration into the polymer also arises in melting and freezing problems which have been modelled as the classical onephase Stefan problem. The classical one-phase Stefan problem has unrealistic singularities existed in the problem at the complete melting time. Hence we investigate the effect of including the kinetic undercooling to the melting problem and this problem is called the one-phase Stefan problem with kinetic undercooling. Interestingly we discover the unrealistic singularities existed in the classical one-phase Stefan problem at the complete melting time are regularised and also find out the small time behaviour of the one-phase Stefan problem with kinetic undercooling is different to the classical one-phase Stefan problem from the small time asymptotic analysis in Section 3.3. In the case of melting very small particles, it is known that surface tension effects are important. The effect of including the surface tension to the melting problem for nanoparticles (no kinetic undercooling) has been investigated in the past, however the one-phase Stefan problem with surface tension exhibits finite-time blow-up. Therefore we investigate the effect of including both the surface tension and kinetic undercooling to the melting problem for nanoparticles and find out the the solution continues to exist until complete melting. The investigation of including kinetic undercooling and surface tension to the melting problems reveals more insight into the regularisations of unphysical singularities in the classical one-phase Stefan problem. This investigation gives a better understanding of melting a particle, and contributes to the current body of knowledge related to melting and freezing due to heat conduction.

Screening in early childhood for risk of later mental health problems : a longitudinal study

Depression in childhood or adolescence is associated with increased rates of depression in adulthood. Does this justify efforts to detect (and treat) those with symptoms of depression in early childhood or adolescence? The aim of this study was to determine how well symptoms of anxiety/depression (A-D) in early childhood and adolescence predict adult mental health. The study sample is taken from a population-based prospective birth cohort study. Of the 8556 mothers initially approached to participate 8458 agreed, of whom 7223 mothers gave birth to a live singleton baby. Children were screened using modified Child Behaviour Checklist (CBCL) scales for internalizing and total problems (T-P) at age 5 and the CBCL and Youth Self Report (YSR) A-D subscale and T-P scale at age 14. At age 21, a sub-sample of 2563 young adults in this cohort were administered the CIDI-Auto. Results indicated that screening at age 5 would detect few later cases of significant mental ill-health. Using a cut-point of 20% for internalizing at child age 5 years the CBCL had sensitivities of only 25% and 18% for major depression and anxiety disorders at 21 years, respectively. At age 14, the YSR generally performed a little better than the CBCL as a screening instrument, but neither performed at a satisfactory level. Of the children who were categorised as having YSR A-D at 14 years 30% and 37% met DSM-IV criteria for major depression and anxiety disorders, respectively, at age 21. Our findings challenge an existing movement encouraging the detection and treatment of those with symptoms of mental illness in early childhood.

The Child Behavior Checklist and Youth Self-Report in adolescents with epilepsy : testing measurement invariance of the Attention and Thought Problems subscales

The objective of this study was to test for the measurement invariance of the Attention and Thought Problems subscales of the Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) in a population-based sample of adolescents with and without epilepsy. Data were obtained from the 14-year follow-up of the Mater University Study of Pregnancy in which 33 adolescents with epilepsy and 1068 healthy controls were included for analysis. Confirmatory factor analysis was used to test for measurement invariance between adolescents with and without epilepsy. Structural equation modeling was used to test for group differences in attention and thought problems as measured with the CBCL and YSR. Measurement invariance was demonstrated for the original CBCL Attention Problems and YSR Thought Problems. After the removal of ambiguous items (“confused” and “daydreams”),measurement invariance was established for the YSR Attention Problems. The original and reduced CBCL Thought Problems were noninvariant. Adolescents with epilepsy had significantly more symptoms of behavioral problems on the CBCL Attention Problems, β = 0.51, p = 0.002, compared with healthy controls. In contrast, no significant differences were found for the YSR Attention and Thought Problems, β = −0.11, p = 0.417 and β = −0.20, p = 0.116, respectively. In this population-based sample of adolescents with epilepsy, the CBCL Attention Problems and YSR Thought Problems appear to be valid measures of behavioral problems, whereas the YSR Attention Problems was valid only after the removal of ambiguous items. Replication of these findings in clinical samples of adolescents with epilepsy that overcome the limitations of the current study is warranted.

Impact of cognitive behaviour therapy via mail for cessation of benzodiazepine use : a series of case reports

Benzodiazepines are widely prescribed to manage sleep disorders, anxiety and muscular tension. While providing short-term relief, continued use induces tolerance and withdrawal, and in older users, increases the risk of falls. However, long-term prescription remains common, and effective interventions are not widely available. This study developed a self-managed cognitive behaviour therapy package for cessation of benzodiazepine use delivered to participants via mail (M-CBT) and trialled its effectiveness as an adjunct to a general practitioner (GP)-managed dose reduction schedule. In the pilot trial, participants were randomly assigned to GP management with immediate or delayed M-CBT. Significant recruitment and engagement problems were experienced, and only three participants were allocated to each condition. After immediate M-CBT, two participants ceased use, while none receiving delayed treatment reduced daily intake by more than 50%. Across the sample, doses at 12 months remained significantly lower than baseline, and qualitative feedback from participants was positive. While M-CBT may have promise, improved engagement of GPs and participants is needed for this approach to substantially impact on community-wide benzodiazepine use.

Factors that influence young people's mental health help‐seeking behaviour : a study based on the Health Belief Model

Aim To identify key predictors and moderators of mental health ‘help-seeking behavior’ in adolescents. Background Mental illness is highly prevalent in adolescents and young adults; however, individuals in this demographic group are among the least likely to seek help for such illnesses. Very little quantitative research has examined predictors of help-seeking behaviour in this demographic group. Design A cross-sectional design was used. Methods A group of 180 volunteers between the ages of 17–25 completed a survey designed to measure hypothesized predictors and moderators of help-seeking behaviour. Predictors included a range of health beliefs, personality traits and attitudes. Data were collected in August 2010 and were analysed using two standard and three hierarchical multiple regression analyses. Findings The standard multiple regression analyses revealed that extraversion, perceived benefits of seeking help, perceived barriers to seeking help and social support were direct predictors of help-seeking behaviour. Tests of moderated relationships (using hierarchical multiple regression analyses) indicated that perceived benefits were more important than barriers in predicting help-seeking behaviour. In addition, perceived susceptibility did not predict help-seeking behaviour unless individuals were health conscious to begin with or they believed that they would benefit from help. Conclusion A range of personality traits, attitudes and health beliefs can predict help-seeking behaviour for mental health problems in adolescents. The variable ‘Perceived Benefits’ is of particular importance as it is: (1) a strong and robust predictor of help-seeking behaviour, and; (2) a factor that can theoretically be modified based on health promotion programmes.

Psychotropics and challenging behaviour in people with an intellectual disability

Hilmer and Gnjidic drew attention to the pharmacological management of behavioural problems in nursing home residents, and called for a reduction in inappropriate prescribing and the development of alternative management strategies.1 We extend these concerns to another vulnerable population — people with intellectual disability. Historically, this population is one of the most medicated groups in modern society.

Antisocial behaviour orders : Unanticipated directions in social network site development

Abstract: Social network technologies, as we know them today have become a popular feature of everyday life for many people. As their name suggests, their underlying premise is to enable people to connect with each other for a variety of purposes. These purposes however, are generally thought of in a positive fashion. Based on a multi-method study of two online environments, Habbo Hotel and Second Life, which incorporate social networking functionality, we she light on forms of what can be conceptualized as antisocial behaviours and the rationales for these. Such behaviours included: scamming, racist/homophobic attacks, sim attacks, avatar attacks, non-conformance to contextual norms, counterfeiting and unneighbourly behaviour. The rationales for sub behaviours included: profit, fun, status building, network disruption, accidental acts and prejudice. Through our analysis we are able to comment upon the difficulties of defining antisocial behaviour in such environments, particularly when such environments are subject to interpretation vis their use and expected norms. We also point to the problems we face in conducting our public and private lives given the role ICTs are playing in the convergence of these two spaces and also the convergence of ICTs themselves.

Regulating supply-chains to address the occupational health and safety problems associated with precarious employment: The case of home-based clothing workers in Australia

Over the past 20 years the labour market, workforce and work organisation of most if not all industrialised countries have been significantly refashioned by the increased use of more flexible work arrangements, variously labelled as precarious employment or contingent work. There is now a substantial and growing body of international evidence that many of these arrangements are associated with a significant deterioration in occupational health and safety (OHS), using a range of measures such as injury rates, disease, hazard exposures and work-related stress. Moreover, there is an emerging body of evidence that these arrangements pose particular problems for conventional regulatory regimes. Recognition of these problems has aroused the concern of policy makers - especially in Europe, North America and Australia - and a number of responses have been adopted in terms of modifying legislation, producing new guidance material and codes of practice and revised enforcement practices. This article describes one such in itiative in Australia with regard to home-based clothing workers. The regulatory strategy developed in one Australian jurisdiction (and now being ‘exported’ into others) seeks to counter this process via contractual tracking mechanisms to follow the work, tie in liability and shift overarching legal responsibility to the top of the supply chain. The process also entails the integration of minimum standards relating to wages, hours and working conditions; OHS and access to workers’ compensation. While home-based clothing manufacture represents a very old type of ‘flexible’ work arrangement, it is one that regulators have found especially difficult to address. Further, the elaborate multi-tiered subcont racting and diffuse work locations found in this industry are also characteristic of newer forms of contingent work in other industries (such as some telework) and the regulatory challenges they pose (such as the tendency of elaborate supply chains to attenuate and fracture statutory responsibilities, at least in terms of the attitudes and behaviour of those involved).

Addressing barriers to help-seeking behaviour through M-mental health services : a social marketing perspective

Although seeking help for mental ill-health is beneficial, the majority of persons afflicted do not access available help services. Young adults (16-24 years old) in particular have the highest prevalence of mental health problems and the lowest rate of help-seeking behaviour. Key barriers to help-seeking for young adults, including cost, privacy concerns, inconvenience, access to health professionals and interpersonal interaction, appear to derive from the face-to-face method of service delivery traditionally used to distribute mental health services. Social marketing employs the principle of value exchange, whereby consumers will choose a behaviour in exchange for receiving valued benefits and/or a reduction in key barriers, to achieve behavioural goals for social good. The appropriation of mobile digital technology to deliver self-help mental health services may reduce the current barriers to help seeking, however, extant literature offers no empirical support for this proposition. Our research addresses this gap by examining the perceptions of young adults regarding M-mental health services. Depth interviews were undertaken with 15 young adults (18-24 years old), who had self-reported mild-moderate stress, anxiety or depression. The data were thematically analysed with the assistance of Nvivo. The findings reveal M-mental health services reduce the barriers to accessing face-to-face help services to a large extent. However, they also present their own barriers to help-seeking that must be considered by social marketers, including negligible cost expectations and service efficacy concerns. Overall, this study highlights the potential of M-mental health services to encourage early intervention and help-seeking behaviour as part of a social marketing strategy to address mental illness in young adults.

The Effect of Post-Pubertal Castration on Behaviour in Beef Cattle

Castration of male beef cattle is advantageous for management, however pre-pubertal (early) castration results in comparative losses in growth rate (Jago et al., 1996). Post-pubertal (late) castration may maintain growth rate but lead to management problems. The behavioural differences between early castrates (9mo) and late castrates (18mo), which may have an effect on growth rate were studied.

Impulsivity, health-related behaviour and disease : A prospective study

In clinical settings impulsivity refers to a symptom of psychiatric disorder, but nonclinically oriented research treats impulsivity as a personality and temperament dimension. This prospective study examined whether impulsivity predicts adverse health-related behaviour and increased risk of health problems in a large, nonclinical sample of 5433 subjects working in 12 Finnish hospitals. The data were collected using two questionnaire surveys at a 2-year interval. After controlling for alcohol use at baseline, higher impulsivity predicted increased alcohol consumption at follow-up in both genders (p < .01) and was associated with increased likelihood of becoming a heavy drinker or taking up smoking (p < .05). Impulsivity also predicted an increased number of cigarettes smoked per day in the follow-up among women (p < .001), but not among men, although adjustment for the number of cigarettes smoked at baseline attenuated these associations (p = .08 for women). In men, higher impulsivity was associated with shorter sleep duration and waking up several times per night independent of baseline characteristics (p < .01), whereas in women, higher impulsivity predicted difficulty in falling asleep and waking up feeling tired after the usual amount of sleep (p < .05). In women, these associations became nonsignificant after adjustment for pre-existing somatic and psychiatric diseases. Finally, higher impulsivity was associated with an increased 2-year incidence of physician-diagnosed peptic ulcer disease (adjusted odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.21 - 4.82) and onset of depression (OR = 1.95, 95% CI = 1.28 - 2.97) after adjustment for a variety of baseline covariates. In conclusion, this study shows that in a nonclinical population, impulsivity appears to be a risk factor for various unhealthy behaviour and health problems.

Rearing strategies of young dairy calves in relation to production, behaviour and welfare

Vasikoiden kasvatus yksilökarsinoissa, imemismahdollisuuden puute maitojuoton yhteydessä sekä pienet juomamäärät ovat tekijöitä, jotka mahdollisesti voivat vähentää vasikoiden hyvinvointia. Vasikoiden kasvatukseen etsitäänkin uusia tapoja, joissa eläinten käyttäytymistarpeet ja hyvinvointi otetaan entistä paremmin huomioon. Tässä väitöskirjassa vasikoiden kasvatusta on tarkasteltu sekä tuotannon että vasikoiden käyttäytymisen ja hyvinvoinnin kannalta. Väitöskirja koostuu kolmesta kokeesta, joista ensimmäisessä tutkittiin vasikoiden kasvatusta ryhmäkarsinoissa ulkona tai sisällä ja vasikoiden kasvatusta sisällä ryhmä- tai yksilökarsinoissa. Toisessa kokeessa vasikoiden annettiin imeä emiään rajoitetusti lypsyn jälkeen viiden tai kahdeksan viikon ajan ja kolmannessa selvitettiin vasikoiden veden juontia, kun vasikat saivat juomarehua vapaasti. Lisäksi kokeiden yhdistetystä aineistosta analysoitiin eri rehujen syöntimäärien suhdetta sekä rehujen vaikutusta kasvuun ennen ja jälkeen maidosta vieroituksen. Tutkimuksessa todettiin, että vasikoita voi ryhmässä kasvattaa kylmissä ja vaihtelevissa sääoloissa ulkona, kunhan ne hoidetaan ja ruokitaan erittäin huolellisesti. Kylmällä ilmalla vasikat saattavat kuitenkin syödä väkirehua vähemmän varsinkin, jos ruokailupaikka on ulkona ja makuualue sisällä. Ryhmässä kasvaneet vasikat aloittivat sekä kuivien rehujen syönnin että märehtimisen nuorempina kuin yksilökarsinassa kasvaneet. Ryhmissä esiintyvää käyttäytymisongelmaa, toisten vasikoiden imemistä, voidaan vähentää hoito- ja ruokintamenetelmillä. Annettaessa vasikoiden imeä emiään rajoitetusti lypsyn jälkeen vasikat oppivat imemään emiään hyvin nopeasti. Lypsytyö vaikeutui muutamien lehmien kohdalla, sillä ne pidättivät maitoa lypsettäessä. Saadessaan imeä rajoitetusti vasikat imivät suurehkoja maitomääriä kerrallaan. Vieroittaminen suurilta maitomääriltä viiden viikon iässä oli kuitenkin liian aikaista, koska vasikat eivät vielä syöneet riittävästi kuivia rehuja. Vieroitus emästä niin viiden kuin kahdeksankin viikon iässä aiheutti vasikoissa levottomuutta ja ääntelyn lisääntymistä. Saadessaan hapatettua juomarehua vapaasti vasikat joivat keskimäärin vain vähän vettä, olipa vesilähteenä avoin ämpäri tai vesinippa. Vasikoiden välillä oli suurta vaihtelua veden juontimäärissä. Viikkoa ennen maidosta vieroitusta vasikat joivat 0-3 l vettä päivässä. Vasikat joivat nipasta kerrallaan vähemmän vettä kuin ämpäristä, ja käyttivät enemmän aikaa päivässä veden juomiseen kuin vesiämpäristä juoneet vasikat. Suurin osa vasikoista joi vettä juomanipoista erikoisella tavalla esimerkiksi painamalla nippaa otsalla ja juomalla tippuvaa vettä. Vesinipat voivat olla siis vasikoille joko vaikeita tai epämukavia käyttää. Vasikoiden juoman maitomäärän lisääntyessä kasvu lisääntyy selvästi. Runsas maidon juominen vähentää kuitenkin kuivien rehujen syöntiä ja vieroitusvaiheessa kasvu voi hidastua. Vasikat olisikin tärkeää vieroittaa vähitellen, ettei muutoksia kasvuun tulisi. Syönti- ja kasvutulokset eivät aina anna oikeaa kuvaa kasvatusmenetelmien eroista eläinten hyvinvoinnin kannalta. Käyttäytyminen on herkkä hyvinvoinnin mittari ja se tulisikin aina huomioida eri kasvatusmenetelmiä arvioitaessa. .

Integrated pest management in cotton: exploiting behaviour-modifying (semiochemical) compounds for managing cotton pests

We review here research on semiochemicals for cotton pest management carried out in successive Cotton Co-operative Research Centres from 1998 to 2012. Australian cotton is now dominated by transgenic (Bt) varieties, which provide a strong platform for integrated pest management of key pests such as Helicoverpa spp., but new technologies are required to manage the development of resistance in Helicoverpa spp. to transgenic cotton and the problems posed by emerging and secondary pests, especially sucking insects. A long-range attractant for Helicoverpa moths, based on plant volatiles, has been commercialised as Magnet®. The product has substantial area-wide impacts on moth populations, and only limited effects on beneficial insects. Potential roles are being investigated for this product in resistance management of Helicoverpa spp. on transgenic cotton. Short-range, non-volatile compounds on organ surfaces of plants that do not support development of Helicoverpa spp. have been identified; these compounds deter feeding or oviposition, or are toxic to insect pests. One such product, Sero X®, is effective on Helicoverpa spp. and sucking pests such as whiteflies (Bemisia tabaci), green mirids (Creontiades dilutus), and other hemipteran insects, and is in the advanced stages of commercialisation.

Season of birth and location of residence: Defining the role of ultraviolet radiation exposure on childhood temperament and behaviour

This thesis added new insight to research knowledge about the role that season and ultraviolet radiation (UV) exposure during pregnancy has on children's temperament and behaviours, using a nation-wide longitudinal study. It was found that young children born in summer months are likely to have problematic behaviours. The thesis also found that summer-born children are likely to receive lowest levels of UV exposure during the gestational period. Finally, this work showed that low gestational UV exposure is associated with an increased risk of behavioural problems in children.

On the behaviour of some physical parameterization methods in high-resolution numerical weather prediction models

Modern-day weather forecasting is highly dependent on Numerical Weather Prediction (NWP) models as the main data source. The evolving state of the atmosphere with time can be numerically predicted by solving a set of hydrodynamic equations, if the initial state is known. However, such a modelling approach always contains approximations that by and large depend on the purpose of use and resolution of the models. Present-day NWP systems operate with horizontal model resolutions in the range from about 40 km to 10 km. Recently, the aim has been to reach operationally to scales of 1 4 km. This requires less approximations in the model equations, more complex treatment of physical processes and, furthermore, more computing power. This thesis concentrates on the physical parameterization methods used in high-resolution NWP models. The main emphasis is on the validation of the grid-size-dependent convection parameterization in the High Resolution Limited Area Model (HIRLAM) and on a comprehensive intercomparison of radiative-flux parameterizations. In addition, the problems related to wind prediction near the coastline are addressed with high-resolution meso-scale models. The grid-size-dependent convection parameterization is clearly beneficial for NWP models operating with a dense grid. Results show that the current convection scheme in HIRLAM is still applicable down to a 5.6 km grid size. However, with further improved model resolution, the tendency of the model to overestimate strong precipitation intensities increases in all the experiment runs. For the clear-sky longwave radiation parameterization, schemes used in NWP-models provide much better results in comparison with simple empirical schemes. On the other hand, for the shortwave part of the spectrum, the empirical schemes are more competitive for producing fairly accurate surface fluxes. Overall, even the complex radiation parameterization schemes used in NWP-models seem to be slightly too transparent for both long- and shortwave radiation in clear-sky conditions. For cloudy conditions, simple cloud correction functions are tested. In case of longwave radiation, the empirical cloud correction methods provide rather accurate results, whereas for shortwave radiation the benefit is only marginal. Idealised high-resolution two-dimensional meso-scale model experiments suggest that the reason for the observed formation of the afternoon low level jet (LLJ) over the Gulf of Finland is an inertial oscillation mechanism, when the large-scale flow is from the south-east or west directions. The LLJ is further enhanced by the sea-breeze circulation. A three-dimensional HIRLAM experiment, with a 7.7 km grid size, is able to generate a similar LLJ flow structure as suggested by the 2D-experiments and observations. It is also pointed out that improved model resolution does not necessary lead to better wind forecasts in the statistical sense. In nested systems, the quality of the large-scale host model is really important, especially if the inner meso-scale model domain is small.