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BACKGROUND: Despite known inequalities, little is understood about the burden and healthcare experiences of Aboriginal and Torres Strait Islander children who sustain a burn injury and their families. METHODS: The Coolamon Study recruited parents and carers whose children (aged <16 years) were Aboriginal and / or Torres Strait Islander children and had presented to burn units across four Australian states, New South Wales (Sydney), Northern Territory (Darwin), Queensland (Brisbane, Townsville) and South Australia (Adelaide), between 2015 and 2018. Consent was obtained and carers completed baseline and subsequent interviews at 3, 6, 12 and 24 months. Data were collected on the injury event, patient care and safety, sociodemographic factors, health related quality of life (PedsQual), and psychological distress (Kessler K-5). RESULTS: Of the 208 participants, 64 % were male; 26 % were aged less than 2 years and 37 % aged 2-4 years. The most common burn mechanisms were scalds (37 %), contact (33 %) and flame burns (21 %), with more severe burns and flame burns occurring in rural and remote settings. Most carers rated their child's care as either excellent or very good (82 %). Family distress, measured by the K-5, lessened over the 24 months, however the changes were not statistically significant. While 77 % of carers reported that they received enough information, 18 % reported they would have liked more, and 3 % reported no information was provided before treatment. Parents described mixed access to information about the types of support available to them, such as accommodation, meals, travel or cultural support. CONCLUSION: Data from this cohort provide rich new information about risk factors and care received from point of injury through to rehabilitation for Aboriginal and Torres Strait Islander children with burns, providing unique insights into what is needed for appropriate, culturally safe care.
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Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility.
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Centriolos , Segregación Cromosómica , Proteínas Asociadas a Microtúbulos , Centro Organizador de los Microtúbulos , Espermatocitos , Espermatogénesis , Centriolos/metabolismo , Centriolos/genética , Animales , Masculino , Ratones , Espermatogénesis/genética , Espermatocitos/metabolismo , Centro Organizador de los Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Meiosis/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genéticaRESUMEN
Photoprotective properties of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to reduce UV-induced DNA damage have been established in several studies. UV-induced DNA damage in skin such as single or double strand breaks is known to initiate several cellular mechanisms including activation of poly(ADP-ribose) (pADPr) polymerase-1 (PARP-1). DNA damage from UV also increases extracellular signal-related kinase (ERK) phosphorylation, which further increases PARP activity. PARP-1 functions by using cellular nicotinamide adenine dinucleotide (NAD+) to synthesise pADPr moieties and attach these to target proteins involved in DNA repair. Excessive PARP-1 activation following cellular stress such as UV irradiation may result in excessive levels of cellular pADPr. This can also have deleterious effects on cellular energy levels due to depletion of NAD+ to suboptimal levels. Since our previous work indicated that 1,25(OH)2D3 reduced UV-induced DNA damage in part through increased repair via increased energy availability, the current study investigated the effect of 1,25(OH)2D3 on UV-induced PARP-1 activity using a novel whole-cell enzyme- linked immunosorbent assay (ELISA) which quantified levels of the enzymatic product of PARP-1, pADPr. This whole cell assay used around 5000 cells per replicate measurement, which represents a 200-400-fold decrease in cell requirement compared to current commercial assays that measure in vitro pADPr levels. Using our assay, we observed that UV exposure significantly increased pADPr levels in human keratinocytes, while 1,25(OH)2D3 significantly reduced levels of UV-induced pADPr in primary human keratinocytes to a similar extent as a known PARP-1 inhibitor, 3-aminobenzamide (3AB). Further, both 1,25(OH)2D3 and 3AB as well as a peptide inhibitor of ERK-phosphorylation significantly reduced DNA damage in UV-exposed keratinocytes. The current findings support the proposal that reduction in pADPr levels may be critical for the function of 1,25(OH)2D3 in skin to reduce UV-induced DNA damage.
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Daño del ADN , Poli(ADP-Ribosa) Polimerasa-1 , Rayos Ultravioleta , Vitamina D , Humanos , Rayos Ultravioleta/efectos adversos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Vitamina D/farmacología , Vitamina D/metabolismo , Vitamina D/análogos & derivados , Daño del ADN/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Queratinocitos/efectos de los fármacos , Calcitriol/farmacología , Calcitriol/metabolismo , Reparación del ADN/efectos de los fármacos , Fosforilación/efectos de los fármacosRESUMEN
Studying essential genes required for dynamic processes in live mice is challenging as genetic perturbations are irreversible and limited by slow protein depletion kinetics. The first-generation auxin-inducible-degron (AID) system is a powerful tool for analyzing inducible protein loss in cultured cells. However, auxin administration is toxic to mice, preventing its long-term use in animals. Here, we use an optimized second-generation AID system to achieve the conditional and reversible loss of the essential centrosomal protein CEP192 in live mice. We show that the auxin derivative 5-Ph-IAA is well tolerated over two weeks and drives near-complete CEP192-mAID degradation in less than one hour in vivo. Prolonged CEP192 loss led to cell division failure and cell death in proliferative tissues. Thus, the second-generation AID system is well suited for rapid and/or sustained protein depletion in live mice, offering a valuable new tool for interrogating protein function in vivo.
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Phosphorylation of histone H3 threonine 3 (H3T3) by Haspin recruits the chromosomal passenger complex to the inner centromere and ensures proper cell cycle progression through mitosis. The mechanism by which Haspin binds to nucleosomes to phosphorylate H3T3 is not known. We report here cryo-EM structures of the Haspin kinase domain bound to a nucleosome. In contrast with previous structures of histone-modifying enzymes, Haspin solely contacts the nucleosomal DNA, inserting into a supergroove formed by apposing major grooves of two DNA gyres. This unique binding mode provides a plausible mechanism by which Haspin can bind to nucleosomes in a condensed chromatin environment to phosphorylate H3T3. We identify key basic residues in the Haspin kinase domain that are essential for phosphorylation of nucleosomal histone H3 and binding to mitotic chromatin. Our structure is the first of a kinase domain bound to a nucleosome and is the first example of a histone-modifying enzyme that binds to nucleosomes solely through DNA contacts.
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PURPOSE: Pediatric burn injuries are a global clinical issue causing significant morbidity. Early adjunctive negative pressure wound therapy improves re-epithelialization rates in children with burns, yet adoption in acute burn care is inconsistent. This investigation aimed to determine barriers to the implementation of adjunctive negative pressure wound therapy for the acute management of pediatric burns and co-design targeted implementation strategies. METHODS: A sequential mixed methods design was used explore barriers to adjunctive negative pressure wound therapy implementation in acute pediatric burn care. An online questionnaire was disseminated to healthcare professionals within four major Australian pediatric hospitals, each with a dedicated burns service. Barriers were coded according to the Consolidated Framework for Implementation Research (CFIR). Semi-structured interviews with senior clinicians tailored implementation strategies to local contexts. A stakeholder consensus meeting consolidated implementation strategies and local processes. RESULTS: Sixty-three healthcare professionals participated in the questionnaire, and semi-structured interviews involved nine senior burn clinicians. We identified eight implementation barriers across all five CFIR domains then co-designed targeted strategies to address identified barriers. Barriers included lack of available resources, limited access to knowledge and information, individual stage of change, patient needs and resources, limited knowledge and beliefs about the intervention, lack of external policies, intervention complexity, and poor implementation planning. CONCLUSION: Multiple contextual factors affect negative pressure wound therapy uptake in acute pediatric burn settings. Results will inform a multi-state stepped-wedge cluster randomized controlled trial. Additional resources, education, training, updated policies, and guidelines are required for successful implementation. It is anticipated that adjunctive negative pressure wound therapy, in conjunction with tailored implementation strategies, will enhance adoption and sustainability. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12622000166774. Registered 1 February 2022.
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Quemaduras , Terapia de Presión Negativa para Heridas , Humanos , Quemaduras/terapia , Australia , Masculino , Niño , Femenino , Encuestas y Cuestionarios , Unidades de Quemados/organización & administraciónRESUMEN
Hydrolethalus Syndrome (HLS) is a lethal, autosomal recessive ciliopathy caused by the mutation of the conserved centriole protein HYLS1. However, how HYLS1 facilitates the centriole-based templating of cilia is poorly understood. Here, we show that mice harboring the HYLS1 disease mutation die shortly after birth and exhibit developmental defects that recapitulate several manifestations of the human disease. These phenotypes arise from tissue-specific defects in cilia assembly and function caused by a loss of centriole integrity. We show that HYLS1 is recruited to the centriole by CEP120 and functions to recruit centriole inner scaffold proteins that stabilize the centriolar microtubule wall. The HLS mutation disrupts the interaction of HYLS1 with CEP120 leading to HYLS1 displacement and degeneration of the centriole distal end. We propose that tissue-specific defects in centriole integrity caused by the HYLS1 mutation prevent ciliogenesis and drive HLS phenotypes.
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Burn wound blister fluid is a valuable matrix for understanding the biological pathways associated with burn injury. In this study, 152 blister fluid samples collected from paediatric burn wounds at three different hospitals were analysed using mass spectrometry proteomic techniques. The protein abundance profile at different days after burn indicated more proteins were associated with cellular damage/repair in the first 24 h, whereas after this point more proteins were associated with antimicrobial defence. The inflammatory proteins persisted at a high level in the blister fluid for more than 7 days. This may indicate that removal of burn blisters prior to two days after burn is optimal to prevent excessive or prolonged inflammation in the wound environment. Additionally, many proteins associated with the neutrophil extracellular trap (NET) pathway were increased after burn, further implicating NETs in the post-burn inflammatory response. NET inhibitors may therefore be a potential treatment to reduce post-burn inflammation and coagulation pathology and enhance burn wound healing outcomes.
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Vesícula , Quemaduras , Trampas Extracelulares , Inflamación , Humanos , Quemaduras/metabolismo , Quemaduras/complicaciones , Quemaduras/inmunología , Trampas Extracelulares/metabolismo , Vesícula/metabolismo , Vesícula/inmunología , Masculino , Femenino , Inflamación/metabolismo , Inflamación/inmunología , Niño , Preescolar , Proteómica , Lactante , Neutrófilos/metabolismo , Cicatrización de Heridas/fisiología , Adolescente , Espectrometría de MasasRESUMEN
The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.
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Ciclosoma-Complejo Promotor de la Anafase , Neoplasias , Humanos , Ciclosoma-Complejo Promotor de la Anafase/genética , Dineínas , Cinesinas/genética , Cinetocoros , Mitosis , Neoplasias/genéticaRESUMEN
The objective of the Australian Traumatic Brain Injury (AUS-TBI) Initiative is to develop a data dictionary to inform data collection and facilitate prediction of outcomes of people who experience moderate-severe TBI in Australia. The aim of this systematic review was to summarize the evidence of the association between demographic, injury event, and social characteristics with outcomes, in people with moderate-severe TBI, to identify potentially predictive indicators. Standardized searches were implemented across bibliographic databases to March 31, 2022. English-language reports, excluding case series, which evaluated the association between demographic, injury event, and social characteristics, and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Abstracts and full text records were independently screened by at least two reviewers in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association. The review findings were discussed with an expert panel to determine the feasibility of incorporation of routine measurement into standard care. The search strategy retrieved 16,685 records; 867 full-length records were screened, and 111 studies included. Twenty-two predictors of 32 different outcomes were identified; 7 were classified as high-level (age, sex, ethnicity, employment, insurance, education, and living situation at the time of injury). After discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous predictors capable of enabling early identification of those at risk for poor outcomes and improved personalization of care through inclusion in routine data collection.
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53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo-like kinase 1 (PLK1) activity is essential for the time-dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP-F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP-F-53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration.
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Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinasas , Humanos , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Cinetocoros/metabolismo , Mitosis , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína p53 Supresora de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Polo-like kinase 4 (PLK4) is a key regulator of centriole biogenesis, but how PLK4 selects a single site for procentriole assembly remains unclear. Using ultrastructure expansion microscopy, we show that PLK4 localizes to discrete sites along the wall of parent centrioles. While there is variation in the number of sites PLK4 occupies on the parent centriole, most PLK4 localize at a dominant site that directs procentriole assembly. Inhibition of PLK4 activity leads to stable binding of PLK4 to the centriole and increases occupancy to a maximum of nine sites. We show that self-phosphorylation of an unstructured linker promotes the release of active PLK4 from the centriole to drive the selection of a single site for procentriole assembly. Preventing linker phosphorylation blocks PLK4 turnover, leading to supernumerary sites of PLK4 localization and centriole amplification. Therefore, self-phosphorylation is a major driver of the spatial patterning of PLK4 at the centriole and plays a critical role in selecting a single centriole duplication site.
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Proteínas de Ciclo Celular , Centriolos , Proteínas Serina-Treonina Quinasas , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Centriolos/genética , Centriolos/metabolismo , Fosforilación , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
OBJECTIVE: This study aimed to compare academic performance and high school completion of young people hospitalised for a burn compared with young people not hospitalised for an injury. DESIGN: A retrospective population-based matched case-comparison cohort study. PARTICIPANTS: Young people aged ≤18 years hospitalised for a burn during 2005-2018 in New South Wales, Australia, with age, sex and residential postcode-matched peers not hospitalised for any injury during 1 July 2001 and 31 December 2018. MAIN OUTCOME MEASURES: Performance below the national minimum standard (NMS) on the National Assessment Plan for Literacy and Numeracy assessments and not completing high school. RESULTS: Young females hospitalised for a burn had a 72% higher risk of poorer reading compared with their peers (adjusted relative risk (ARR) 1.72; 95% CI 1.33 to 2.23), while young males hospitalised with a burn showed no higher risk (ARR 1.14; 95% CI 0.91 to 1.43). Young males (ARR 1.05; 95% CI 0.81 to 1.35) and females (ARR 1.34; 95% CI 0.93 to 1.94) hospitalised with a burn had no higher risk of not reaching the NMS for numeracy compared with peers. Young people hospitalised with a burn had at least twice the risk of not completing year 10 (ARR 3.86; 95% CI 1.68 to 8.86), year 11 (ARR 2.45; 95% CI 1.89 to 3.18) and year 12 (ARR 2.09; 95% CI 1.63 to 2.67) compared with matched counterparts. CONCLUSIONS: Young females hospitalised with a burn displayed poorer academic performance for reading compared with matched peers, while males and females were more likely to leave school earlier. Identifying unmet learning support needs of young burn survivors should be investigated.
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Quemaduras , Hospitalización , Masculino , Femenino , Humanos , Adolescente , Estudios Retrospectivos , Estudios de Cohortes , Quemaduras/epidemiología , Estudios de Casos y ControlesRESUMEN
The hormonal form of vitamin D3, 1,25(OH)2D3, reduces UV-induced DNA damage. UV exposure initiates pre-vitamin D3 production in the skin, and continued UV exposure photoisomerizes pre-vitamin D3 to produce "over-irradiation products" such as lumisterol3 (L3). Cytochrome P450 side-chain cleavage enzyme (CYP11A1) in skin catalyzes the conversion of L3 to produce three main derivatives: 24-hydroxy-L3 [24(OH)L3], 22-hydroxy-L3 [22(OH)L3], and 20,22-dihydroxy-L3 [20,22(OH)L3]. The current study investigated the photoprotective properties of the major over-irradiation metabolite, 24(OH)L3, in human primary keratinocytes and human skin explants. The results indicated that treatment immediately after UV with either 24(OH)L3 or 1,25(OH)2D3 reduced UV-induced cyclobutane pyrimidine dimers and oxidative DNA damage, with similar concentration response curves in keratinocytes, although in skin explants, 1,25(OH)2D3 was more potent. The reductions in DNA damage by both compounds were, at least in part, the result of increased DNA repair through increased energy availability via increased glycolysis, as well as increased DNA damage recognition proteins in the nucleotide excision repair pathway. Reductions in UV-induced DNA photolesions by either compound occurred in the presence of lower reactive oxygen species. The results indicated that under in vitro and ex vivo conditions, 24(OH)L3 provided photoprotection against UV damage similar to that of 1,25(OH)2D3.
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BACKGROUND: Aboriginal and Torres Strait Islander peoples have a unique place in Australia as the original inhabitants of the land. Similar to other First Nations people globally, they experience a disproportionate burden of injury and chronic health conditions. Discharge planning ensures ongoing care to avoid complications and achieve better health outcomes. Analysing discharge interventions that have been implemented and evaluated globally for First Nations people with an injury or chronic conditions can inform the implementation of strategies to ensure optimal ongoing care for Aboriginal and Torres Strait Islander people. METHODS: A systematic review was conducted to analyse discharge interventions conducted globally among First Nations people who sustained an injury or suffered from a chronic condition. We included documents published in English between January 2010 and July 2022. We followed the reporting guidelines and criteria set in Preferred Reporting Items for Systematic Review (PRISMA). Two independent reviewers screened the articles and extracted data from eligible papers. A quality appraisal of the studies was conducted using the Mixed Methods Appraisal Tool and the CONSIDER statement. RESULTS: Four quantitative and one qualitative study out of 4504 records met inclusion criteria. Three studies used interventions involving trained health professionals coordinating follow-up appointments, linkage with community care services and patient training. One study used 48-hour post discharge telephone follow-up and the other text messages with prompts to attend check-ups. The studies that included health professional coordination of follow-up, linkage with community care and patient education resulted in decreased readmissions, emergency presentations, hospital length of stay and unattended appointments. CONCLUSION: Further research on the field is needed to inform the design and delivery of effective programs to ensure quality health aftercare for First Nations people. We observed that discharge interventions in line with the principal domains of First Nations models of care including First Nations health workforce, accessible health services, holistic care, and self-determination were associated with better health outcomes. REGISTRATION: This study was prospectively registered in PROSPERO (ID CRD42021254718).
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Servicios de Salud del Indígena , Alta del Paciente , Humanos , Cuidados Posteriores , Aborigenas Australianos e Isleños del Estrecho de Torres , Australia , Enfermedad CrónicaRESUMEN
INTRODUCTION: Parents of children hospitalised in a burn unit experience psychological trauma and later post-traumatic stress. Aboriginal and Torres Strait Islander families whose child has been admitted to a burn unit encounter additional burdens through a culturally unsafe healthcare system. Psychosocial interventions can help reduce anxiety, distress and trauma among children and parents. There remains a lack of interventions or resources that reflect Aboriginal and Torres Strait Islander people's perspective of health. The objective of this study is to codevelop a culturally appropriate informative resource to assist Aboriginal and Torres Strait Islander parents whose child has been hospitalised in a burn unit. METHODS: In this participatory research study, the development of a culturally safe resource will build on Aboriginal and Torres Strait Islander families' experiences and voices, complemented by the knowledge and expertise of an Aboriginal Health Worker (AHW) and burn care experts. Data will be collected through recorded yarning sessions with families whose child has been admitted to a burn unit, the AHW and burn care experts. Audiotapes will be transcribed and data will be analysed thematically. Analysis of yarning sessions and resource development will follow a cyclical approach. ETHICS AND DISSEMINATION: This study has been approved by the Aboriginal Health and Medical Research Council (AH&MRC) (1690/20) and the Sydney Children's Hospitals Network ethics committee (2020/ETH02103). Findings will be reported to all participants and will be disseminated with the broader community, the funding body and health workers at the hospital. Dissemination with the academic community will be through peer-reviewed publications and presentations in relevant conferences.
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Aborigenas Australianos e Isleños del Estrecho de Torres , Quemaduras , Servicios de Salud del Indígena , Niño , Humanos , Quemaduras/psicología , Quemaduras/terapia , Asistencia Sanitaria Culturalmente Competente , Investigación sobre Servicios de Salud , Grupos de PoblaciónRESUMEN
OBJECTIVES: Hospitalisation rates for injury, including at playgrounds, have not changed in the past decade. There are nine Australian Standards specific to playgrounds. The impact (if any) of these standards on playground injury resulting in hospitalisation is unknown. METHODS: Retrospective data for patients under 18 years presenting to emergency departments and/or admitted between October 2015 and December 2019 due to an injury documented as occurring at a playground were retrieved by the Illawarra Shoalhaven Local Health District Planning, Information and Performance Department. Maintenance and Australian Standard (AS) compliance data for the 401 local playgrounds were requested from the four Local Governments in Illawarra Shoalhaven Local Health District. Descriptive statistics were used. RESULTS: A total of 548 children were treated in emergency departments and/or admitted following playground injury. There was an overall increase of 39.3% in playground injury across the study period, and expenditure rose from $43,478 in 2011 to $367,259 in 2019 (a 744.7% increase). CONCLUSIONS: Playground injury has not decreased in the Illawarra Shoalhaven. Data regarding maintenance and AS compliance are lacking. This is not unique to our region. IMPLICATIONS FOR PUBLIC HEALTH: Without a national approach to adequately resource and monitor playground injury, it is not possible to assess the impact of Australian Standards or any injury prevention program.
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Juego e Implementos de Juego , Heridas y Lesiones , Niño , Humanos , Adolescente , Seguridad , Estudios Retrospectivos , Australia , Hospitalización , Heridas y Lesiones/epidemiología , Heridas y Lesiones/prevención & controlRESUMEN
The calcium-sensing receptor (CaSR) is an important regulator of epidermal function. We previously reported that knockdown of the CaSR or treatment with its negative allosteric modulator, NPS-2143, significantly reduced UV-induced DNA damage, a key factor in skin cancer development. We subsequently wanted to test whether topical NPS-2143 could also reduce UV-DNA damage, immune suppression, or skin tumour development in mice. In this study, topical application of NPS-2143 (228 or 2280 pmol/cm2) to Skh:hr1 female mice reduced UV-induced cyclobutane pyrimidine dimers (CPD) (p < 0.05) and oxidative DNA damage (8-OHdG) (p < 0.05) to a similar extent as the known photoprotective agent 1,25(OH)2 vitamin D3 (calcitriol, 1,25D). Topical NPS-2143 failed to rescue UV-induced immunosuppression in a contact hypersensitivity study. In a chronic UV photocarcinogenesis protocol, topical NPS-2143 reduced squamous cell carcinomas for only up to 24 weeks (p < 0.02) but had no other effect on skin tumour development. In human keratinocytes, 1,25D, which protected mice from UV-induced skin tumours, significantly reduced UV-upregulated p-CREB expression (p < 0.01), a potential early anti-tumour marker, while NPS-2143 had no effect. This result, together with the failure to reduce UV-induced immunosuppression, may explain why the reduction in UV-DNA damage in mice with NPS-2143 was not sufficient to inhibit skin tumour formation.
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Receptores Sensibles al Calcio , Neoplasias Cutáneas , Femenino , Animales , Ratones , Humanos , Ratones Pelados , Receptores Sensibles al Calcio/metabolismo , Rayos Ultravioleta , Daño del ADN , Neoplasias Cutáneas/metabolismo , Dímeros de Pirimidina/metabolismo , Piel/metabolismoRESUMEN
BACKGROUND: Quality and safety in Australian healthcare is inequitably distributed, highlighted by gaps in the provision of quality care for Aboriginal and Torres Strait Islander children. Burns have potential for long-term adverse outcomes, and quality care, including culturally safe care, is critical to recovery. This study aimed to develop and apply an Aboriginal Patient Journey Mapping (APJM) tool to investigate the quality of healthcare systems for burn care with Aboriginal and Torres Strait Islander children. STUDY DESIGN: Interface research methodology, using biomedical and cultural evidence, informed the modification of an existing APJM tool. The tool was then applied to the journey of one family accessing a paediatric tertiary burn care site. Data were collected through yarning with the family, case note review and clinician interviews. Data were analysed using Emden's core story and thematic analysis methods. Reflexivity informed consideration of the implications of the APJM tool, including its effectiveness and efficiency in eliciting information about quality and cultural safety. RESULTS: Through application of a modified APJM tool, gaps in quality care for Aboriginal and Torres Strait Islander children and families were identified at the individual, service and system levels. Engagement in innovative methodology incorporating more than biomedical standards of care, uncovered critical information about the experiences of culturally safe care in complex patient journeys. CONCLUSION: Based on our application of the tool, APJM can identify and evaluate specific aspects of culturally safe care as experienced by Aboriginal and Torres Strait Islander peoples and be used for quality improvement.