Remote neuronal activity drives glioma progression through SEMA4F.

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

Significant healthcare resource utilisation in the management of skin and soft tissue infections in the Torres Strait, Australia.

INTRODUCTION: Aboriginal and Torres Strait Islander Peoples (First Nations Australians) living in remote communities are hospitalised with skin and soft tissue infections (SSTIs) at three times the rate of non-First Nations Australians. The Torres Strait in tropical northern Australia has a highly dispersed population mainly comprising First Nations Australians. This study aimed to define the health service utilisation and health system costs associated with SSTIs in the Torres Strait and to improve the quality of regional healthcare delivery. METHODS: The research team conducted a retrospective, de-identified audit of health records for a 2-year period, 2018-2019. The aim was to define health service utilisation, episodes of outpatient care, emergency department care, inpatient care and aeromedical retrieval services for SSTIs. RESULTS: Across 2018 - 2019, there were 3509 outpatient episodes of care for SSTIs as well as 507 emergency department visits and 100 hospitalisations. For individuals with an SSTI, the mean outpatient clinic episode cost $240; the mean emergency department episode cost $400.85, the mean inpatient episode cost $8403.05 while an aeromedical retrieval service cost $18,670. The total costs to the health system for all services accessed for SSTI management was $6,169,881 per year, 3% of the total annual health service budget. CONCLUSION: Healthcare costs associated with SSTIs in the Torres Strait are substantial. The implementation of effective preventative and primary care interventions may enable resources to be reallocated to address other health priorities in the Torres Strait.

Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers.

INTRODUCTION: Meningiomas are the most common primary intracranial tumor. Recently, various genetic classification systems for meningioma have been described. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored. METHODS: 88 tumor samples were analyzed in this study. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA). RESULTS: Fifty-seven patients had no history of smoking, twenty-two were past smokers, and nine were current smokers. The clinical data showed no major differences in natural history across smoking status. WES revealed absence of AKT1 mutation rate in current or past smokers compared to non-smokers (p = 0.046). Current smokers had increased mutation rate in NOTCH2 compared to past and never smokers (p < 0.05). Mutational signature from current and past smokers showed disrupted DNA mismatch repair (cosine-similarity = 0.759 and 0.783). DEG analysis revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = - 3.97, padj = 0.0347 and Log2FC = - 4.18, padj = 0.0304) and never smokers (Log2FC = - 3.86, padj = 0.0235 and Log2FC = - 4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR < 25% each). CONCLUSION: In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.

Marginal allografts in liver transplantation have a limited impact on length of stay.

The study of marginal liver transplant outcomes, including post-transplant length of stay (LOS), is necessary for determining the practicality of their use. 50 155 patients who received transplants from 2012 to 2020 were retrospectively analyzed with data from the Scientific Registry of Transplant Recipients database using Kaplan-Meier survival curves and multivariable Cox regression. Six different definitions were used to classify an allograft as being marginal: 90th percentile Donor Risk Index (DRI) allografts, donation after cardiac death (DCD) donors, national share donors, donors over 70, donors with > 30% macrovesicular steatosis, or 90th percentile Discard Risk Index donors. 24% (n = 12 124) of subjects received marginal allografts. Average LOS was 15.6 days among those who received standard allografts. Among those who received marginal allografts, LOS was found to be highest in those who received 90th percentile DRI allografts at 15.6 days, and lowest in those who received DCD allografts at 12.7 days. Apart from fatty livers (95% CI .86-.98), marginal allografts were not associated with a prolonged LOS. We conclude that accounting for experience and recipient matching, transplant centers may be more aggressive in their use of extended criteria donors with limited fear of increasing LOS and its associated costs.

Significant improvements, but consistent disparities in survival for African Americans after liver transplantation.

Despite improvements in survival across races in the past 20 years, African Americans have worse liver transplant outcomes after orthotopic liver transplantation (OLT). This study aims at quantifying the change in disparities between African Americans and other races in survival after OLT. We retrospectively analyzed the United Network for Organ Sharing (UNOS) database for patient data for candidates who received a liver transplant between January 1, 2007 and December 31, 2017. Multivariate Cox proportional hazards regression indicated similar decreases in mortality over time for each race with a decrease in mortality for African Americans: 2010-2012 (HR = .930), 2012-2015 (HR = .882), and 2015-2017 (HR = .883) when compared to 2007-2010. Risk of mortality for African Americans compared to Caucasians varied across the 4 eras: 2007-2010 (HR = 1.083), 2010-2012 (HR = 1.090), 2012-2015 (HR = 1.070), and 2015-2017 (HR = 1.125). While African Americans have seen increases in survival in the past decade, a similar increase in survival for other races leaves a significant survival disparity in African Americans.

Varied histomorphology and clinical outcomes of FGFR3-TACC3 fusion gliomas.

Targeted therapies for driver gene fusions in cancers have yielded substantial improvements in care. Here, the authors outline a case series of 6 patients with FGFR3-TACC3 fusion in primary brain tumors ranging from polymorphous low-grade neuroepithelial tumor of the young to papillary glioneuronal tumors and glioblastoma (GBM). Previous studies indicated the FGFR3-TACC3 fusion provides survival benefit to GBM patients. Consistent with this, 2 patients with GBM had unexpectedly good outcomes and survived for 5 and 7 years, respectively. In contrast, 2 patients with initially lower graded tumors survived only 3 years and 1 year, respectively. One patient received erdafitinib, a targeted FGFR inhibitor, for 3 months at late disease recurrence and no response was seen. There were varied histomorphological features, including many cases that lacked the characteristic FGFR3-TACC3 pathology. The findings of this cohort suggest that molecular testing is justified, even for glioma cases lacking classic histopathological signatures. Currently, FGFR3-TACC3 fusion gliomas are often classified on the basis of histopathological features. However, further research is needed to examine whether IDH1/2-wild-type tumors with FGFR3-TACC3 fusion should be classified as a subtype on the basis of this molecular fusion. Because patients with IDH1/2-wild-type GBM with FGFR3-TACC3 fusion have improved survival, routine molecular testing for this mutation in patients enrolled in clinical trials and subsequent stratification may be warranted.

Healthy Skin, Healthy Mepla: A skin health promotional event for children in the Torres Strait.

ISSUE ADDRESSED: Skin infections such as impetigo and scabies are common in Aboriginal Australian and Torres Strait Islander children living in rural and remote settings. Effective health promotion is a key element when addressing health literacy aimed at reducing the burden of skin disease. Community-driven health promotion provides a potentially effective and sustainable model for improved health outcomes. METHODS: A one-day community-driven skin health promotional event was conducted on Waiben [Thursday Island] with the aim of improving local Torres Strait Islander children's appreciation of the importance of skin health through art, music and creation of a video. Participants completed written pre- and post-questionnaires to determine their response. RESULTS: Fifty-two children participated in the event; median (range) age was 11 (9-12) years and all identified as Torres Strait Islander. Overall, 34 of 50 children (68%) felt that participating in this workshop improved their skin health knowledge. CONCLUSIONS: Skin health promotion can be successful achieved through a locally conceived, locally driven and locally owned approach. SO WHAT?: This skin health promotional event could be a model for other health promotion activities in the Torres Strait.

Epidemiological consequences of enduring strain-specific immunity requiring repeated episodes of infection.

Group A Streptococcus (GAS) skin infections are caused by a diverse array of strain types and are highly prevalent in disadvantaged populations. The role of strain-specific immunity in preventing GAS infections is poorly understood, representing a critical knowledge gap in vaccine development. A recent GAS murine challenge study showed evidence that sterilising strain-specific and enduring immunity required two skin infections by the same GAS strain within three weeks. This mechanism of developing enduring immunity may be a significant impediment to the accumulation of immunity in populations. We used an agent-based mathematical model of GAS transmission to investigate the epidemiological consequences of enduring strain-specific immunity developing only after two infections with the same strain within a specified interval. Accounting for uncertainty when correlating murine timeframes to humans, we varied this maximum inter-infection interval from 3 to 420 weeks to assess its impact on prevalence and strain diversity, and considered additional scenarios where no maximum inter-infection interval was specified. Model outputs were compared with longitudinal GAS surveillance observations from northern Australia, a region with endemic infection. We also assessed the likely impact of a targeted strain-specific multivalent vaccine in this context. Our model produced patterns of transmission consistent with observations when the maximum inter-infection interval for developing enduring immunity was 19 weeks. Our vaccine analysis suggests that the leading multivalent GAS vaccine may have limited impact on the prevalence of GAS in populations in northern Australia if strain-specific immunity requires repeated episodes of infection. Our results suggest that observed GAS epidemiology from disease endemic settings is consistent with enduring strain-specific immunity being dependent on repeated infections with the same strain, and provide additional motivation for relevant human studies to confirm the human immune response to GAS skin infection.

Estimation of the force of infection and infectious period of skin sores in remote Australian communities using interval-censored data.

Prevalence of impetigo (skin sores) remains high in remote Australian Aboriginal communities, Fiji, and other areas of socio-economic disadvantage. Skin sore infections, driven primarily in these settings by Group A Streptococcus (GAS) contribute substantially to the disease burden in these areas. Despite this, estimates for the force of infection, infectious period and basic reproductive ratio-all necessary for the construction of dynamic transmission models-have not been obtained. By utilising three datasets each containing longitudinal infection information on individuals, we estimate each of these epidemiologically important parameters. With an eye to future study design, we also quantify the optimal sampling intervals for obtaining information about these parameters. We verify the estimation method through a simulation estimation study, and test each dataset to ensure suitability to the estimation method. We find that the force of infection differs by population prevalence, and the infectious period is estimated to be between 12 and 20 days. We also find that optimal sampling interval depends on setting, with an optimal sampling interval between 9 and 11 days in a high prevalence setting, and 21 and 27 days for a lower prevalence setting. These estimates unlock future model-based investigations on the transmission dynamics of skin sores.

Elevated serum sodium in recipients of liver transplantation has a substantial impact on outcomes.

Dysnatremias are a rare but significant event in liver transplantation. While recipient pre-transplant hypernatremia has been demonstrated to increase post-transplant mortality, the degree of hypernatremia and the impact of its resolution have been less well characterized. Here, we used multivariate Cox regression with a comprehensive list of donor and recipient factors in order to conduct a robust multivariate retrospective database study of 54,311 United Network for Organ Sharing (UNOS) liver transplant patients to analyze the effect of pre-transplant serum sodium on post-transplant mortality, post-transplant length of hospitalization, and post-transplant graft survival. Mortality and graft failure increased in a stepwise fashion with increasing pre-transplant hypernatremia: 145 -150 mEq/L (HR = 1.118 and HR = 1.113), 150-155 mEq/L (HR = 1.324 and HR = 1.306), and > 155 mEq/L (HR = 1.623 and HR = 1.661). Pre-transplant hypo- and hypernatremia also increased length of post-transplant hospitalization: < 125 mEq/L (HR = 1.098), 125-130 mEq/L (HR = 1.060), 145 -150 mEq/L (HR = 1.140), and 150-155 mEq/L (HR = 1.358). Resolution of hypernatremia showed no significant difference in mortality compared with normonatremia, while unresolved hypernatremia significantly increased mortality (HR = 1.254), including a durable long-term increased mortality risk for patients with creatinine < 2 mg/dL and MELD < 25. Pre-transplant hypernatremia serves as a morbid prognostic indicator for post-transplant morbidity and mortality.

Factors associated with long-term graft survival in pediatric kidney transplant recipients.

Pediatric kidney transplant recipients generally have good outcomes post-transplantation. However, the younger age and longer life span after transplantation in the pediatric population make understanding the multifactorial nature of long-term graft survival critical. This investigation analyzes factors associated with 10-year survival to identify areas for improvement in patient care. Kaplan-Meier with log-rank test and univariable and multivariable logistic regression methods were used to retrospectively analyze 7785 kidney transplant recipients under the age of 18 years from January 1, 1998, until March 9, 2008, using United Network for Organ Sharing (UNOS) data. Our end-point was death-censored 10-year graft survival after excluding recipients whose grafts failed within one year of transplant. Recipients aged 5-18 years had lower 10-year graft survival, which worsened as age increased: 5-9 years (OR: 0.66; CI: 0.52-0.83), 10-14 years (OR: 0.43; CI: 0.33-0.55), and 15-18 years (OR: 0.34; CI: 0.26-0.44). Recipient African American ethnicity (OR: 0.67; CI: 0.58-0.78) and Hispanic donor ethnicity (OR: 0.82; CI: 0.72-0.94) had worse outcomes than other donor and recipient ethnicities, as did patients on dialysis at the time of transplant (OR: 0.82; CI: 0.73-0.91). Recipient private insurance status (OR: 1.35; CI: 1.22-1.50) was protective for 10-year graft survival. By establishing the role of age, race, and insurance status on long-term graft survival, we hope to guide clinicians in identifying patients at high risk for graft failure. This study highlights the need for increased allocation of resources and medical care to reduce the disparity in outcomes for certain patient populations.

Primary Prevention of Cardiovascular Disease in Minority Indigenous Populations: A Systematic Review.

INTRODUCTION: Cardiovascular disease (CVD) is the commonest cause of death across the globe; incidence and prevalence rates are increasing. Together, CVD and diabetes mellitus are responsible for a quarter of the health gap observed between Aboriginal Australians and Torres Strait Islanders, and non-Indigenous Australians. Numerous programs have been proposed and implemented to Close the Gap; ideally, these should be evidence-based. OBJECTIVE: The aim of this review is to evaluate primary prevention measures and programs that aim to reduce CVD risk in minority Indigenous populations around the world. METHODS: A search of PubMed, the Cochrane Library and the Elsevier Scopus Database was initially conducted using the terms "cardiovascular disease", "population groups", "primary prevention", "health services, indigenous", "indigenous health", "risk assessment" and "risk management". Results were then assessed per inclusion/exclusion criteria. A second reviewer independently evaluated the publications and review process to ensure agreement. RESULTS: The initial search produced 37 publications; 19 met the inclusion criteria and were incorporated into a comparative table. Most were descriptive, mixed-methods, audit or intervention studies. Heterogeneity of study design prevented statistical analysis. CONCLUSION: Addressing CVD risk in minority Indigenous populations is a multifactorial challenge; there is substantial room for improvement in routine risk assessment and management. Holistic approaches need to embrace local cultural perceptions of health and wellbeing. Validated risk reduction tools, individualised management plans, polypills and computer based decision support tools are promising to improve outcomes for those at risk.

Diaphragm fatigue and inspiratory muscle metaboreflex in men and women matched for absolute diaphragmatic work during pressure-threshold loading.

KEY POINTS: The female diaphragm fatigues at a slower rate compared to that of males, with blunted cardiovascular consequences (i.e. inspiratory muscle metaboreflex). It is unclear if these findings are a function of relative or absolute diaphragmatic work. We asked if sex differences in diaphragm fatigue and the inspiratory muscle metaboreflex persisted during inspiratory loading performed at equal absolute intensities. We found that matching men and women for absolute diaphragmatic work resulted in an equal degree of diaphragm fatigue, despite women performing significantly greater work relative to body mass. Metabolite-induced reflex influences in sympathetic outflow originating from the diaphragm are attenuated in women, with potential implications for blood flow distribution during exercise. ABSTRACT: In response to inspiratory pressure-threshold loading (PTL), women have greater inspiratory muscle endurance time, slower rate of diaphragm fatigue development, and a blunted pressor response compared to men. It is unclear if these differences are due to discrepancies in absolute diaphragm force output. We tested the hypothesis that following inspirations performed at equal absolute intensities, females would develop a similar level of diaphragm fatigue and an attenuated cardiovascular response relative to men. Healthy young men (n = 8, age = 24 ± 3 years) and women (n = 8, age = 23 ± 3 years) performed PTL whilst targeting a transdiaphragmatic pressure (Pdi ) of 92 cmH2 O for 5 min. Diaphragm fatigue was assessed via twitch Pdi (Pdi,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial blood pressure were monitored continuously. During PTL, the absolute amount of diaphragm work was not different between men (13,399 ± 2019 cmH2 O s) and women (12,986 ± 1846 cmH2 O s; P > 0.05); however, women performed the PTL task at a higher relative P¯di /Pdi,max . Following inspiratory PTL, the magnitude of reduction in Pdi,tw was similar between men (-27.1 ± 7.2%) and women (-23.8 ± 13.8%; P > 0.05). There were significant increases in HR over time (P < 0.05), but this did not differ on the basis of sex (P > 0.05). Mean arterial blood pressure increased significantly over time in both men and women (P < 0.05); however, the rate of change was higher in men (6.24 ± 2.54 mmHg min-1 ) than in women (4.15 ± 2.52 mmHg min-1 ) (P < 0.05). We conclude that the female diaphragm is protected against severe fatigue when inspiratory work is excessive and as a result does not evoke overt sympathoexcitation.

Safety and tolerability of experimental hookworm infection in humans with metabolic disease: study protocol for a phase 1b randomised controlled clinical trial.

BACKGROUND: Abdominal obesity and presence of the metabolic syndrome (MetS) significantly increase the risk of developing diseases such as Type 2 diabetes mellitus (T2DM) with escalating emergence of MetS and T2DM constituting a significant public health crisis worldwide. Lower prevalence of inflammatory and metabolic diseases such as T2DM in countries with higher incidences of helminth infections suggested a potential role for these parasites in the prevention and management of certain diseases. Recent studies confirmed the potential protective nature of helminth infection against MetS and T2DM via immunomodulation or, potentially, alteration of the intestinal microbiota. This Phase 1b safety and tolerability trial aims to assess the effect of inoculation with helminths on physical and metabolic parameters, immune responses, and the microbiome in otherwise healthy women and men. METHODS: Participants eligible for inclusion are adults aged 18-50 with central obesity and a minimum of one additional feature of MetS recruited from the local community with a recruitment target of 54. In a randomised, double-blind, placebo-controlled design, three groups will receive either 20 or 40 stage three larvae of the human hookworm Necator americanus or a placebo. Eligible participants will provide blood and faecal samples at their baseline and 6-monthly assessment visits for a total of 24 months with an optional extension to 36 months. During each scheduled visit, participants will also undergo a full physical examination and complete diet (PREDIMED), physical activity, and patient health (PHQ-9) questionnaires. Outcome measurements include tolerability and safety of infection with Necator americanus, changes in metabolic and immunological parameters, and changes in the composition of the faecal microbiome. DISCUSSION: Rising cost of healthcare associated with obesity-induced metabolic diseases urgently calls for new approaches in disease prevention. Findings from this trial will provide valuable information regarding the potential mechanisms by which hookworms, potentially via alterations in the microbiota, may positively influence metabolic health. TRIAL REGISTRATION: The protocol was registered on ANZCTR.org.au on 05 June 2017 with identifier ACTRN12617000818336. Alternatively, a Google search using the above trial registration number will yield a direct link to the trial protocol within the ANZCTR website.

Implementing the Baby One Program: a qualitative evaluation of family-centred child health promotion in remote Australian Aboriginal communities.

BACKGROUND: A healthy start predicts better health in later life. Many remote-living Aboriginal and Torres Strait Islander Australian families lack access to consistent, culturally-safe health services. This paper presents a study of implementation of the Baby One Program (BOP). The BOP was designed as a family-centred, Indigenous Healthworker-led, home-visiting model of care focused on promoting family health to give children the best start to life. It was developed by Aboriginal community-controlled Apunipima Cape York Health Council and delivered in Queensland Cape York remote communities. We aimed to determine how the BOP was implemented, enablers, strategies used and formative implementation outcomes. METHODS: The qualitative approach utilised theoretical and purposive sampling to explore people's experiences of a program implementation process. Data were generated from semi-structured interviews with four family members enrolled in the BOP and 24 Apunipima staff members. In addition, twenty community members, including two program users, participated in a men's community focus group. The findings are presented according to themes arising from the data. RESULTS: The BOP was rolled out in nine remote Cape York communities between July 2014 and December 2015 and there was high uptake. Indigenous Healthworkers were supported by midwives and maternal and child health nurses to deliver health education to 161 eligible families. The key to effective implementation of family-centred care appeared to be the relationships formed between health practitioners, especially Indigenous Healthworkers, and families. The data revealed the following themes: challenging environments for new families and valuing cultural ways, resourcing program delivery, working towards a team approach, negotiating the cultural interface, engaging families, exchanging knowledge through 'yarning', strengthening the workforce, and seeing health changes in families. Healthworker education and training, and knowledge exchange between Healthworkers, midwives and nurses was critical to program effectiveness. The program continues to grow despite substantial logistic, financial and practical challenges. CONCLUSIONS: This study describes an evolving process and explores how health providers connect with families and how the program responds to family and cultural issues. Program development is ongoing; strengthened by more community-level involvement, embedded strategies for ongoing self-evaluation and continuous quality improvements that are responsive to family needs.

Skills, systems and supports: An Aboriginal Community Controlled Health Service (Apunipima) approach to building health promotion evaluation capacity of staff.

ISSUE ADDRESSED: Building the health promotion evaluation capacity of a workforce requires more than a focus on individual skills and confidence. We must also consider the organisational systems and supports that enable staff to embed learnings into practice. This paper describes the processes used to build health promotion evaluation capacity of staff in an Aboriginal Community Controlled Health Service (ACCHS). METHODS: To build health promotion evaluation capacity three approaches were used: (i) workshops and mentoring; (ii) strengthening systems to support program reporting; and (iii) recruitment of staff with skills and experience. Pre- and post-questionnaires determined levels of individual skills and confidence, updated systems were assessed for adequacy to support new health promotion practices and surveys captured the usefulness of workshops and mentoring. RESULTS: There was increased participant skills and confidence. Participants completed program impact evaluation reports and results were successfully presented at national conferences. The health promotion team was then able to update in-house systems to support new health promotion practices. Ongoing collaboration with experienced in-house researchers provided basic research training and professional mentoring. CONCLUSIONS: Building health promotion evaluation capacity of staff in an ACCHS can be achieved by providing individual skill development, strengthening organisational systems and utilising professional support. SO WHAT?: Health promotion practitioners have an ongoing professional obligation to improve the quality of routine practice and embrace new initiatives. This report outlines a process of building evaluation capacity that promotes quality reporting of program impacts and outcomes, reflects on ways to enhance program strengths, and communicates these findings internally and to outside professional bodies. This is particularly significant for ACCHSs responsible for addressing the high burden of preventable disease in Aboriginal and Torres Strait Islander populations.

Coming to town: Reaching agreement on a thorny issue.

OBJECTIVE: To describe the process of gaining consensus across regional organisations in formulating measures to improve coordination of care for people from remote Far North Queensland communities coming to town (Cairns) to access health care. DESIGN: This is a descriptive study that includes survey data from workshop participants. SETTING: Coming to town for health care poses great challenges, especially for Indigenous Australians from remote communities. Numerous organisations are involved, communications are fragmented and there is no central coordinating body. The system frequently fails to deliver necessary services. This generates preventable cost burdens through missed flights, missed appointments, missed treatment opportunities and extra administration. Workshop organisers invited key service providers from across Far North Queensland. MAIN OUTCOME MEASURES: Using real-case scenarios, the task was to identify and prioritise the central issues and explore ways to address them. Participants jointly crafted the final recommendations and also posted suggestions on a 'wish-list' board. A participant assessment survey was conducted at the end of the workshop, followed by an online survey 6 weeks later. RESULTS: There were 32 participants. The concluding survey indicated the workshop was well received and people valued the collaboration. There were six primary recommendations plus numerous wish-list suggestions. The best-supported recommendation was establishment of a coming to town Hub with a local coordinating team and community-based representatives. CONCLUSION: Implementation of the workshop recommendations and support of all key service providers should be culturally acceptable and resource-efficient with better health outcomes for travellers, their families and communities.

Screening for depression in young Indigenous people: building on a unique community initiative.

Gurriny Yealamucka Health Service Aboriginal Corporation (GYHSAC) is an Indigenous community-controlled health organisation providing comprehensive primary care to the people of Yarrabah in far north Queensland, Australia. GYHSAC conducts an annual Young Person's Health Check (YPC) for people aged 15-25 years based on the Medical Benefits Schedule Item 715. However, the YPC is constantly evolving to meet the needs of the community, and in 2016, in response to concerns about psychological risk among Indigenous youth, GYHSAC teamed up with James Cook University to trial an adapted PHQ-9 depression screening tool (aPHQ-9) as part of the YPC. This study describes the 2016 YPC event, reports the prevalence of depressive symptoms, examines local issues related to the use of the screening tool and proposes recommendations for future health screening. Experienced health professionals conducted the aPHQ-9 assessment in a private area of the clinic. One-in-five young people were found to have moderate-severe symptoms or self-harm ideation in the previous 2 weeks; they were referred to the mental health service. The aPHQ-9 screening process was found to be straightforward and well accepted by staff and youth. Importantly, it provided valuable 'space' to facilitate communication on sensitive issues and was a conduit for speedy referral and follow up by trained staff. Based on our experience, we recommend dedicated depression screening in future routine community health checks for young people and adults.

Doing it hard in the bush: Aligning what gets measured with what matters.

What gets measured gets managed. Funding of health services is substantially determined by operational activity and specific outcome indicators. In day-to-day clinical decision-making, surrogate markers, such as glycosylated haemoglobin and blood pressure, are commonly used to modify risks of 'hard' outcomes that include kidney failure, ischaemic cardiac events, stroke and all-cause mortality. In many settings, surrogates are all we have to go on. As a consequence, current health funding models heavily rely on surrogate-based key performance indicators [KPIs]. While surrogates are convenient and provide immediate information, there is an obligation to ensure that they are appropriate, reliable and validated in context. In contrast, hard outcomes, the real consequences of illness, are usually realised over an extended timeframe. Additionally, and for a host of reasons, hard endpoints have the greatest social, emotional and economic impact for people at the far end of the health system; those in rural and remote settings - 'in the bush' - especially Indigenous Australians. We propose a health service assessment approach that aligns short-term decision-making with patient-centred and longer term hard outcomes, one that takes into account community, cultural and environmental factors, especially remoteness. Communities should have a major say in determining what health indicators are measured and managed.

Short-course oral co-trimoxazole versus intramuscular benzathine benzylpenicillin for impetigo in a highly endemic region: an open-label, randomised, controlled, non-inferiority trial.

BACKGROUND: Impetigo affects more than 110 million children worldwide at any one time. The major burden of disease is in developing and tropical settings where topical antibiotics are impractical and lead to rapid emergence of antimicrobial resistance. Few trials of systemic antibiotics are available to guide management of extensive impetigo. As such, we aimed to compare short-course oral co-trimoxazole with standard treatment with intramuscular benzathine benzylpenicillin in children with impetigo in a highly endemic setting. METHODS: In this randomised, controlled, non-inferiority trial, Indigenous Australian children aged 3 months to 13 years with purulent or crusted non-bullous impetigo were randomly assigned (1:1:1) to receive benzathine benzylpenicillin (weight-banded injection), twice-daily co-trimoxazole for 3 days (4 mg/kg plus 20 mg/kg per dose), or once-daily co-trimoxazole for 5 days (8 mg/kg plus 40 mg/kg per dose). At every visit, participants were randomised in blocks of six and 12, stratified by disease severity. Randomisation was done by research nurses and codes were in sealed, sequentially numbered, opaque envelopes. Independent reviewers masked to treatment allocation compared digital images of sores from days 0 and 7. The primary outcome was treatment success at day 7 in a modified intention-to-treat analysis. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12609000858291. FINDINGS: Between Nov 26, 2009, and Nov 20, 2012, 508 patients were randomly assigned to receive benzathine benzylpenicillin (n=165 [156 analysed]), twice-daily co-trimoxazole for 3 days (n=175 [173 analysed]), or once-daily co-trimoxazole for 5 days (n=168 [161 analysed]). Treatment was successful in 133 (85%) children who received benzathine benzylpenicillin and 283 (85%) who received pooled co-trimoxazole (absolute difference 0·5%; 95% CI -6·2 to 7·3), showing non-inferiority of co-trimoxazole (10% margin). Results for twice-daily co-trimoxazole for 3 days and once-daily co-trimoxazole for 5 days were similar. Adverse events occurred in 54 participants, 49 (90%) of whom received benzathine benzylpenicillin. INTERPRETATION: Short-course co-trimoxazole is a non-inferior, alternative treatment to benzathine benzylpenicillin for impetigo; it is palatable, pain-free, practical, and easily administered. FUNDING: Australian National Health and Medical Research Council.