Cultural and linguistic disparities in dental utilisation in New South Wales, Australia.

OBJECTIVE: To examine the patterns and predictors of dental utilisation in culturally and linguistically diverse (CALD) and non-CALD groups in New South Wales. DESIGN: Secondary analysis of the 2013 and 2015 NSW Adult Population Health Survey (n=24,707). MAIN OUTCOME: Dental utilisation, defined as a dental visit within the last 12 months. CALD groups were defined using country of birth and language. Andersen's theoretical model was used. Chi-square test and multivariate logistic regression analysis adjusted for potential confounding. Sample weights adjusted for sampling design. RESULTS: Most (69%) of the population were Australian born; 20% spoke a language other than English at home. Dental utilisation was 58.9% and 63.9% for CALD and non-CALD groups respectively. The foreign-born non-English speaking group had the highest level of education (60%) but lower levels of dental utilisation (OR:0.81, CI 0.69-0.94) than all groups. Australian born non-English speakers had similar levels of dental utilisation to the reference group (OR:1.27, CI 0.99-1.63). CONCLUSION: There are significant disparities in dental care utilisation among CALD populations. Foreign born, non-English speaking CALD migrants, and people experiencing socioeconomic disadvantage, are at greatest risk of inadequate dental utilisation. Furthermore, the combination of predisposing factors, language and cultural barriers compound disparities in oral health care utilisation. This data highlights the need for oral healthcare services that are sensitive to population needs, to reduce disparities among CALD communities residing in NSW.

Profiling cytotoxic microRNAs in pediatric and adult glioblastoma cells by high-content screening, identification, and validation of miR-1300.

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application.

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-ß-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

Moving from advocacy to activism? The fourth WHO global forum on human resources for health and implications for dentistry.

As we debate shaping the future oral health workforce within the UK, to meet the needs of current and future populations, it is helpful to take an international perspective on this very important issue. Globally, there is a strong recognition that human resources for health (HRH) are fundamentally important to deliver effective care, accessible to all people. This paper reviews the outcome of the fourth global forum held by the World Health Organisation (WHO) in Dublin which highlighted the urgency for action. The main objectives of the forum were to advance the implementation of (i) the WHO Global Strategy on HRH 2030 and (ii) the United Nations High-Level Commission's Health Employment and Economic Growth recommendations. From an oral health perspective, the global burden of oral disease remains huge with untreated dental caries, periodontal disease and tooth loss ranking among the most prevalent conditions worldwide. Major considerations are how dental education, practice delivery and/or oral health systems as a whole could and should innovate to accommodate the growing needs of the population. As dental professionals, it also becomes necessary for us to engage and play a proactive role in this change process. Due to growing differences between population needs and available services, it is necessary for oral health personnel to work more closely with the broader health workforce so as to identify solutions that are in the best interests of the patients and populations at large.

Indigenous cultural competence: A dental faculty curriculum review.

BACKGROUND: Indigenous Australians have more than double the rate of poor oral health than their non-Indigenous counterparts. Cultural competence of dental and oral health practitioners is fundamental to health care and quality of life in addressing health disparities in minority cultural groups in Australia. Higher education curricula reviews have identified the need for institutions to incorporate Indigenous culture and knowledge more widely into the curricula to improve educational outcomes for Indigenous Australians and to increase cultural competence for all students. AIM: The aim of this research was to provide a baseline analysis of Indigenous cultural competence curricula practices to ascertain changes required within Faculty of Dentistry programmes at the University of Sydney to enable students to become more culturally competent upon graduation. METHODS: Staff and students of the Doctor of Dental Medicine and Bachelor of Oral Health programmes at the Faculty of Dentistry, University of Sydney participated in an online survey. Quantitative analysis of the survey data was conducted using integrated research electronic data capture survey tools, with open-ended questions being coded to common responses for those questions. RESULTS: A total of 69 staff (71%) and 191 students (51%) participated in the online survey. The majority of participants perceived there was limited Indigenous content in the curriculum. Most participants reported that Indigenous curriculum was integrated into several units of study. The main pedagogical method for curriculum delivery was lectures, followed by case studies and group discussions. CONCLUSION: Although some Indigenous content exists in dental faculty curriculum, in-depth investigation is required to develop a comprehensive, evidenced-based Indigenous cultural competence teaching framework, for integration into Doctor of Dental Medicine and Bachelor of Oral Health curricula.

Simultaneous 68Ga DOTATATE Positron Emission Tomography/Magnetic Resonance Imaging in Meningioma Target Contouring: Feasibility and Impact Upon Interobserver Variability Versus Positron Emission Tomography/Computed Tomography and Computed Tomography/Magnetic Resonance Imaging.

AIMS: The increasing use of highly conformal radiation techniques to treat meningioma confers a greater need for accurate targeting. Several groups have shown that positron emission tomography/computed tomography (PET/CT) information alters meningioma targets contoured by single observers, but whether this translates into improved accuracy has not been defined. As magnetic resonance imaging (MRI) is the cornerstone of meningioma target contouring, simultaneous PET/MRI may be superior to PET/CT. We assessed whether 68Ga DOTATATE PET imaging (from PET/CT and PET/MRI) reduced interobserver variability (IOV) in meningioma target volume contouring. MATERIALS AND METHODS: Ten patients with meningioma underwent simultaneous 68Ga DOTATATE PET/MRI followed by PET/CT. They were selected as it was anticipated that target volume definition in their cases would be particularly challenging. Three radiation oncologists contoured target volumes according to an agreed protocol: gross tumour volume (GTV) and clinical target volume (CTV) on CT/MRI alone, CT/MRI+PET(CT) and CT/MRI+PET(MRI). GTV/CTV Kouwenhoven conformity levels (KCL), regions of contour variation and qualitative differences between PET(CT) and PET(MRI) were evaluated. RESULTS: There was substantial IOV in contouring. GTV mean KCL: CT/MRI 0.34, CT/MRI+PET(CT) 0.38, CT/MRI+PET(MRI) 0.39 (P = 0.06). CTV mean KCL: CT/MRI 0.31, CT/MRI+PET(CT) 0.35, CT/MRI+PET(MRI) 0.35 (P = 0.04 for all groups; P > 0.05 for individual pairs). One observer consistently contoured largest and one smallest. Observers rarely decreased volumes in relation to PET. Most IOV occurred in bone followed by dural tail, postoperative bed and venous sinuses. Tumour edges were qualitatively clearer on PET(MRI) versus PET(CT), but this did not affect contouring. CONCLUSION: IOV in contouring challenging meningioma cases was large and only slightly improved with the addition of 68Ga DOTATATE PET. Simultaneous PET/MRI for meningioma contouring is feasible, but did not improve IOV versus PET/CT. Whether volumes can be safely reduced according to PET requires evaluation.

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer.

The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.

New vaccine administration practice recommendations from the Canadian Immunization Guide.

BACKGROUND: The Canadian Immunization Guide (CIG) is published online by the Public Health Agency of Canada and summarizes guidance on vaccines for human use into a single resource. Chapters are reviewed and updated on a regular basis. Vaccine administration is a critical part of any immunization program. Recently, the CIG chapter on vaccine administration practices was updated. OBJECTIVE: To provide highlights of recent changes to the Vaccine Administration Practices chapter of the CIG. APPROACH: Vaccine-specific guidance in the CIG is based on National Committee on Immunization (NACI) and Committee to Advise on Tropical Medicine and Travel (CATMAT) recommendations as well as new recommendations developed by the CIG Working Group members and NACI Secretariat technical staff. New recommendations are based on a review of the literature, including systematic reviews when available, a review of guidance provided by other National Immunization Technical Advisory Groups and expert opinion. The revisions are approved by the Working Group chair, as well as NACI. RESULTS: Highlights of new recommendations include the following: vaccine providers should adhere to jurisdictional or organizational policies and procedures regarding combining the contents of multi-dose vials; clinical judgement should be used when selecting needle length for intramuscular injections that takes into account the vaccine recipient's weight, gender and age; filter needles are not recommended for vaccine administration as they may filter out active ingredients such as adjuvants; an injection site other than in an area where lymphatic drainage may be impaired should be considered; there is no evidence or theoretical rationale for avoiding injection through a tattoo or superficial birthmark; and immunization pain management strategies have now been developed for all ages. CONCLUSION: Recommendations in vaccine administration practices have recently been changed in some important ways. The Public Health Agency of Canada is committed to providing information on immunization in an easily accessible, reader-friendly format for healthcare providers and policy-makers.

Myeloid translocation genes differentially regulate colorectal cancer programs.

Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1-/- mice have progressive depletion of all intestinal secretory cells, and Mtg16-/- mice have a decrease in goblet cells. Furthermore, both Mtgr1-/- and Mtg16-/- mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc1638/+-dependent intestinal tumorigenesis. Mtgr1-/- mice, but not Mtg16-/- mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of chromatin immunoprecipitation sequencing data sets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1-/- tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context-dependent effect on intestinal tumorigenesis.

Job satisfaction among 'migrant dentists' in Australia: implications for dentist migration and workforce policy.

BACKGROUND: Migrants occupy a significant proportion of the dental workforce in Australia. The objectives of this study were to assess the level of job satisfaction of employed migrant dentists in Australia, and to examine the association between various migrant dentist characteristics and job satisfaction. METHODS: All migrant dentists resident in Australia were surveyed using a five-point Likert scale that measured specific aspects of job, career and satisfaction with area and type of practice. RESULTS: A total of 1022 migrant dentists responded to this study; 974 (95.4%) were employed. Responses for all scales were skewed towards strongly agree (scores ≥4). The overall scale varied by age group, marital status, years since arrival to Australia and specialist qualification (chi-square, p < 0.05). In a multivariate logistic regression model, there was a trend towards greater satisfaction amongst older age groups. Dentists who migrated through the examination pathway (mainly from low- and middle-income countries) had a lower probability of being satisfied with the area and type of practice (OR = 0.71; 0.51-0.98), compared with direct-entry migrant dentists (from high-income countries). CONCLUSIONS: The high level of job satisfaction of migrant dentists reflects well on their work-related experiences in Australia. The study offers policy suggestions towards support for younger dentists and examination pathway migrants, so they have appropriate skills and standards to fit the Australian health care environment.

Development of life story experience (LSE) scales for migrant dentists in Australia: a sequential qualitative-quantitative study.

INTRODUCTION: The integration of qualitative and quantitative approaches introduces new avenues to bridge strengths, and address weaknesses of both methods. OBJECTIVE: To develop measure(s) for migrant dentist experiences in Australia through a mixed methods approach. METHODS: The sequential qualitative-quantitative design involved first the harvesting of data items from qualitative study, followed by a national survey of migrant dentists in Australia. Statements representing unique experiences in migrant dentists' life stories were deployed the survey questionnaire, using a five-point Likert scale. Factor analysis was used to examine component factors. RESULTS: Eighty-two statements from 51 participants were harvested from the qualitative analysis. A total of 1,022 of 1,977 migrant dentists (response rate 54.5%) returned completed questionnaires. Factor analysis supported an initial eight-factor solution; further scale development and reliability analysis led to five scales with a final list of 38 life story experience (LSE) items. Three scales were based on home country events: health system and general lifestyle concerns (LSE1; 10 items), society and culture (LSE4; 4 items) and career development (LSE5; 4 items). Two scales included migrant experiences in Australia: appreciation towards Australian way of life (LSE2; 13 items) and settlement concerns (LSE3; 7 items). CONCLUSION: The five life story experience scales provided necessary conceptual clarity and empirical grounding to explore migrant dentist experiences in Australia. Being based on original migrant dentist narrations, these scales have the potential to offer in-depth insights for policy makers and support future research on dentist migration.

Isolation and characterization of a virus infecting the freshwater algae Chrysochromulina parva.

Water samples from Lake Ontario, Canada were tested for lytic activity against the freshwater haptophyte algae Chrysochromulina parva. A filterable lytic agent was isolated and identified as a virus via transmission electron microscopy and molecular methods. The virus, CpV-BQ1, is icosahedral, ca. 145nm in diameter, assembled within the cytoplasm, and has a genome size of ca. 485kb. Sequences obtained through PCR-amplification of DNA polymerase (polB) genes clustered among sequences from the family Phycodnaviridae, whereas major capsid protein (MCP) sequences clustered among sequences from either the Phycodnaviridae or Mimiviridae. Based on quantitative molecular assays, C. parva׳s abundance in Lake Ontario was relatively stable, yet CpV-BQ1׳s abundance was variable suggesting complex virus-host dynamics. This study demonstrates that CpV-BQ1 is a member of the proposed order Megavirales with characteristics of both phycodnaviruses and mimiviruses indicating that, in addition to its complex ecological dynamics, it also has a complex evolutionary history.

The importance of workforce surveillance, research evidence and political advocacy in the context of international migration of dentists.

The international migration of dentists is an issue of pressing significance that poses several complex policy challenges. Policy-making is mainly constrained by the lack of workforce surveillance, research evidence and political advocacy - all three are required to work together, yet with different purposes. We first discuss the inconsistencies in migrant dentist surveillance in major country-level governmental systems (immigration departments, dentist registration authorities and workforce agencies). We argue that the limitations in surveillance collections affect independent research and in turn scholarly contributions to dental workforce policy. Differences in country-level surveillance collections also hinder valid cross-country comparisons on migrant dentist data, impeding global policy efforts. Due to these limitations, advocacy, or the political process to influence health policy, suffers, but is integral to future challenges on dentist migration. Country-level advocacy is best targeted at improving migrant dentist surveillance systems. Research interest can be invigorated through targeted funding allocations for migration research and by improving the availability of dentist surveillance data for research purposes. At the global level, the WHOs global code of practice for international recruitment of health personnel (a crucial advocacy tool) needs to be strengthened. Global organisations such as the FDI World Dental Federation have an important role to play in advocating for improved migrant dentist workforce surveillance and research evidence, especially in low- and middle-income countries.

Cell migration in paediatric glioma; characterisation and potential therapeutic targeting.

BACKGROUND: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. METHODS: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. RESULTS: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. CONCLUSIONS: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours.

Benchmarking of a treatment planning system for spot scanning proton therapy: comparison and analysis of robustness to setup errors of photon IMRT and proton SFUD treatment plans of base of skull meningioma.

PURPOSE: Base of skull meningioma can be treated with both intensity modulated radiation therapy (IMRT) and spot scanned proton therapy (PT). One of the main benefits of PT is better sparing of organs at risk, but due to the physical and dosimetric characteristics of protons, spot scanned PT can be more sensitive to the uncertainties encountered in the treatment process compared with photon treatment. Therefore, robustness analysis should be part of a comprehensive comparison between these two treatment methods in order to quantify and understand the sensitivity of the treatment techniques to uncertainties. The aim of this work was to benchmark a spot scanning treatment planning system for planning of base of skull meningioma and to compare the created plans and analyze their robustness to setup errors against the IMRT technique. METHODS: Plans were produced for three base of skull meningioma cases: IMRT planned with a commercial TPS [Monaco (Elekta AB, Sweden)]; single field uniform dose (SFUD) spot scanning PT produced with an in-house TPS (PSI-plan); and SFUD spot scanning PT plan created with a commercial TPS [XiO (Elekta AB, Sweden)]. A tool for evaluating robustness to random setup errors was created and, for each plan, both a dosimetric evaluation and a robustness analysis to setup errors were performed. RESULTS: It was possible to create clinically acceptable treatment plans for spot scanning proton therapy of meningioma with a commercially available TPS. However, since each treatment planning system uses different methods, this comparison showed different dosimetric results as well as different sensitivities to setup uncertainties. The results confirmed the necessity of an analysis tool for assessing plan robustness to provide a fair comparison of photon and proton plans. CONCLUSIONS: Robustness analysis is a critical part of plan evaluation when comparing IMRT plans with spot scanned proton therapy plans.

Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma.

DNA methylation plays an important role in cancer biology and methylation events are important prognostic and predictive markers in many tumor types. We have used methylation-specific multiplex ligation-dependent probe amplification to survey the methylation status of MGMT and 25 tumor suppressor genes in 73 glioblastoma cases. The data obtained was correlated with overall survival and response to treatment. The study revealed that methylation of promoter regions in TP73 (seven patients), THBS1 (eight patients) and PYCARD (nine patients) was associated with improved outcome, whereas GATA5 (21 patients) and WT1 (24 patients) promoter methylation were associated with poor outcome. In patients treated with temozolomide and radiation MGMT and PYCARD promoter methylation events remained associated with improved survival whereas GATA5 was associated with a poor outcome. The identification of GATA5 promoter methylation in glioblastoma has not previously been reported. Furthermore, a cumulative methylation score separated patients into survival groups better than any single methylation event. In conclusion, we have identified specific methylation events associated with patient outcome and treatment response in glioblastoma, and these may be of functional and predictive/prognostic significance. This study therefore provides novel candidates and approaches for future prospective validation.