An exploration of the determinants of overweight and obesity and the capacity to intervene in North-West Tasmania: A stakeholder consultation.

ISSUE ADDRESSED: The capacity of communities to develop effective obesity prevention initiatives varies and should be a focus for obesity prevention intervention planning and investment. This research aimed at engaging and consulting local community stakeholders to identify determinants, needs, strategic priorities and capacity to act on overweight and obesity prevention in North-West (NW) Tasmania. METHODS: A series of semi-structured interviews and thematic analyses was implemented to explore the knowledge, insights, experiences and attitudes of stakeholders. RESULTS: Mental health and obesity were identified as major concerns and were often reported to share similar determinants. This study has identified health promotion capacity assets (existing partnerships, community capital, local leadership and some pockets of health promotion activity), and a range of capacity deficits (limited investment in health promotion, a small workforce, limited access to pertinent health information). CONCLUSIONS: This study has identified health promotion capacity assets (existing partnerships, community capital, local leadership and some pockets of health promotion activity), and a range of capacity deficits (limited investment in health promotion, a small workforce, limited access to pertinent health information). SO WHAT?: Broad upstream socio-economic, cultural and environmental determinants underpin the conditions by which the local community develops overweight/obesity and/or health and wellbeing outcomes. Including stakeholder consultations as a significant technique within a comprehensive plan of action aimed at achieving a sustainable, long-term strategy for obesity prevention and/or health promotion, should be considered in future programs.

Enhancing Food Literacy and Food Security through School Gardening in Rural and Regional Communities.

A qualitative case study approach with in-depth, semi-structured interviews of key school staff, and student feedback was used to assess a school kitchen and garden program in the regional area of North-West Tasmania, Australia. A detailed program description was produced to conduct a realist evaluation with a Context-Mechanism-Outcome configuration, followed by a program theory evaluation through the construction of a retrospective program logic model. Dedicated kitchen and garden spaces, knowledgeable teachers committed to the program, provision of sufficient materials and consumables, and support from the school and community were found to be the basic requirements to establish a program. Additionally, it is essential to integrate both the kitchen and garden teaching components into the school curriculum. The positive outcomes (e.g., engagement, participation, knowledge, skills, behavioral change) of the program were dependent on the underlying factors, including dedicated support of school leadership, teaching staff, and the parent body for effective student engagement in the teaching spaces and for wider engagement from families and the community. The students' feedback provided supporting evidence of increased food literacy with improvements in their understanding, abilities, and attitudes towards gardening, producing healthy food, and preparing food. This may further lead to enhanced food security for students' families and the broader community.

Habitual Diets Are More Expensive than Recommended Healthy Diets.

Understanding food prices and affordability is crucial for promoting healthy dietary habits and informing policy actions. We assessed changes in the cost and affordability of habitual and recommended healthy diets in Northwest Tasmania from 2021 to 2023. The recommended diet was 16-22% less expensive than the habitual diet during the period. Notably, 60% of the total cost of the habitual diet was spent on discretionary items. The cost of the habitual diet increased by 9% in this period, whereas the cost of the recommended diet increased by only 2%. The habitual diet was unaffordable for households with median gross, minimum wage disposable or welfare-dependent incomes. The recommended diet, however, was affordable for some groups but posed a risk of food stress for those with median gross and minimum wage disposable income and remained unaffordable for those who were welfare dependent. Our findings reveal that adhering to a healthy Australian Dietary Guidelines-recommended diet can be more cost-effective than following a habitual unhealthy diet. However, adopting a healthy diet can be challenging for low-income families. Interventions such as financial support, nutrition education, community gardens and food hubs, as well as price regulation and subsidies for farmers, can help address food insecurity in Northwest Tasmania.

School Gardening and Health and Well-Being of School-Aged Children: A Realist Synthesis.

School environments can create healthy settings to foster children's health and well-being. School gardening is gaining popularity as an intervention for healthier eating and increased physical activity. We used a systematic realist approach to investigate how school gardens improve health and well-being outcomes for school-aged children, why, and in what circumstances. The context and mechanisms of the specific school gardening interventions (n = 24) leading to positive health and well-being outcomes for school-aged children were assessed. The impetus of many interventions was to increase fruit and vegetable intake and address the prevention of childhood obesity. Most interventions were conducted at primary schools with participating children in Grades 2 through 6. Types of positive outcomes included increased fruit and vegetable consumption, dietary fiber and vitamins A and C, improved body mass index, and improved well-being of children. Key mechanisms included embedding nutrition-based and garden-based education in the curriculum; experiential learning opportunities; family engagement and participation; authority figure engagement; cultural context; use of multi-prong approaches; and reinforcement of activities during implementation. This review shows that a combination of mechanisms works mutually through school gardening programs leading to improved health and well-being outcomes for school-aged children.

"An Ounce of Prevention is Worth a Pound of Cure": Proposal for a Social Prescribing Strategy for Obesity Prevention and Improvement in Health and Well-being.

BACKGROUND: Social and behavioral determinants of health are increasingly recognized as central to effective person-centered intervention in clinical practice, disease management, and public health. Accordingly, social prescribing (SP) has received increased attention in recent times. The rampant global prevalence of obesity indicates that the customary, reductionistic, and disease-oriented biomedical approach to health service delivery is inadequate/ineffective at arresting the spread and mitigating the damaging consequences of the condition. There is an urgent need to shift the focus from reactive downstream disease-based treatments to more proactive, upstream, preventive action. In essence, this requires more effort to affect the paradigm shift from the traditional "biomedical approach of care" to a "biopsychosocial model" required to arrest the increasing prevalence of obesity. To this end, an SP approach, anchored in systems thinking, could be an effective means of moderating prevalence and consequences of obesity at a community level. OBJECTIVE: The proposed SP intervention has the following three key objectives: (1) build a sustainable program for Circular Head based on SP, peer education, and health screening to minimize the incidence of obesity and related lifestyle diseases; (2) increase service and workforce connectivity and collaboration and initiate the introduction of new services and activities for obesity prevention and community health promotion; and (3) enhance health and well-being and minimize preventable adverse health outcomes of obesity and related lifestyle diseases through enhancement of food literacy and better nutrition, enhancement of physical literacy and habitual personal activity levels, and improvement of mental health, community connectedness, and reduction of social isolation. METHODS: This paper describes a prospective SP strategy aimed at obesity prevention in Circular Head, a local government area in Northwest (NW) Tasmania. SP is a prominent strategy used in the Critical Age Periods Impacting the Trajectory of Obesogenic Lifestyles Project, which is an initiative based in NW Tasmania focused on assessing obesity prevention capacity. A social prescription model that facilitates the linkage of primary health screening with essential health care, education, and community resources through a dedicated "navigator" will be implemented. Four interlinked work packages will be implemented as part of the initial plan with each either building on existing resources or developing new initiatives. RESULTS: A multimethod approach to triangulate insights from quantitative and qualitative research that enables the assessment of impact on individuals, community groups, and the health care system will be implemented within the initial pilot phase of the project. CONCLUSIONS: Literature is replete with rhetoric advocating complex system approaches to curtail obesity. However, real-life examples of whole-of-systems interventions operationalized in ways that generate relevant evidence or effective policies are rare. The diverse approach for primary prevention of obesity-related lifestyle diseases and strategies for improvement of health and well-being described in this instance will contribute toward closing this evidence gap. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/41280.

Domains of Capacity Building in Whole-Systems Approaches to Prevent Obesity-A "Systematized" Review.

Despite increased awareness of its risks, for the most part, contemporary efforts for obesity prevention have been patchy at best. As such, the burgeoning interest in whole-systems approaches (WSAs) that acknowledge the complex, dynamic nature of overweight and obesity and operate across multiple levels of society is particularly timely. Many components of "community capacity building" (CB), an essential but often neglected aspect of obesity prevention, overlap with "best practice principles" in effective/optimal community-based obesity-prevention initiatives. Rhetoric urging WSAs and community CB in public health abounds although operative and efficacious contemporary examples of these approaches to reducing obesity levels are scarce. The aim of this investigation was to undertake a systematized review of the level of capacity building incorporated in published literature on WSAs targeting obesity to better understand how domains of CB have been incorporated. A PubMed search and a recently published systematic review were utilized to identify WSAs to obesity prevention between 1995-2020. A team-based approach to qualitative thematic data analysis was used to systematically assess and describe each intervention regarding explicit capacity-building practice. Despite not being specifically designed for building capacity, a significant proportion of the WSAs studied in the current report had implemented several CB domains.

Physical Activity and Food Environments in and around Schools: A Case Study in Regional North-West Tasmania.

A better understanding of the physical activity (PA) infrastructure in schools, the walkability of neighborhoods close to schools, and the food environments around schools, particularly in rural, socioeconomically challenged areas such as the North-West (NW) of Tasmania, could be important in the wider effort to improve the health of school-age children. Accordingly, this research aimed to assess PA resources, walkability, and food environments in and around schools in three socioeconomically disadvantaged, regional/rural Local Government Areas (LGAs) of Tasmania, Australia. A census of schools (including assessment of the PA infrastructure quality within school grounds), a walkability assessment, and a census of food outlets surrounding schools (through geospatial mapping) were executed. Most of the schools in the study region had access to an oval, basketball/volleyball/netball court, and free-standing exercise equipment. In all instances (i.e., regardless of school type), the quality of the available infrastructure was substantially higher than the number of incivilities observed. Most schools also had good (i.e., within the first four deciles) walkability. Numerous food outlets were within the walking zones of all schools in the study region, with an abundance of food outlets that predominantly sold processed unhealthy food.

Why some do but too many don't? Barriers and enablers to physical activity in regional Tasmania - an exploratory, mixed-methods study.

BACKGROUND: The interconnectedness of physical inactivity and sedentarism, obesity, non-communicable disease (NCD) prevalence, and socio-economic costs, are well known. There is also strong research evidence regarding the mutuality between well-being outcomes and the neighbourhood environment. However, much of this evidence relates to urban contexts and there is a paucity of evidence in relation to regional communities. A better understanding of available physical activity (PA) infrastructure, its usage, and community perceptions regarding neighbourhood surroundings, could be very important in determining requirements for health improvement in regional communities. The aims of this research were to 1. Explore and evaluate the public's perception of the PA environment; and 2. Evaluate the quantity, variety, and quality of existing PA infrastructure in regional Northwest (NW) Tasmania. METHODS: A mixed methods approach guided data collection, analysis, and presentation. Quality of PA infrastructure was assessed using the Physical Activity Resource Assessment (PARA) instrument and public perception about PA environment was evaluated using the International Physical Activity Questionnaire - Environmental (IPAQ-E) module. Quantitative data were analysed using descriptive summative methods and a team-based researcher triangulation approach was utilised for qualitative data. RESULTS: Overall, a wide array of high-quality PA infrastructure (with minimal incivilities such as auditory annoyance, litter, graffiti, dog refuse, and vandalism etc.) was available. Survey respondents rated neighbourhoods positively. The overall quality of PA infrastructure, rated on a scale from 0 to 3, was assessed as high (all rated between 2 to 3) with minimal incivilities (rated between 0 and 1.5). Of note, survey respondents confirmed the availability of numerous free-to-access recreational tracks and natural amenities across the 3 local government areas (LGAs) studied. Importantly, most respondents reported minimal disruption to their routine PA practices due to the COVID-19 pandemic. CONCLUSION: This exploratory research confirmed the availability of a wide range of high-quality PA infrastructure across all three LGAs and there was an overwhelming public appreciation of this infrastructure. The challenge remains to implement place-based PA interventions that address extant barriers and further increase public awareness and utilisation of high-quality PA infrastructure.

A Spatial Analysis of Access to Physical Activity Infrastructure and Healthy Food in Regional Tasmania.

Prevalence of physical inactivity and obesity continues to increase in regional areas such as North-West (NW) Tasmania and show no signs of abating. It is possible that limited access to physical activity infrastructure (PAI) and healthier food options are exacerbating the low levels of habitual physical activity and obesity prevalence in these communities. Despite a burgeoning research base, concomitant exploration of both physical activity and food environments in rural and regional areas remain scarce. This research evaluated access (i.e., coverage, variety, density, and proximity) to physical activity resources and food outlets in relation to socioeconomic status (SES) in three NW Tasmanian communities. In all three study areas, the PAI and food outlets were largely concentrated in the main urban areas with most recreational tracks and natural amenities located along the coastline or river areas. Circular Head had the lowest total number of PAI (n = 43) but a greater proportion (30%) of free-to-access outdoor amenities. There was marked variation in accessibility to infrastructure across different areas of disadvantage within and between sites. For a considerable proportion of the population, free-to-access natural amenities/green spaces and recreational tracks (73 and 57%, respectively) were beyond 800 m from their households. In relation to food accessibility, only a small proportion of the food outlets across the region sells predominantly healthy (i.e., Tier 1) foods (~6, 13, and 10% in Burnie, Circular Head and Devonport, respectively). Similarly, only a small proportion of the residents are within a reasonable walking distance (i.e., 5-10 min walk) from outlets. In contrast, a much larger proportion of residents lived close to food outlets selling predominantly energy-dense, highly processed food (i.e., Tier 2 outlets). Circular Head had at least twice as many Tier 1 food stores per capita than Devonport and Burnie (0.23 vs. 0.10 and 0.06; respectively) despite recording the highest average distance (4.35 and 5.66 km to Tier 2/Tier 1 stores) to a food outlet. As such, it is possible that both food and physical activity environment layouts in each site are contributing to the obesogenic nature of each community.

EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas.

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res; 77(16); 4268-78. ©2017 AACR.

Whole-genome characterization of chemoresistant ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Rescue of the Friedreich ataxia knockout mutation in transgenic mice containing an FXN-EGFP genomic reporter.

Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. We previously generated BAC-based transgenic mice containing an FXN-EGFP genomic reporter construct in which the EGFP gene is fused in-frame immediately following the final codon of exon 5a of the human FXN gene. These transgenic mice were mated with mice heterozygous for a knockout mutation of the murine Fxn gene, to generate mice homozygous for the Fxn knockout mutation and hemizygous or homozygous for the human transgene. Rescue of the embryonic lethality that is associated with homozygosity for the Fxn knockout mutation was observed. Rescue mice displayed normal behavioral and histological parameters with normal viability, fertility and life span and without any signs of aberrant phenotype. Immunoblotting demonstrated the production of full-length frataxin-EGFP fusion protein that appears to act as a bifunctional hybrid protein. This study shows frataxin replacement may be a viable therapeutic option. Further, these mice should provide a useful resource for the study of human FXN gene expression, frataxin function, the evaluation of pharmacologic inducers of FXN expression in a whole-animal model and provide a useful source of cells for stem cell transplantation studies.

Detection of interruptions in the GAA trinucleotide repeat expansion in the FXN gene of Friedreich ataxia.

Friedreich ataxia is a neurodegenerative disorder caused by the expansion of a GAA trinucleotide repeat sequence within the first intron of the FXN gene. Interruptions in the GAA repeat may serve to alleviate the inhibitory effects of the GAA expansion on FXN gene expression and to decrease pathogenicity. We have developed a simple and rapid PCR- and restriction enzyme-based assay to assess the purity of GAA repeat sequences.

c-MYC coordinately regulates ribosomal gene chromatin remodeling and Pol I availability during granulocyte differentiation.

Loss of c-MYC is required for downregulation of ribosomal RNA (rRNA) gene (rDNA) transcription by RNA Polymerase I (Pol I) during granulocyte differentiation. Here, we demonstrate a robust reduction of Pol I loading onto rDNA that along with a depletion of the MYC target gene upstream binding factor (UBF) and a switch from epigenetically active to silent rDNA accompanies this MYC reduction. We hypothesized that MYC may coordinate these mechanisms via direct regulation of multiple components of the Pol I transcription apparatus. Using gene expression arrays we identified a 'regulon' of Pol I factors that are both downregulated during differentiation and reinduced in differentiated granulocytes upon activation of the MYC-ER transgene. This regulon includes the novel c-MYC target genes RRN3 and POLR1B. Although enforced MYC expression during granulocyte differentiation was sufficient to increase the number of active rRNA genes, its activation in terminally differentiated cells did not alter the active to inactive gene ratio despite increased rDNA transcription. Thus, c-MYC dynamically controls rDNA transcription during granulocytic differentiation through the orchestrated transcriptional regulation of core Pol I factors and epigenetic modulation of number of active rRNA genes.

UBF levels determine the number of active ribosomal RNA genes in mammals.

In mammals, the mechanisms regulating the number of active copies of the approximately 200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1-induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation.

Transgenic mice expressing the Peripherin-EGFP genomic reporter display intrinsic peripheral nervous system fluorescence.

The development of homologous recombination methods for the precise modification of bacterial artificial chromosomes has allowed the introduction of disease causing mutations or fluorescent reporter genes into human loci for functional studies. We have introduced the EGFP gene into the human PRPH-1 locus to create the Peripherin-EGFP (hPRPH1-G) genomic reporter construct. The hPRPH1-G reporter was used to create transgenic mice with an intrinsically fluorescent peripheral nervous system (PNS). During development, hPRPH1-G expression was concomitant with the acquisition of neuronal cell fate and growing axons could be observed in whole embryo mounts. In the adult, sensory neurons were labeled in both the PNS and central nervous system, while motor neurons in the spinal cord had more limited expression. The fusion protein labeled long neuronal processes, highlighting the peripheral circuitry of hPRPH1-G transgenic mice to provide a useful resource for a range of neurobiological applications.

Evaluation of an FRDA-EGFP genomic reporter assay in transgenic mice.

Friedreich ataxia is an autosomal recessive neurodegenerative disorder caused by a GAA trinucleotide expansion in the first intron of the Friedreich ataxia gene (FRDA) that causes reduced synthesis of frataxin, a mitochondrial protein likely to be involved in biosynthesis of iron-sulfur clusters. This leads to increased oxidative stress, progressive loss of large sensory neurons, and hypertrophic cardiomyopathy. To elucidate the mechanisms regulating FRDA expression and to develop an in vivo assay for agents that might upregulate FRDA expression in a therapeutically relevant manner, we have generated transgenic mice with a BAC genomic reporter construct consisting of an in-frame fusion between FRDA and the gene coding for enhanced green fluorescent protein (EGFP). Production of full-length frataxin-EGFP fusion protein was demonstrated by immunoblotting. EGFP expression was observed as early as day E3.5 of development. Most tissues of adult transgenic mice were fluorescent. The level of FRDA-EGFP expression in peripheral blood, bone marrow, and cells obtained from enzymatically disaggregated tissues was quantitated by flow cytometry. There was a twofold increase in EGFP expression in mice homozygous for the transgene when compared to hemizygous mice. These transgenic mice are a valuable tool for the examination of spatial and temporal aspects of FRDA gene expression and for the preclinical evaluation of pharmacological inducers of FRDA expression in a whole-animal model. In addition, tissues from these mice should also be valuable for stem cell transplantation studies.

Human BAC-mediated rescue of the Friedreich ataxia knockout mutation in transgenic mice.

Three independent transgenic mouse lines were generated with the human Friedreich ataxia gene, FRDA, in an 188-kb bacterial artificial chromosome (BAC) genomic sequence. Three copies of the transgene per diploid mouse genome were integrated in a single site in each mouse line. Transgenic mice were mated with mice heterozygous for a knockout mutation of the murine Frda gene, to generate mice homozygous for the Frda knockout mutation and hemizygous or homozygous for the human transgene. Rescue of the embryonic lethality that is associated with homozygosity for the Frda knockout mutation was observed in all three lines. Rescued mice displayed normal behavioral and biochemical parameters. RT-PCR analysis demonstrated that human FRDA mRNA is expressed in all the lines. The relative expression of the human FRDA and mouse Frda genes showed a similar pattern in different tissues in all three lines, indicating position-independent control of expression of the human FRDA transgene. However, large differences in the human:mouse mRNA ratio were observed between different tissues in all three lines. The human transgene is expressed at much higher levels in the brain, liver, and skeletal muscle than the endogenous gene, while expression of the human transgene in blood is only 25-30% of the mouse gene. These studies will facilitate the development of humanized mouse models of Friedreich ataxia through introduction of a GAA trinucleotide expansion or specific known point mutations in the normal human FRDA locus and the study of the regulation of gene expression from the FRDA locus.