What can primary care services do to help First Nations people with unhealthy alcohol use? A systematic review : Australia, New Zealand, USA and Canada

Background First Nations peoples of Australia, New Zealand, the United States of America (USA) and Canada are more likely to be non-drinkers than other people in these countries. However, those who do drink may be at greater risk of alcohol-related harms (at a population level) due to the ongoing impacts from colonisation and associated oppression. Addressing unhealthy drinking (drinking above recommended limits including alcohol use disorders) in primary care settings is one important way to increase accessibility of treatment. Methods This systematic review identifies peer-reviewed studies of alcohol treatments delivered in primary care or other non-residential settings for First Nations peoples of Australia, New Zealand, USA and Canada. Literature searches were conducted in seven academic databases from their inception until March, 2020. We assessed evidence of treatment or implementation effectiveness, perceived acceptability or accessibility, and the study quality as assessed by the AXIS tool and by a measure of community participation in the research process. Results Twenty-eight studies were included, published between 1968 and 2018. Studies reported on a range of alcohol treatments, from brief intervention to ambulatory withdrawal management, relapse prevention medicines, and cultural therapies. Brief intervention was the most studied approach. Cultural healing practices and bicultural approaches were a key theme amongst several studies. Four studies measured treatment effectiveness, including one randomised controlled trial (naltrexone vs naltrexone plus sertraline vs placebo) and two uncontrolled trials of disulfiram. Of the six implementation studies, three were (hybrid) effectiveness-implementation designs. Most of the remaining studies (n = 21) focused on treatment accessibility or acceptability. Community participation in the research process was poorly reported in most studies. Conclusions Research evidence on how best to care for First Nations peoples with unhealthy alcohol use is limited. Trials of naltrexone and disulfiram presented promising results. Cultural and bicultural care were perceived as highly important to clinical staff and clients in several studies. More effectiveness studies on the full scope of alcohol treatments are needed. Greater community participation in research and more transparent reporting of this in study methods will be key to producing quality research that combines scientific rigour with cultural appropriateness

Interleukin-21 Is Critically Required in Autoimmune and Allogeneic Responses to Islet Tissue in Murine Models

OBJECTIVE-Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. RESEARCH DESIGN AND METHODS-NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed. RESULTS-Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. CONCLUSIONS-Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes. Diabetes 60:867-875, 20111151sciescopu

Gene Dosage–limiting Role of Aire in Thymic Expression, Clonal Deletion, and Organ-specific Autoimmunity

Inactivation of the autoimmune regulator (Aire) gene causes a rare recessive disorder, autoimmune polyendocrine syndrome 1 (APS1), but it is not known if Aire-dependent tolerance mechanisms are susceptible to the quantitative genetic changes thought to underlie more common autoimmune diseases. In mice with a targeted mutation, complete loss of Aire abolished expression of an insulin promoter transgene in thymic epithelium, but had no effect in pancreatic islets or the testes. Loss of one copy of Aire diminished thymic expression of the endogenous insulin gene and the transgene, resulting in a 300% increase in islet-reactive CD4 T cells escaping thymic deletion in T cell receptor transgenic mice, and dramatically increased progression to diabetes. Thymic deletion induced by antigen under control of the thyroglobulin promoter was abolished in Aire homozygotes and less efficient in heterozygotes, providing an explanation for thyroid autoimmunity in APS1. In contrast, Aire deficiency had no effect on thymic deletion to antigen controlled by a systemic H-2K promoter. The sensitivity of Aire-dependent thymic deletion to small reductions in function makes this pathway a prime candidate for more subtle autoimmune quantitative trait loci, and suggests that methods to increase Aire activity would be a potent strategy to lower the incidence of organ-specific autoimmunity

The landscape of COVID-19 trials in Australia

This perspective explores the landscape of COVID-19 trials recruiting in Australia using trial registry data. We identified 56 trials addressing treatment and prevention of COVID-19, and 12 trials addressing indirect effects of the pandemic. Whilst there was substantial innovation in drug development and digital health, the potential of innovation in methodology, such as adaptive trials, remains largely untapped. Data sharing intentions were low, sample sizes were too small to detect differences in clinical outcomes, such as mortality, and lack of core outcome collection precludes evidence synthesis. Infrastructure for innovation would support coordination of research efforts, and reduce research waste

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation

Latest update of the clinical trials landscape in Australia (2006 – 2020)

The latest update of the clinical trials landscape in Australia (2006 – 2020) uses trial registration data to gain an understanding of the clinical trials occurring in Australia. This report is an update of the original report covering 2006-2015 and includes new data from 2016 to 2020. These data are sourced from the Australian New Zealand Clinical Trials Registry (ANZCTR) and US-based ClinicalTrials.gov registry. The purpose of this report is to provide a comprehensive outline of the key characteristics of clinical trials over time. Reporting on clinical trial activity is a crucial step in understanding where improvements may be needed in the clinical trials sector. This report can be used as a reference point when promoting Australian clinical trial activity at national or international forums. It is intended to be used by all those working in or with clinical trials including clinical trial investigators, researchers, funders, industry, policymakers, trial participants and the public. Previous reports analysing trial activity in Australia have helped to identify research gaps and prioritise funding schemes and to inform the design of new national infrastructure that facilitates clinical trial data sharing. We hope this updated report will be of similar use and help to inform the health research agenda in government and industry

Latest update of the clinical trials landscape in Australia (2006 – 2020)

The latest update of the clinical trials landscape in Australia (2006 – 2020) uses trial registration data to gain an understanding of the clinical trials occurring in Australia. This report is an update of the original report covering 2006-2015 and includes new data from 2016 to 2020. These data are sourced from the Australian New Zealand Clinical Trials Registry (ANZCTR) and US-based ClinicalTrials.gov registry. The purpose of this report is to provide a comprehensive outline of the key characteristics of clinical trials over time. Reporting on clinical trial activity is a crucial step in understanding where improvements may be needed in the clinical trials sector. This report can be used as a reference point when promoting Australian clinical trial activity at national or international forums. It is intended to be used by all those working in or with clinical trials including clinical trial investigators, researchers, funders, industry, policymakers, trial participants and the public. Previous reports analysing trial activity in Australia have helped to identify research gaps and prioritise funding schemes and to inform the design of new national infrastructure that facilitates clinical trial data sharing. We hope this updated report will be of similar use and help to inform the health research agenda in government and industry

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3(+) regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21: IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.This work was supported by grants from the Diabetes Australia Research Trust and the National Health and Medical Research Council

CD45-mediated control of TCR tuning in naive and memory CD8(+) T cells

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naive T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8(+) T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8(+) T cells than naive cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8(+) T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens. (c) The Author(s) 20161991sciescopu

A randomised controlled trial of the efficacy of the ABCD Parenting Young Adolescents Program: rationale and methodology

Background: The transition to adolescence is a time of increased vulnerability for risk taking and poor health, social and academic outcomes. Parents have an important role in protecting their children from these potential harms. While the effectiveness of parenting programs in reducing problem behavior has been demonstrated, it is not known if parenting programs that target families prior to the onset of significant behavioral difficulties in early adolescence (9-14 years) improve the wellbeing of adolescents and their parents. This paper describes the rationale and methodology of a randomised controlled trial testing the efficacy of a parenting program for the promotion of factors known to be associated with positive adolescent outcomes, such as positive parenting practices, parent-adolescent relationships and adolescent behavior.Methods/Design: One hundred and eighty parents were randomly allocated to an intervention or wait list control group. Parents in the intervention group participated in the ABCD Parenting Young Adolescents Program, a 6-session behavioral family intervention program which also incorporates acceptance-based strategies. Participants in the Wait List control group did not receive the intervention during a six month waiting period. The study was designed to comply with recommendations of the CONSORT statement. The primary outcome measures were reduction in parent-adolescent conflict and improvements in parent-adolescent relationships. Secondary outcomes included improvements in parent psychosocial wellbeing, parenting self-efficacy and perceived effectiveness, parent-adolescent communication and adolescent behavior.Conclusions: Despite the effectiveness of parenting programs in reducing child behavioral difficulties, very few parenting programs for preventing problems in adolescents have been described in the peer reviewed literature. This study will provide data which can be used to examine the efficacy of a universal parenting interventions for the promotion of protective factors associated with adolescent wellbeing and will add to the literature regarding the relationships between parent, parenting and adolescent factors