Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling.

The occurrence of cognitive disturbances upon CNS inflammation or infection has been correlated with increased levels of the cytokine tumor necrosis factor-α (TNFα). To date, however, no specific mechanism via which this cytokine could alter cognitive circuits has been demonstrated. Here, we show that local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses. Astrocytic TNFR1 signaling is necessary for the hippocampal synaptic alteration and contextual learning-memory impairment observed in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS). This process may contribute to the pathogenesis of cognitive disturbances in MS, as well as in other CNS conditions accompanied by inflammatory states or infections.

Household material hardship and distress among parents of children with advanced cancer: A report from the PediQUEST Response trial.

BACKGROUND: The prevalence and characteristics of household material hardship (HMH) in families of children with advanced cancer and its association with parent distress are unknown and herein described. METHODS: Parents of children aged ≥2 years with advanced cancer at five cancer centers completed baseline surveys as part of the PediQUEST Response trial. HMH (housing, energy, and food) was operationalized as binary (≥1 HMH domains), ordinal (zero, one, or two or more HMH domains), and housing based (none, nonhousing [food and/or energy], only housing, or housing + other). Associations between HMH and parent distress measured by the State-Trait Anxiety Inventory-State and the 10-item Center for Epidemiologic Studies Depression Scale were estimated via linear models adjusting for confounders. RESULTS: Among 150 parents, 41% reported ≥1 HMH (housing, 28% [only housing, 8%; housing + other, 20%]; energy, 19%; food, 27%). HMH was more prevalent among Hispanic, other non-White race, Spanish-speaking, and single parents and those with lower education (associate degree or less) or who were uninsured/Medicaid-only insured. Parents endorsing HMH reported higher anxiety (mean difference [MD], 9.2 [95% CI, 3.7-14.7]) and depression (MD, 4.1 [95% CI, 1.7-6.5]) scores compared to those without HMH. Distress increased with the number of hardships, particularly housing insecurity. Specifically, parents experiencing housing hardship, alone or combined, reported higher distress (housing only: anxiety: MD, 10.2 [95% CI, 1.8-18.5]; depression: MD, 4.9 [95% CI, 1.3-8.6]; housing + other HMH: anxiety: MD, 12.0 [95% CI, 5.2-18.9]; depression: MD, 4.8 [95% CI, 1.8-7.8]). CONCLUSIONS: HMH is highly prevalent in pediatric advanced cancer, especially among historically marginalized families. Future research should investigate whether interventions targeting HMH, particularly housing stabilization efforts, can mitigate parent distress. PLAIN LANGUAGE SUMMARY: In our cohort of parents of children with advanced cancer, household material hardship (HMH) was highly prevalent and significantly associated with higher parent distress. Housing hardship was the primary driver of this association. Families of children with advanced cancer may benefit from systematic HMH screening as well as targeted HMH interventions, especially stabilizing housing.

Understanding weight status and dietary intakes among Australian school children by remoteness: a cross-sectional study.

OBJECTIVE: To determine whether primary school children's weight status and dietary behaviours vary by remoteness as defined by the Australian Modified Monash Model (MMM). DESIGN: A cross-sectional study design was used to conduct secondary analysis of baseline data from primary school students participating in a community-based childhood obesity trial. Logistic mixed models estimated associations between remoteness, measured weight status and self-reported dietary intake. SETTING: Twelve regional and rural Local Government Areas in North-East Victoria, Australia. PARTICIPANTS: Data were collected from 2456 grade 4 (approximately 9-10 years) and grade 6 (approximately 11-12 years) students. RESULTS: The final sample included students living in regional centres (17·4 %), large rural towns (25·6 %), medium rural towns (15·1 %) and small rural towns (41·9 %). Weight status did not vary by remoteness. Compared to children in regional centres, those in small rural towns were more likely to meet fruit consumption guidelines (OR: 1·75, 95 % CI (1·24, 2·47)) and had higher odds of consuming fewer takeaway meals (OR: 1·37, 95 % CI (1·08, 1·74)) and unhealthy snacks (OR = 1·58, 95 % CI (1·15, 2·16)). CONCLUSIONS: Living further from regional centres was associated with some healthier self-reported dietary behaviours. This study improves understanding of how dietary behaviours may differ across remoteness levels and highlights that public health initiatives may need to take into account heterogeneity across communities.

Use of PDSA Cycles to Increase Aspiration Risk and Swallow Screening Documentation in the Hospitalized General Medical Patient Care Population.

BACKGROUND: Aspiration, while hospitalized, can lead to increases in length of stay and health care costs. Nurses must identify patients at risk of aspiration early to initiate appropriate precautions. LOCAL PROBLEM: An increase in-hospital patient aspirations at a Midwestern hospital prompted a review of events, which identified opportunities to improve identification of patients' risk factors and completion of the bedside swallow screening. METHODS: Interventions were identified via a causal factor tree analysis and an impact-effort grid then deployed using the Plan-Do-Study-Act (PDSA) methodology. INTERVENTIONS: Interventions deployed included game based-learning, a unit-based champion, and the use of visual cues to identify patients at risk for aspiration. RESULTS: After 3 PDSA cycles, documentation of patients' aspiration risk factors on admission increased by 40%, with a 51.3% increase in bedside swallow screening results. CONCLUSION: Iterative PDSA cycles successfully tested staff engagement strategies to improve aspiration risk and swallow screening documentation compliance.

Amyloid-Beta Mediates Homeostatic Synaptic Plasticity.

The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP-/- mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-ß and not by APPsα, and it is neither observed in APP+/+ tissue treated with ß- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased amyloid-ß levels.

Survival of brain tumour patients with epilepsy.

Pro-tumorigenic electrochemical synapses between neurons and brain tumour cells in preclinical studies suggest unfavourable effects of epilepsy on patient survival. We investigated associations of epilepsy and survival in three cohorts of brain tumour patients (meningioma, glioblastoma and brain metastases). Cohorts were segregated into three groups for comparative analyses: (i) no epilepsy; (ii) epilepsy without status epilepticus; and (iii) status epilepticus. Status epilepticus was considered a surrogate of extensive neuronal hyperexcitability. The main outcome was progression-free survival (meningioma) and overall survival (glioblastoma and brain metastases), adjusted for established prognostic factors and onset of epilepsy by time-dependent multivariate Cox modelling. The primary analysis population comprised 1792 patients (742 meningioma, 249 glioblastoma, 801 brain metastases). Epilepsy was associated with favourable prognostic factors. However, on multivariate analyses, status epilepticus was associated with inferior overall survival of patients with glioblastoma [status epilepticus versus no epilepsy multivariate hazard ratio (HR) 3.72, confidence interval (CI) 1.78-7.76, P < 0.001] and brain metastases (status epilepticus versus no epilepsy HR 2.30, CI 1.10-4.79, P = 0.026). Among brain metastases patients, but not among patients with meningioma or glioblastoma, epilepsy was similarly associated with inferior overall survival (epilepsy versus no epilepsy HR 2.16, CI 1.60-2.93, P < 0.001). We conclude that epilepsy may convey inferior survival of patients with malignant brain tumours.

Maternal mental health and infant emotional reactivity: a 20-year two-cohort study of preconception and perinatal exposures.

BACKGROUND: Maternal mental health during pregnancy and postpartum predicts later emotional and behavioural problems in children. Even though most perinatal mental health problems begin before pregnancy, the consequences of preconception maternal mental health for children's early emotional development have not been prospectively studied. METHODS: We used data from two prospective Australian intergenerational cohorts, with 756 women assessed repeatedly for mental health problems before pregnancy between age 13 and 29 years, and during pregnancy and at 1 year postpartum for 1231 subsequent pregnancies. Offspring infant emotional reactivity, an early indicator of differential sensitivity denoting increased risk of emotional problems under adversity, was assessed at 1 year postpartum. RESULTS: Thirty-seven percent of infants born to mothers with persistent preconception mental health problems were categorised as high in emotional reactivity, compared to 23% born to mothers without preconception history (adjusted OR 2.1, 95% CI 1.4-3.1). Ante- and postnatal maternal depressive symptoms were similarly associated with infant emotional reactivity, but these perinatal associations reduced somewhat after adjustment for prior exposure. Causal mediation analysis further showed that 88% of the preconception risk was a direct effect, not mediated by perinatal exposure. CONCLUSIONS: Maternal preconception mental health problems predict infant emotional reactivity, independently of maternal perinatal mental health; while associations between perinatal depressive symptoms and infant reactivity are partially explained by prior exposure. Findings suggest that processes shaping early vulnerability for later mental disorders arise well before conception. There is an emerging case for expanding developmental theories and trialling preventive interventions in the years before pregnancy.

Synaptopodin regulates denervation-induced homeostatic synaptic plasticity.

Synaptopodin (SP) is a marker and essential component of the spine apparatus (SA), an enigmatic cellular organelle composed of stacked smooth endoplasmic reticulum that has been linked to synaptic plasticity. However, SP/SA-mediated synaptic plasticity remains incompletely understood. To study the role of SP/SA in homeostatic synaptic plasticity we here used denervation-induced synaptic scaling of mouse dentate granule cells as a model system. This form of plasticity is of considerable interest in the context of neurological diseases that are associated with the loss of neurons and subsequent denervation of connected brain regions. In entorhino-hippocampal slice cultures prepared from SP-deficient mice, which lack the SA, a compensatory increase in excitatory synaptic strength was not observed following partial deafferentation. In line with this finding, prolonged blockade of sodium channels with tetrodotoxin induced homeostatic synaptic scaling in wild-type, but not SP-deficient, slice cultures. By crossing SP-deficient mice with a newly generated transgenic mouse strain that expresses GFP-tagged SP under the control of the Thy1.2 promoter, the ability of dentate granule cells to form the SA and to homeostatically strengthen excitatory synapses was rescued. Interestingly, homeostatic synaptic strengthening was accompanied by a compensatory increase in SP cluster size/stability and SA stack number, suggesting that activity-dependent SP/SA remodeling could be part of a negative feedback mechanism that aims at adjusting the strength of excitatory synapses to persisting changes in network activity. Thus, our results disclose an important role for SP/SA in homeostatic synaptic plasticity.

Centripetal integration of past events in hippocampal astrocytes regulated by locus coeruleus.

An essential feature of neurons is their ability to centrally integrate information from their dendrites. The activity of astrocytes, in contrast, has been described as mostly uncoordinated across cellular compartments without clear central integration. Here we report conditional integration of calcium signals in astrocytic distal processes at their soma. In the hippocampus of adult mice of both sexes, we found that global astrocytic activity, as recorded with population calcium imaging, reflected past neuronal and behavioral events on a timescale of seconds. Salient past events, indicated by pupil dilations, facilitated the propagation of calcium signals from distal processes to the soma. Centripetal propagation to the soma was reproduced by optogenetic activation of the locus coeruleus, a key regulator of arousal, and reduced by pharmacological inhibition of α1-adrenergic receptors. Together, our results suggest that astrocytes are computational units of the brain that slowly and conditionally integrate calcium signals upon behaviorally relevant events.

Prevalence of toddlers meeting 24-hour movement guidelines and associations with parental perceptions and practices.

OBJECTIVES: Whether toddlers (1-2 years) meet 24-hour Movement Guidelines and how parental practices and perceptions are related to compliance are uncertain. This study: a) estimated the proportion of toddlers meeting individual and combined movement guidelines; and b) examined associations between parental perceptions/practices and toddlers' compliance with movement guidelines. DESIGN: Cross-sectional study. METHODS: Australian parents self-reported their parenting practices/perceptions (routines, co-participation, restrictions, concerns, knowledge) and toddlers' movement behaviours in the baseline assessment of Let's Grow (n=1145), a randomised controlled trial. The World Health Organization's Guidelines on Physical Activity, Sedentary Behaviour, and Sleep for children under 5 years were used to estimate the prevalence of compliance with individual and combined movement guidelines. Logistic models assessed cross-sectional associations. RESULTS: The prevalence of meeting guidelines was 30.9% for screen time, 82.3% for sleep, 81.6% for physical activity, 20.1% for combined, and 2.1% meeting none. Parents' knowledge of the guidelines, fewer concerns and more favourable restrictions concerning movement behaviours were associated with greater compliance with individual and combined movement guidelines. Routines for screen time and for combined behaviours were associated with adherence to their respective guidelines. Less co-participation in screen time and more co-participation in physical activity were associated with greater compliance with the relevant guidelines. CONCLUSIONS: Given only 20% of toddlers met all guidelines, strategies early in life to establish healthy movement behaviours, especially screen time, are needed. Future studies could target the parental practices/perceptions identified in this study to support toddlers with optimal sleep and physical activity and reduced screen time.

NMDA-receptor inhibition increases spine stability of denervated mouse dentate granule cells and accelerates spine density recovery following entorhinal denervation in vitro.

Neuronal networks are reorganized following brain injury. At the structural level this is in part reflected by changes in the spine turnover of the denervated neurons. Using the entorhinal cortex lesion in vitro model, we recently showed that mouse dentate granule cells respond to entorhinal denervation with coordinated functional and structural changes: During the early phase after denervation spine density decreases, while excitatory synaptic strength increases in a homeostatic manner. At later stages spine density increases again, and synaptic strength decreases back to baseline. In the present study, we have addressed the question of whether the denervation-induced homeostatic strengthening of excitatory synapses could not only be a result of the deafferentation, but could, in turn, affect the dynamics of the spine reorganization process following entorhinal denervation in vitro. Using a computational approach, time-lapse imaging of neurons in organotypic slice cultures prepared from Thy1-GFP mice, and patch-clamp recordings we provide experimental evidence which suggests that the strengthening of surviving synapses can lead to the destabilization of spines formed after denervation. This activity-dependent pruning of newly formed spines requires the activation of N-methyl-d-aspartate receptors (NMDA-Rs), since pharmacological inhibition of NMDA-Rs resulted in a stabilization of spines and in an accelerated spine density recovery after denervation. Thus, NMDA-R inhibitors may restore the ability of neurons to form new stable synaptic contacts under conditions of denervation-induced homeostatic synaptic up-scaling, which may contribute to their beneficial effect seen in the context of some neurological diseases.

Potential Mediating Roles of Children's Health-Related Quality of Life and Weight-Related Behaviors in the Relationship Between Socio-Educational Advantage and Weight Status.

Background: Socioeconomic status is inversely associated with weight status in developed countries. Underlying mechanisms are still to be clarified. Our aim was to determine if weight-related behaviors and health-related quality of life (HRQoL) mediate the relationship between socio-educational advantage and weight status in Australian children 9 to 13 years of age. Methods: Secondary analysis of data collected by two cluster randomized trials (2019 wave). We measured children's (n = 3978) height, weight, diet, physical activity, sedentary behavior, and HRQoL. Socio-.educational advantage was assessed at school level using the Index of Community Socio-Educational Advantage (ICSEA). A counterfactual framework was used to explore potential mediators in the relationship between socio-educational disadvantage and (1) overweight/obesity and (2) BMI z-score (BMIz). Results: Low socio-educational advantage was associated with increased overweight/obesity and BMIz. The overweight/obesity association was mediated by sedentary behavior (natural indirect effect as a proportion of total, 7.5%) sugar-sweetened beverage (SSB) consumption (12.7%), physical functioning (11.9%), psychosocial health (10.9%), school (6.8%) and social functioning (15.6%), and total HRQoL score (13.8%). The ICSEA-BMIz relationship was mediated by sedentary behavior (5.7%), sleep duration (4.1%), SSB (10.6%), physical functioning (9.9%), psychosocial health (9.1%), school (5.5%) and social (13.7%) functioning, and total HRQoL score (11.7%). Conclusion: Victorian Children with low socio-educational advantage were more likely to be living with overweight or obesity. This relationship was mediated by children's sedentary behavior, SSB consumption, and HRQoL. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12616000980437 (registered July 26, 2016, retrospectively registered) and ACTRN12618001986268 (registered December 11, 2018, prospectively registered). https://www.anzctr.org.au/Trial/Registration.

Four-Year Accelerometry Outcomes from a Cluster Randomized Whole of Systems Trial of Prevention Strategies for Childhood Obesity.

Background: We investigated the effect of the Whole of Systems Trial of Prevention Strategies for Childhood Obesity (WHO STOPS) intervention on children's objectively measured physical activity and sedentary time (ST). Methods: We conducted a cluster randomized controlled trial with children in grades 4 (∼9-10 years old) and grade 6 (∼11-12 years old) from 10 communities in the Great South Coast region of Victoria, Australia. Communities were randomly allocated (1:1) to receive the WHO STOPS intervention in 2015. WHO STOPS was a whole of community systems-based approach to preventing childhood obesity. Outcome data were collected using a repeat cross-sectional design in 2015, 2017, and 2019. Children were asked to wear a hip-mounted accelerometer for 7 days. Age-specific Axis 1 activity counts were converted into duration (minutes/day) spent engaged in moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and ST. Linear mixed regression models were fitted to estimate the effects of the intervention on the three activity outcomes across the study period. Results: Analyses were based on valid accelerometer data from 1406 children (intervention n = 745; control n = 661). Results for MVPA, LPA, and ST were nonsignificant. Between 2015 and 2017, there were positive, but nonsignificant, changes in mean MVPA favoring intervention boys [3.7 minutes/day; 95% confidence interval (CI): -5.7 to 13.1] and girls (5.5 minutes/day; 95% CI: -1.5 to 12.6). By 2019, these effects had attenuated. Conclusions: Although the WHO STOPS intervention did not significantly change activity levels, the magnitudes of the effects on MVPA suggest that further research with whole-of-community interventions in larger samples would be worthwhile. Clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR.org.au) identifier 12616000980437.

Onset of Postural Instability in Parkinson's Disease Depends on Age rather than Disease Duration.

Background: Postural instability and falls are considered a major factor of impaired quality of life in patients with advanced Parkinson's disease (PD). The knowledge of the time at which postural instability occurs will help to provide the evidence required to introduce fall-prevention strategies at the right time in PD. Objective: To investigate whether postural instability of patients with different age at disease onset is associated with age or with disease duration of PD. Methods: Patients diagnosed with sporadic PD between 1991 and 2017 and postural instability (according to the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, item 3.12 postural instability) were included, with strict inclusion criteria including regular follow-ups, agreement on data use, and exclusion of comorbidities affecting the free stand. Results: Applying these strict inclusion criteria, we included 106 patients. Those younger than 50 years at PD onset took significantly longer to develop postural instability (n = 23 patients, median: 18.4 years) compared with patients with later onset of PD (50-70 years, n = 66, median: 14.2 years, p < 0.001; and >70 years, n = 17, median: 5.7 years, p < 0.001, Kruskal-Wallis test followed by Dunn's multiple comparisons test). There was no association between total MDS-UPDRS III (as a measure of motor symptom severity) at onset of postural instability. Conclusions: In PD, postural instability is primarily associated with the age of the patient and not with disease duration.

Relationship between "Blue Space" Proximity and Children's Weight Status, Health Behaviors, and Health-Related Quality of Life among a Sample of Regional Victorian Primary School Children.

Background: Access to green space (e.g., parks and gardens) has been associated with child health and wellbeing, whereas blue space (e.g., coasts, lakes, and rivers) is understudied. Our aim was to determine whether proximity to the coast was associated with primary school children's weight status, modifiable health-related behaviors, and health-related quality of life (HRQoL). Methods: Exploratory cross-sectional analysis of baseline data from the Whole of Systems Trial of Prevention Strategies for Childhood Obesity (WHOSTOPS) study, to estimate gender-specific differences in weight and behaviors across four bands of distance from the coast (<5 km, 5 to <25 km, 25 to <50 km, ≥50 km). Linear and logistic models, with robust standard errors, adjusted for school year level, area-level socioeconomic position and rurality, and allowing for distance by gender interaction were fitted on data from 1216 children (aged 8.5-13 years). Main outcomes were weight status (categorical), physical activity (PA) (categorical), and global HRQoL score (continuous). Results: Compared with girls living in towns ≥50 km from the coast, those living within 5 km had lower odds for overweight/obesity [odds ratio (OR) = 0.50; 95% confidence interval (CI): 0.37-0.67] and higher mean moderate-to-vigorous PA minutes (accelerometry) (ß = 8.7; 95% CI: 2.0-15.5) and global HRQoL (ß = 3.2; 95% CI: 1.4-5.0). Compared with boys living ≥50 km from the coast, those living within 5 km had higher odds of meeting self-reported PA guidelines (≥60 minutes/day) for ≥5 days (OR = 2.33; 95% CI: 1.75-3.10), and higher mean global HRQoL scores (ß = 5.6; 95% CI: 1.9-9.3). Conclusions: Living close to the coast was associated with some favorable health outcomes and behaviors, which differed between girls and boys.

Reflexive Evidence and Systems interventions to Prevention Obesity and Non-communicable Disease (RESPOND): protocol and baseline outcomes for a stepped-wedge cluster-randomised prevention trial.

INTRODUCTION: Systems science methodologies have been used in attempts to address the complex and dynamic causes of childhood obesity with varied results. This paper presents a protocol for the Reflexive Evidence and Systems interventions to Prevention Obesity and Non-communicable Disease (RESPOND) trial. RESPOND represents a significant advance on previous approaches by identifying and operationalising a clear systems methodology and building skills and knowledge in the design and implementation of this approach among community stakeholders. METHODS AND ANALYSIS: RESPOND is a 4-year cluster-randomised stepped-wedge trial in 10 local government areas in Victoria, Australia. The intervention comprises four stages: catalyse and set up, monitoring, community engagement and implementation. The trial will be evaluated for individuals, community settings and context, cost-effectiveness, and systems and implementation processes. Individual-level data including weight status, diet and activity behaviours will be collected every 2 years from school children in grades 2, 4 and 6 using an opt-out consent process. Community-level data will include knowledge and engagement, collaboration networks, economic costs and shifts in mental models aligned with systems training. Baseline prevalence data were collected between March and June 2019 among >3700 children from 91 primary schools. ETHICS AND DISSEMINATION: Ethics approval: Deakin University Human Research Ethics Committee (HREC 2018-381) or Deakin University's Faculty of Health Ethics Advisory Committee (HEAG-H_2019-1; HEAG-H 37_2019; HEAG-H 173_2018; HEAG-H 12_2019); Victorian Government Department of Education and Training (2019_003943); Catholic Archdiocese of Melbourne (Catholic Education Melbourne, 2019-0872) and Diocese of Sandhurst (24 May 2019). The results of RESPOND, including primary and secondary outcomes, and emerging studies developed throughout the intervention, will be published in the academic literature, presented at national and international conferences, community newsletters, newspapers, infographics and relevant social media. TRIAL REGISTRATION NUMBER: ACTRN12618001986268p.

Healthy weight, health behaviours and quality of life among Aboriginal children living in regional Victoria.

OBJECTIVE: To report the prevalence of healthy weight and related behaviours among Victorian Aboriginal and non-Aboriginal children and explore associations between these factors and health-related quality of life (HRQoL). METHODS: Analysis of cross-sectional data from two cluster randomised controlled trials using logistic and linear mixed models. The sample included Aboriginal (n=303) and non-Aboriginal (n=3,026) children aged 8-13 years. RESULTS: More than two-thirds of Aboriginal children met guidelines for fruit (75.9%), sweetened drinks (66.7%), sleep (73.1%), screen time (67.7%) and objectively measured physical activity (83.6%); and 79.1% reported consuming take-away foods less than once per week. Aboriginal children were more likely to meet vegetable consumption guidelines (OR=1.42, 95%CI: 1.05, 1.93), but less likely to have a healthy weight (OR=0.66, 95%CI: 0.52, 0.85) than non-Aboriginal children. Mean HRQoL scores were significantly higher among non-Aboriginal children and both Aboriginal and non-Aboriginal children meeting health guidelines. CONCLUSIONS: Most Aboriginal children in this study met guidelines for fruit, physical activity, screen time and sleep, and those meeting these guidelines had significantly higher HRQoL. IMPLICATIONS FOR PUBLIC HEALTH: Promoting nutrition, physical activity and sleep is likely to benefit all children. Aboriginal community-controlled organisations can use these data to design culturally-specific programs that may improve disparities in healthy weight and HRQoL.

Mediation effects that emulate a target randomised trial: Simulation-based evaluation of ill-defined interventions on multiple mediators.

Many epidemiological questions concern potential interventions to alter the pathways presumed to mediate an association. For example, we consider a study that investigates the benefit of interventions in young adulthood for ameliorating the poorer mid-life psychosocial outcomes of adolescent self-harmers relative to their healthy peers. Two methodological challenges arise. First, mediation methods have hitherto mostly focused on the elusive task of discovering pathways, rather than on the evaluation of mediator interventions. Second, the complexity of such questions is invariably such that there are no well-defined mediator interventions (i.e. actual treatments, programs, etc.) for which data exist on the relevant populations, outcomes and time-spans of interest. Instead, researchers must rely on exposure (non-intervention) data, that is, on mediator measures such as depression symptoms for which the actual interventions that one might implement to alter them are not well defined. We propose a novel framework that addresses these challenges by defining mediation effects that map to a target trial of hypothetical interventions targeting multiple mediators for which we simulate the effects. Specifically, we specify a target trial addressing three policy-relevant questions, regarding the impacts of hypothetical interventions that would shift the mediators' distributions (separately under various interdependence assumptions, jointly or sequentially) to user-specified distributions that can be emulated with the observed data. We then define novel interventional effects that map to this trial, simulating shifts by setting mediators to random draws from those distributions. We show that estimation using a g-computation method is possible under an expanded set of causal assumptions relative to inference with well-defined interventions, which reflects the lower level of evidence that is expected with ill-defined interventions. Application to the self-harm example in the Victorian Adolescent Health Cohort Study illustrates the value of our proposal for informing the design and evaluation of actual interventions in the future.

Young-adult compared to adolescent onset of regular cannabis use: A 20-year prospective cohort study of later consequences.

INTRODUCTION: This paper compares consequences of cannabis use initiated after high school with those of cannabis initiation in adolescence, with estimates of the proportion of adverse consequences accounted for by adult-onset and adolescent-onset cannabis users. METHODS: A state-representative sample in Victoria, Australia (n = 1792) participated in a 10-wave longitudinal study and was followed from age 15 to 35 years. Exposure variable: Patterns of cannabis use across 20 years. Outcomes at age 35: Alcohol use, smoking, illicit drug use, relationship status, financial hardship, depression, anxiety and employment status. RESULTS: Substantially more participants (13.6%) initiated regular use after high school (young-adult onset) than in adolescence (7.7%, adolescent onset). By the mid-30s, both young-adult and adolescent-onset regular users were more likely than minimal/non-users (63.5%) to have used other illicit drugs (odds ratio [OR] > 20.4), be a high-risk alcohol drinker (OR > 3.7), smoked daily (OR > 7.2) and less likely to be in relationships (OR < 0.4). As the prevalence of the young-adult-onset group was nearly double of the adolescent-onset group, it accounted for a higher proportion of adverse consequences than the adolescent-onset group. DISCUSSION AND CONCLUSIONS: Cannabis users who began regular use in their teens had poorer later life outcomes than non-using peers. The larger group who began regular cannabis use after leaving high school accounted for most cannabis-related harms in adulthood. Given the legalisation of cannabis use in an increasing number of jurisdictions, we should increasingly expect harms from cannabis use to lie in those commencing use in young adulthood.