Set design for A Raisin in the Sun

My husband and I chose to go to Walt Disney World for our honeymoon, because of his interest in animation. When we arrived the world that surrounded us was fascinating. It was amazing and strange how, for the time we were there, this fantasy land became a form of reality for us. While at Walt Disney World, I became very interested in set design. The environments created within Disney World allowed one to be entertained and amused, while traveling through dream lands. Being able to design with this kind of playfulness is very stimulating to me. Upon returning home from Disney World, I began my education at Rochester Institute of Technology (R.I.T). I was introduced to many new technical skills, which I never had the opportunity to learn, during my Fine Arts education. Throughout the year I struggled with these technical skills, and as the year came to a close I understood the necessity for them. However, I still lacked the emotional playfulness that I was exposed to while visiting Disney World. With that in mind I began thinking about my thesis. I wanted to create a three dimensional environment unlike any I had created during my stay at R.I.T. When I was discussing various thesis topics with my advisor, she suggested designing a stage set for a local theatre in Rochester. I was thrilled with the suggestion

MYCN and the p53-MDM2/MDMX-p14ARF network in neuroblastoma amd response to MDM2-p53 antagonists

Background: MYCN-amplification is a major negative prognostic marker, occurring in 25-30% of neuroblastomas. MYCN plays contradictory roles in promoting cell growth and sensitizing cells to apoptosis, and we have recently shown that p53 is a direct transcriptional target of MYCN, and may be an important mechanism of MYCN-induced apoptosis. Although p53 mutations are rare in neuroblastoma at diagnosis, the p53/MDM2/p14ARF pathway is inactivated in 35% of cases through MDM2-amplification or p14ARF inactivation. Neuroblastoma is therefore an ideal target for p53 reactivation using MDM2-p53 antagonists. MDMX, a homologue of MDM2, is another negative regulator of p53 which is often overexpressed in cancers and has been shown to compromise the effects of MDM2-p53 antagonists in various cancer types. MDMX expression and the effect on MDM2-p53 antagonists has not been investigated in neuroblastoma. Hypotheses 1) Reactivation of p53 by inhibition of its negative regulator MDM2, using the MDM2-p53 antagonists Nutlin-3 and MI-63, will result in p53-mediated growth arrest and apoptosis preferentially in MYCN-amplified cells 2) MDMX knockdown increases and p14ARF knockdown decreases the sensitivity of neuroblastoma cell lines to MDM2-p53 antagonists. Methods: The effect of MYCN, MDM2, MDMX and p14ARF was investigated on the response to MDM2-p53 antagonists using siRNA in a panel of 21 neuroblastoma cell lines. Sensitivity was measured by growth inhibition, apoptosis assays including caspase activity and fluorescent activated cell sorting, and the effect on the p53 response measured by Western blotting. Results: Using the SHEP Tet21N MYCN regulatable system, MYCN(-) cells were more resistant to both Nutlin-3 and MI-63 mediated growth inhibition and apoptosis compared to MYCN(+) cells and siRNA mediated knockdown of MYCN in 4 MYCN-amplified cell lines resulted in decreased p53 expression and activation, as well as decreased levels of apoptosis following treatment with MDM2-p53 antagonists. In a panel of cell lines treated with Nutlin-3 and MI-63, the sub-set amplified for MYCN had a significantly lower mean GI50 value and increased caspase 3/7 activity compared to the non-MYCN-amplified group of cell lines, but p53 mutant cell lines were resistant to the antagonists regardless of MYCN status. Knockdown of MDM2 did not alter the apoptotic response to Nutlin-3 or MI-63 but surprisingly, knockdown of MDMX resulted in decreased levels of apoptosis. MDMX expression varied amongst the neuroblastoma cell lines and positively correlated with caspase 3/7 activity following MDM2-p53 antagonist treatment. p14ARF impaired cell lines underwent less apoptosis following MDM2-p53 antagonist treatment and following Nutlin-3 treatment, 3 of 4 p14ARF impaired cell lines underwent a pronounced G1 arrest. p14ARF knockdown alone resulted in decreased caspase 3/7 activity, and following MDM2-p53 antagonist treatment there was decreased caspase 3 cleavage and activity, and decreased PARP cleavage. Conclusions: Amplification or overexpression of MYCN sensitizes neuroblastoma cell lines with wildtype p53 to MDM2-p53 antagonists and these compounds may therefore be particularly effective in treating high risk MYCN-amplified disease. This data also suggests that neuroblastomas with high MDMX expression may be more susceptible to MDM2-p53 antagonist treatment, but that cells with inactivated p14ARF predominantly undergo a G1 arrest which may protect them from apoptosis. MDMX and p14ARF status may therefore be important in addition to MYCN in determining the outcome of neuroblastomas treated with MDM2-p53 antagonists.EThOS - Electronic Theses Online ServiceBACRCancer Research UKNewcastle UniversityGBUnited Kingdo

Estimating the Size of Clustered Hidden Populations

Successive sampling population size estimation (SS-PSE) is a method used by government agencies and aid organizations around the world to estimate the size of hidden populations using data from respondent-driven sampling (RDS) surveys. SS-PSE ad-dresses a specific need in estimation and helps us evaluate the vulnerability of areas to HIV and other epidemics by estimating the size of populations that are at higher risk of contracting and spreading HIV. However, SS-PSE relies on several assumptions, one of which requires the underlying social network of the hidden population to be fully connected. Without the connected network assumption, SS-PSE could be more widely applicable to clustered populations of interest. This dissertation proposes two modifications to SS-PSE for estimating the size of clustered hidden populations. Theoretical justification is given for these novel methods, along with a simulation study to evaluate their performance and an example of how they can be applied to real data using case studies from three Armenian cities

Living well with dementia: An exploratory matched analysis of minority ethnic and white people with dementia and carers participating in the IDEAL programme

Objectives: The increasing heterogeneity of the population of older people is reflected in an increasing number of people with dementia and carers drawn from minority ethnic groups. Data from the IDEAL study are used to compare indices of ‘living well’ among people with dementia and carers from ethnic minority groups with matched white peers. Methods: We used an exploratory cross-sectional case-control design to compare ‘living well’ for people with dementia and carers from minority ethnic and white groups. Measures for both groups were quality of life, life satisfaction, wellbeing, loneliness, and social isolation and, for carers, stress, relationship quality, role captivity and caring competence. Results: The sample of people with dementia consisted of 20 minority ethnic and 60 white participants and for carers 15 and 45 respectively. People with dementia from minority ethnic groups had poorer quality of life (−4.74, 95% CI: −7.98 to −1.50) and higher loneliness (1.72, 95% CI: 0.78–2.66) whilst minority ethnic carers had higher stress (8.17, 95% CI: 1.72–14.63) and role captivity (2.00, 95% CI: 0.43–3.57) and lower relationship quality (−9.86, 95% CI: −14.24 to −5.48) than their white peers. Conclusion: Our exploratory study suggests that people with dementia from minority ethnic groups experience lower quality of life and carers experience higher stress and role captivity and lower relationship quality than their white peers. Confirmatory research with larger samples is required to facilitate analysis of the experiences of specific minority ethnic groups and examine the factors contributing to these disadvantages

Trajectories of cognitive and perceived functional decline in people with dementia: Findings from the IDEAL programme

INTRODUCTION: Impaired cognition and instrumental activities of daily living (iADL) are key diagnostic features of dementia; however, few studies have compared trajectories of cognition and iADL. METHODS: Participants from the IDEAL study comprised 1537, 1183, and 851 people with dementia, and 1277, 977, and 749 caregivers at baseline, 12 and 24 months, respectively. Addenbrooke's Cognitive Examination-III and Functional Activities Questionnaire were used to measure cognition and iADL, respectively. Scores were converted to deciles. RESULTS: Self-rated iADL declined on average by -0.08 (-0.25, 0.08) decile points per timepoint more than cognition. Informant-rated iADL declined on average by -0.31 (-0.43, -0.18) decile points per timepoint more than cognition. DISCUSSION: Cognition and self-rated iADL declined at a similar rate. Informant-rated iADL declined at a significantly greater rate than cognition. Therefore, either cognition and perceived iADL decline at different rates or informants overestimate increasing iADL difficulties compared to both cognition and self-ratings. Highlights: Self-ratings of the degree of functional difficulties were consistent with cognition Decline in self-rated everyday activities was consistent with cognitive decline Informant-ratings of everyday activities declined more than cognition

Navigating pregnancy and early motherhood in prison: a thematic analysis of mothers’ experiences

BACKGROUND: Maternal imprisonment negatively impacts mothers and their children and is likely to have lifelong and intergenerational sequelae. In many jurisdictions nationally and internationally, young children (usually those less than 5 years) can reside with their mothers in prison. However, there is considerable debate regarding the impact of prison environments on incarcerated mothers and their children who are born, and/or raised in prison. Research to date on the pregnancy and mothering experiences of imprisoned mothers and their preferences for care arrangements for their babies and young children is limited. METHODS: This study was part of the Transforming Corrections to Transform Lives project, in which workshops were conducted with imprisoned mothers to understand their needs while in custody and post-release, and the kind of supports and system changes that are required to meet those needs. Incarcerated mothers (n = 75) participated in seven workshops conducted across four Queensland prisons. Themes were generated through reflexive thematic analysis. RESULTS: Three themes characterised mothers’ experiences of being pregnant and undertaking a mothering role of a young child while in prison. First, for most mothers, imprisonment adds vulnerability and isolation during pregnancy and childbirth. Second, although mothers felt that residing together with their children in prison motivated them to change for a better future, they were concerned about the potential negative impact of the prison environment on the child’s development. Lastly, most mothers voiced losing autonomy and agency to practice motherhood independently within custodial settings. Mothers expressed a need for the correctional system to be adapted, so it is better equipped to address the unique and additional needs of mothers with young children. CONCLUSION: Mothers’ experiences indicated that the correctional system and policies, which were predominantly designed for men, do not adequately address the varied and complex needs of pregnant women, mothers, and their young children. Imprisonment of pregnant women and mothers with young children should be the last resort, and they should be provided with holistic, individually tailored support, most preferably in community settings, to address their multiple intersecting needs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40352-022-00196-4

The Role of Nutrition in Influencing Mechanisms Involved in Environmentally Mediated Diseases

Human exposure to environmental contaminants such as persistent chlorinated organics, heavy metals, pesticides, phthalates, flame retardants, electronic waste and airborne pollutants around the world, and especially in Southeast Asian regions, are significant and require urgent attention. Given this widespread contamination and abundance of such toxins as persistent organic pollutants (POPs) in the ecosystem, it is unlikely that remediation alone will be sufficient to address the health impacts associated with this exposure. Furthermore, we must assume that the impact on health of some of these contaminants results in populations with extraordinary vulnerabilities to disease risks. Further exacerbating risk; infectious diseases, poverty and malnutrition are common in the Southeast Asian regions of the world. Thus, exploring preventive measures of environmental exposure and disease risk through new paradigms of environmental toxicology, optimal and/or healthful nutrition and health is essential. For example, folic acid supplementation can lower blood arsenic levels, and plant-derived bioactive nutrients can lower cardiovascular and cancer risks linked to pollutant exposure. Data also indicate that diets enriched with bioactive food components such as polyphenols and omega-3 polyunsaturated fatty acids can prevent or decrease toxicant-induced inflammation. Thus, consuming healthy diets that exhibit high levels of antioxidant and anti-inflammatory properties, is a meaningful way to reduce the vulnerability to non-communicable diseases linked to environmental toxic insults. This nutritional paradigm in environmental toxicology requires further study in order to improve our understanding of the relationship between nutrition or other lifestyle modifications and toxicant-induced diseases. Understanding mechanistic relationships between nutritional modulation of environmental toxicants and susceptibility to disease development are important for both cumulative risk assessment and the design and implementation of future public health programs and behavioral interventions

Reflections and Experiences of a Co-Researcher involved in a Renal Research Study

Background Patient and Public Involvement (PPI) is seen as a prerequisite for health research. However, current Patient and public involvement literature has noted a paucity of recording of patient and public involvement within research studies. There have been calls for more recordings and reflections, specifically on impact. Renal medicine has also had similar criticisms and any reflections on patient and public involvement has usually been from the viewpoint of the researcher. Roles of patient and public involvement can vary greatly from sitting on an Advisory Group to analysing data. Different PPI roles have been described within studies; one being a co-researcher. However, the role of the co-researcher is largely undefined and appears to vary from study to study. Methods The aims of this paper are to share one first time co-researcher's reflections on the impact of PPI within a mixed methods (non-clinical trial) renal research study. A retrospective, reflective approach was taken using data available to the co-researcher as part of the day-to-day research activity. Electronic correspondence and documents such as meeting notes, minutes, interview thematic analysis and comments on documents were re-examined. The co-researcher led on writing this paper. Results This paper offers a broad definition of the role of the co-researcher. The co-researcher reflects on undertaking and leading on the thematic analysis of interview transcripts, something she had not previously done before. The co-researcher identified a number of key themes; the differences in time and responsibility between being a coresearcher and an Advisory Group member; how the role evolved and involvement activities could match the co-researchers strengths (and the need for flexibility); the need for training and support and lastly, the time commitment. It was also noted that it is preferable that a co-researcher needs to be involved from the very beginning of the grant application. Conclusions The reflections, voices and views of those undertaking PPI has been largely underrepresented in the literature. The role of co-researcher was seen to be rewarding but demanding, requiring a large time commitment. It is hoped that the learning from sharing this experience will encourage others to undertake this role, and encourage researchers to reflect on the needs of those involved.Peer reviewedFinal Published versio

Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis

Are profiles of social, cultural, and economic capital related to living well with dementia? Longitudinal findings from the IDEAL programme

Rationale: Research exploring social, cultural, and economic capital among people with dementia is scarce. Objective: We describe levels of social, cultural, and economic capital in people with dementia at baseline and levels of social and cultural capital 12 and 24 months later. We identify groups of people with dementia having different combinations of capital and explore whether the identified groups differ in personal characteristics at baseline and in quality of life (QoL), satisfaction with life (SwL), and well-being over time. Method: Baseline, 12-months, and 24-months data from 1537 people with dementia (age, mean = 76.4 years; SD = 8.5; Alzheimer's Disease = 55.4%) enrolled in the IDEAL cohort were analyzed. Social (interactions with friends, civic participation, social participation, neighborhood trust, social network), cultural (education, cultural participation) and economic (annual income) capital, QoL, SwL, well-being, and personal characteristics were assessed. Results: Compared to people their age, people with dementia reported slightly lower frequency of interactions with friends, social networks and social support, civic and cultural participation, education, and annual income. However, social engagement, cultural participation, and annual income are low among British older adults. Latent profile analysis identified four groups that, based on their levels of social, cultural, and economic capital were named socially and economically privileged (18.0% of participants); financially secure (21.0% of participants); low capital (36.9% of participants); and very low capital (24.1% of participants). Latent growth curve models showed that over time QoL, SwL, and well-being remained largely stable for all groups. Compared to the low capital group, the socially and economically privileged and financially secure groups had higher QoL and well-being whereas the group with very low capital had poorer QoL, SwL, and well-being. Conclusions: New policies and efforts from the government, philanthropic foundations, the voluntary and primary care sectors are needed to address social, cultural, and economic disadvantage among people with dementia