Mental health-related service and medicine use among a cohort of urban Aboriginal children and young people: Data linkage study.

OBJECTIVE: The objective was to describe mental health service and psychotropic medicine use among a cohort of Aboriginal young people and quantify their relation to sociodemographic, family and health factors. METHODS: In a prospective cohort study with data linkage, 892 Aboriginal children aged 0-17 years living in urban and regional areas of New South Wales, Australia, were included. We assessed mental health-related service use, paediatric service use and psychotropic medicine dispensing claims covered by the Australian Government Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme from July 2012 to June 2017. RESULTS: Most children (71%) did not have a record of mental health service or psychotropic medication use. 18.7% had ⩾1 mental health-related service claim; 26.7% had ⩾1 paediatric service claim; and 20.3% had ⩾1 psychotropic medicine dispensing claim. General practitioner services were the most accessed mental health-related service (17.4%) and 12.7% had been dispensed attention-deficit hyperactivity disorder medicines. Child characteristics associated with treatment included emotional and behavioural problems (prevalence ratio: 1.97, 95% confidence interval = [1.46, 2.64] for mental health services; prevalence ratio: 2.87, 95% confidence interval = [2.07, 3.96] for medicines) and risky behaviour (prevalence ratio: 1.56, 95% confidence interval = [1.12, 2.16] for mental health services; prevalence ratio: 2.28, 95% confidence interval = [1.54, 3.37] for medicines). Parent-related factors included chronic illness (prevalence ratio: 1.42, 95% confidence interval = [1.03, 1.95] for mental health services; prevalence ratio: 2.00, 95% confidence interval = [1.49, 2.69] for medicines) and functional limitations (prevalence ratio: 1.61, 95% confidence interval = [1.16, 2.24] for mental health services; prevalence ratio: 1.86, 95% confidence interval = [1.34, 2.59] for medicines). CONCLUSIONS: Most Aboriginal children and young people did not have claims for mental health services or medicines. Aboriginal children with emotional and behavioural problems, or parents with health problems were more likely to have mental health service or medicine claims.

Revisiting laminin and extracellular matrix remodeling in metastatic squamous cell carcinoma: What have we learned after more than four decades of research?

Patients with squamous cell carcinoma (SCC) have significantly lower survival upon the development of distant metastases. The extracellular matrix (ECM) is a consistent yet dynamic influence on the metastatic capacity of SCCs. The ECM encompasses a milieu of structural proteins, signaling molecules, and enzymes. Just over 40 years ago, the fibrous ECM glycoprotein laminin was identified. Roughly four decades of research have revealed a pivotal role of laminins in metastasis. However, trends in ECM alterations in some cancers have been applied broadly to all metastatic diseases, despite evidence that these characteristics vary by tumor type. We will summarize how laminins influence the SCC metastatic process exclusively. Enhanced laminin protein deposition occurs at the invasive edge of SCC tumors, which correlates with elevated levels of laminin-binding ß1 integrins on SCC cells, increased MMP-3 presence, worse prognosis, and lymphatic dissemination. Although these findings are significant, gaps in knowledge of the formation of a premetastatic niche, the processes of intra- and extravasation, and the contributions of the ECM to SCC metastatic cell dormancy persist. Bridging these gaps requires novel in vitro systems and animal models that reproduce tumor-stromal interactions and spontaneous metastasis seen in the clinic. These advances will allow accurate assessment of laminins to predict responders to transforming growth factor-ß inhibitors and immunotherapy, as well as potential combinatorial therapies with the standard of care. Such clinical interventions may drastically improve quality of life and patient survival by explicitly targeting SCC metastasis.

Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell-like properties and phosphoinositide 3-kinase inhibitor insensitivity.

Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a "precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells ± PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance.

Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models.

BACKGROUND: Immunocompetent animal models are required to study tumor-host interactions, immunotherapy, and immunotherapeutic combinations, however the currently available immunocompetent lung cancer models have substantial limitations. While orthotopic models potentially help fill this gap, the utility of these models has been limited by the very small number of murine lung cancer cell lines capable of forming orthotopic tumors in immunocompetent C57BL/6 hosts. METHODS: Primary lung tumors with specific genetic alterations were created in C57BL/6 background mice. These tumors were then passaged through other animals to increase tumorigenicity and select for the ability to grow in a non-self animal. Once tumors demonstrated growth in a non-self host, cell lines were established. Successful cell lines were evaluated for the ability to produce orthotopic lung tumors in immunocompetent hosts. RESULTS: We produced six murine lung cancer lines capable of orthotopic lung tumor formation in immunocompetent C57BL/6 animals. These lines demonstrate the expected genetic alterations based on their primary tumor genetics. CONCLUSIONS: These novel cell lines will be useful for evaluating tumor-host interactions, the impact of specific oncogenic alterations on the tumor microenvironment, and immunotherapeutic approaches. This method of generating murine lines capable of orthotopic growth can likely be applied to other tumors and will broaden the applicability of pre-clinical testing of immunotherapeutic treatment regimens.

Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15+ Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

Lessons learned from SMAD4 loss in squamous cell carcinomas.

SMAD4 is a potent tumor suppressor and a central mediator of the TGFß signaling pathway. SMAD4 genetic loss is frequent in squamous cell carcinomas (SCCs). Reports of SMAD4 expression in SCCs vary significantly possibly due to inter-tumor heterogeneity or technical reasons. SMAD4 loss is an initiation event for SCCs. In tumor epithelial cells, SMAD4 loss causes increased proliferation, decreased apoptosis, and "Brca-like" genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in the expansion of cancer stem cells. Epithelial SMAD4 loss causes overexpression of TGFß that is released into the tumor microenvironment and contributes to SCC progression through proinflammatory and immune evasive mechanisms. SMAD4 loss, while not a direct therapeutic target, is associated with multiple targetable pathways that require further therapeutic studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied for its values in prognostic and therapeutic predictions. Such information will potentially guide future biomarker-driven clinical trial designs and improve SCC patient outcomes.

mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.

Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism.

Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis.

BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear. METHODS: Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays. RESULTS: We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility. CONCLUSION: These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.

Psychosocial factors associated with the mental health of indigenous children living in high income countries: a systematic review.

BACKGROUND: Indigenous children living in high income countries have a consistently high prevalence of mental health problems. We aimed to identify psychosocial risk and protective factors for mental health in this setting. METHODS: A systematic review of studies published between 1996 and 2016 that quantitatively evaluated the association between psychosocial variables and mental health among Indigenous children living in high income countries was conducted. Psychosocial variables were grouped into commonly occurring domains. Individual studies were judged to provide evidence for an association between a domain and either good mental health, poor mental health, or a negligible or inconsistent association. The overall quality of evidence across all studies for each domain was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: Forty-seven papers were eligible (mainland US 30 [64%], Canada 8 [17%], Australia 7 [15%], Hawaii 4 [9%]), including 58,218 participants aged 4-20 years. Most papers were cross-sectional (39, 83%) and measured negative mental health outcomes (41, 87%). Children's negative cohesion with their families and the presence of adverse events appeared the most reliable predictors of increased negative mental health outcomes. Children's substance use, experiences of discrimination, comorbid internalising symptoms, and negative parental behaviour also provided evidence of associations with negative mental health outcomes. Positive family and peer relationships, high self-esteem and optimism were associated with increased positive mental health outcomes. CONCLUSIONS: Quantitative research investigating Indigenous children's mental health is largely cross-sectional and focused upon negative outcomes. Indigenous children living in high income countries share many of the same risk and protective factors associated with mental health. The evidence linking children's familial environment, psychological traits, substance use and experiences of discrimination with mental health outcomes highlights key targets for more concerted efforts to develop initiatives to improve the mental health of Indigenous children.

Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.

Health professional and community perspectives on reducing barriers to accessing specialist health care in metropolitan Aboriginal communities: A semi-structured interview study.

AIM: To describe the perspectives of health professionals and communities on an innovative health service delivery project, Hearing EAr health and Language Services (HEALS). HEALS was a government funded initiative to improve access to specialist ear, nose and throat and speech pathology services for Aboriginal families living in metropolitan areas. METHODS: Semi-structured interviews were conducted with 21 health-care professionals (clinicians, health service managers and Aboriginal health workers) and 16 care givers of children who participated in HEALS. Interviews took place at four Aboriginal Community Controlled Health Services in metropolitan Australia or by telephone. Interview transcripts were analysed thematically. RESULTS: We identified five major themes: leveraging partnerships (building on collaborative research, integrating and expanding existing networks, engaging the Aboriginal community), intrinsic and extrinsic motivation (seizing opportunities for altruism, empowered by collegiality, taking pride in achievements), removing common barriers (circumventing waiting times and cost, providing culturally appropriate services, raising awareness), strategic service delivery (proactive service delivery, encouraging flexibility and innovation, offering convenience and support), and service shortfall (pressured timeframes, desire for more sustainable services). CONCLUSION: HEALS facilitated improved health-care access by providing prompt, no-cost services that were strategically targeted to address multiple barriers. HEALS' model of care was built upon strong pre-existing research partnerships, the knowledge and support of five Aboriginal Community Controlled Health Services, and the willingness and motivation of local health-care professionals to help Close the Gap. HEALS highlights the importance of tailoring health services to the needs of Aboriginal families, and provides a framework for other health service delivery initiatives.

Parental views on otitis media: systematic review of qualitative studies.

UNLABELLED: This study aims to describe parental experiences and perspectives of caring for a child with otitis media. We conducted a systematic review of qualitative studies on parental perspectives on caring for a child with otitis media. We searched electronic databases to July 2015. Seventeen studies involving 284 participants from six countries were included. We identified seven themes: diminishing competency (guilt over failure to identify symptoms, helpless and despairing, fear of complications, disempowered and dismissed); disrupting life schedules (disturbing sleep, interfering with work, burden on family); social isolation (stigma and judgement, sick consciousness); threatening normal development (delaying growth milestones, impairing interpersonal skills, impeding education); taking ownership (recognising symptoms, diagnostic closure, working the system, protecting against physical trauma, contingency planning); valuing support (needing respite, depending on community, clinician validation); and cherishing health (relief with treatment success, inspiring resilience). CONCLUSION: The additional medical responsibilities and anxieties of parents caring for a child with otitis media, often discounted by clinicians, can be disempowering and disruptive. Chronicity can raise doubt about treatment efficacy and parental competency, and fears regarding their child's development. Care that fosters parental confidence and addresses their concerns about the child's development may improve treatment outcomes for children with otitis media. WHAT IS KNOWN: • Otitis media is a leading cause of conductive hearing loss in children. • Parental perception of the treatment burden of otitis media can potentially affect their confidence and ability to care for their child. What is New: • We identified five themes to reflect parental perspectives: diminishing competency, disrupting life schedules, social isolation, threatening normal development, taking ownership, valuing support, and cherishing health. • Parents may perceive caring for a child with otitis media as disempowering and disruptive and with reoccurrence doubt treatment efficacy and their parental competency and develop fears regarding their child's development.

Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.

Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.

Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers.

INTRODUCTION: Human epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25% of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear. METHODS: We utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers. RESULTS: Treatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110α, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110α and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110α and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing. CONCLUSIONS: These studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing.

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium.

ErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosine kinases. We report here that ErbB3 loss in the luminal mammary epithelium of mice impaired Akt and MAPK signaling and reduced luminal cell proliferation and survival. ERBB3 mRNA expression levels were highest in luminal mammary populations and lowest in basal cell/stem cell populations. ErbB3 loss in mammary epithelial cells shifted gene expression patterns toward a mammary basal cell/stem cell signature. ErbB3 depletion-induced gene expression changes were rescued upon activation of Akt and MAPK signaling. Interestingly, proliferation and expansion of the mammary basal epithelium (BE) occurred upon ErbB3 targeting in the luminal epithelium, but not upon its targeting in the BE. Multiple cytokines, including interleukin 6, were induced upon ErbB3 depletion in luminal epithelium cells, which increased growth of BE cells. Taken together, these results suggest that ErbB3 regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine- and paracrine-signaling mechanisms.

Effectiveness of the Go4Fun program: a comparison of face-to-face and digital delivery.

Objectives and importance of study: Despite an increasing trend in digitally delivered health promotion programs, evidence of their effectiveness compared to face-to-face approaches is limited. Go4Fun is a 10-week, scaled-up healthy lifestyle program in New South Wales (NSW) for children 7-13 years who are above a healthy weight and their families, delivered either face-to-face or digitally. We compared the impact of Standard Go4Fun (face-to-face) and Go4Fun Online (digital) on children's weight and health behaviour outcomes and whether attendance levels influenced outcomes. STUDY TYPE: Pre-post study. METHODS: We conducted a secondary analysis of Go4Fun cohort data from 1893 face-to-face and 1283 digital participants (January 2018 to May 2022). Outcomes of interest were body mass index z-score (zBMI), physical activity, sedentary behaviour, and fruit, vegetable, sugary drink and takeaway food consumption. RESULTS: A higher proportion of Standard Go4Fun children lived in major cities, in areas of greatest disadvantage and spoke a language other than English at home than in Go4Fun Online. Children in both Standard Go4Fun and Go4Fun Online demonstrated improvements in all outcomes; however, children in Go4Fun Online showed significantly larger improvements. On average, digital participants had a reduction in zBMI of 0.11 more than the reduction seen in face-to-face participants (95% Confidence Interval [CI] -0.12, -0.09), increased the days/week of moderate-to-vigorous-physical-activity by 30% more (95% CI 24%, 36%), were more likely to eat ≥ 2 serves of fruit/day (compared to < 2, Odds Ratio [OR] 1.85; 95% CI: 1.36, 2.52) or eat ≥ 3 serves of vegetables/day (compared to < 3, OR 1.96; CI: 1.58, 2.42). Across both modes, with each additional session attended, the odds of eating ≥ 3 serves of vegetables/day increased by 10% (95% CI 1.02, 1.19). There were no significant differences for other health outcomes. CONCLUSIONS: Our evaluation demonstrated that both face-to-face and digital program delivery helped children above a healthy weight to improve their weight and health behaviour outcomes. Go4Fun Online achieved significantly greater improvements in outcomes, which is encouraging for the future of digital interventions. Participation in Standard Go4Fun by more children with obesity from disadvantaged areas and non-English speaking backgrounds suggests that ongoing delivery of both modes of Go4Fun could facilitate program reach among all children above a healthy weight.

Socioeconomic disadvantage and engagement with digital contact tracing for COVID-19 in Western Sydney: A secondary analysis of surveillance data.

OBJECTIVE: COVID-19 outcomes were highly inequitably distributed in Australia and worldwide. The digitalisation of public health interventions offers resource-efficiency and increased capacity for pandemic responses, but risks excluding the elderly and disadvantaged, reinforcing existing inequalities. Despite this, there has been little evaluation of the determinants of uptake of digital contact tracing. This paper describes the use of digital contact tracing for COVID-19 in a population in metropolitan Sydney and the determinants of engagement in this population. METHODS: Routinely collected surveillance data for residents of Western Sydney Local Health District, returning a positive SARS-CoV-2 result between 1st August 2021 and 12th February 2022, were extracted including responses to a digital contact tracing questionnaire. Individual records were linked to area-level socioeconomic indices of disadvantage. Descriptive analyses explored characteristics of non-responders and geospatial variation. Logistic regression was undertaken to evaluate the effect of age, sex and socioeconomic disadvantage on the odds of response. RESULTS: Of the 133 055 individuals included, 130 645 (98%) were issued a digital contact tracing questionnaire, and 106 432 (81%) responded. Odds of responding were lower in males (odds ratio: 0.79), individuals aged 80+ (odds ratio: 0.17) and the most disadvantaged communities (odds ratio: 0.32). CONCLUSIONS: Digital data collection for contact tracing was a scalable and efficient tool in the context of the Western Sydney Local Health District COVID-19 response. However, older people and individuals in disadvantaged communities were less likely to engage. IMPLICATIONS FOR PUBLIC HEALTH: Responses to future pandemics should leverage the resource-efficiency of digital interventions but should avoid compounding existing health inequalities.

Aboriginal Young People's Experiences of Accessibility in Mental Health Services in Two Regions of New South Wales, Australia.

This article assesses the accessibility of mainstream mental health services (MMHSs) in two regions of New South Wales (NSW), Australia, based on experiences and perspectives of Aboriginal young people aged 16-25. Semi-structured yarning interviews were conducted with thirteen Aboriginal young people in two regions of NSW. Thematic analysis was undertaken by all research team members to identify major themes from the data and conceptual connections between them. The identified themes from individual analysis and coding were triangulated during several analysis meetings to finalise the key themes and findings. Aboriginal young people had no experience of engaging with early-intervention MMHSs. MMHSs were identified as inaccessible, with most participants unaware that MMHSs existed in each region. Due to MMHSs being inaccessible, many Aboriginal young people presented to emergency departments (EDs) during a crisis. Aboriginal Community Controlled Health Services (ACCHSs) were identified as key providers of accessible, culturally meaningful, and effective social and emotional wellbeing (SEWB) service support for Aboriginal young people in NSW. If health and wellbeing outcomes are to improve for Aboriginal young people in NSW, MMHSs must increase accessibility for Aboriginal young people requiring SEWB support.

Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. METHODS: Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. RESULTS: In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. CONCLUSIONS: Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.

IL-22RA2 Is a SMAD7 Target Mediating the Alleviation of Dermatitis and Psoriatic Phenotypes in Mice.

Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study sought to identify the mechanisms and developmental therapeutics for these diseases using genetic models and pharmacological approaches. We found that mice overexpressing SMAD7 in keratinocytes but not mice overexpressing the N-terminal domain of SMAD7 (i.e., N-SMAD7) were resistant to imiquimod-induced T helper 1/17- and T helper 2-type inflammation. We generated a Tat-PYC-SMAD7 (truncated SMAD7 protein encompassing C-terminal SMAD7 and PY motif fused with cell-penetrating Tat peptide). Topically applied Tat-PYC-SMAD7 to inflamed skin entered cells upon contact and attenuated imiquimod-, 2,4-dinitrofluorobenzene-, and tape-stripping-induced inflammation. RNA-sequencing analyses of mouse skin exposed to these insults showed that in addition to inhibiting TGFß/NF-κB, SMAD7 blunted IL-22/signal transducer and activator of transcription 3 activation and associated pathogenesis, which is due to SMAD7 transcriptionally upregulating IL-22 antagonist IL-22RA2. Mechanistically, SMAD7 facilitated nuclear translocation and DNA binding of C/EBPß to IL22RA2 promoter for IL22RA2 transactivation. Consistent with the observations in mice mentioned earlier, transcript levels of IL22RA2 were increased in human atopic dermatitis and psoriasis lesions with clinical remission. Our study identified the anti-inflammation functional domain of SMAD7 and suggests the mechanism and feasibility for developing SMAD7-based biologics as a topical therapy for skin inflammatory disorders.