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Background: Uveal melanoma is the most common non-cutaneous melanoma and is an intraocular malignancy affecting nearly 7,000 individuals per year worldwide. Of these, approximately 50% will progress to metastatic disease for which there are currently no effective curative therapies. Despite advances in molecular profiling and metastatic stratification of uveal melanoma tumors, little is known regarding their underlying biology of metastasis. Our group has identified a disseminated neoplastic cell population characterized by co-expression of immune and melanoma proteins, circulating hybrid cells (hybrids), in patients with uveal melanoma. Compared to circulating tumor cells, which lack expression of immune proteins, hybrids are detected at an increased prevalence in peripheral blood and can be used as a non-invasive biomarker to predict metastatic progression. Methods: To ascertain mechanisms underlying enhanced hybrid cell dissemination we identified hybrid cells within primary uveal melanoma tumors using single cell RNA sequencing (n = 8) and evaluated their gene expression and predicted ligand-receptor interactions in relation to other melanoma and immune cells within the primary tumor. We then verified expression of upregulated hybrid pathways within patient-matched tumor and peripheral blood hybrids (n = 4) using cyclic immunofluorescence and quantified their protein expression relative to other non-hybrid tumor and disseminated tumor cells. Results: Among the top upregulated genes and pathways in hybrid cells were those involved in enhanced cell motility and cytoskeletal rearrangement, immune evasion, and altered cellular metabolism. In patient-matched tumor and peripheral blood, we verified gene expression by examining concordant protein expression for each pathway category: TMSB10 (cell motility), CD74 (immune evasion) and GPX1 (metabolism). Both TMSB10 and GPX1 were expressed on significantly higher numbers of disseminated hybrid cells compared to circulating tumor cells, and CD74 and GPX1 were expressed on more disseminated hybrids than tumor-resident hybrids. Lastly, we identified that hybrid cells express ligand-receptor signaling pathways implicated in promoting metastasis including GAS6-AXL, CXCL12-CXCR4, LGALS9-P4HB and IGF1-IGFR1. Conclusion: These findings highlight the importance of TMSB10, GPX1 and CD74 for successful hybrid cell dissemination and survival in circulation. Our results contribute to the understanding of uveal melanoma tumor progression and interactions between tumor cells and immune cells in the tumor microenvironment that may promote metastasis. [ABSTRACT FROM AUTHOR]

Introduction: Despite a decline in unintended teenage pregnancy in Australia, rates remain higher amongst justice-involved adolescent girls, who are more likely to be from disadvantaged socio-economic backgrounds, have histories of abuse, substance use and/or mental health issues. Furthermore, exposure to the criminal justice system may alter access to education and employment and opportunities, potentially resulting in distinct risk-factor profiles. We examine factors associated with unintended pregnancy, non-contraceptive use and Long-Acting Reversible Contraception (LARC) in a sample of sexually active, justice-involved adolescent girls from Western Australia and Queensland. Methods: Data from the Mental Health, Sexual Health and Reproductive Health of Young People in Contact with the Criminal Justice System (MeH-JOSH) Study was analysed on 118 sexually active adolescent girls. Participants were aged between 14 and 17 years, purposefully sampled based on justice-system involvement and completed an anonymous telephone survey. We constructed two multivariate models taking reproductive outcomes as the dependent variables. Results: Over one quarter (26%, 30/118) reported a past unintended pregnancy, 54 did not use any contraception at their last sexual encounter, and 17 reported LARC use. Following adjustments in the multivariate analysis, lifetime ecstasy use was associated with both unintended pregnancy (aOR 3.795, p = 0.022) and non-contraception use (aOR 4.562, p = 0.004). A history of physical abuse was also associated with both any contraception (aOR 3.024, p = 0.041) and LARC use (aOR 4.892, p = 0.050). Identifying as Aboriginal & Torres Strait Islander, education/employment status and geographic location appeared to have no association. Conclusion: Our findings suggest that justice-involved adolescent girls have distinct risk factors associated with unplanned pregnancy and contraception use compared to the general population, but more research is required to understand the mechanisms and contexts underlying these risk factors. How exposure to physical violence may encourage contraception and LARC use, in particular, warrants further attention as does the association with ecstasy use. [ABSTRACT FROM AUTHOR]

Introduction: Estimates of the prevalence of intellectual disability or autism spectrum disorder (ASD) may vary depending on the methodology, geographical location, and sources of ascertainment. The National Disability Insurance Scheme (NDIS) in Australia was introduced progressively from 2016 to provide individualized funding for eligible people with a significant and permanent disability. Methods: Its recent inclusion as a source of ascertainment in the populationbased Intellectual Disability Exploring Answers (IDEA) database in Western Australia has allowed comparisons of the prevalence of intellectual disability and ASD before and after its introduction. Results: Prevalence of intellectual disability in 2020 was 22.5 per 1,000 (/1,000) live births compared with previous estimates in 2010 of 17/1,000, and for ASD, the estimate was 20.7/1,000 in 2020 compared with 5.1/1,000 in 2010. Whilst the prevalence of ASD in Aboriginal individuals was about two-thirds that of non-Aboriginals, there was an increased prevalence of ASD in Aboriginal children under 10 years compared with non-Aboriginal children. Discussion: The concurrent relaxation of ASD diagnostic practice standards in Western Australia associated with the administration of access to the NDIS and the release of the National Guidelines empowering single diagnosticians to determine the appropriateness of engaging additional diagnosticians to form a multidisciplinary team on ASD diagnosis, appear to be important factors associated with the increase in ASD diagnoses both with and without intellectual disability. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a major public health problem that may be associated with numerous behavioral problems, including impulsivity, aggression and violence. Rates of self-reported TBI are high within offender populations, but the extent to which TBI is causally implicated in causing illegal behavior is unclear. This study examined the psychological and functional correlates of histories of traumatic brain injury in a sample of impulsive violent offenders. Methods: Study participants, all men, had been recruited to participate in a randomized controlled trial of sertraline to reduce recidivism. Study entry criteria were an age of at least 18 years, a documented history of two or more violent offenses and a score of 70 or above on the Barratt Impulsiveness Scale. An extensive list of standardized questionnaires was administered to obtain information on previous TBI and other neuropsychiatric conditions or symptoms. Results: In the sample of 693 men, 66% were aged between 18 and 35 years old, and 55% gave a history of TBI ("TBI+"). Overall, 55% of study participants reported at least one TBI. High levels of neuropsychiatric symptomatology were reported. In 75% of TBI+ individuals, their most severe TBI (by self-report) was associated with loss of consciousness (LOC) < 30 min. Compared to TBI- (those without history of TBI) participants, TBI+ individuals were more impulsive (Eysenck Impulsivity), irritable, angry, and reported higher levels of assaultive behavior, depressive symptomology, alcohol use disorder, suicidal ideation, suicide attempts, and lower quality of life. Potential "dose effects" of TBI severity and frequency in terms of neuropsychiatric symptomatology were identified. Conclusion: Like other studies of offender populations, single and multiple TBIs were very common. The associations of TBI, TBI severity, and TBI frequency (i.e., TBI "burden") with adverse neuropsychiatric phenomena suggest TBI contributes importantly to offender morbidity but the select nature of the sample and crosssectional study design constrain the interpretation of these findings. [ABSTRACT FROM AUTHOR]

Background: It is unclear what factors are associated with sexually transmissible infections (STI) and HIV testing and diagnosis among justice-involved adolescents, and if these differ for Aboriginal or Torres Strait Islander peoples. Methods: A cross-sectional survey of 465 justice-involved adolescents (aged 14–17 years) from Australia was conducted between 2016 and 2018. Participants were asked about sexual behaviours, STI/HIV knowledge, and prior STI diagnoses and testing. Results: Approximately 38% (n = 130) of those sexually active had ever been screened for STI/HIV and 17.8% (n = 23) had been diagnosed with an STI. No participant reported living with HIV. For Aboriginal participants, being male (aOR 3.6, 95% CI 1.3–10.1) and having under three sexual partners in the past 12 months (aOR 3.1, 95% CI 1.2–8.0) was associated with never having had an STI/HIV test. For non-Aboriginal participants, being male (aOR 2.7, 95%CI 1.2–5.7), single (aOR 2.4, 95% CI 1.2–4.9), attending school (aOR 2.4, 95% CI 1.1–5.1), not having sought sexual health information (aOR 2.8, 95% CI 1.4–5.8), and having a lower STI/HIV knowledge score (aOR 2.3, 95% CI 1.1–5.0) were associated with never having had an STI/HIV test. Factors associated with STI diagnosis were non-heterosexual sexual orientation (aOR 5.6, 95% CI 1.1–28.2), transactional sex (aOR 11.2, 95% CI 3.0–41.3), and having sought sexual health information (aOR 3.5, 95% CI 1.0–12.5). Conclusions: Males, particularly Aboriginal male adolescents, should be engaged with sexual health promotion and testing services as soon as they come into contact with the justice system. Approaches should consider different cultural, gender and sexual orientations. This paper reports on the sexual behaviours of Aboriginal and non-Aboriginal adolescents who have come into contact with the Australian justice system and looks at factors associated with testing for sexually transmissible infections (STI) and HIV, and diagnosis of sexually transmissible infections. Findings suggest there are different factors associated with STI/HIV testing for Aboriginal and non-Aboriginal justice-involved adolescents. Sexual health education should start early and consider gender, cultural and sexual orientation differences. [ABSTRACT FROM AUTHOR]

This paper uses first person inquiry and presentational form to argue the case for a sensory approach to understanding professional connection and disconnection with children who may be being abused. The approach is underpinned by an epistemology or theory of knowledge which stems from a participatory world-view where appearances are not permanent or separate from us: the act of perception takes place between the active sensible world and our own bodies, where ‘otherness’ expresses itself directly to our senses. Thus perception, conceived in this way, can lead to right action in the moment; or discounting what is actually being said by a child and disconnection. Buber’s notion of the ‘I-You’ is used to explore feelings and the movement to relation when professionals witness children’s ‘stories of suffering’ (Buber, 1965; Laub, 1992; Jones, 2008). The paper concludes by arguing the case for practitioners to become researchers of their own practice in rigorously facilitated inquiry groups. It is argued that this form of practitioner-research serves to quality assure frontline practice, and create new knowledge (or practice wisdom) such that feelings can be constructively worked with to improve connection with the lived reality for children.

Simple Summary: Advances in our understanding of the complex spatial interactions between tumor epithelia and tumor microenvironmental cells have been driven by highly multiplexed imaging technologies. These techniques are capable of labeling many more biomarkers than conventional immunostaining methods. However, multiplexed imaging techniques suffer from low detection sensitivity, cell loss—particularly in fragile samples—and challenges with antibody labeling. Herein, we developed and optimized a DNA antibody barcoding strategy for cyclic immunofluorescence (cyCIF) that can be amplified to increase the detection efficiency of low-abundance antigens. Stained fluorescence signals can be readily removed using ultraviolet light treatment, preserving tissue and fragile cell sample integrity. Advances in our understanding of the complex, multifaceted interactions between tumor epithelia, immune infiltrate, and tumor microenvironmental cells have been driven by highly multiplexed imaging technologies. These techniques are capable of labeling many more biomarkers than conventional immunostaining methods. However, multiplexed imaging techniques suffer from low detection sensitivity, cell loss—particularly in fragile samples—, and challenges with antibody labeling. Herein, we developed and optimized an oligonucleotide antibody barcoding strategy for cyclic immunofluorescence (cyCIF) that can be amplified to increase the detection efficiency of low-abundance antigens. Stained fluorescence signals can be readily removed using ultraviolet light treatment, preserving tissue and fragile cell sample integrity. We also extended the oligonucleotide barcoding strategy to secondary antibodies to enable the inclusion of difficult-to-label primary antibodies in a cyCIF panel. Using both the amplification oligonucleotides to label DNA barcoded antibodies and in situ hybridization of multiple fluorescently labeled oligonucleotides resulted in signal amplification and increased signal-to-background ratios. This procedure was optimized through the examination of staining parameters including staining oligonucleotide concentration, staining temperature, and oligonucleotide sequence design, resulting in a robust amplification technique. As a proof-of-concept, we demonstrate the flexibility of our cyCIF strategy by simultaneously imaging with the original oligonucleotide conjugated antibody (Ab-oligo) cyCIF strategy, the novel Ab-oligo cyCIF amplification strategy, as well as direct and indirect immunofluorescence to generate highly multiplexed images. [ABSTRACT FROM AUTHOR]

Argues that the voices of those who have been abused in residential care need to be considered in research on child abuse in residential settings. Considers the high percentage of child perpetrators, the focus on child control and restraint rather than development, and the potential dangers of dominant, charismatic leaders, and politically motivated, acceptable leaders. (Author/KB)

Multiple factors lead to the development and maintenance of chronic heart failure. Blockade of ErbB-2 or ErbB-4 tyrosine kinase receptor signaling leads to dilated cardiomyopathy. ErbB-1 may protect the heart against stress-induced injury and its ligand; epidermal growth factor (EGF) increases myocardial contractility, whereas heparinbinding EGF is essential for normal cardiac function. However, the role of ErbB-1 in control of cardiac function is not clear. We hypothesized that ErbB-1 is essential for maintaining adult cardiac function. Using the ecdysone-inducible gene expression system, we expressed humanized cardiomyocyte-specific dominant-negative ErbB-1 mutant receptors (hErbB-l-mut) in young adult mice that block endogenous cardiac ErbB-1 signaling. Molecular, morphological, and physiological tests (under anesthesia) were performed. As a result, hErbB-l-mut was expressed selectively in cardiomyocytes leading to the blockade of endogenous ErbB-1 phosphorylation and ErbB-2 transphosphorylation. An increase in left ventricular mass, atrial natriuretic factor expression, and histological changes were indicative of cardiac hypertrophy. Cardiac dilation, numerous cardiac lesions, and the loss of the clear boundary between cardiac fibrils were noted histologically. Early and long-term hErbB-l-rout induction led to a significant decrease in fractional shortening and to significant increases in left ventricular end-systolic diameter and volume. The treatment of adenylyl cyclase activator (forskolin analog) normalized the depressed cardiac function. Resting cardiac function returned to normal after reversing mutant expression. A 4-day survival rate of transverse-aortic constricted hErbB-l-mut mice was only 20% compared with 100% in controls. In conclusion, these observations indicate that the blockade of cardiac ErbB-1 signaling leads to the blockade of ErbB-2 signaling and that together they result in cardiac dysfunction. dilated cardiomyopathy; cardiac function; tyrosine kinase; remodeling

Introduction: This study investigated substance use and help‐seeking among justice‐involved young people to inform and improve service provision during and after contact with the justice system. Methods: Young people (14–17 years) in the community with current or prior contact with the justice system were recruited in Queensland and Western Australia, Australia using purposive sampling between 2016 and 2018. A cross‐sectional survey was delivered by computer‐assisted telephone interview. Information was collected on sociodemographic and health factors; lifetime and frequency of use of alcohol, tobacco and other drugs; and use of health services related to substance use and mental health. Results: Of the 465 justice‐involved young people surveyed, most had used alcohol (89%), tobacco (86%) or other drugs (81%). Of the latter, cannabis use was most prevalent (79%), followed by ecstasy (26%) and amphetamine (22%). Young people engaging in higher risk drug use (daily use, injecting use) were more likely to also have an alcohol use disorder, be disengaged from education, unemployed, have attempted suicide and experienced incarceration. Of the cohort, 24% had received treatment at an alcohol and drug service in the past year and 30% had seen a health professional about emotional/behavioural problems. Males and Aboriginal and Torres Strait Islander young people were less likely to have sought professional help. Conclusion: The high levels of substance use and disproportionate levels of help‐seeking observed in this study illustrate the importance of delivering tailored, comprehensive and coordinated trauma‐informed and culturally safe alcohol and drug services to justice‐involved young people. [ABSTRACT FROM AUTHOR]

Objectives: To overcome key knowledge gaps in relation to justice involved and vulnerable young people and their sexual health and to compare this group with their peers from other youth health surveys in Australia to determine the extent of the issues. Methods: Young people, aged between 14 and 17 years, who had ever been or were currently involved with the criminal justice system were purposively sampled. The survey was anonymous and delivered using Computer Assisted Telephone Interview (CATI). Results: A total of 465 justice involved MeH-JOSH young people, aged between 14 and 17 years, participated in the study: 44% Aboriginal and/or Torres Strait Islander (Indigenous) and 37% not attending school. Of the total valid responses, 76% (n = 348) reported having ever had sex, with sexual initiation at a median age of 14 years. We compared these data with their peers in other Australian surveys and found that young people in our study had a higher engagement in sex and start having sex at a younger age, reporting more sexual partners at all ages. Conclusions: The sexual behaviours of young people involved in the justice system in this study suggest they may be at a greater risk for sexually transmissible infections than their age-matched peers in the general population. Policymakers should elevate them to a priority population for targeting sexual health services and health promotion. [ABSTRACT FROM AUTHOR]

Aims: The use of incretin‐based therapy, rather than or complementary to, insulin therapy is an active area of research in hospitalized patients with type 2 diabetes (T2D). We determined the glycaemic efficacy and safety of linagliptin compared to a basal‐bolus insulin regimen in hospitalized surgical patients with T2D. Materials and Methods: This prospective open‐label multicentre study randomized T2D patients undergoing non‐cardiac surgery with admission blood glucose (BG) of 7.8 to 22.2 mmol/L who were under treatment with diet, oral agents or total insulin dose (TDD) ≤ 0.5 units/kg/day to either linagliptin (n = 128) daily or basal‐bolus (n = 122) with glargine once daily and rapid‐acting insulin before meals. Both groups received supplemental insulin for BG > 7.8 mmol/L. The primary endpoint was difference in mean daily BG between groups. Results: Mean daily BG was higher in the linagliptin group compared to the basal‐bolus group (9.5 ± 2.6 vs 8.8 ± 2.3 mmol/L/dL, P = 0.03) with a mean daily BG difference of 0.6 mmol/L (95% confidence interval 0.04, 1.2). In patients with randomization BG < 11.1 mmol/L (63% of cohort), mean daily BG was similar in the linagliptin and basal‐bolus groups (8.9 ± 2.3 vs 8.7 ± 2.3 mmol/L, P = 0.43); however, patients with BG ≥ 11.1 mmol/L who were treated with linagliptin had higher BG compared to the basal‐bolus group (10.9 ± 2.6 vs 9.2 ± 2.2 mmol/L, P < 0.001). Linagliptin resulted in fewer hypoglycaemic events (1.6% vs 11%, P = 0.001; 86% relative risk reduction), with similar supplemental insulin and fewer daily insulin injections (2.0 ± 3.3 vs 3.1 ± 3.3, P < 0.001) compared to the basal‐bolus group. Conclusions: For patients with T2D undergoing non‐cardiac surgery who presented with mild to moderate hyperglycaemia (BG < 11.1 mmol/L), daily linagliptin is a safe and effective alternative to multi‐dose insulin therapy, resulting in similar glucose control with lower hypoglycaemia. [ABSTRACT FROM AUTHOR]

Positive margin status due to incomplete removal of tumor tissue during radical prostatectomy for high-risk localized prostate cancer requires reoperation or adjuvant therapy, which increases morbidity and mortality. Adverse effects of prostate cancer treatments commonly include erectile dysfunction, urinary incontinence, and bowel dysfunction, making successful initial curative prostatectomy imperative. Current intraoperative tumor margin assessment is largely limited to frozen section analysis, which is a lengthy, labor-intensive process that is obtrusive to the clinical workflow within the operating room (OR). Therefore, a rapid method for prostate cancer margin assessment in the OR could improve outcomes for patients. Dual probe difference specimen imaging (DDSI), which uses paired antibody-based probes that are labeled with spectrally distinct fluorophores, was shown herein for prostate cancer margin assessment. The paired antibody-based probes consisted of a targeted probe to prostate-specific membrane antigen (PSMA) and an untargeted probe, which were used as a cocktail to stain resected murine tissue specimens including prostate tumor, adipose, muscle, and normal prostate. Ratiometric images (i.e., DDSI) of the difference between targeted and untargeted probe uptake were calculated and evaluated for accuracy using receiver operator characteristic curve analysis with area under the curve values used to evaluate the utility of the DDSI method to detect PSMA positive prostate cancer. Targeted and untargeted probe uptake was similar between the high and low PSMA expressing tumor due to nonspecific probe uptake after topical administration. The ratiometric DDSI approach showed substantial contrast difference between the PSMA positive tumors and their respective normal tissues (prostate, adipose, muscle). Furthermore, DDSI showed substantial contrast difference between the high PSMA expressing tumors and the minimally PSMA expressing tumors due to the ratiometric correction for the nonspecific uptake patterns in resected tissues. Previous work has shown that ratiometic imaging has strong predictive value for breast cancer margin status using topical administration. Translation of the ratiometric DDSI methodology herein from breast to prostate cancers demonstrates it as a robust, ratiometric technique that provides a molecularly specific imaging modality for intraoperative margin detection. Using the validated DDSI protocol on resected prostate cancers permitted rapid and accurate assessment of PSMA status as a surrogate for prostate cancer margin status. Future studies will further evaluate the utility of this technology to quantitatively characterize prostate margin status using PSMA as a biomarker. [ABSTRACT FROM AUTHOR]

Introduction Empirical evidence on family and community risk and protective factors influencing the comparatively high rates of potentially preventable hospitalisations and deaths among Aboriginal and Torres Strait Islander infants and children is limited. As is evidence on geographical variation in these risks. The 'Defying the Odds' study aims to explore the impact of perinatal outcomes, maternal social and health outcomes and level of culturally secure service availability on the health outcomes of Western Australian (WA) Aboriginal infants and children aged 0-5 years. Methods and analysis The study combines a retrospective cohort study that uses state-wide linked health and administrative data from 12 data sources for multiple generations within Aboriginal families in WA, with specifically collected survey data from health and social services supporting Aboriginal families in regions of WA. Data sources include perinatal/birth registration, hospital, emergency department, mental health services, drug and alcohol service use, mortality, infectious disease notifications, and child protection and family services. Multilevel regression models will be used to examine the intensity of admissions and presentations, mortality, intensity of long stays and morbidityfree survival (no admissions) for Aboriginal children born in WA in 2000-2013. Relationships between maternal (and grand-maternal) health and social factors and child health outcomes will be quantified. Community-level variation in outcomes for Aboriginal children and factors contributing to this variation will be examined, including the availability of culturally secure services. Online surveys were sent to staff members at relevant services to explore the scope, reach and cultural security of services available to support Aboriginal families across selected regions of WA. Ethics and dissemination Ethics approvals have been granted for the study. Interpretation and dissemination are guided by the study team's Aboriginal leadership and reference groups. Dissemination will be through direct feedback and reports to health services in the study and via scientific publications and policy recommendations. [ABSTRACT FROM AUTHOR]