Healthy together Victoria and childhood obesity study: effects of a large scale, community-based cluster randomised trial of a systems thinking approach for the prevention of childhood obesity among secondary school students 2014-2016.

BACKGROUND: Healthy Together Victoria (HTV) was a Victorian Government initiative that sought to reduce the prevalence of overweight and obesity through targeting chronic disease risk factors including physical activity, poor diet quality, smoking, and harmful alcohol use. The intervention involved a boosted workforce of > 170 local-level staff in 12 communities; employed to deliver system activation around health and wellbeing for individuals, families and communities. A cluster randomised trial (CRT) of a systems thinking approach to obesity prevention was embedded within HTV. We present the two-year changes in overweight and obesity and associated behaviours among secondary school students across Victoria, Australia. METHODS: Twenty-three geographically bounded areas were randomised to intervention (12 communities) or comparison (11 communities). Randomly selected secondary schools within each community were invited to participate in the trial in 2014 and 2016. Students in Grade 8 (aged approximately 13-15 years) and Grade 10 (aged approximately 15-16 years) at participating schools were recruited using an opt-out approach across July-September 2014 and 2016. Primary outcomes were body mass index (BMI) and waist circumference. Secondary outcomes were physical activity, sedentary behaviour, diet quality, health-related quality of life, and depressive symptoms. Linear mixed models were fit to estimate the intervention effect adjusting for child/school characteristics. RESULTS: There were 4242 intervention children and 2999 control children in the final analysis. For boys, the two-year change showed improvement in intervention versus control for waist circumference (difference in change: - 2.5 cm; 95% confidence interval [CI]: - 4.6, - 0.5) and consumption of sugar-sweetened beverages per day (< 1 serve: 8.5 percentage points; 95% CI: 0.6, 16.5). For girls, there were no statistically significant differences between conditions. CONCLUSIONS: HTV seemed to produce favourable changes in waist circumference and sugar-sweetened beverage consumption for boys, however, no effect on BMI was observed. Although the HTV intervention was cut short, and the period between data collection points was relatively short, the changes observed in HTV contribute to the growing evidence of whole-of-community interventions targeting childhood obesity. TRIAL REGISTRATION: This trial is unregistered. The intervention itself was a policy setting delivered by government and our role was the collection of data to evaluate the effect of this natural experiment. That is, this study was not a trial from the classical point of view and we were not responsible for the intervention.

Association between the school physical activity environment, measured and self-reported student physical activity and active transport behaviours in Victoria, Australia.

BACKGROUND: Environments within schools including the physical, social-cultural and policy/practice environments have the potential to influence children's physical activity (PA) behaviours and weight status. This Australian first study comprehensively examined the association(s) of physical, social-cultural and policy/practice environments with PA, active transport (AT) and weight status among regional primary school children. METHODS: Data were from two childhood obesity monitoring systems in regional Victoria, Australia. Measured height and weight were collected from students in Year 2 (aged approx. 7-8 years), Year 4 (9-10 years), and Year 6 (11-12 years). Self-reported PA behaviour, including AT were collected from students in Year 4 and 6 and a sub-sample wore an ActiGraph (wGT3X-BT) accelerometer for 7-days. A school physical activity environment audit was completed by the school principal and responses were used to calculate school physical activity environment scores (PAES) and active transport environment scores (ATES). Mixed effects logistic regression was used to assess the relationship between the proportion of students meeting the PA guidelines (≥60mins/day of moderate-to-vigorous PA) and PAES tertiles (low, medium, high) and those using AT and school ATES tertiles, controlling for gender, school size/type and socioeconomic composition. RESULTS: The analysed sample included 54/146 (37%) schools and 3360/5376 (64%) students. In stratified analysis, girls in schools with a medium PAES score were more likely to meet the objectively measured PA guideline compared to low PAES score (OR 2.3, 95%CI 1.27, 4.16). Similarly, students in schools with a medium or high ATES score had higher odds of self-reported AT (medium OR 3.15, 95%CI 1.67, 5.94; high OR 3.71, 95%CI: 1.80, 7.64). No association between PAES or ATES and weight status were observed. Self-reported AT among boys (OR 1.59, 95%CI 1.19, 2.13) and girls (OR 1.56, 95%CI 1.08, 2.27) was associated with higher odds of meeting self-reported PA guidelines on all 7-days than those who did not report using AT. CONCLUSIONS: In this study of regional Victorian primary schools, PA environments were only associated with girls' adherence to PA guidelines. School AT environments were strongly associated with students' AT behaviours and with increased likelihood of students being physically active.

Metformin Treatment Attenuates Brain Inflammation and Rescues PACAP/VIP Neuropeptide Alterations in Mice Fed a High-Fat Diet.

High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin's therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin's beneficial effects.

Challenges with Cell-based Therapies for Type 1 Diabetes Mellitus.

Type 1 diabetes (T1D) is a chronic, lifelong metabolic disease. It is characterised by the autoimmune-mediated loss of insulin-producing pancreatic ß cells in the islets of Langerhans (ß-islets), resulting in disrupted glucose homeostasis. Administration of exogenous insulin is the most common management method for T1D, but this requires lifelong reliance on insulin injections and invasive blood glucose monitoring. Replacement therapies with beta cells are being developed as an advanced curative treatment for T1D. Unfortunately, this approach is limited by the lack of donated pancreatic tissue, the difficulties in beta cell isolation and viability maintenance, the longevity of the transplanted cells in vivo, and consequently high costs. Emerging approaches to address these limitations are under intensive investigations, including the production of insulin-producing beta cells from various stem cells, and the development of bioengineered devices including nanotechnologies for improving islet transplantation efficacy without the need for recipients taking toxic anti-rejection drugs. These emerging approaches present promising prospects, while the challenges with the new techniques need to be tackled for ultimately clinical treatment of T1D. This review discussed the benefits and limitations of the cell-based therapies for beta cell replacement as potential curative treatment for T1D, and the applications of bioengineered devices including nanotechnology to overcome the challenges associated with beta cell transplantation.

In vitro evaluation of a hybrid drug-delivery nanosystem for fibrosis prevention in cell therapy for Type 1 diabetes.

Background: Implantation of insulin-secreting cells has been trialed as a treatment for Type 1 diabetes mellitus; however, the host immunogenic response limits their effectiveness. Methodology: The authors developed a core-shell nanostructure of upconversion nanoparticle-mesoporous silica for controlled local delivery of an immunomodulatory agent, MCC950, using near-infrared light and validated it in in vitro models of fibrosis. Results: The individual components of the nanosystem did not affect the proliferation of insulin-secreting cells, unlike fibroblast proliferation (p < 0.01). The nanosystem is effective at releasing MCC950 and preventing fibroblast differentiation (p < 0.01), inflammation (IL-6 expression; p < 0.05) and monocyte adhesion (p < 0.01). Conclusion: This MCC950-loaded nanomedicine system could be used in the future together with insulin-secreting cell implants to increase their longevity as a curative treatment for Type 1 diabetes mellitus.

This work describes a new drug-delivery system that can release an immunomodulatory drug in a controlled manner and prevent fibrosis, which is part of the immune response when a foreign body is implanted. This system can be particularly useful for insulin-secreting cell implants, used to replace multiple daily injections of insulin and improve the quality of life of people with Type 1 diabetes mellitus. By preventing the immune response that leads to fibrosis, the longevity of these cellular implants can be extended without the need for frequent replacement procedures. This innovative nanosystem can release the required amount of immunomodulatory drug, which could be stimulated with the use of special light, hence showing the ability for local and extended delivery. This type of system has the potential to reduce the side effects associated with oral daily administration of immunomodulatory agents in people with Type 1 diabetes mellitus.

The Impact of Helminth Infection on the Incidence of Metabolic Syndrome: A Systematic Review and Meta-Analysis.

Background: There are a growing number of publications that report an absence of inflammatory based disease among populations that are endemic to parasitic worms (helminths) demonstrating the ability of these parasites to potentially regulate human immune responses. The aim of this systematic review and meta-analysis was to determine the impact of helminth infection on metabolic outcomes in human populations. Methods: Using PRISMA guidelines, six databases were searched for studies published up to August 2020. Random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals using the Review Manager Software version 5.4.1. Results: Fourteen studies were included in the review. Fasting blood glucose was significantly lower in persons with infection (MD -0.22, 95% CI -0.40- -0.04, P=0.02), HbA1c levels were lower, although not significantly, and prevalence of the metabolic syndrome (P=0.001) and type 2 diabetes was lower (OR 1.03, 95% CI 0.34-3.09, P<0.0001). Infection was negatively associated with type 2 diabetes when comparing person with diabetes to the group without diabetes (OR 0.44, 95% CI 0.29-0.67, P=0.0001). Conclusions: While infection with helminths was generally associated with improved metabolic function, there were notable differences in efficacy between parasite species. Based on the data assessed, live infection with S. mansoni resulted in the most significant positive changes to metabolic outcomes. Systematic Review Registration: Website: PROSPERO Identified: CRD42021227619.

Non-viral gene delivery utilizing RALA modulates sFlt-1 secretion, important for preeclampsia.

Background: Overexpression of sFlt-1 or modulation of FKBPL, key antiangiogenic proteins, are important in the pathogenesis of preeclampsia. Methods: A newly developed nonviral gene-delivery system, RALA, capable of overexpressing sFlt-1 (e15a isoform) was delivered in vivo in transgenic haploinsufficient (Fkbpl+/-) mice. RALA was also used in vitro to deliver human Flt1 (hFlt1) in trophoblast cells. Results: Serum stable and nontoxic RALA/DNA-based nanoparticles induced an increase in sFlt-1 protein levels in the blood and total protein in the urine; the effect was more pronounced in Fkbpl+/- mice. In vitro, RALA-hFlt nanoparticles significantly reduced secretion of sFlt-1 in trophoblast cells. Conclusion: The RALA-based genetic nanodelivery system can be safely and effectively applied to emulate preeclampsia-like features or reduce sFlt-1 levels in vitro.

Lay abstract In this study, the investigators utilized a safe and effective approach to modulate an important circulating protein in pregnancy, sFlt-1, associated with the pregnancy complication, preeclampsia. Preeclampsia is a complex and multifactorial disease and a leading cause of death in pregnancy with no current effective treatment strategies. This is likely due to a lack of reliable preclinical models that replicate human disease. The authors demonstrate the feasibility of a new preeclampsia-like model based on the dysfunction of two key vascular proteins, sFlt-1 and FKBPL (an important protein involved in the development of new blood vessels), that could be utilized in the future for testing and development of new treatments targeting these important mechanisms in preeclampsia.

Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia.

BACKGROUND: Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. METHODS: The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. RESULTS: The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein  expression  (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06). CONCLUSIONS: The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.

Associations between School Food Environments, Body Mass Index and Dietary Intakes among Regional School Students in Victoria, Australia: A Cross-Sectional Study.

(1) Background: Childhood overweight and obesity is a significant and preventable problem worldwide. School environments have been suggested to be plausible targets for interventions seeking to improve the quality of children's dietary intake. The objective of this study was to determine the extent to which the current characteristics of the school food environment were associated with primary school students' dietary intake and Body Mass Index (BMI) z scores in a representative sample in regional Victoria. (2) Methods: This study included 53 schools, comprising a sample of 3,496 students in year levels two (aged 7-8 years), four (9-10 years) and six (11-12 years). Year four and six students completed dietary questionnaires. Principals from each school completed a survey on school food environment characteristics. Mixed-effects logistic regression was used to assess the relationship between students' dietary intake and school food environment scores, controlling for confounders such as socio-economic status, school size and sex. Food environment scores were also analysed against the odds of being healthy weight (defined as normal BMI z score). (3) Results: Mixed associations were found for the relationship between students' dietary intake and food environment scores. Meeting the guidelines for vegetable intake was not associated with food environment scores, but students were more likely (OR: 1.68 95% CI 1.26, 2.24) to meet the guidelines if they attended a large school (>300 enrolments) and were female (OR: 1.28 95% CI: 1.02, 1.59). Healthy weight was not associated with school food environment scores, but being a healthy weight was significantly associated with less disadvantage (OR: 1.24 95% CI 1.05, 1.45). Conclusion: In this study, the measured characteristics of school food environments did not have strong associations with dietary intakes or BMI among students.