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.
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.
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.
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.
•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.
Charitable donation; Major depression; Reward processing; Subgenual anterior cingulate; Striatum
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.
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.
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.
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.
Liver; Hepatectomy; Post-operative care
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.
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.
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.
Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.
Antidepressive agents; Cortisol; Depressive disorder; Metyrapone; Antiglucocorticoid treatment; Treatment refractory depression
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.
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.
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.
Biologic prosthesis; Hernia; Necrotizing soft tissue infection
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.
OXTR; genetics; oxytocin; social-cognition; cooperation
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.
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.
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.
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.
Amygdala; connectivity; depression; emotion; fusiform gyrus; orbitofrontal cortex
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.
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.
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.
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.
Health economics; Resource allocation; Indigenous Australians; Primary health care services; Health service delivery; Health equity
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
In this paper I will describe some of the sentinel events in Aboriginal and Torres Strait Islander health policy and strategy during 2003 and the early part of 2004. This will involve discussion on the:
• National Strategic Framework in Aboriginal and Torres Strait Islander Health
• National Strategic Framework for Aboriginal and Torres Strait Islander Peoples Mental Health and Social and Emotional Well Being 2004–2009
• National Aboriginal and Torres Strait Islander Health Performance Framework
• The roll-out of the Primary Health Care Access Program
• The National Aboriginal and Torres Strait Islander Social Survey and the National Indigenous Health Survey
These developments are consistent with a policy agenda that has evolved, in general terms, since the release of the National Aboriginal Health Strategy in 1989. However, I will also consider significant developments in the broader context for Aboriginal and Torres Strait Islander affairs, particularly the decision made in early 2004 by the Howard government to abolish the Aboriginal and Torres Strait Islander Commission (ATSIC). While the key events and developments that are reported in this paper elaborate on an agenda that has been developing for more than a decade, the decision to abolish ATSIC is likely to have a revolutionary impact on the future development of Aboriginal health strategy.
Twenty-six patients in infancy and early childhood with severe pulmonary valve stenosis and intact ventricular septum are reviewed. They were selected from a larger series of 112 patients with pulmonary stenosis of any degree, on account of early onset of symptoms and the severity of the stenosis proven by cardiac catheterization and angiocardiography, at operation or at necropsy. Our criteria for severity in this series were: presence of symptoms within the first two years of life; right ventricular and right atrial hypertrophy on electrocardiography; and right ventricular pressure equal to or higher than systemic blood pressure. The warning signs prompting valvotomy are deterioration of the following features: cyanosis and dyspnoea; congestive cardiac failure; tricuspid incompetence; cardiac enlargement and pulmonary oligaemia on radiograph; and right ventricular and right atrial hypertrophy on electrocardiography. The lives of 13 patients were saved by timely valvotomy. These patients are all well six months to six years after operation. Five patients died before any operation could be performed. Eight patients died within 48 hours of operation. Had some of these patients been operated on earlier the evidence indicates that they would have had a better prognosis. Therefore the importance of early recognition, prompt treatment, and emergency valvotomy, if necessary, is emphasized.