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1.  Priority setting in Indigenous health: assessing priority setting process and criteria that should guide the health system to improve Indigenous Australian health 
Introduction
The health of Indigenous Australians is worse than that of other Australians. Most of the determinants of health are preventable and the poor health outcomes are inequitable. The Australian Government recently pledged to close that health gap. One possible way is to improve the priority setting process to ensure transparency and the use of evidence such as epidemiology, equity and economic evaluation.
The purpose of this research was to elicit the perceptions of Indigenous and non-Indigenous decision-makers on several issues related to priority setting in Indigenous-specific health care services. Specifically, we aimed to:
1. identify the criteria used to set priorities in Indigenous-specific health care services;
2. determine the level of uptake of economic evaluation evidence by decision-makers and how to improve its uptake; and
3. identify how the priority setting process can be improved from the perspective of decision-makers.
Methods
We used a paper survey instrument, adapted from Mitton and colleagues’ work, and a face-to-face interview approach to elicit decision-makers’ perceptions in Indigenous-specific health care in Victoria, Australia. We used mixed methods to analyse data from the survey. Responses were summarised using descriptive statistics and content analysis. Results were reported as numbers and percentages.
Results
The size of the health burden; sustainability and acceptability of interventions; historical trends/patterns; and efficiency are key criteria for making choices in Indigenous health in Victoria. There is a need for an explicit priority setting approach, which is systematic, and is able to use available data/evidence, such as economic evaluation evidence. The involvement of Indigenous Australians in the process would potentially make the process acceptable.
Conclusions
An economic approach to priority setting is a potentially acceptable and useful tool for Aboriginal Community Controlled Health Services (ACCHS). It has the ability to use evidence and ensure due process at the same time. The use of evidence can ensure that health outcomes for Indigenous peoples can be maximised – hence, increase the potential for ‘closing the gap’ between Indigenous and other Australians.
doi:10.1186/1475-9276-13-45
PMCID: PMC4065599  PMID: 24906391
2.  Enhanced subgenual cingulate response to altruistic decisions in remitted major depressive disorder 
NeuroImage : Clinical  2014;4:701-710.
Background
Major depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown.
Methods
Using a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD.
Results
Compared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture.
Conclusions
We showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called “warm glow” of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.
Highlights
•Patients show enhanced activation in the sgACC while making altruistic decisions.•Patients show elevated STR response to equitable decisions.•These abnormal neural responses may be associated with depression vulnerability.
doi:10.1016/j.nicl.2014.04.010
PMCID: PMC4053655  PMID: 24936421
Charitable donation; Major depression; Reward processing; Subgenual anterior cingulate; Striatum
3.  Serum arterial lactate concentration predicts mortality and organ dysfunction following liver resection 
Background
The aim of this study was to determine if the post-operative serum arterial lactate concentration is associated with mortality, length of hospital stay or complications following hepatic resection.
Methods
Serum lactate concentration was recorded at the end of liver resection in a consecutive series of 488 patients over a seven-year period. Liver function, coagulation and electrolyte tests were performed post-operatively. Renal dysfunction was defined as a creatinine rise of >1.5x the pre-operative value.
Results
The median lactate was 2.8 mmol/L (0.6 to 16 mmol/L) and was elevated (≥2 mmol/L) in 72% of patients. The lactate concentration was associated with peak post-operative bilirubin, prothrombin time, renal dysfunction, length of hospital stay and 90-day mortality (P < 0.001). The 90-day mortality in patients with a post-operative lactate ≥6 mmol/L was 28% compared to 0.7% in those with lactate ≤2 mmol/L. Pre-operative diabetes, number of segments resected, the surgeon’s assessment of liver parenchyma, blood loss and transfusion were independently associated with lactate concentration.
Conclusions
Initial post-operative lactate concentration is a useful predictor of outcome following hepatic resection. Patients with normal post-operative lactate are unlikely to suffer significant hepatic or renal dysfunction and may not require intensive monitoring or critical care.
doi:10.1186/2047-0525-2-21
PMCID: PMC3964326  PMID: 24472571
Liver; Hepatectomy; Post-operative care
4.  Study protocol for the randomised controlled trial: Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) 
BMC Psychiatry  2013;13:205.
Background
Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service.
Methods/design
Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone.
Discussion
Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments.
Trial registration
Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.
doi:10.1186/1471-244X-13-205
PMCID: PMC3750720  PMID: 23914988
Antidepressive agents; Cortisol; Depressive disorder; Metyrapone; Antiglucocorticoid treatment; Treatment refractory depression
5.  Avoidance of total abdominal wall loss despite torso soft tissue clostridial myonecrosis: a case report 
Introduction
Clostridial necrotizing soft tissue infections are often fatal. Myonecrosis of the torso is a particularly lethal combination given the classic need for radical debridement of the abdominal and thoracic walls, and therefore total exposure of the intraperitoneal and intrathoracic viscera. This case is unusual do to our ability to preserve anatomical separation between the viscera and the atmosphere.
Case presentation
We present a 42-year-old Caucasian man with obesity and diabetes who developed clostridial myonecrosis of his right torso following a mesenteric lymph node biopsy. This required an aggressive debridement (sparing subcutaneous flaps and internal oblique aponeurosis) followed by reconstruction of his right hemi-torso with a biologic prosthesis to prevent subsequent hernia formation.
Conclusion
Although basic principles associated with radical debridement were maintained, a full thickness torso wall resection was avoided. This provided reconstruction advantages that included endogenous subcutaneous flap coverage, separation of the peritoneal cavity by the internal oblique aponeurosis, and prevention of a subsequent hernia below the arcuate line. This technique would be of interest to any surgeon or clinician who treats patients with life-threatening torso soft tissue infections.
doi:10.1186/1752-1947-7-5
PMCID: PMC3599755  PMID: 23298523
Biologic prosthesis; Hernia; Necrotizing soft tissue infection
6.  Navigating the complex path between the oxytocin receptor gene (OXTR) and cooperation: an endophenotype approach 
Although cooperation represents a core facet of human social behavior there exists considerable variability across people in terms of the tendency to cooperate. One factor that may contribute to individual differences in cooperation is a key gene within the oxytocin (OT) system, the OT reception gene (OXTR). In this article, we aim to bridge the gap between the OXTR gene and cooperation by using an endophenotype approach. We present evidence that the association between the OXTR gene and cooperation may in part be due to how the OXTR gene affects brain systems involved in emotion recognition, empathy/theory of mind, social communication and social reward seeking. There is evidence that the OXTR gene is associated with the functional anatomy of the amygdala, visual cortex (VC), anterior cingulate and superior temporal gyrus (STG). However, it is currently unknown how the OXTR gene may be linked to the functional anatomy of other relevant brain regions that include the fusiform gyrus (FG), superior temporal sulcus (STS), ventromedial prefrontal cortex (VMPFC), temporoparietal junction (TPJ) and nucleus accumbens (NAcc). We conclude by highlighting potential future research directions that may elucidate the path between OXTR and complex behaviors such as cooperation.
doi:10.3389/fnhum.2013.00801
PMCID: PMC3842510  PMID: 24348360
OXTR; genetics; oxytocin; social-cognition; cooperation
7.  Reversed Frontotemporal Connectivity During Emotional Face Processing in Remitted Depression 
Biological Psychiatry  2012;72(7):604-611.
Background
Vulnerability to relapse persists after remission of an acute episode of major depressive disorder. This has been attributed to abnormal biases in the processing of emotional stimuli in limbic circuits. However, neuroimaging studies have not so far revealed consistent evidence of abnormal responses to emotional stimuli in limbic structures, such as the amygdala, in remitted depression. This suggests the problem might lie in the integrated functioning of emotion processing circuits.
Methods
We recruited 22 unmedicated patients in remission from major depressive disorder (rMDD) and 21 age-matched healthy control subjects. Functional magnetic resonance imaging was performed during a face emotion processing task. Dynamic causal modeling was used with Bayesian model selection to determine the most likely brain networks and valence-specific modulation of connectivity in healthy control subjects and rMDD.
Results
In healthy volunteers, sad faces modulated bi-directional connections between amygdala and orbitofrontal cortex and between fusiform gyrus and orbitofrontal cortex. Happy faces modulated unidirectional connections from fusiform gyrus to orbitofrontal cortex. In rMDD, the opposite pattern was observed, with evidence of happy faces modulating bidirectional frontotemporal connections and sad faces modulating unidirectional fusiform–orbitofrontal connections.
Conclusions
Participants with rMDD have abnormal modulation of frontotemporal effective connectivity in response to happy and sad face emotions, despite normal activations within each region. Specifically, processing of mood incongruent happy information was associated with a more richly modulated frontotemporal brain network, whereas mood congruent sad information was associated with less network modulation. This supports a hypothesis of dysfunction within cortico–limbic connections in individuals vulnerable to depression.
doi:10.1016/j.biopsych.2012.04.031
PMCID: PMC3657140  PMID: 22682158
Amygdala; connectivity; depression; emotion; fusiform gyrus; orbitofrontal cortex
8.  Differences in primary health care delivery to Australia’s Indigenous population: a template for use in economic evaluations 
Background
Health economics is increasingly used to inform resource allocation decision-making, however, there is comparatively little evidence relevant to minority groups. In part, this is due to lack of cost and effectiveness data specific to these groups upon which economic evaluations can be based. Consequently, resource allocation decisions often rely on mainstream evidence which may not be representative, resulting in inequitable funding decisions. This paper describes a method to overcome this deficiency for Australia’s Indigenous population. A template has been developed which can adapt mainstream health intervention data to the Indigenous setting.
Methods
The ‘Indigenous Health Service Delivery Template’ has been constructed using mixed methods, which include literature review, stakeholder discussions and key informant interviews. The template quantifies the differences in intervention delivery between best practice primary health care for the Indigenous population via Aboriginal Community Controlled Health Services (ACCHSs), and mainstream general practitioner (GP) practices. Differences in costs and outcomes have been identified, measured and valued. This template can then be used to adapt mainstream health intervention data to allow its economic evaluation as if delivered from an ACCHS.
Results
The template indicates that more resources are required in the delivery of health interventions via ACCHSs, due to their comprehensive nature. As a result, the costs of such interventions are greater, however this is accompanied by greater benefits due to improved health service access. In the example case of the polypill intervention, 58% more costs were involved in delivery via ACCHSs, with 50% more benefits. Cost-effectiveness ratios were also altered accordingly.
Conclusions
The Indigenous Health Service Delivery Template reveals significant differences in the way health interventions are delivered from ACCHSs compared to mainstream GP practices. It is important that these differences are included in the conduct of economic evaluations to ensure results are relevant to Indigenous Australians. Similar techniques would be generalisable to other disadvantaged minority populations. This will allow resource allocation decision-makers access to economic evidence that more accurately represents the needs and context of disadvantaged groups, which is particularly important if addressing health inequities is a stated goal.
doi:10.1186/1472-6963-12-307
PMCID: PMC3468365  PMID: 22954136
Health economics; Resource allocation; Indigenous Australians; Primary health care services; Health service delivery; Health equity
9.  Hyperthermia Stimulates HIV-1 Replication 
PLoS Pathogens  2012;8(7):e1002792.
HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42–45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38–40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.
Author Summary
Fever is a complex reaction triggered in response to pathogen infection. It induces diverse effects on the human body and especially on the immune system. The functions of immune cells are positively affected by fever, helping them to fight infection. Fever consists in a physiological elevation of temperature and in inflammation. While the role of inflammatory molecules on HIV-1 replication has been widely studied, little is known about the direct effect of temperature on viral replication. Here, we report that hyperthermia (39.5°C) boosts HIV-1 replication in CD4+ T cells. In single-cycle infection experiments, hyperthermia increased HIV-1 infection up to 7-fold. This effect was mediated in part by an increased activation of the HIV-1 promoter by the viral protein Tat. Our results also indicate that hyperthermia may help HIV-1 to reactivate from latency. We also show that the Heat Shock Protein Hsp90, which levels are increased at 39.5°C, mediates in a large part the positive effect of hyperthermia on HIV-1 infection. Our work suggests that in HIV-1-infected patients, fever episodes may facilitate viral replication.
doi:10.1371/journal.ppat.1002792
PMCID: PMC3395604  PMID: 22807676
10.  Prescribing antidepressants for depression: time to be dimensional and inclusive 
The article by Middleton and Moncrieff questions the role of antidepressants in treating depression on both philosophical and practical grounds; namely that depression isn't a brain disease to be treated by a drug and that antidepressants are ineffective except as placebos. We argue that their stance is unhelpful and factually incorrect and that a more dimensional and integrative approach is needed in order to be able to best tailor treatment to individual needs. This involves a personalised assessment of the likely benefits and risks of both psychological and drug approaches when recommending treatment for someone with depression.
doi:10.3399/bjgp11X548992
PMCID: PMC3020051  PMID: 21401994
antidepressants; depression; placebo; psychological treatment; randomised controlled trials
11.  Affective Cognition and its Disruption in Mood Disorders 
Neuropsychopharmacology  2010;36(1):153-182.
In this review, we consider affective cognition, responses to emotional stimuli occurring in the context of cognitive evaluation. In particular, we discuss emotion categorization, biasing of memory and attention, as well as social/moral emotion. We discuss limited neuropsychological evidence suggesting that affective cognition depends critically on the amygdala, ventromedial frontal cortex, and the connections between them. We then consider neuroimaging studies of affective cognition in healthy volunteers, which have led to the development of more sophisticated neural models of these processes. Disturbances of affective cognition are a core and specific feature of mood disorders, and we discuss the evidence supporting this claim, both from behavioral and neuroimaging perspectives. Serotonin is considered to be a key neurotransmitter involved in depression, and there is a considerable body of research exploring whether serotonin may mediate disturbances of affective cognition. The final section presents an overview of this literature and considers implications for understanding the pathophysiology of mood disorder as well as developing and evaluating new treatment strategies.
doi:10.1038/npp.2010.77
PMCID: PMC3055516  PMID: 20571485
emotion; cognition; depression; amygdala; anterior cingulate; serotonin; emotion; cognition; depression; amygdala; anterior cingulate; serotonin
12.  A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis 
PLoS ONE  2011;6(6):e21253.
Background
Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF.
Methodology and Principal Findings
miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts.
Conclusion
These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.
doi:10.1371/journal.pone.0021253
PMCID: PMC3119674  PMID: 21712985
13.  Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders 
Neuropsychopharmacology  2009;35(5):1109-1119.
Decision making, choosing the best option from the possible outcomes, is impaired in many psychiatric conditions including affective disorders. We tested the hypothesis that variations in serotonergic genes (TPH2, TPH1, SLC6A4, HTR1A), which influence serotonin availability, affect choice behavior in a probabilistic gambling task. A population cohort (N=1035) completed a paper-and-pencil gambling task, filled out personality and symptom questionnaires and gave consent for the use of their DNA in a genetic association study. A subgroup of subjects (N=69) also completed a computer version of the task. The gambling task was designed to estimate an individual's tendency to take a risk when choosing between a smaller but more certain ‘win' and a larger, less probable one. We genotyped seven haplotype tagging SNPs in the TPH2 gene, and previously reported functional polymorphisms from the other genes (rs1800532, 5HTTLPR, and rs6295). Carriers of the more prevalent TPH2 haplotype, which was previously associated with less active enzyme variant, showed reduced risk taking on both tasks compared with subjects not carrying the common haplotype. The effect of TPH2 haplotypes on risk-taking was independent of current depression and anxiety symptoms, neuroticism and impulsiveness scores. We did not find an association between functional polymorphisms in the TPH1, SLC6A4, HTR1A genes and risk-taking behavior. In conclusion, our study demonstrates the role of the TPH2 gene and the serotonin system in risk taking and suggests that TPH2 gene may contribute to the expression of psychiatric phenotypes through altered decision making.
doi:10.1038/npp.2009.216
PMCID: PMC3055398  PMID: 20043001
risk taking; TPH2; haplotype analysis; depression; psychiatric disorders; Serotonin; Neurogenetics; Behavioral Science; Mood/Anxiety/Stress Disorders; risk-taking; TPH2; haplotype analysis
14.  Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein* 
The Journal of Biological Chemistry  2010;285(50):39314-39328.
Chemical genetics is an emerging approach to investigate the biology of host-pathogen interactions. We screened several inhibitors of ATP-dependent DNA motors and detected the gyrase B inhibitor coumermycin A1 (C-A1) as a potent antiretroviral. C-A1 inhibited HIV-1 integration and gene expression from acutely infected cell, but the two activities mapped to distinct targets. Target discovery identified Hsp90 as the C-A1 target affecting viral gene expression. Chromatin immunoprecipitation revealed that Hsp90 associates with the viral promoter and may directly regulate gene expression. Molecular docking suggested that C-A1 binds to two novel pockets at the C terminal domain of Hsp90. C-A1 inhibited Hsp90 dimer formation, suggesting that it impairs viral gene expression by preventing Hsp90 dimerization at the C terminus. The inhibition of HIV-1 integration imposed by C-A1 was independent of Hsp90 and mapped to the capsid protein, and a point mutation at residue 105 made the virus resistant to this block. HIV-1 susceptibility to the integration block mediated by C-A1 was influenced by cyclophilin A. Our chemical genetic approach revealed an unexpected function of capsid in HIV-1 integration and provided evidence for a role of Hsp90 in regulating gene expression in mammalian cells. Both activities were amenable to inhibition by small molecules and represent novel antiretroviral drug targets.
doi:10.1074/jbc.M110.155275
PMCID: PMC2998086  PMID: 20937817
DNA Gyrase; Drug Action; Heat Shock Protein; HIV; Protein Targeting; Coumermycin A1; Hsp90; Integration; Capsid; Chemical Genetics
15.  Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD 
Chest  2010;138(5):1140-1147.
Background:
Asthma and COPD are characterized by airway dysfunction and inflammation. Neutrophilic airway inflammation is a common feature of COPD and is recognized in asthma, particularly in severe disease. The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD is uncertain.
Methods:
We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD.
Results:
The median (interquartile range) IL-17A cells/mm2 submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P = .04). In COPD, IL-17A+ cells/mm2 submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P = .046). IL-17F+ cells/mm2 submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P = .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count (rs = 0.5, P = .005). The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P < .0001) and was correlated with post-bronchodilator FEV1% predicted (r = −0.5, P = .008) and FEV1/FVC (r = −0.4, P = .04).
Conclusions:
Our findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation.
doi:10.1378/chest.09-3058
PMCID: PMC2972626  PMID: 20538817
16.  Study protocol: national research partnership to improve primary health care performance and outcomes for Indigenous peoples 
Background
Strengthening primary health care is critical to reducing health inequity between Indigenous and non-Indigenous Australians. The Audit and Best practice for Chronic Disease Extension (ABCDE) project has facilitated the implementation of modern Continuous Quality Improvement (CQI) approaches in Indigenous community health care centres across Australia. The project demonstrated improvements in health centre systems, delivery of primary care services and in patient intermediate outcomes. It has also highlighted substantial variation in quality of care. Through a partnership between academic researchers, service providers and policy makers, we are now implementing a study which aims to 1) explore the factors associated with variation in clinical performance; 2) examine specific strategies that have been effective in improving primary care clinical performance; and 3) work with health service staff, management and policy makers to enhance the effective implementation of successful strategies.
Methods/Design
The study will be conducted in Indigenous community health centres from at least six States/Territories (Northern Territory, Western Australia, New South Wales, South Australia, Queensland and Victoria) over a five year period. A research hub will be established in each region to support collection and reporting of quantitative and qualitative clinical and health centre system performance data, to investigate factors affecting variation in quality of care and to facilitate effective translation of research evidence into policy and practice. The project is supported by a web-based information system, providing automated analysis and reporting of clinical care performance to health centre staff and management.
Discussion
By linking researchers directly to users of research (service providers, managers and policy makers), the partnership is well placed to generate new knowledge on effective strategies for improving the quality of primary health care and fostering effective and efficient exchange and use of data and information among service providers and policy makers to achieve evidence-based resource allocation, service planning, system development, and improvements of service delivery and Indigenous health outcomes.
doi:10.1186/1472-6963-10-129
PMCID: PMC2882384  PMID: 20482810
17.  General surgery 2.0: the emergence of acute care surgery in Canada 
Canadian Journal of Surgery  2010;53(2):79-83.
Over the past 5 years, there has been a groundswell of support in Canada for the development of organized, focused and multidisciplinary approaches to caring for acutely ill general surgical patients. Newly forged acute care surgery (ACS) services are beginning to provide prompt, evidence-based and goal-directed care to acutely ill general surgical patients who often present with a diverse range of complex pathologies and little or no pre- or postoperative planning. Through a team-based structure with attention to processes of care and information sharing, ACS services are well positioned to improve outcomes, while finding and developing efficiencies and reducing costs of surgical and emergency health care delivery. The ACS model also offers enhanced opportunities for surgical education for students, residents and practicing surgeons, and it will provide avenues to strengthen clinical and academic bonds between the community and academic surgical centres. In the near future, cooperation of ACS services from community and academic hospitals across the country will lead to the formation of systems of acute surgical care whose development will be informed by rigorous data collection and research and evidence-based quality-improvement initiatives. In an era of increasing subspecialization, ACS is a strong unifying force in general surgery and a platform for collective advocacy for an important patient population.
PMCID: PMC2845950  PMID: 20334738
18.  Setting and meeting priorities in Indigenous health research in Australia and its application in the Cooperative Research Centre for Aboriginal Health 
Priority setting is about making decisions. Key issues faced during priority setting processes include identifying who makes these decisions, who sets the criteria, and who benefits. The paper reviews the literature and history around priority setting in research, particularly in Aboriginal health research. We explore these issues through a case study of the Cooperative Research Centre for Aboriginal Health (CRCAH)'s experience in setting and meeting priorities.
Historically, researchers have made decisions about what research gets done. Pressures of growing competition for research funds and an increased public interest in research have led to demands that appropriate consultation with stakeholders is conducted and that research is of benefit to the wider society. Within Australian Aboriginal communities, these demands extend to Aboriginal control of research to ensure that Aboriginal priorities are met.
In response to these demands, research priorities are usually agreed in consultation with stakeholders at an institutional level and researchers are asked to develop relevant proposals at a project level. The CRCAH's experience in funding rounds was that scientific merit was given more weight than stakeholders' priorities and did not necessarily result in research that met these priorities. After reviewing these processes in 2004, the CRCAH identified a new facilitated development approach. In this revised approach, the setting of institutional priorities is integrated with the development of projects in a way that ensures the research reflects stakeholder priorities.
This process puts emphasis on identifying projects that reflect priorities prior to developing the quality of the research, rather than assessing the relevance to priorities and quality concurrently. Part of the CRCAH approach is the employment of Program Managers who ensure that stakeholder priorities are met in the development of research projects. This has enabled researchers and stakeholders to come together to collaboratively develop priority-driven research. Involvement by both groups in project development has been found to be essential in making decisions that will lead to robust and useful research.
doi:10.1186/1478-4505-7-25
PMCID: PMC2788537  PMID: 19925681
19.  A cost-based equity weight for use in the economic evaluation of primary health care interventions: case study of the Australian Indigenous population 
Background
Efficiency and equity are both important policy objectives in resource allocation. The discipline of health economics has traditionally focused on maximising efficiency, however addressing inequities in health also requires consideration. Methods to incorporate equity within economic evaluation techniques range from qualitative judgements to quantitative outcomes-based equity weights. Yet, due to definitional uncertainties and other inherent limitations, no method has been universally adopted to date. This paper proposes an alternative cost-based equity weight for use in the economic evaluation of interventions delivered from primary health care services.
Methods
Equity is defined in terms of 'access' to health services, with the vertical equity objective to achieve 'equitable access for unequal need'. Using the Australian Indigenous population as an illustrative case study, the magnitude of the equity weight is constructed using the ratio of the costs of providing specific interventions via Indigenous primary health care services compared with the costs of the same interventions delivered via mainstream services. Applying this weight to the costs of subsequent interventions deflates the costs of provision via Indigenous health services, and thus makes comparisons with mainstream more equitable when applied during economic evaluation.
Results
Based on achieving 'equitable access', existing measures of health inequity are suitable for establishing 'need', however the magnitude of health inequity is not necessarily proportional to the magnitude of resources required to redress it. Rather, equitable access may be better measured using appropriate methods of health service delivery for the target group. 'Equity of access' also suggests a focus on the processes of providing equitable health care rather than on outcomes, and therefore supports application of equity weights to the cost side rather than the outcomes side of the economic equation.
Conclusion
Cost-based weights have the potential to provide a pragmatic method of equity weight construction which is both understandable to policy makers and sensitive to the needs of target groups. It could improve the evidence base for resource allocation decisions, and be generalised to other disadvantaged groups who share similar concepts of equity. Development of this decision-making tool represents a potentially important avenue for further health economics research.
doi:10.1186/1475-9276-8-34
PMCID: PMC2768712  PMID: 19807930
20.  Is peer review useful in assessing research proposals in Indigenous health? A case study 
Background
There has been considerable examination and critique of traditional (academic) peer review processes in quality assessment of grant applications. At the same time, the use of traditional research processes in Indigenous research has been questioned. Many grant funding organisations have changed the composition of their peer review panels to reflect these concerns but the question remains do these reforms go far enough? In this project we asked people working in areas associated with Aboriginal health research in a number of capacities, their views on the use of peer review in assessing Indigenous research proposals.
Methods
In semi-structured interviews we asked 18 individuals associated with an Australian Indigenous research funding organisation to reflect on their experience with peer review in quality assessment of grant applications. We also invited input from a steering group drawn from a variety of organisations involved in Aboriginal research throughout Australia and directly consulted with three Aboriginal-controlled health organisations.
Results
There was consensus amongst all participants that traditional academic peer review is inappropriate for quality assessment in Indigenous research. Many expressed the view that using a competitive grant review system in Aboriginal health was counterintuitive, since good research transfer is based on effective collaboration. The consensus within the group favoured a system which built research in a collaborative manner incorporating a variety of different stakeholders in the process. In this system, one-off peer review was still seen as valuable in the form of a "critical friend" who provided advice as to how to improve the research proposal.
Conclusion
Peer review in the traditional mould should be recognised as inappropriate in Aboriginal research. Building research projects relevant to policy and practice in Indigenous health may require a shift to a new way of selecting, funding and conducting research.
doi:10.1186/1478-4505-7-2
PMCID: PMC2654449  PMID: 19216770
22.  Use of Multiplex Terminal Restriction Fragment Length Polymorphism for Rapid and Simultaneous Analysis of Different Components of the Soil Microbial Community▿ 
Applied and Environmental Microbiology  2006;72(11):7278-7285.
A multiplex terminal restriction fragment length polymorphism (M-TRFLP) fingerprinting method was developed and validated for simultaneous analysis of the diversity and community structure of two or more microbial taxa (up to four taxa). The reproducibility and robustness of the method were examined using soil samples collected from different habitats. DNA was PCR amplified separately from soil samples using individual taxon-specific primers for bacteria, archaea, and fungi. The same samples were also subjected to a multiplex PCR with the primers for all three taxa. The terminal restriction fragment length polymorphism profiles generated for the two sets of PCR products were almost identical not only in terms of the presence of peaks but also in terms of the relative peak intensity. The M-TRFLP method was then used to investigate rhizosphere bacterial, fungal, and rhizobial/agrobacterial communities associated with the dwarf shrub Calluna vulgaris growing in either open moorland, a mature pine forest, or a transition zone between these two habitats containing naturally regenerating pine trees. Rhizosphere microbial communities associated with Vaccinium myrtillus collected from the native pine forest were also investigated. In this study, individual PCR products from the three taxa were also pooled before restriction digestion and fragment size analysis. The terminal restriction fragment length polymorphism profiles obtained with PCR products amplified individually and with multiplexed and pooled PCR products were found to be consistent with each other in terms of the number, position, and relative intensity of peaks. The results presented here confirm that M-TRFLP analysis is a highly reproducible and robust molecular tool for simultaneous investigation of multiple taxa, which allows more complete and higher resolution of microbial communities to be obtained more rapidly and economically.
doi:10.1128/AEM.00510-06
PMCID: PMC1636152  PMID: 16936053
23.  Mutual obligation, shared responsibility agreements & indigenous health strategy 
Since 2004 the Howard Coalition government has implemented a new policy framework and administrative arrangements as part of its program of reform in Indigenous affairs. In this paper I will describe both the parameters of this reform program and review the processes established to support the implementation of national Indigenous health strategy. In particular, I will consider both the shift from a policy framework based on 'self-determination' to one based on 'mutual obligation', and the implementation of Shared Responsibility Agreements (SRAs) that are based on the latter principle. I will use the example of the Mulan SRA to illustrate the difficulties in articulating the 'new arrangements' with current approaches to Indigenous health planning and strategy implementation. I conclude that 'new arrangements' pose a number of problems for Indigenous health planning and strategy that need to be addressed.
doi:10.1186/1743-8462-3-10
PMCID: PMC1626072  PMID: 16999873
24.  Comparison of the uptake of health assessment items for Aboriginal and Torres Strait Islander people and other Australians: Implications for policy 
Background
Health Assessment (HA) items were introduced in 1999 for Aboriginal and Torres Strait Islander people aged at least 55 years and all Australians aged over 75 years. In 2004 a new item was introduced for HAs among adult Aboriginal and Torres Strait Islander people aged 15–54 years. The new item has been applauded as a major policy innovation however this enthusiasm has been tempered with concern about potential barriers to its uptake. In this study we aim to determine whether there are disparities in uptake of HA items for Aboriginal and Torres Strait Islander people compared to other Australians.
Method
The analysis was based on Health Insurance Commission data. Indigenous status was ascertained based on the item number used. Logistic regression was used to compare uptake of HA items for older people among Aboriginal and Torres Strait Islander people compared to other Australians. Adjustments were made for dual eligibility. Uptake of the HA items for older people was compared to the uptake of the new item for Aboriginal and Torres Strait Islander people aged 15–44 years.
Results
Our analyses suggest a significant and persistent disparity in the uptake of items for older patients among Aboriginal and Torres Strait Islander people compared to other Australians. A similar disparity appears to exist in the uptake of the new adult Aboriginal and Torres Strait Islander HA item.
Conclusion
Further engagement of primary care providers and the community around the uptake of the new HA items may be required to ensure that the anticipated health benefits eventuate.
doi:10.1186/1743-8462-2-21
PMCID: PMC1239906  PMID: 16150154

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