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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]

Background: Evidence suggests that Aboriginal babies in Western Australia are not receiving adequate primary health care in their first 3 months of life, leading to questions about enablers and constraints to delivering such care. This paper presents findings from a qualitative research project investigating health providers' perceptions and experiences of best and current practice in discharge planning, postnatal care and health education for Aboriginal mothers and their newborn babies. Methods: Constructivist grounded theory guided this research involving 58 semi-structured interviews conducted with health providers who deliver care to Aboriginal mothers and infants. Participants were recruited from hospital-based and primary health sites in metropolitan Perth, and regional and remote locations in Western Australia. Results: Structural factors enabling best practice in discharge planning, postnatal care, and health education for mothers included health providers following best practice guidelines and adequate staffing levels. Organisational enablers included continuity of care throughout pregnancy, birth and postnatally. In particular, good communication between services around discharge planning, birth notifications, and training in culturally respectful care. Structural and organisational constraints to delivering best practice and compromising continuity of care were identified as beyond individual control. These included poor communication between different health and social services, insufficient hospital staffing levels leading to early discharge, inadequate cultural training, delayed receipt of birth notifications and discharge summaries received by Aboriginal primary health services. Conclusion: Findings highlight the importance of examining current policies and practices to promote best practice in postnatal care to improve health outcomes for mothers and their Aboriginal babies. [ABSTRACT FROM AUTHOR]

A number of highly multiplexed immunostaining and imaging methods have advanced spatial proteomics of cancer for improved treatment strategies. While a variety of methods have been developed, the most widely used methods are limited by harmful signal removal techniques, difficulties with reagent production and antigen sensitivity. Multiplexed immunostaining employing oligonucleotide (oligos)-barcoded antibodies is an alternative approach that is growing in popularity. However, challenges remain in consistent conjugation of oligos to antibodies with maintained antigenicity as well as non-destructive, robust and cost-effective signal removal methods. Herein, a variety of oligo conjugation and signal removal methods were evaluated in the development of a robust oligo conjugated antibody cyclic immunofluorescence (Ab-oligo cyCIF) methodology. Both non- and site-specific conjugation strategies were assessed to label antibodies, where site-specific conjugation resulted in higher retained binding affinity and antigen-specific staining. A variety of fluorescence signal removal methods were also evaluated, where incorporation of a photocleavable link (PCL) resulted in full fluorescence signal removal with minimal tissue disruption. In summary, this work resulted in an optimized Ab-oligo cyCIF platform capable of generating high dimensional images to characterize the spatial proteomics of the hallmarks of cancer. [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]

Persistently high, worldwide mortality from cancer highlights the unresolved challenges of disease surveillance and detection that impact survival. Development of a non-invasive, blood-based biomarker would transform survival from cancer. We demonstrate the functionality of ultra-high content analyses of a newly identified population of tumor cells that are hybrids between neoplastic and immune cells in patient matched tumor and peripheral blood specimens. Using oligonucleotide conjugated antibodies (Ab-oligo) permitting cyclic immunofluorescence (cyCIF), we present analyses of phenotypes among tumor and peripheral blood hybrid cells. Interestingly, the majority of circulating hybrid cell (CHC) subpopulations were not identified in tumor-associated hybrids. These results highlight the efficacy of ultra-high content phenotypic analyses using Ab-oligo based cyCIF applied to both tumor and peripheral blood specimens. The combination of a multiplex phenotypic profiling platform that is gentle enough to analyze blood to detect and evaluate disseminated tumor cells represents a novel approach to exploring novel tumor biology and potential utility for developing the population as a blood-based biomarker in cancer. [ABSTRACT FROM AUTHOR]

Persistently high, worldwide mortality from cancer highlights the unresolved challenges of disease surveillance and detection that impact survival. Development of a non-invasive, blood-based biomarker would transform survival from cancer. We demonstrate the functionality of ultra-high content analyses of a newly identified population of tumor cells that are hybrids between neoplastic and immune cells in patient matched tumor and peripheral blood specimens. Using oligonucleotide conjugated antibodies (Ab-oligo) permitting cyclic immunofluorescence (cyCIF), we present analyses of phenotypes among tumor and peripheral blood hybrid cells. Interestingly, the majority of circulating hybrid cell (CHC) subpopulations were not identified in tumor-associated hybrids. These results highlight the efficacy of ultra-high content phenotypic analyses using Ab-oligo based cyCIF applied to both tumor and peripheral blood specimens. The combination of a multiplex phenotypic profiling platform that is gentle enough to analyze blood to detect and evaluate disseminated tumor cells represents a novel approach to exploring novel tumor biology and potential utility for developing the population as a blood-based biomarker in cancer. [ABSTRACT FROM AUTHOR]

Purpose: The rise in the incarceration of Aboriginal and Torres Strait Islander mothers is a major public health issue with multiple sequelae for Aboriginal children and the cohesiveness of Aboriginal communities. The purpose of this paper is to review the available literature relating to Australian Aboriginal women prisoners' experiences of being a mother.Design/methodology/approach: The literature search covered bibliographic databases from criminology, sociology and anthropology, and Australian history. The authors review the literature on: traditional and contemporary Aboriginal mothering roles, values and practices; historical accounts of the impacts of white settlement of Australia and subsequent Aboriginal affairs policies and practices; and women's and mothers' experiences of imprisonment.Findings: The review found that the cultural experiences of mothering are unique to Aboriginal mothers and contrasted to non-Aboriginal concepts. The ways that incarceration of Aboriginal mothers disrupts child rearing practices within the cultural kinship system are identified.Practical Implications: Aboriginal women have unique circumstances relevant to the concept of motherhood that need to be understood to develop culturally relevant policy and programs. The burden of disease and cycle of incarceration within Aboriginal families can be addressed by improving health outcomes for incarcerated Aboriginal mothers and female carers.Originality/value: To the authors' knowledge, this is the first literature review on Australian Aboriginal women prisoners' experiences of being a mother. [ABSTRACT FROM AUTHOR]

Aboriginal and Torres Strait Islander women comprise the fastest growing subgroup among the prisoner population and are severely over-represented in Australian prisons. Despite the striking over-representation, research into their health and other needs has, to date, been limited. This paper describes the consultation process undertaken in Western Australia for the Social and Cultural Resilience and Emotional Wellbeing of Aboriginal Mothers in Prison project (hereafter, the Aboriginal Mothers in Prison project). The project aims to better understand the health, treatment and other needs of Aboriginal mothers in prison in Western Australia and New South Wales, and was conducted over two phases, the consultation phase and the applied research phase. This paper focuses on the results of the first phase of the research. It outlines the history of the development of ethics in this field and reviews the formal documents available to guide researchers working with Aboriginal and Torres Strait Islander peoples, tenets of which were infused throughout the research process. The paper then discusses how key stakeholders were identified in the area and provides an overview of the central findings from the consultation phase. In addition, the paper illustrates how being true to the consultation process and actively incorporating the feedback of diverse (and sometimes competing) stakeholders ensures the project acknowledges, respects and actions (where possible) the needs and concerns of the various agencies and individuals with investment in the issue. [ABSTRACT FROM AUTHOR]

Hypertension is a common disease that leads to significant cardiovascular morbidity and mortality. Adequate blood pressure control is essential in preventing end organ complications. One of the most popular antihypertensive strategies for the treatment of elevated blood pressure is to attenuate the actions of the renin-angiotensin-aldosterone system. The agents include the angiotensin converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibitors, and aldosterone antagonists. The ARBs inhibit the action of angiotensin II by binding to the angiotensin II type 1 receptor. The inhibition of angiotensin II results in a dose dependent decrease in peripheral resistance, reduction in vascular smooth muscle contraction, and reduced synthesis of aldosterone in the kidneys. Azilsartan medoxomil is a highly selective ARB. It was approved by the US Food and Drug Administration in February 2011 for the treatment of hypertension in adults. It is the eighth ARB to be added to the market. This article will discuss the pharmacologic and clinical characteristics of azilsartan medoxomil to help differentiate it from other ARBs that are used for the management of hypertension. [ABSTRACT FROM AUTHOR]

Over the past few years, first line managers in child care have faced mounting pressure on their time from both the national performance management agenda and the professional demands associated with the Framework for the Assessment of Children in Need and their Families and Working Together to Safeguard Children: A Guide to Inter-Agency Working to Safeguard and Promote the Welfare of Children. This paper briefly discusses the policy context surrounding this period of unprecedented change and focuses on the potential erosion of the reflective space in supervision as first line managers struggle to cope with the ever-increasing expectations. An argument is made for the creative use of multi-agency action learning/research projects within the workplace to supplement individual supervision and promote reflective multi-agency child care practice; some examples of successful projects are given. [ABSTRACT FROM AUTHOR]

The roots of adult civic and political participation originate in pre-adult experiences (Verba et al. 1995) and high school extracurricular activities offer students opportunities to develop interpersonal and leadership skills. In this research, we ask whether adolescents also learn gendered norms of political discourse through extracurricular activities. This project assessed gender differences in participation at the 1999 Model United Nations of the Southwest (MUNSW) at the University of Oklahoma. Important differences in participation were observed in the number and character of speaking turns taken by male and female delegates. We find that contextual factors, such as the sex of the committee chair, the issue areas addressed by the committee, and the timing of the session in the conference significantly influence who participates in the discourse, but the percentage of female participants surprisingly does not. The character of the political discourse suggests norms dominated by masculinity. [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]

This paper explores professional decision-making in cases of child neglect within the context of child protection practice in Britain. The literature on the nature of neglect is reviewed. Difficulties associated with decision-making are then examined within a framework that addresses the social, political and organizational context of child protection practice. It is argued that the current system, which focuses on incidents of abuse rather than the context of children's lives, provides inadequate protection for many children experiencing chronic neglect. Conclusions are drawn with regard to the development of practice that supports vulnerable parents while still remaining the child's welfare as paramount. © 1998 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Significance: Advanced genetic characterization has informed cancer heterogeneity and the challenge it poses to effective therapy; however, current methods lack spatial context, which is vital to successful cancer therapy. Conventional immunolabeling, commonplace in the clinic, can provide spatial context to protein expression. However, these techniques are spectrally limited, resulting in inadequate capacity to resolve the heterogenous cell subpopulations within a tumor. Aim: We developed and optimized oligonucleotide conjugated antibodies (Ab-oligo) to facilitate cyclic immunofluorescence (cyCIF), resulting in high-dimensional immunostaining. Approach: We employed a site-specific conjugation strategy to label antibodies with unique oligonucleotide sequences, which were hybridized in situ with their complementary oligonucleotide sequence tagged with a conventional fluorophore. Antibody concentration, imaging strand concentration, and configuration as well as signal removal strategies were optimized to generate maximal staining intensity using our Ab-oligo cyCIF strategy. Results: We successfully generated 14 Ab-oligo conjugates and validated their antigen specificity, which was maintained in single color staining studies. With the validated antibodies, we generated up to 14-color imaging data sets of human breast cancer tissues. Conclusions: Herein, we demonstrated the utility of Ab-oligo cyCIF as a platform for highly multiplexed imaging, its utility to measure tumor heterogeneity, and its potential for future use in clinical histopathology. [ABSTRACT FROM AUTHOR]

The overrepresentation of Aboriginal and Torres Strait Islander (respectfully referred to hereafter as “Aboriginal”) children in the child protection system is a concern in Australia, with Aboriginal children placed in out-of-home care at a rate 11 times that of non-Aboriginal children. This study utilised linked administrative data to determine the longitudinal child protection pathways from birth to age 10 years for a cohort of 15,815 Aboriginal children born in Western Australia between 2000 and 2006. In total, 9,269 (59%) children did not have any contact with child protection between one year prior to birth and their 11th birthday. Conversely, 6,546 (41%) Aboriginal children were involved with child protection during the study period, with 1,405 (9%) children placed in out-of-home care. Infants who had a child protection notification were more likely than other age groups to have a substantiated notification of abuse and neglect and placed in out-of-home care. More than half (56%) of all children were predominantly placed in kinship care; however, only 22% had their first placement with kinship carers. Aboriginal-led strategies together with the support and commitment of all levels of government are required to reduce entry into care and improve outcomes for Aboriginal children in care.IMPLICATIONSAboriginal-led strategies and wholistic responses can reduce the overrepresentation of Aboriginal children reported to child protection systems, and support families and communities.Infancy stands out as a key point of system involvement. This stage offers an opportunity where early intervention and family support strategies may prevent first time involvement with the child protection services and promote kinship placement, reunification with parents, and community-led supportive care.Aboriginal-led strategies and wholistic responses can reduce the overrepresentation of Aboriginal children reported to child protection systems, and support families and communities.Infancy stands out as a key point of system involvement. This stage offers an opportunity where early intervention and family support strategies may prevent first time involvement with the child protection services and promote kinship placement, reunification with parents, and community-led supportive care. [ABSTRACT FROM AUTHOR]

Background: Indigenous people are insightful and informed about their own health and wellness, yet their visions, strengths and knowledge are rarely incorporated into health research. This can lead to subpar engagement or irrelevant research practices, which exacerbates the existing health inequities Indigenous people experience compared to the non-Indigenous population. Data consistently underscores the importance of Indigenous self-determination in research as a means to address health inequities. However, there are few formal methods to support this goal within the existing research context, which is dominated by Western perspectives. Main text: Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) is a patient-oriented research network in Canada that recognizes the need to create the space to facilitate Indigenous self-determination in research. Indigenous members of the network therefore created and evolved a unique group, called the Indigenous Peoples' Engagement and Research Council (IPERC). IPERC plays a critical role in informing Can-SOLVE CKD research priorities, as well as creating tools to support Indigenous-specific research and engagement. This approach ensures that Indigenous voices and knowledge are critical threads within the fabric of the network's operations and research projects. Here, we describe the methods taken to create a council such as IPERC, and provide examples of initiatives by the council that aim to increase Indigenous representation, participation and partnership in research. We share lessons learned on what factors contribute to the success of IPERC, which could be valuable for other organizations interested in creating Indigenous-led research councils. Conclusion: Indigenous self-determination in research is critical for addressing health inequities. Here, we present a unique model, led by a council of diverse Indigenous people, which could help reduce health equities and lead to a better era of research for everyone. [ABSTRACT FROM AUTHOR]

This study aimed to identify key transitional pathways in the criminal justice system from adolescence to adulthood and the risk factors associated with the escalation of criminal justice involvement over time. We retrospectively linked offending records from 1994 to 2022 and mental health records from 2001 to 2022 for a cohort of 1556 adolescents identified through four health surveys in New South Wales, Australia. Transition probabilities were calculated using the Aalen-Johansen method, and the hazards of transition-specific covariates were estimated. The median age of adolescent entry was 15 years. The cohort was predominantly male (87.5%) and non-Indigenous (65.6%). Among incarcerated adolescents, 76.8% transitioned to adult incarceration. Transition probabilities were the highest among those aged 10–13 years. Among those with mental disorders, psychosis was associated with transitions to adolescent and adult incarceration. Other risk factors for future incarceration include being male, Indigenous, socio-economically disadvantaged, having a history of adolescent incarceration, and being diagnosed with substance use and behavioural disorders. Younger adolescents have higher transition probabilities to more intense criminal justice involvement. Legislative and policy reforms are needed to delay the onset of adolescent criminal justice involvement and ensure age-appropriate rehabilitative strategies to reduce recidivism. • Multi-state modelling can be used to assess criminal justice transitions from adolescence to adulthood. • Younger adolescents have higher probabilities of further incarceration after entry into the criminal justice system. • Adolescent incarceration is associated with adult incarceration and has a leveling effect regardless of age at entry. • Mental disorders increase the risk of incarceration during adolescence and adulthood. [ABSTRACT FROM AUTHOR]

Twenty-four sites in northern Tasmania on Ferrosols formed on Tertiary basalt were sampled in 1997, 2005, and 2010. The farming systems at the sites during this period were either (a) continuous pasture, (b) continuous cropping of vegetable, cereal, and other cash crops in rotation, or (c) a mix of pasture and cropping (intermittent cropping). Average organic carbon (OC) concentrations across all sites and both sample depths (0–150 mm and 150–300 mm) decreased from 4.0% in 1997 to 3.5% in 2005 and 3.3% in 2010 (P< 0.001). Average OC was greater at 0–150 mm (4.1%) than at 150–300 mm (3.1%) (P< 0.001). Average total soil nitrogen (N) in 2010 (0.42%) at 0–150 mm was not significantly different (P = 0.07) from the average in 1997 (0.38%). Soil pH in water (pHw) showed the opposite trend to OC, increasing with time from 6.0 in 1997 to 6.2 in 2010. This reflects the consistent use of calcite and dolomite in Tasmanian farming because the natural pHwof these soils is less than 5.5. Exchangeable calcium and magnesium were also greater in 2010 compared with 1997. Bicarbonate-extractable phosphorus (P) averaged across both depths increased (P< 0.001) steadily from 77 mg kg−1in 1997 to 95 mg kg−1in 2005 to 126 mg kg−1in 2010. At the five sites that remained under continuous cropping throughout the study, average 2010 OC in the topsoil was 3.2%, a decrease of 0.5% since 1997; pHwwas unchanged at 6.4; and bicarbonate-extractable P increased by an average of 73 mg kg−1to 211 mg kg−1. For the three sites that remained in pasture the corresponding topsoil changes were 0.3% less OC to an average of 4.8%; pHw0.4 units greater at 6.0; and 41 mg kg−1more bicarbonate-extractable P to an average of 99 mg kg−1. At the six sites converted from continuous pasture to intermittent cropping the average 2010 topsoil OC was 4.5%, a loss of 1.3%; pHwincreased by 0.5 units to 6.1; and bicarbonate-extractable P increased by 35 mg kg−1to 97 mg kg−1. There was a highly significant (R2= 0.82) exponential relationship between topsoil OC in 2010 and the number of years each site had been cropped during the 38 years 1972–2010, for which reliable records were available (OC = 4.933e−0.018years), which suggested an equilibrium topsoil OC concentration of about 2.5% under continuous cropping on these soils. These results indicate that Tasmanian farmers on Ferrosols continue to increase the pHwand P fertility of their soils and that increasing cropping intensity on these soils comes at the expense of soil carbon. [ABSTRACT FROM AUTHOR]

The administration of insulin is recommended to patients with severe sepsis and hyperglycemia. Previously, we demonstrated that insulin may have direct anti- inflammatory properties and counteracted fluid losses from the circulation by normalizing the interstitial fluid pressure (PIF). PIF is one of the Starling forces determining fluid flux over the capillary wall, and a lowered PIF is one of the driving forces in early edema formation in inflammatory reactions. Here we demonstrate that insulin restores a lipopolysaccharide (LPS)-lowered P1~ via a mechanism involving integrin ~ In C57 black mice (n = 6), LPS lowered PIF from -0.2 ± 0.2 to -1.6 ± 0.3 (P < 0.05) and after insulin averaged -0.8 ± 0.2 mmHg (P = 0.098 compared with after LPS). Corre- sponding values in wild-type BALB/c mice (n = 5) were -0.8 ± 0.1, - 2.1 ± 0.3 (P < 0.05), and -0.8 ± 0.3 mmHg (P < 0.05 compared with LPS) after insulin administration~ In BALB/c integrin f33- deficient (13) mice (n = 6), LPS lowered PIF from -0.1 ± 0.2 to -1.5 ± 0.3 mmHg (P < 0.05). Insulin did not, however, restore PIF in these mice (averaged -1.7 ± 0.3 mmHg after insulinadministra- tion). Cell-mediated collagen gel contraction can serve as an in vitro model for in vivo measurements of PIF. Insulin induced crV~3-integrin- dependent collagen gel contraction mediated by C2C12 cells. Our findings suggest a beneficiary effect of insulin for patients with sepsis with regard to the fluid balance, and this effect may in part be due to a normalization of PIF by a mechanism involving the integrin aV133. [ABSTRACT FROM AUTHOR]

Purpose: Personalized medicine has largely failed to produce curative therapies in advanced cancer patients. Evaluation of in situ drug target availability (DTA) concomitant with local protein expression is critical to an accurate assessment of therapeutic efficacy, but tools capable of both are currently lacking. Procedure: We developed and optimized a fluorescence imaging platform termed TRIPODD (Therapeutic Response Imaging through Proteomic and Optical Drug Distribution), resulting in the only methodology capable of simultaneous quantification of single-cell DTA and protein expression with preserved spatial context within a tumor. Using TRIPODD, we demonstrate the feasibility of combining two complementary fluorescence imaging techniques, intracellular paired agent imaging (iPAI) and cyclic immunofluorescence (cyCIF), conducted with oligonucleotide-conjugated antibodies (Ab-oligos) on tissue samples. Results: We successfully performed sequential imaging on a single tissue section of iPAI to capture single-cell DTA and local protein expression heterogeneity using Ab-oligo cyCIF. Fluorescence imaging data acquisition was followed by spatial registration resulting in high dimensional data correlating DTA to protein expression at the single-cell level where uptake of a targeted probe alone was not well correlated to protein expression. Conclusion: Herein, we demonstrated the utility of TRIPODD as a powerful imaging platform capable of interpreting tumor heterogeneity for a mechanistic understanding of therapeutic response and resistance through quantification of drug target availability and proteomic response with preserved spatial context at single-cell resolution. [ABSTRACT FROM AUTHOR]

Objective. We ask: How do socialization experiences shape adolescent perceptions of and the performance of gender in political leadership roles? We examine a political simulation, Model United Nations, which attracts academically motivated students aspiring to elite roles in politics and government. Methods. Using observational and survey data, we explore adolescent behavior in the simulation as both a learning experience and as a reflection of students' perceptions of leadership behavior. Results. Three critical observations emerge. First, the Model United Nations is a domain in which young women do not play an equal part. Female delegates take far fewer speaking turns. However, contextual factors, including membership on a committee that deals with less masculine issues and on a committee with a female chair, increase the likelihood of female turn-taking. Second, though participants come to the event with very similar motivations, young women leave less satisfied with their personal effectiveness than do young men. Finally, female delegates are judged less favorably by themselves and others and thus as less successful in the simulation. Conclusions. These findings have normative implications for the recruitment of young women to politics. [ABSTRACT FROM AUTHOR]

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]

Reducing the over-representation of Aboriginal children in the child protection system is a key target for the Australian government. We aimed to provide more recent evidence on the population-level cumulative incidence of contacts for Aboriginal children with child protective services (CPS) in Western Australia (WA). Linked administrative data was provided for WA CPS between 2000 and 2015 for 33,709 Aboriginal children born in WA between 2000 and 2013. Descriptive summaries and cumulative incidence estimates were used to examine changes in CPS contact trends over time and within sibling groups. There was an increase in early-childhood contacts for children born more recently, with 7.6 % and 2.3 % of children born in 2000–2001 having a notification and placement in out-of-home care by age one, respectively, compared to 15.1 % and 4.3 % of children born in 2012–2013. Among sibling groups where at least one sibling had a CPS contact, approximately half of children had their first contacts on the same date as another sibling. For children born after one of their siblings had been placed in out-of-home care, 31.9 % had themselves been placed in out-of-home care by age one. Multiple children tend to be placed into out-of-home care when at least one sibling is, which is likely to have a significant impact on families affected. The additional risk of placement also carries over to children born after the first removal in a sibling group, highlighting the need for further support to prevent future removals. [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]

Background: Aboriginal infants have poorer birth outcomes than non-Aboriginal infants. Harmful use of tobacco, alcohol, and other substances is higher among Aboriginal women, as is violence, due to factors such as intergenerational trauma and poverty. We estimated the proportion of small for gestational age (SGA) births, preterm births, and perinatal deaths that could be attributed to these risks.Methods: Birth, hospital, mental health, and death records for Aboriginal singleton infants born in Western Australia from 1998 to 2010 and their parents were linked. Using logistic regression with a generalized estimating equation approach, associations with birth outcomes and population attributable fractions were estimated after adjusting for demographic factors and maternal health during pregnancy.Results: Of 28,119 births, 16% of infants were SGA, 13% were preterm, and 2% died perinatally. 51% of infants were exposed in utero to at least one of the risk factors and the fractions attributable to them were 37% (SGA), 16% (preterm) and 20% (perinatal death).Conclusions: A large proportion of adverse outcomes were attributable to the modifiable risk factors of substance use and assault. Significant improvements in Aboriginal perinatal health are likely to follow reductions in these risk factors. These results highlight the importance of identifying and implementing risk reduction measures which are effective in, and supported by, Aboriginal women, families, and communities. [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]

Background: Hepatitis C virus infection (HCV) has a significant global health burden with an estimated 2%–3% of the world's population infected, and more than 350,000 dying annually from HCV-related conditions including liver failure and liver cancer. Prisons potentially offer a relatively stable environment in which to commence treatment as they usually provide good access to health care providers, and are organised around routine and structure. Uptake of treatment of HCV, however, remains low in the community and in prisons. In this study, we explored factors affecting treatment uptake inside prisons and hypothesised that prisoners have unique issues influencing HCV treatment uptake as a consequence of their incarceration which are not experienced in other populations. Method and Findings: We undertook a qualitative study exploring prisoners' accounts of why they refused, deferred, delayed or discontinued HCV treatment in prison. Between 2010 and 2013, 116 Australian inmates were interviewed from prisons in New South Wales, Queensland, and Western Australia. Prisoners experienced many factors similar to those which influence treatment uptake of those living with HCV infection in the community. Incarceration, however, provides different circumstances of how these factors are experienced which need to be better understood if the number of prisoners receiving treatment is to be increased. We developed a descriptive model of patient readiness and motivators for HCV treatment inside prisons and discussed how we can improve treatment uptake among prisoners. Conclusion: This study identified a broad and unique range of challenges to treatment of HCV in prison. Some of these are likely to be diminished by improving treatment options and improved models of health care delivery. Other barriers relate to inmate understanding of their illness and stigmatisation by other inmates and custodial staff and generally appear less amenable to change although there is potential for peer-based education to address lack of knowledge and stigma. [ABSTRACT FROM AUTHOR]

Abstract: The loss of dopaminergic neurons induced by the parkinsonian toxins paraquat, rotenone, and 1-methyl-4-phenylpyridinium (MPP+) is associated with oxidative stress. However, controversial reports exist regarding the source/compartmentalization of reactive oxygen species (ROS) generation and its exact role in cell death. We aimed to determine in detail the role of superoxide anion (O2 •-), oxidative stress, and their subcellular compartmentalization in dopaminergic cell death induced by parkinsonian toxins. Oxidative stress and ROS formation were determined in the cytosol, intermembrane (IMS), and mitochondrial matrix compartments, using dihydroethidine derivatives and the redox sensor roGFP, as well as electron paramagnetic resonance spectroscopy. Paraquat induced an increase in ROS and oxidative stress in both the cytosol and the mitochondrial matrix prior to cell death. MPP+ and rotenone primarily induced an increase in ROS and oxidative stress in the mitochondrial matrix. No oxidative stress was detected at the level of the IMS. In contrast to previous studies, overexpression of manganese superoxide dismutase (MnSOD) or copper/zinc SOD (CuZnSOD) had no effect on alterations in ROS steady-state levels, lipid peroxidation, loss of mitochondrial membrane potential (ΔΨm), and dopaminergic cell death induced by MPP+ or rotenone. In contrast, paraquat-induced oxidative stress and cell death were selectively reduced by MnSOD overexpression, but not by CuZnSOD or manganese-porphyrins. However, MnSOD also failed to prevent ΔΨm loss. Finally, paraquat, but not MPP+ or rotenone, induced the transcriptional activation of the redox-sensitive antioxidant response elements (ARE) and nuclear factor kappa-B (NF-κB). These results demonstrate a selective role of mitochondrial O2 •- in dopaminergic cell death induced by paraquat, and show that toxicity induced by the complex I inhibitors rotenone and MPP+ does not depend directly on mitochondrial O2 •- formation. [Copyright &y& Elsevier]

Abstract: The studies presented here demonstrate the protective effect of acetyl-l-carnitine (ALC) against alcohol-induced oxidative neuroinflammation, neuronal degeneration, and impaired neurotransmission. Our findings reveal the cellular and biochemical mechanisms of alcohol-induced oxidative damage in various types of brain cells. Chronic ethanol administration to mice caused an increase in inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine adduct formation in frontal cortical neurons but not in astrocytes from brains of these animals. Interestingly, alcohol administration caused a rather selective activation of NADPH oxidase (NOX), which, in turn, enhanced levels of reactive oxygen species (ROS) and 4-hydroxynonenal, but these were predominantly localized in astrocytes and microglia. Oxidative damage in glial cells was accompanied by their pronounced activation (astrogliosis) and coincident neuronal loss, suggesting that inflammation in glial cells caused neuronal degeneration. Immunohistochemistry studies indicated that alcohol consumption induced different oxidative mediators in different brain cell types. Thus, nitric oxide was mostly detected in iNOS-expressing neurons, whereas ROS were predominantly generated in NOX-expressing glial cells after alcohol ingestion. Assessment of neuronal activity in ex vivo frontal cortical brain tissue slices from ethanol-fed mice showed a reduction in long-term potentiation synaptic transmission compared with slices from controls. Coadministration of ALC with alcohol showed a significant reduction in oxidative damage and neuronal loss and a restoration of synaptic neurotransmission in this brain region, suggesting that ALC protects brain cells from ethanol-induced oxidative injury. These findings suggest the potential clinical utility of ALC as a neuroprotective agent that prevents alcohol-induced brain damage and development of neurological disorders. [ABSTRACT FROM AUTHOR]