A sequential Monte Carlo approach to design for population pharmacokinetics studies

Here we present a sequential Monte Carlo approach that can be used to find optimal designs. Our focus is on the design of phase III clinical trials where the derivation of sampling windows is required, along with the optimal sampling schedule. The search is conducted via a particle filter which traverses a sequence of target distributions artificially constructed via an annealed utility. The algorithm derives a catalogue of highly efficient designs which, not only contain the optimal, but can also be used to derive sampling windows. We demonstrate our approach by designing a hypothetical phase III clinical trial.

Energy and population policies in Australia

The Australian Government is about to release Australia’s first sustainable population policy. Sustainable population growth, among other things, implies sustainable energy demand. Current modelling of future energy demand both in Australia and by agencies such as the International Energy Agency sees population growth as one of the key drivers of energy demand. Simply increasing the demand for energy in response to population policy is sustainable only if there is a radical restructuring of the energy system away from energy sources associated with environmental degradation towards one more reliant on renewable fuels and less reliant on fossil fuels. Energy policy can also address the present nexus between energy consumption per person and population growth through an aggressive energy efficiency policy. The paper considers the link between population policies and energy policies and considers how the overall goal of sustainability can be achieved. The methods applied in this analysis draw on the literature of sustainable development to develop elements of an energy planning framework to support a sustainable population policy. Rather than simply accept that energy demand is a function of population increase moderated by an assumed rate of energy efficiency improvement, the focus is on considering what rate of energy efficiency improvement is necessary to significantly reduce the standard connections between population growth and growth in energy demand and what policies are necessary to achieve this situation. Energy efficiency policies can only moderate unsustainable aspects of energy demand and other policies are essential to restructure existing energy systems into on-going sustainable forms. Policies to achieve these objectives are considered. This analysis shows that energy policy, population policy and sustainable development policies are closely integrated. Present policy and planning agencies do not reflect this integration and energy and population policies in Australia have largely developed independently and whether the outcome is sustainable is largely a matter of chance. A genuinely sustainable population policy recognises the inter-dependence between population and energy policies and it is essential that this is reflected in integrated policy and planning agencies

Energy and population policies in Australia

The Australian Government is about to release Australia’s first sustainable population policy. Sustainable population growth, among other things, implies sustainable energy demand. Current modelling of future energy demand both in Australia and by agencies such as the International Energy Agency sees population growth as one of the key drivers of energy demand. Simply increasing the demand for energy in response to population policy is sustainable only if there is a radical restructuring of the energy system away from energy sources associated with environmental degradation towards one more reliant on renewable fuels and less reliant on fossil fuels. Energy policy can also address the present nexus between energy consumption per person and population growth through an aggressive energy efficiency policy. The paper considers the link between population policies and energy policies and considers how the overall goal of sustainability can be achieved. The methods applied in this analysis draw on the literature of sustainable development to develop elements of an energy planning framework to support a sustainable population policy. Rather than simply accept that energy demand is a function of population increase moderated by an assumed rate of energy efficiency improvement, the focus is on considering what rate of energy efficiency improvement is necessary to significantly reduce the standard connections between population growth and growth in energy demand and what policies are necessary to achieve this situation. Energy efficiency policies can only moderate unsustainable aspects of energy demand and other policies are essential to restructure existing energy systems into on-going sustainable forms. Policies to achieve these objectives are considered. This analysis shows that energy policy, population policy and sustainable development policies are closely integrated. Present policy and planning agencies do not reflect this integration and energy and population policies in Australia have largely developed independently and whether the outcome is sustainable is largely a matter of chance. A genuinely sustainable population policy recognises the inter-dependence between population and energy policies and it is essential that this is reflected in integrated policy and planning agencies

Comparing the medium-term effects of exercise or dietary restriction on appetite regulation and compensatory responses

Previous studies have shown that exercise (Ex) interventions create a stronger coupling between energy intake (EI) and energy expenditure (EE) leading to increased homeostasis of the energy-balance (EB) regulatory system compared to a diet intervention where an un-coupling between EI and EE occurs. The benefits of weight loss from Ex and diet interventions greatly depend on compensatory responses. The present study investigated an 8-week medium-term Ex and diet intervention program (Ex intervention comprised of 500kcal EE five days per week over four weeks at 65-75% maximal heart rate, whereas the diet intervention comprised of a 500kcal decrease in EI five days per week over four weeks) and its effects on compensatory responses and appetite regulation among healthy individuals using a between- and within-subjects design. Effects of an acute dietary manipulation on appetite and compensatory behaviours and whether a diet and/or Ex intervention pre-disposes individuals to disturbances in EB homeostasis were tested. Energy intake at an ad libitum lunch test meal after a breakfast high- and low-energy pre-load (the high energy pre-load contained 556kcal and the low energy pre-load contained 239kcal) were measured at the Baseline (Weeks -4 to 0) and Intervention (Weeks 0 to 4) phases in 13 healthy volunteers (three males and ten females; mean age 35 years [sd + 9] and mean BMI 25 kg/m2 [sd + 3.8]) [participants in each group included Ex=7, diet=5 (one female in the diet group dropped out midway), thus, 12 participants completed the study]. At Weeks -4, 0 and 4, visual analogue scales (VAS) were used to assess hunger and satiety and liking and wanting (L&W) for nutrient and taste preferences using a computer-based system (E-Prime v1.1.4). Ad libitum test meal EI was consistently lower after the HE pre-load compared to the LE pre-load. However, this was not consistent during the diet intervention however. A pre-load x group interaction on ad libitum test meal EI revealed that during the intervention phase the Ex group showed an improved sensitivity to detect the energy content between the two pre-loads and improved compensation for the ad libitum test meal whereas the diet group’s ability to differentiate between the two pre-loads decreased and showed poorer compensation (F[1,10]=2.88, p-value not significant). This study supports previous findings of the effect Ex and diet interventions have on appetite and compensatory responses; Ex increases and diet decreases energy balance sensitivity.

Feedback information and consumer motivation : the moderation role of positive and negative reference values in self-regulation

Marketers spend considerable resources to motivate people to consume their products and services as a means of goal attainment (Bagozzi and Dholakia, 1999). Why people increase, decrease, or stop consuming some products is based largely on how well they perceive they are doing in pursuit of their goals (Carver and Scheier, 1992). Yet despite the importance for marketers in understanding how current performance influences a consumer’s future efforts, this topic has received little attention in marketing research. Goal researchers generally agree that feedback about how well or how poorly people are doing in achieving their goals affects their motivation (Bandura and Cervone, 1986; Locke and Latham, 1990). Yet there is less agreement about whether positive and negative performance feedback increases or decreases future effort (Locke and Latham, 1990). For instance, while a customer of a gym might cancel his membership after receiving negative feedback about his fitness, the same negative feedback might cause another customer to visit the gym more often to achieve better results. A similar logic can apply to many products and services from the use of cosmetics to investing in mutual funds. The present research offers managers key insights into how to engage customers and keep them motivated. Given that connecting customers with the company is a top research priority for managers (Marketing Science Institute, 2006), this article provides suggestions for performance metrics including four questions that managers can use to apply the findings.

The relationship between abdominal obesity and depression in the general population : a systematic review and meta-analysis

Obesity has been widely regarded as a public health concern because of its adverse impact on individuals’ health. Systematic reviews have been published in examining the effect of obesity on depression, but with major emphasis on general obesity as measured by the body mass index. Despite a stronger effect of abdominal obesity on individuals’ physical health outcomes, to our best knowledge, no systematic review was undertaken with regard to the relationship between abdominal obesity and depression. This paper reports the results of a systematic review and meta-analysis of cross-sectional studies examining the relationship between abdominal obesity and depression in a general population. Multiple electronic databases were searched until the end of September 2009. 15 articles were systematically reviewed and meta-analyzed. The analysis showed that the odds ratio of having depression for individuals with abdominal obesity was 1.38 (95% CI, 1.22–1.57) as compared to those who are not obese. Furthermore, it was found that this relationship did not vary with potential confounders including gender, age, measurement of depression and abdominal obesity, and study quality.

Phase two of the National Credit Reforms : examining the regulation of payday lenders

This study seeks to analyse the adequacy of the current regulation of the payday lending industry in Australia, and consider whether there is a need for additional regulation to protect consumers of these services. The report examines the different regulatory approaches adopted in comparable OECD countries, and reviews alternative models for payday regulation, in particular, the role played by responsible lending. The study also examines the consumer protection mechanisms now in existence in Australia in the National Consumer Credit Protection Act 2009 (Cth) (NCCP) and the National Credit Code (NCC) contained in Schedule 1 of that Act and in the Australian Securities and Investments Commission Act 2001 (Cth).

Attachment Security and Alexithymia in a Heavy Drinking Population

Attachment difficulties have been proposed as a key risk factor for the development of alexithymia, a multifaceted personality trait characterised by difficulties identifying and describing feelings, a lack of imagination and an externally oriented thinking style. The present study investigated the relationship between attachment and alexithymia in an alcohol dependent population. Participants were 210 outpatients in a Cognitive Behavioural Treatment Program assessed on the Toronto Alexithymia Scale (TAS-20) and the Revised Adult Attachment Scale (RAAS). Significant relationships between anxious attachment and alexithymia factors were confirmed. Furthermore, alexithymic alcoholics reported significantly higher levels of anxious attachment and significantly lower levels of closeness (secure attachment) compared to non-alexithymic alcoholics. These findings highlight the importance of assessing and targeting anxious attachment among alexithymic alcoholics in order to improve alcohol treatment outcomes. Keywords: Attachment, alexithymia, alcohol dependence.

The application of Bowen’s family system theory (BFST) to the Malay population in Malaysia

The rapid economic development and social changes in Malaysia recently have led to many psychosocial problems in young people, such as drug addiction, child sexual abuse and mental illness. The Malaysian government is beginning to focus more attention on its social welfare and human service needs in order to alleviate these psychosocial problems. Although counselling is accepted and widespread in Malaysia, the practice of family therapy is not as accepted as it is still a widely held belief that family problems need to be kept within the family. However, changes are imminent and thus the theoretical basis of family therapy needs to be culturally relevant. Bowen‟s Family Systems Theory (BFST) is already one of the major theories taught to tertiary counselling students in Malaysian universities. The main tenet of Bowen‟s theory is that the family as a system may be unstable unless each member of the family is well differentiated. High differentiation levels in the family allow a person to both leave the family‟s boundaries in search of uniqueness and to continually return to the family fold in order to establish a more mature sense of belonging. The difficulty, however, is that while Bowen has claimed that his theory is universal nearly all of the research confirming the theory has been conducted in the United States of America. The only known study outside America, however, did show that Bowen‟s theory applied to a Filipino population but, one of the theory‟s propositions that differentiation is intergenerational was not supported in this non-American sample. The American sample that was compared to the Malay sample was taken from Skowron and Friedlander‟s (1998) study. One hundred and twenty-seven faculty staff in an American university completed the Differentiation of Self Inventory (DSI) to measure level of differentiation of self. This thesis therefore, set out to determine whether Bowen‟s theory applied to another non-American sample, the Malaysian community. The research also investigated if the intergenerational effect was present in the Malaysian sample as well as explored the role of socio-economic status on Bowen‟s theory of differentiation and gender effect. Three hundred and seventy-four families completed four measures to examine these research questions: the Differentiation of Self Inventory (DSI), the Family Inventory of Life Event (FILE), the Depression Anxiety and Stress Scale (DASS) and the Connor-Davidson Resilience Scale (CD-RISC). The results of the study showed that differentiation of self is a valid construct for the Malay population. However, all four subscales of the Differentiation of Self Inventory (DSI); emotional reactivity (ER), emotional cut-off (EC), fusion with other (FO) and I position (IP), showed significant differences compared to the American sample from Skowron and Friedlander‟s (1998) study. The Malay sample scored higher in emotional reaction (ER), fusion with other (FO), but lower on emotional cut-off (EC) and I position (IP) than the American sample. The intergenerational effect was found in the Malay population as the parent‟s level of differentiation correlated with their children‟s level of differentiation. It was found that stress as measured by the Family Inventory of Life Event (FILE) and as measured by the Depression Anxiety and Stress Scale (DASS) were not correlated with the level of differentiation of self in parents. However, gender had a significant effect in predicting the level of differentiation among parents in Malay population with females scores higher on emotional reactivity (ER) and fusion with other (FO) than males. An additional finding was that resilience can be predicted from the level of differentiation of self in children in the Malay sample. There was also a positive correlation between the level of differentiation of self in parents and resilience in their children. Findings from this study indicate that the concept of differentiation of self is applicable to a Malay sample; however, the implementation of the theory should be applied with cultural sensitivity.

Active regulation of the epidermal calcium profile

A distinct calcium profile is strongly implicated in regulating the multi-layered structure of the epidermis. However, the mechanisms that govern the regulation of this calcium profile are currently unclear. It clearly depends on the relatively impermeable barrier of the stratum corneum (passive regulation) but may also depend on calcium exchanges between keratinocytes and extracellular fluid (active regulation). Using a mathematical model that treats the viable sublayers of unwounded human and murine epidermis as porous media and assumes that their calcium profiles are passively regulated, we demonstrate that these profiles are also actively regulated. To obtain this result, we found that diffusion governs extracellular calcium motion in the viable epidermis and hence intracellular calcium is the main source of the epidermal calcium profile. Then, by comparison with experimental calcium profiles and combination with a hypothesised cell velocity distribution in the viable epidermis, we found that the net influx of calcium ions into keratinocytes from extracellular fluid may be constant and positive throughout the stratum basale and stratum spinosum, and that there is a net outflux of these ions in the stratum granulosum. Hence the calcium exchange between keratinocytes and extracellular fluid differs distinctly between the stratum granulosum and the underlying sublayers, and these differences actively regulate the epidermal calcium profile. Our results also indicate that plasma membrane dysfunction may be an early event during keratinocyte disintegration in the stratum granulosum.

The expression, regulation and function of kallikrein 4 in prostate cancer

Prostate cancer is a significant health problem faced by aging men. Currently, diagnostic strategies for the detection of prostate cancer are either unreliable, yielding high numbers of false positive results, or too invasive to be used widely as screening tests. Furthermore, the current therapeutic strategies for the treatment of the disease carry considerable side effects. Although organ confined prostate cancer can be curable, most detectable clinical symptoms occur in advanced disease when primary tumour cells have metastasised to distant sites - usually lymph nodes and bone. Many growth factors and steroids assist the continued growth and maintenance of prostatic tumour cells. Of these mitogens, androgens are important in the development of the normal prostate but are also required to sustain the growth of prostate cancer cells in the early stage of the disease. Not only are androgens required in the early stage of disease, but also many other growth factors and hormones interact to cause uncontrolled proliferation of malignant cells. The early, androgen sensitive phase of disease is followed by an androgen insensitive phase, whereby androgens are no longer required to stimulate the growth of the tumour cells. Growth factors such as transforming growth factor  and  (TGF/), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factors (IGFs), Vitamin D and thyroid hormone have been suggested to be important at this stage of disease. Interestingly, some of the kallikrein family of genes, including prostate specific antigen (PSA), the current serum diagnostic marker for prostate cancer, are regulated by androgens and many of the aforementioned growth factors. The kallikrein gene family is a group of serine proteases that are involved in a diverse range of physiological processes: regulation of local blood flow, angiogenesis, tissue invasion and mitogenesis. The earliest members of the kallikrein gene family (KLK1-KLK3) have been strongly associated with general disease states, such as hypertension, inflammation, pancreatitis and renal disease, but are also linked to various cancers. Recently, this family was extended to include 15 genes (KLK1-15). Several newer members of the kallikrein family have been implicated in the carcinogenesis and tumour metastasis of hormone-dependent cancers such as prostate, breast, endometrial and ovarian cancer. The aims of this project were to investigate the expression of the newly identified kallikrein, KLK4, in benign and malignant prostate tissues, and prostate cancer cell lines. This thesis has demonstrated the elevated expression of KLK4 mRNA transcripts in malignant prostate tissue compared to benign prostates. Additionally, expression of the full length KLK4 transcript was detected in the androgen dependent prostate cancer cell line, LNCaP. Based on the above finding, the LNCaP cell line was chosen to assess the potential regulation of full length KLK4 by androgen, thyroid hormone and epidermal growth factor. KLK4 mRNA and protein was found to be up-regulated by androgen and a combination of androgen and thyroid hormone. Thyroid hormone alone produced no significant change in KLK4 mRNA or protein over the control. Epidermal growth factor treatment also resulted in elevated expression levels of KLK4 mRNA and protein. To assess the potential functional role(s) of KLK4/hK4 in processes associated with tumour progression, full length KLK4 was transfected into PC-3 cells - a prostate cancer cell line originally derived from a secondary bone lesion. The KLK4/hK4 over-expressing cells were assessed for their proliferation, migration, invasion and attachment properties. The KLK4 over-expressing clones exhibited a marked change in morphology, indicative of a more aggressive phenotype. The KLK4 clones were irregularly shaped with compromised adhesion to the growth surface. In contrast, the control cell lines (parent PC-3 and empty vector clones) retained a rounded morphology with obvious cell to cell adhesion, as well as significant adhesion to their growth surface. The KLK4 clones exhibited significantly greater attachment to Collagen I and IV than native PC-3s and empty vector controls. Over a 12 hour period, in comparison to the control cells, the KLK4 clones displayed an increase in migration towards PC-3 native conditioned media, a 3 fold increase towards conditioned media from an osteoblastic cell line (Saos-2) and no change in migration towards conditioned media from neonatal foreskin fibroblast cells or 20% foetal bovine serum. Furthermore, the increase in migration exhibited by the KLK4 clones was partially blocked by the serine protease inhibitor, aprotinin. The data presented in this thesis suggests that KLK4/hK4 is important in prostate carcinogenesis due to its over-expression in malignant prostate tissues, its regulation by hormones and growth factors associated with prostate disease and the functional consequences of over-expression of KLK4/hK4 in the PC-3 cell line. These results indicate that KLK4/hK4 may play an important role in tumour invasion and bone metastasis via increased attachment to the bone matrix protein, Collagen I, and enhanced migration due to soluble factors produced by osteoblast cells. This suggestion is further supported by the morphological changes displayed by the KLK4 over-expressing cells. Overall, this data suggests that KLK4/hK4 should be further studied to more fully investigate the potential value of KLK4/hK4 as a diagnostic/prognostic biomarker or in therapeutic applications.