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Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo, this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing.
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Carcinogênese , Carcinógenos , Animais , Humanos , Carcinógenos/toxicidade , Testes de Carcinogenicidade/métodos , Testes de Mutagenicidade/métodos , Dano ao DNA , Técnicas In VitroRESUMO
Genetic toxicity testing assesses the potential of compounds to cause DNA damage. There are many genetic toxicology screening assays designed to assess the DNA damaging potential of chemicals in early drug development aiding the identification of promising drugs that have low-risk potential for causing genetic damage contributing to cancer risk in humans. Despite this, in vitro tests generate a high number of misleading positives, the consequences of which can lead to unnecessary animal testing and/or the abandonment of promising drug candidates. Understanding chemical Mode of Action (MoA) is vital to identifying the true genotoxic potential of substances and, therefore, the risk translation into the clinic. Here we demonstrate a simple, robust protocol for staining fixed, human-lymphoblast p53 proficient TK6 cells with antibodies against É£H2AX, p53 and pH3S28 along with DRAQ5™ DNA staining that enables analysis of un-lysed cells via microscopy approaches such as imaging flow cytometry. Here, we used the Cytek® Amnis® ImageStream®X Mk II which provides a high-throughput acquisition platform with the sensitivity of flow cytometry and spatial morphological information associated with microscopy. Using the ImageStream manufacturer's software (IDEAS® 6.2), a masking strategy was developed to automatically detect and quantify micronucleus events (MN) and characterise biomarker populations. The gating strategy developed enables the generation of a template capable of automatically batch processing data files quantifying cell-cycle, MN, É£H2AX, p53 and pH3 populations simultaneously. In this way, we demonstrate how a multiplex system enables DNA damage assessment alongside MN identification using un-lysed cells on the imaging flow cytometry platform. As a proof-of-concept, we use the tool chemicals carbendazim and methyl methanesulphonate (MMS) to demonstrate the assay's ability to correctly identify clastogenic or aneugenic MoAs using the biomarker profiles established.
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Biomarcadores , Dano ao DNA , Citometria de Fluxo , Testes para Micronúcleos , Proteína Supressora de Tumor p53 , Testes para Micronúcleos/métodos , Humanos , Citometria de Fluxo/métodos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Biomarcadores/metabolismo , Linhagem Celular , Mutagênicos/toxicidade , Citometria por Imagem/métodos , Histonas/metabolismoRESUMO
The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.
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Contaminação de Medicamentos , Mutação , Nitrosaminas , Animais , Medição de Risco , Nitrosaminas/toxicidade , Mutação/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Camundongos , Relação Dose-Resposta a Droga , Dimetilnitrosamina/toxicidade , Animais Geneticamente Modificados , Dietilnitrosamina/toxicidade , Humanos , Carcinógenos/toxicidade , Ratos , MasculinoRESUMO
We examined participation rates, engagement, and weight-loss outcomes of comparison group participants in a diabetes prevention trial who enrolled in a digitally delivered diabetes prevention program (ie, an active intervention) after the original trial ended. We evaluated these outcomes by using the Wilcoxon signed-rank test and 1-sample z test. We found a high participation rate (73%) among comparison group participants and comparable weight-loss outcomes at 12 months (6.8 lb) after initiating participation in the active intervention relative to intervention group participants during the original trial. Findings support providing evidence-based interventions for comparison or control group participants post-trial. Findings also support examining the cost-effectiveness of post-trial interventions, regardless of the limitations of acquiring post-trial data on weight in an uncontrolled setting.
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Diabetes Mellitus Tipo 2 , Redução de Peso , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/prevenção & controleRESUMO
Phenylketonuria (PKU) is a rare metabolic condition characterised by an inability to metabolise phenylalanine (Phe), found in many foods. When pregnant with PKU, women must adhere to a strict low-Phe diet. If they do not, foetal abnormalities or pregnancy loss can occur. Pregnancies are therefore closely clinically monitored and dominated by dietary management, leaving little "space" for women's emotional experience. This article explores the emotional impact of PKU during pregnancy and how this effects pre-natal bonding. Based on interviews with six women with PKU, conducted whilst they were pregnant, this article explores their unusual and previously undocumented experience. Image-making during interviews allowed women to uncover aspects of their experience that might otherwise have remained hidden. Interpretative phenomenological analysis of the transcripts and images generated five themes summarising the women's experiences. Some themes reiterated findings from previous studies, for example, the huge cognitive burden associated with PKU pregnancies and the importance of both expert and informal support to successful pregnancy management. However, new understanding also emerged, including rich description of the emotional load of these pregnancies and strategies that women use to manage this. Anxiety about baby safety was central to their experiences, and the effect of this on pre-natal bonding was explored. This article calls for increased formal and informal support for women with the emotional aspects of their PKU pregnancies, for example, the creation of "attachment-aware" services that support women with their anxiety, promoting strong pre-natal attachment and subsequently protecting maternal and infant mental health throughout pregnancy and beyond.
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BACKGROUND: Malaria is a parasitic disease caused by various species of the blood parasite Plasmodium; of all the parasitic diseases, malaria has the highest prevalence and mortality with an estimated 247 million cases and 619,000 deaths recorded worldwide as of 2021. Malaria causes febrile illness with several changes in blood cell parameters. Some of these changes include leucopenia, thrombocytopenia, and anaemia. If these changes could be correlated with the degree of parasitaemia, it can serve as a guide to physicians when treating malaria. This study was therefore aimed at correlating haematological parameters with levels of parasitaemia during malaria infection. METHODS: The study was a cross-sectional study involving 89 malaria positive patients. About 5 ml of blood was collected from each participant who gave his or her informed consent to partake in the study. A full blood count was performed on their samples to determine their haematological parameters using a haematology auto-analyzer. A parasite count was also performed via microscopy to determine the degree of parasitaemia. The data obtained from the study was entered into a database and statistically analysed using Statistical Package for Social Sciences (SPSS) version 23 and Microsoft Excel 2016. RESULTS: The study comprised of 89 participants out of which 35 were males and 54 were females with the mean age of 26.15 years. Secondary education participants were the highest with quaternary education the lowest. The highest parasite count recorded was 398,174 parasites/µl of blood, lowest count was 101 with the average being 32,942.32584. There was also a significant positive Pearson's correlation between total WBC and parasitaemia and with the WBC differentials, neutrophils, lymphocytes and monocytes had positive correlations while eosinophils and basophils had negative correlations. Furthermore, platelets, total RBC's, haemoglobin, MCH, MCHC and Hct all showed negative correlations. Linear regression also showed a linear relationship between parasite density and the various haematological parameters. CONCLUSION: The linear relationship (correlation) between WBC and MCH were the only significant ones at 95% and 99% confidence interval, respectively based on a two-tail t-test. Also, based on the regression analysis, the changes caused by WBC and PLT were the only significant changes at 95% confidence level in a two-tailed t-test.
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Hematologia , Malária , Trombocitopenia , Humanos , Feminino , Masculino , Adulto , Pacientes Ambulatoriais , Estudos Transversais , Malária/epidemiologia , Parasitemia/epidemiologiaRESUMO
BACKGROUND: COVID-19 outbreaks have disproportionately affected Residential Aged Care Facilities (RACFs) around the world, with devastating impacts for residents and their families. Many factors such as community prevalence, facility layout, and infection control practices have been linked to resident outcomes. At present, there are no scoring systems designed to quantify these factors and assess their level of association with resident attack rates and mortality rates. METHODS: We constructed a novel Infection Prevention and Control (IPC) scoring system to quantify facility layout, ability to cohort residents, and IPC practices in RACFs. We conducted a retrospective observational cohort study of COVID-19 outbreaks, applying our IPC scoring system to all COVID-19 outbreaks occurring in RACFs in Sydney Local Health District during the Delta and Omicron waves of the COVID-19 pandemic in New South Wales, Australia. RESULTS: Twenty-six COVID-19 outbreaks in 23 facilities in the Delta wave, and 84 outbreaks in 53 facilities in the Omicron wave were included in the study. A linear Generalised Estimating Equation model was fitted to the Omicron data. Higher IPC scores were associated with higher attack rates and mortality rates. Facilities with IPC scores greater than 75.0% had attack rates 19.6% higher [95% CI: 6.4%-32.8%] and mortality rates 1.7% higher [95% CI: 0.6%-2.7%] than facilities with an IPC score of less than 60.0%. CONCLUSIONS: The results of this study suggest the utility of the IPC scoring system for identifying facilities at greater risk of adverse outcomes from COVID-19 outbreaks. While further validation and replication of accuracy is required, the IPC scoring system could be used and adapted to improve planning, policy, and resource allocation for future outbreaks.
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COVID-19 , Humanos , Idoso , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Estudos Retrospectivos , Austrália/epidemiologia , Surtos de Doenças/prevenção & controleRESUMO
N-nitrosamines (NAs) are a class of compounds of which many, especially of the small dialkyl type, are indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, which are traditionally expressed on a mass basis. Here we demonstrate that AIs that are not experimentally derived for a specific compound, but via statistical extrapolation or read across to a suitable analog, should be expressed on a molar scale or corrected for the target substance's molecular weight. This would account for the mechanistic aspect that each nitroso group can, at maximum, account for a single DNA mutation and the number of molecules per mass unit is proportional to the molecular weight (MW). In this regard we have re-calculated the EMA 18 ng/day regulatory default AI for unknown nitrosamines on a molar scale and propose a revised default AI of 163 pmol/day. In addition, we provide MW-corrected AIs for those nitrosamine drug substance related impurities (NDSRIs) for which EMA has pre-assigned AIs by read-across. Regulatory acceptance of this fundamental scientific tenet would allow one to derive nitrosamine limits for NDSRIs that both meet the health-protection goals and are technically feasible.
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Nitrosaminas , Peso Molecular , Mutagênicos/toxicidade , Dano ao DNA , DNARESUMO
BACKGROUND: Complex trauma is a significant public health issue with detrimental health, interpersonal and psychological impacts, which can impede client recovery and result in multiple representations. 'Trauma Informed Practice' (TIP) is an evidence-based model which ensures safe and effective services for clients and staff. This study examines health professional's use of TIP, and the motivators, enablers and barriers to implementation in a multidisciplinary setting. METHODS: A mixed methods study with 24 front-line clinicians and managers within a community health setting in Australia. A purpose designed, expert validated TIP checklist was completed, followed by semi-structured focus groups. Survey data was reported using descriptive statistics. Focus group data was digitally recorded, transcribed and thematically analysed. RESULTS: Ten key factors were identified motivating, restricting or enabling TIP implementation. Seven were organisational factors including supportive and informed management, flexibility of service models, levels of service demands, resource availability, education opportunities, good client outcomes, and reporting requirements. Philosophical approach, team orientation, and vicarious trauma/stress management were three individual professional factors. Critically, alignment in two ways was necessary for successful implementation, that is: in knowledge and understanding across organisational role levels - clinician, manager and executive; and, in professional philosophy and team orientation of individual clinicians. CONCLUSION: Providing TIP is essential for ensuring optimum client outcomes for trauma survivors and for maintaining workforce wellbeing. Although the increasing uptake to TIP is evident within the health setting, further attention is required to address the tension between service models focused on efficiently servicing whole populations and those attuned to effectively meeting the needs of high risk groups. A complex strategy to unite therapeutic and managerial goals is necessary if client, professional and organisational needs are to be effectively met.
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Saúde Pública , Sobreviventes , Austrália , Aconselhamento , Grupos Focais , HumanosRESUMO
Genetic toxicology is an essential component of compound safety assessment. In the face of a barrage of new compounds, higher throughput, less ethically divisive in vitro approaches capable of effective, human-relevant hazard identification and prioritisation are increasingly important. One such approach is the ToxTracker assay, which utilises murine stem cell lines equipped with green fluorescent protein (GFP)-reporter gene constructs that each inform on distinct aspects of cellular perturbation. Encouragingly, ToxTracker has shown improved sensitivity and specificity for the detection of known in vivo genotoxicants when compared to existing 'standard battery' in vitro tests. At the current time however, quantitative genotoxic potency correlations between ToxTracker and well-recognised in vivo tests are not yet available. Here we use dose-response data from the three DNA-damage-focused ToxTracker endpoints and from the in vivo micronucleus assay to carry out quantitative, genotoxic potency estimations for a range of aromatic amine and alkylating agents using the benchmark dose (BMD) approach. This strategy, using both the exponential and the Hill BMD model families, was found to produce robust, visually intuitive and similarly ordered genotoxic potency rankings for 17 compounds across the BSCL2-GFP, RTKN-GFP and BTG2-GFP ToxTracker endpoints. Eleven compounds were similarly assessed using data from the in vivo micronucleus assay. Cross-systems genotoxic potency correlations for the eight matched compounds demonstrated in vitro-in vivo correlation, albeit with marked scatter across compounds. No evidence for distinct differences in the sensitivity of the three ToxTracker endpoints was found. The presented analyses show that quantitative potency determinations from in vitro data enable more than just qualitative screening and hazard identification in genetic toxicology.
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Dano ao DNA , Testes de Mutagenicidade/métodos , Mutagênicos/farmacologia , Animais , Linhagem Celular , Genes Reporter , Proteínas de Fluorescência Verde , Camundongos , Testes para Micronúcleos , Células-TroncoRESUMO
Current in vitro genotoxicity tests can produce misleading positive results, indicating an inability to effectively predict a compound's subsequent carcinogenic potential in vivo. Such oversensitivity can incur unnecessary in vivo tests to further investigate positive in vitro results, supporting the need to improve in vitro tests to better inform risk assessment. It is increasingly acknowledged that more informative in vitro tests using multiple endpoints may support the correct identification of carcinogenic potential. The present study, therefore, employed a holistic, multiple-endpoint approach using low doses of selected carcinogens and non-carcinogens (0.001-770 µM) to assess whether these chemicals caused perturbations in molecular and cellular endpoints relating to the Hallmarks of Cancer. Endpoints included micronucleus induction, alterations in gene expression, cell cycle dynamics, cell morphology and bioenergetics in the human lymphoblastoid cell line TK6. Carcinogens ochratoxin A and oestradiol produced greater Integrated Signature of Carcinogenicity scores for the combined endpoints than the "misleading" in vitro positive compounds, quercetin, 2,4-dichlorophenol and quinacrine dihydrochloride and toxic non-carcinogens, caffeine, cycloheximide and phenformin HCl. This study provides compelling evidence that carcinogens can successfully be distinguished from non-carcinogens using a holistic in vitro test system. Avoidance of misleading in vitro outcomes could lead to the reduction and replacement of animals in carcinogenicity testing.
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Testes de Carcinogenicidade , Carcinógenos/toxicidade , Determinação de Ponto Final , Projetos de Pesquisa , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Forma Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Fosforilação , Medição de Risco , Proteína Supressora de Tumor p53/metabolismoRESUMO
The in vitro micronucleus assay is a globally significant method for DNA damage quantification used for regulatory compound safety testing in addition to inter-individual monitoring of environmental, lifestyle and occupational factors. However, it relies on time-consuming and user-subjective manual scoring. Here we show that imaging flow cytometry and deep learning image classification represents a capable platform for automated, inter-laboratory operation. Images were captured for the cytokinesis-block micronucleus (CBMN) assay across three laboratories using methyl methanesulphonate (1.25-5.0 µg/mL) and/or carbendazim (0.8-1.6 µg/mL) exposures to TK6 cells. Human-scored image sets were assembled and used to train and test the classification abilities of the "DeepFlow" neural network in both intra- and inter-laboratory contexts. Harnessing image diversity across laboratories yielded a network able to score unseen data from an entirely new laboratory without any user configuration. Image classification accuracies of 98%, 95%, 82% and 85% were achieved for 'mononucleates', 'binucleates', 'mononucleates with MN' and 'binucleates with MN', respectively. Successful classifications of 'trinucleates' (90%) and 'tetranucleates' (88%) in addition to 'other or unscorable' phenotypes (96%) were also achieved. Attempts to classify extremely rare, tri- and tetranucleated cells with micronuclei into their own categories were less successful (≤ 57%). Benchmark dose analyses of human or automatically scored micronucleus frequency data yielded quantitation of the same equipotent concentration regardless of scoring method. We conclude that this automated approach offers significant potential to broaden the practical utility of the CBMN method across industry, research and clinical domains. We share our strategy using openly-accessible frameworks.
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Aprendizado Profundo , Citometria de Fluxo/métodos , Testes para Micronúcleos/métodos , Mutagênicos/toxicidade , Automação Laboratorial , Benzimidazóis/administração & dosagem , Benzimidazóis/toxicidade , Carbamatos/administração & dosagem , Carbamatos/toxicidade , Linhagem Celular , Citocinese/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Metanossulfonato de Metila/administração & dosagem , Metanossulfonato de Metila/toxicidade , Mutagênicos/administração & dosagemRESUMO
Lidocaine has not been associated with cancer in humans despite 8 decades of therapeutic use. Its metabolite, 2,6-xylidine, is a rat carcinogen, believed to induce genotoxicity via N-hydroxylation and DNA adduct formation, a non-threshold mechanism of action. To better understand this dichotomy, we review literature pertaining to metabolic activation and genotoxicity of 2,6-xylidine, identifying that it appears resistant to N-hydroxylation and instead metabolises almost exclusively to DMAP (an aminophenol). At high exposures (sufficient to saturate phase 2 metabolism), this may undergo metabolic threshold-dependent activation to a quinone-imine with potential to redox cycle producing ROS, inducing cytotoxicity and genotoxicity. A new rat study found no evidence of genotoxicity in vivo based on micronuclei in bone marrow, comets in nasal tissue or female liver, despite high level exposure to 2,6-xylidine (including metabolites). In male liver, weak dose-related comet increases, within the historical control range, were associated with metabolic overload and acute systemic toxicity. Benchmark dose analysis confirmed a non-linear dose response. The weight of evidence indicates 2,6-xylidine is a non-direct acting (metabolic threshold-dependent) genotoxin, and is not genotoxic in vivo in rats in the absence of acute systemic toxic effects, which occur at levels 35 × beyond lidocaine-related exposure in humans.
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Compostos de Anilina/toxicidade , Mutagênicos/toxicidade , Ativação Metabólica , Anestésicos Locais/farmacocinética , Anestésicos Locais/toxicidade , Compostos de Anilina/farmacocinética , Animais , Humanos , Lidocaína/farmacocinética , Lidocaína/toxicidade , Testes de Mutagenicidade , Mutagênicos/farmacocinéticaRESUMO
The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines.
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Dietilnitrosamina/toxicidade , Mutagênicos/toxicidade , Carcinógenos , Relação Dose-Resposta a Droga , Humanos , Mutagênese , Nitrosaminas/toxicidade , Testes de ToxicidadeRESUMO
Small cardamom (Elettaria cardamomum), grown in limited coastal tropical countries is one of the costliest and widely exported agri-produce having global turnover of >10 billion USD. Mosaic/marble disease is one of the major impediments that requires understanding of disease at molecular level. Neither whole genome sequence nor any genomic resources are available, thus RNA seq approach can be a rapid and economical alternative. De novo transcriptome assembly was done with Illumina Hiseq data. A total of 5317 DEGs, 2267 TFs, 114 pathways and 175,952 genic region putative markers were obtained. Gene regulatory network analysis deciphered molecular events involved in marble disease. This is the first transcriptomic report revealing disease mechanism mediated by perturbation in auxin homeostasis and ethylene signalling leading to senescence. The web-genomic resource (SCMVTDb) catalogues putative molecular markers, candidate genes and transcript information. SCMVTDb can be used in germplasm improvement against mosaic disease in endeavour of small cardamom productivity. Availability of genomic resource, SCMVTDb: http://webtom.cabgrid.res.in/scmvtdb/.
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Elettaria/genética , Genoma de Planta , Interações Hospedeiro-Patógeno , Transcriptoma , Elettaria/virologia , Regulação da Expressão Gênica de Plantas , Mutação INDEL , Repetições de Microssatélites , Vírus do Mosaico/patogenicidade , Doenças das Plantas/genética , Doenças das Plantas/virologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
INTRODUCTION: The early closure of the Voluntary Dental Graduate Year Program and the Oral Health Therapy Graduate Year Program by the Australian Government adversely impacted New South Wales (NSW) Aboriginal Community Controlled Health Services (ACCHSs). This led to the co-design of a small-scale oral health therapy graduate year program for ACCHSs known as the Dalang Project, which enabled oral health therapists to engage with local Aboriginal communities and implement culturally competent, practical and evidence-based oral health promotion activities. This article provides an overview of the Dalang Project and its evaluation. METHODS: All graduates of the Dalang Project were invited via email and social media to complete an online survey. The survey included questions about their year in the Dalang Project, why they applied, what they liked and disliked about the project, where they planned to work post-placement, and examples of the most significant changes they observed in the communities where they were placed. Host sites were also surveyed and data were collated on clinical services performed as well as oral health promotion activity. RESULTS: Prior to commencing the Dalang Project only 4 of the 15 respondents came from rural or regional areas. Nine of the 15 respondents were considering working in a regional, rural or remote area prior to applying for the Dalang Project. Twelve respondents were working at the time of the survey and half were working in regional, rural or remote locations in NSW and one in the Northern Territory. All reported that they would be more likely to work in an ACCHS as a result of being a part of the Dalang Project. The majority of respondents said they would recommend the program to future graduates. A total of 63 schools, 21 preschools and 15 community health services received regular dental health education through the Dalang Project. A total of 3250 toothbrushes and fluoride toothpastes were distributed to children and families through the Dalang Project. A key part of the program was the installation of refrigerated and filtered water fountains in schools where there was no free filtered or refrigerated water supply. The inclusion of this component in the program was part of the co-design process and links the program to the wider population health strategies in NSW to help prevent childhood obesity. CONCLUSION: The Dalang Project is an example of a successful co-designed project that has positively impacted oral health service delivery for Aboriginal children and has provided a valuable experience for new graduate oral health therapists working in ACCHSs. Overall, the Dalang Project was found to be a positive professional experience for the oral health therapists with many remaining in rural, remote and regional locations after completing the program.
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Assistência Odontológica , Saúde Bucal , Serviços de Saúde Rural , Criança , Promoção da Saúde , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico , New South Wales , Northern Territory , Obesidade InfantilRESUMO
In vitro genotoxicity studies are a quick and high throughput approach to assess the genotoxic potential of chemicals; however, the reliability of these tests and their relevance to in vivo effects depends on the choice of representative cell line and optimisation of assay conditions. For chemicals like urethane that require specific metabolic activation to cause genotoxicity, it is important that in vitro tests are conducted using cell lines exhibiting the activity and induction of CYP450 enzymes, including CYP2E1 enzyme that is important in the metabolism of urethane, at a concentration representing actual or perceived chemical exposure. We compared 2D MCL-5 cells and HepG2 cells with 3D HepG2 hanging drop spheroids to determine the genotoxicity of urethane using the micronucleus assay. Our 2D studies with MCL-5 did not show any statistically significant genotoxicity [99% relative population doubling (RPD)] compared to controls for concentrations and time point tested in vitro. HepG2 cells grown as 2D indicated that exposure to urethane of up to 30 mM for 23 h did not cause any genotoxic effect (102% RPD) but, at higher concentrations, genotoxicity was produced with only 89-85% RPD. Furthermore, an exposure of 20-50 mM for 23 h using 3D hanging drop spheroid assays revealed a higher MN frequency, thus exhibiting in vitro genotoxicity of urethane in metabolically active cell models. In comparison with previous studies, this study indicated that urethane genotoxicity is dose, sensitivity of cell model (2D vs. 3D) and exposure dependent.
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Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Uretana/toxicidade , Biomarcadores , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Respiração Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos/métodos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esferoides CelularesRESUMO
INTRODUCTION: There is a maldistribution of dental professionals working in rural and remote regions of Australia. This study investigates dental graduates from a newly established rural clinical school (RCS) at Charles Sturt University (CSU), New South Wales, Australia, and records graduates' workforce locations and views on working in both metropolitan and rural practice. MATERIALS AND METHODS: In late 2015 to early 2016, CSU graduates of 2013 and 2014 were asked to complete a telephone interview related to their employment choices. Thirty-nine interviews (68% of contactable graduates) were completed. Qualitative framework analysis was applied to identify trends and themes. RESULTS: More than half of the graduates were working rurally, with 67% working full-time and 77% in private practice. Key influencing factors on graduates related to rural employment were as follows: family and personal relationships, developing clinical skills, rural community, lifestyle, professional support, mentorship, job availability, full-time employment and financial incentives. Key barriers to working rurally included leaving family and friends, small patient base, low salary, partner factors, and professional and personal isolation. CONCLUSION: More than half of the CSU graduates were working in rural communities, demonstrating initially positive rural workforce outcomes. Reasons for choosing to work rurally were complex and spanned a broad spectrum of social, personal, professional development and support, community, economic, environmental and lifestyle factors. Future workforce strategies should apply a broad multifactorial approach to consider the complex interrelated employment factors. Furthermore, increased evaluation is required of the CSU programme, with increased workforce outcomes and exploration of employment retention factors.
Assuntos
Serviços de Saúde Rural , População Rural , Austrália , Escolha da Profissão , Educação em Odontologia , Emprego , Humanos , Área de Atuação Profissional , Instituições AcadêmicasRESUMO
The interpretation of injuries to children and infants poses a number of difficulties to any medical practitioner involved in their care or tasked with the investigation their death. This includes differentiating accidental from non-accidental trauma and the consideration of medical factors making a child more prone to injury. Non-fatal but life-threatening upper airway obstruction is unfortunately a well-recognized pattern of abuse which may precede a fatal episode. In this experimental study, we aimed to model theoretical digit marks to the head using infant and young child resuscitation dummies, exposed to various methods of deliberate upper airway obstruction. This work has demonstrated that digit marks can be left anywhere on the head and face. However, the distribution of these marks varies dramatically based on how the airway was obstructed. Moreover, digit marks also appeared to be linked together in fairly reproducible patterns. Given the findings in this study, the identification of one or more fingertip type bruises anywhere on an infant or child's face or scalp, should raise the index of suspicion that the individual may have been subject to deliberate upper airway obstruction. This should prompt healthcare professionals to examine the child for markers of mechanical asphyxia, in order to accurately interpret any inadequately explained bruising to the head and face.
Assuntos
Obstrução das Vias Respiratórias , Asfixia , Contusões , Traumatismos Faciais , Dedos , Maus-Tratos Infantis , Pré-Escolar , Medicina Legal/métodos , Humanos , Lactente , Manequins , Fotografação , Couro Cabeludo/lesõesRESUMO
The publisher would like to apologize for the failed cross-linking to the following Letter to the Editor by Paul A.