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Valvular heart disease (VHD) is a major contributor to loss of physical function, quality of life and longevity. The epidemiology of VHD varies substantially around the world, with a predominance of functional and degenerative disease in high-income countries, and a predominance of rheumatic heart disease in low-income and middle-income countries. Reflecting this distribution, rheumatic heart disease remains by far the most common manifestation of VHD worldwide and affects approximately 41 million people. By contrast, the prevalence of calcific aortic stenosis and degenerative mitral valve disease is 9 and 24 million people, respectively. Despite a reduction in global mortality related to rheumatic heart disease since 1900, the death rate has remained fairly static since 2000. Meanwhile, deaths from calcific aortic stenosis have continued to rise in the past 20 years. Epidemiological data on other important acquired and congenital forms of VHD are limited. An ageing population and advances in therapies make an examination of the changing global epidemiology of VHD crucial for advances in clinical practice and formulation of health policy. In this Review, we discuss the global burden of VHD, geographical variation in the presentation and clinical management, and temporal trends in disease burden. Valvular heart disease (VHD) is a major contributor to loss of physical function, quality of life and longevity. In this Review, Prendergast and colleagues discuss the global burden of VHD, geographical variation in the presentation and clinical management, and temporal trends in disease burden.

Diabetes is a major burden on Australia’s Indigenous population, with high rates of disease and vascular complications. Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. MicroRNAs (miRNAs) are key players in the regulation of angiogenesis. HDL-cholesterol (HDL-c) levels are inversely associated with the risk of developing diabetic complications and HDL can carry miRNAs. HDL-miRNA profiles differ in disease states and may present as biomarkers with the capacity to act as bioactive signalling molecules. Recent studies have demonstrated that HDL becomes dysfunctional in a diabetic environment, losing its vasculo-protective effects and becoming more pro-atherogenic. We sought to determine whether HDL-associated miRNA profiles and HDL functionality were predictive of the severity of diabetic vascular complications in Australia’s Indigenous population. HDL was isolated from plasma samples from Indigenous participants without diabetes (‘Healthy’), with type 2 diabetes mellitus (‘T2DM’) and with diabetes-associated macrovascular complications (specifically peripheral artery disease, ‘T2DM+Comp’). To assess HDL angiogenic capacity, human coronary artery endothelial cells were treated with PBS, reconstituted HDL (rHDL, positive control) or isolated HDL and then exposed to high-glucose (25 mmol/l) conditions. The expression levels of two anti-angiogenic miRNAs (miR-181c-5p and miR-223-3p) and one pro-angiogenic miRNA (miR-27b-3p) were measured in the HDL fraction, plasma and treated human coronary artery endothelial cells by quantitative real-time PCR. In vitro endothelial tubule formation was assessed using the Matrigel tubulogenesis assay. Strikingly, we found that the levels of the anti-angiogenic miRNA miR-181c-5p were 14-fold higher (1454 ± 1346%) in the HDL from Aboriginal people with diabetic complications compared with both the Healthy (100 ± 121%, p

Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.

Background Associations between kidney disease and periodontal disease are not well documented among Aboriginal people of Australia. The purpose of this investigation was to report and compare demographic, oral health, anthropometric and systemic health status of Aboriginal Australians with kidney disease and to compare against relevant Aboriginal Australians and Australian population estimates. This provides much needed evidence to inform dental health service provision policies for Aboriginal Australians with kidney disease. Methods Sample frequencies and means were assessed in adults represented in six datasets including: (1) 102 Aboriginal Australians with kidney disease residing in Central Australia who participated in a detailed oral health assessment; (2) 312 Aboriginal participants of the Northern Territory’s PerioCardio study; (3) weighted estimates from 4775 participants from Australia’s National Survey of Adult Oral Health (NSAOH); (4) Australian 2016 Census (all Australians); (5) National Health Survey 2017–2018 (all Australians) and; (6) Australian Health Survey: Biomedical Results for Chronic Diseases, 2011–2012 (all Australians). Oral health status was described by periodontal disease and experience of dental caries (tooth decay). Statistically significant differences were determined via non-overlapping 95% confidence intervals. Results Aboriginal Australians with kidney disease were significantly older, less likely to have a tertiary qualification or be employed compared with both PerioCardio study counterparts and NSAOH participants. Severe periodontitis was found in 54.3% of Aboriginal Australians with kidney disease, almost 20 times the 2.8% reported in NSAOH. A higher proportion of Aboriginal Australians with kidney disease had teeth with untreated caries and fewer dental restorations when compared to NSAOH participants. The extent of periodontal attachment loss and periodontal pocketing among Aboriginal Australians with kidney disease (51.0%, 21.4% respectively) was several magnitudes greater than PerioCardio study (22.0%, 12.3% respectively) and NSAOH (5.4%, 1.3% respectively) estimates. Conclusions Aboriginal Australians with kidney disease exhibited more indicators of poorer oral health than both the general Australian population and a general Aboriginal population from Australia’s Northern Territory. It is imperative that management of oral health among Aboriginal Australians with kidney disease be included as part of their ongoing medical care.

In this work, we present a computational investigation on the photoexcitation of indigo carmine (IC). Physical insights regarding IC photoexcitation and photolysis were obtained from a fundamental perspective through quantum chemistry computations. Density functional theory (DFT) was used to investigate the ground state while its time-dependent formalism (TD-DFT) was used for probing excited state properties, such as vertical excitation energies, generalized oscillator strengths (GOS), and structures. All the computations were undertaken using two different approaches: M06-2X/6-311+G(d,p) and CAM-B3LYP/6-311+G(d,p), in water. Results determined using both methods are in systematic agreement. For instance, the first singlet excited state was found at 2.28 eV (with GOS = 0.4730) and 2.19 eV (GOS = 0.4695) at the TD-DFT/CAM-B3LYP/6-311+G(d,p) and TD-DFT/M06-2X/6-311+G(d,p) levels of theory, respectively. Excellent agreement was observed between the computed and the corresponding experimental UV-Vis spectra. Moreover, results suggest IC undergoes photodecomposition through excited state chemical reaction rather than via a direct photolysis path. To the best of our knowledge, this work is the first to tackle the photoexcitation, and its potential connections to photodegradation, of IC from a fundamental chemical perspective, being presented with expectations to motivate further studies.

Objective Periodontal disease is associated with chronic kidney disease (CKD), with both conditions being highly prevalent among Australia’s Aboriginal population. This paper reflects on the lessons learned following implementation of a periodontal intervention in the Central Australian region of the Northern Territory among Aboriginal adults with CKD. Results Between Oct 2016 and May 2019, research staff recruited 102 eligible participants. This was far below the anticipated recruitment rate. The challenges faced, and lessons learned, were conceptualised into five specific domains. These included: (1) insufficient engagement with the Aboriginal community and Aboriginal community-controlled organisations; (2) an under-appreciation of the existing and competing patient commitments with respect to general health and wellbeing, and medical treatment to enable all study commitments; (3) most study staff employed from outside the region; (4) potential participants not having the required number of teeth; (5) invasive intervention that involved travel to, and time at, a dental clinic. A more feasible research model, which addresses the divergent needs of participants, communities and service partners is required. This type of approach, with sufficient time and resourcing to ensure ongoing engagement, partnership and collaboration in co-design throughout the conduct of research, challenges current models of competitive, national research funding.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Aboriginal women are frequently called upon to support their families and other community members. At times, such supporting roles can be burdensome for these women. Many Aboriginal women live with chronic conditions. We explored the ways in which the women’s caring roles impacted on how they maintained their own health. Methods The aim of this manuscript is to explore the psychosocial factors associated with the management of health and chronic disease in Aboriginal women. An interpretive phenomenological approach was used for the analysis of 72 in-depth semi-structured interviews. These interviews were conducted in four community controlled Aboriginal health services, in urban, rural and remote settings, across two states and a territory in Australia. Results Women living with chronic disease experience multiple challenges while caring for family, such as intergenerational trauma, mental health issues relating to addiction, domestic and family violence and incarceration. When these women become ill, they also have to take care of themselves. These women provided informal and unfunded care in response to a range of complex family and community problems. This continuous caring for family affected the women’s ability to maintain their health and manage their own chronic conditions. Conclusion The caring roles and responsibilities Aboriginal women have in their community impact on their health. Aboriginal women provide much needed refuge and support to family and the wider community. Underfunded and over-burdened formal support services are not meeting the needs of many Aboriginal women. Improved culturally secure resources and social services are required within communities to support Aboriginal women to successfully manage their own health.

Non-invasive molecular imaging techniques are accruing more interest in the last decades. Several radiolabelling elements have been FDA-approved and are currently used to characterize tumors. In this study, the DNA intercalating agent doxorubicin was radiolabelled with 125I. Several parameters for the radiolabelling reaction were investigated and optimized. A maximum yield of 94 ± 0.3% was reached after reacting 20 μg of doxorubicin with 200 μg Chloramine-T at pH 5 for 30 min. The in vivo stability of 125I-doxorubicin is validated by the low propensity for thyroid uptake in mice. The preclinical T/NT ratio was approximately 6.4 at 30 min. Docking and molecular dynamics confirmed that the radiolabelling of doxorubicin did not affect (or slightly improved its binding to DNA). Overall, 125I-doxorubicin was demonstrated to be a promising non-invasive probe for solid tumor imaging.

While statins have formed the cornerstone of strategies for cardiovascular prevention, the residual risk related to low-density lipoprotein cholesterol (LDL-C) and other lipoprotein factors provides a landscape for development of new therapies. However, a number of lipid-modifying therapies have failed to reduce cardiovascular event rates in contemporary clinical trials of statin-treated patients. The factors considered in outcome measure selection for clinical trials of novel lipid-lowering therapies are reviewed. Evaluation of lipid-modifying drugs in clinical trials spans a spectrum from their effects on conventional circulating lipid parameters through to their impact on atherosclerotic plaque and ultimately clinical outcomes. The design of these trials has an important impact on the result and ultimate interpretation of these studies.

The clinical reality of residual risk despite statin (HMG-CoA reductase inhibitor) therapy and emergence of statin intolerance support the need to develop additional lipid-lowering strategies. Proprotein convertase subtilisin kexin type 9 (PCSK9) has received considerable attention by virtue of genetic and clinical studies that have revealed its pivotal role in the regulation of cholesterol homeostasis. Monoclonal antibodies have been developed targeting PCSK9, which have been demonstrated to produce profound low-density lipoprotein cholesterol (LDL-C) lowering when provided as monotherapy or in combination with statins. With the reports that the PCSK9 inhibitor evolocumab has a favorable impact on both plaque progression and cardiovascular outcomes, these findings begin to translate the benefits of PCSK9 inhibition from lipids to the vessel wall and ultimately to clinical outcomes. The clinical implications for the use of these agents are reviewed in this article.

Lipid second messengers have essential roles in cellular function and contribute to the molecular mechanisms that underlie inflammation, malignant transformation, invasiveness, neurodegenerative disorders, and infectious and other pathophysiological processes. The phospholipase D (PLD) isoenzymes PLD1 and PLD2 are one of the major sources of signal-activated phosphatidic acid (PtdOH) generation downstream of a variety of cell-surface receptors, including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and integrins. Recent advances in the development of isoenzyme-selective PLD inhibitors and in molecular genetics have suggested that PLD isoenzymes in mammalian cells and pathogenic organisms may be valuable targets for the treatment of several human diseases. Isoenzyme-selective inhibitors have revealed complex inter-relationships between PtdOH biosynthetic pathways and the role of PtdOH in pathophysiology. PLD enzymes were once thought to be undruggable owing to the ubiquitous nature of PtdOH in cell signalling and concerns that inhibitors would be too toxic for use in humans. However, recent promising discoveries suggest that small-molecule isoenzyme-selective inhibitors may provide novel compounds for a unique approach to the treatment of cancers, neurodegenerative disorders and other afflictions of the central nervous system, and potentially serve as broad-spectrum antiviral and antimicrobial therapeutics.

In this work, we present a computational study on the antioxidant potential of myricetin 3-O-α-L-rhamnopyranoside (Compound M3) and myricetin 4′-O-α-L-rhamnopyranoside (Compound M4′). Structural parameters, bond dissociation enthalpies (BDEs), ionization potentials (IPs), proton dissociation enthalpies (PDEs), proton affinities (PAs), and electron transfer enthalpies (ETEs), which are properties connected with different mechanisms related to antioxidant activity, were determined using density functional theory (DFT) with B3LYP, LC-ωPBE, M06-2X, and BMK functionals along with the 6-311G(d,p) and 6-311+G(d,p) basis sets in the gas phase, water, and pentylethanoate. The values obtained were compared with results previously available in the literature for myricetin (the parent molecule and a well-known antioxidant) and myricetin 3,4′-di-O-α-L-rhamnopyranoside (Compound M3,4′). As the BDEs are considerably lower than the IPs, the HAT mechanism is preferred over SET for the compounds M3 and M4′. The present study indicates Compound M3 as having its lowest bond dissociation enthalpy from the several different OH groups with similar value to the lowest for myricetin (74.72 kcal/mol versus 74.8 kcal/mol, respectively, at the B3LYP/6-311G(d,p) level of theory in the gas phase) and, thus, presenting antioxidant potential as good as its parent molecule. On the other hand, Compound M4′ presented 78.97 kcal/mol as the lowest BDE at the B3LYP/6-311G(d,p) level of theory in the gas phase, that is very close to the 78.34 kcal/mol computed using the same approach for Compound M3,4′. Therefore, the present investigation indicated Compound M4′ as being a slightly inferior antioxidant (with antioxidant potential comparable to Compound M3,4′) than Compound M3. In addition, the inclusion of the sugar moiety studied here in the position 4′-ArOH of myricetin seems to have a more marked impact (downward) on the antioxidant activity than the glycosylation in the position 3-ArOH.

To close health disparities between Indigenous and non-Indigenous Australians, the Australian government in 2010 reduced medication copayments for Indigenous Australians living with, or at risk of, a chronic disease. Patients were registered for this incentive by their general practitioner. To assess rates of hospitalizations for chronic conditions among Indigenous Australians before and after copayment reductions. Observational time-trend study of hospitalizations for chronic conditions sensitive to medication adherence.. Indigenous persons age 15 years and older in 16 urban, regional, and remote locations. The population ranged from 40,953 in 2009 to 42,651 in 2011. Hospitalizations for diabetes, asthma, chronic obstructive pulmonary disease, hypertension, heart failure, and cardiovascular events. Approximately 22 % of Indigenous persons registered for the medication copayment incentive in the first 18 months of implementation. In areas with rates of incentive uptake exceeding 22 %, the age-standardized rate of hospitalizations for chronic conditions among Indigenous Australians declined from 103.4/1000 (95 % CI 88.8/1000 to 118.0/1000) in 2009 to 60.0/1000 (95 % CI 49.3/1000 to 70.7/1000) in 2011. In areas with below-average uptake of the incentive, we observed non-significant reductions in age-standardized hospitalization rates (from 63.3/1000 [95 % CI 52.9/1000 to 73.7/1000] in 2009 to 58.0/1000 [95 % CI 48.5/1000 to 67.5/1000] in 2011). Among Indigenous Australians, the rate of admission for acute conditions (pneumonia, influenza, urinary tract infection, pyelonephritis, and dehydration) was 38.4/1000 (95 % CI 32.4/1000 to 44.3/1000) in 2009 and 36.2/1000 (95 % CI 30.4/1000 to 41.8/1000) in 2011. Among the non-Indigenous population, we found substantially lower rates of hospitalizations and modest declines from 2009 to 2011. Though we cannot make causal inferences from the results of this study, we observed marked declines in hospitalizations for chronic conditions among Indigenous Australians following targeted reductions in medication copayments for this population. These declines were largely limited to areas with higher uptake of the copayment incentive and were not observed for admissions related to acute conditions.

Background: Aboriginal and Torres Strait Islander men experience worse health outcomes and are the most marginalized and disadvantaged population group in Australia. Primary health care services are critical to providing both clinical and social and emotional support, however, remain underutilized by Aboriginal and Torres Strait Islander men. This review aims to better understand the utilization of primary health care services by Indigenous men and assess the effectiveness of strategies implemented to improve utilization. Methods: A four-step search strategy was employed across four databases to find peer-reviewed publications and grey literature from Australia, New Zealand, Canada and America. The search began in March 2015 and included the following databases PubMed, CINAHL, Informit (Indigenous collection) and Embase. Additional databases and websites were also searched for grey literature, reference lists of included publications were searched for additional studies and relevant experts were consulted. Results: The literature search found seven articles that met the inclusion criteria; four describing three research projects, plus three expert opinion pieces. The search was unable to find published research on strategies implemented to improve primary health care utilization by Indigenous men. There is limited published research focused on the utilization of primary health care by Indigenous men. From the identified papers Indigenous men described factors impacting utilization which were categorized into three primary organizing themes; those related to health services, the attitudes of Indigenous men and knowledge. It is evident from the identified papers that improvements in Indigenous health can only occur if future programs are developed in collaboration with health services and Indigenous men to address differing requirements. Conclusions: Currently, health systems in Australia are limited in their ability to improve the health and wellbeing of Aboriginal and Torres Strait Islander males without such strategies. Future research should focus on evaluating the implementation of men specific utilization strategies. It is through evidence-based research that subsequent policies and programs can be made and implemented to improve Indigenous men's health. Refereed/Peer-reviewed

Background Indigenous populations have poorer health outcomes compared to their non-Indigenous counterparts. The evolution of Indigenous primary health care services arose from mainstream health services being unable to adequately meet the needs of Indigenous communities and Indigenous peoples often being excluded and marginalised from mainstream health services. Part of the solution has been to establish Indigenous specific primary health care services, for and managed by Indigenous peoples. There are a number of reasons why Indigenous primary health care services are more likely than mainstream services to improve the health of Indigenous communities. Their success is partly due to the fact that they often provide comprehensive programs that incorporate treatment and management, prevention and health promotion, as well as addressing the social determinants of health. However, there are gaps in the evidence base including the characteristics that contribute to the success of Indigenous primary health care services in providing comprehensive primary health care. This systematic scoping review aims to identify the characteristics of Indigenous primary health care service delivery models. Method This systematic scoping review was led by an Aboriginal researcher, using the Joanna Briggs Institute Scoping Review Methodology. All published peer-reviewed and grey literature indexed in PubMed, EBSCO CINAHL, Embase, Informit, Mednar, and Trove databases from September 1978 to May 2015 were reviewed for inclusion. Studies were included if they describe the characteristics of service delivery models implemented within an Indigenous primary health care service. Sixty-two studies met the inclusion criteria. Data were extracted and then thematically analysed to identify the characteristics of Indigenous PHC service delivery models. Results Culture was the most prominent characteristic underpinning all of the other seven characteristics which were identified – accessible health services, community participation, continuous quality improvement, culturally appropriate and skilled workforce, flexible approach to care, holistic health care, and self-determination and empowerment. Conclusion While the eight characteristics were clearly distinguishable within the review, the interdependence between each characteristic was also evident. These findings were used to develop a new Indigenous PHC Service Delivery Model, which clearly demonstrates some of the unique characteristics of Indigenous specific models.

The HBrO2 isomers have been analyzed computationally to confirm the previous experimental assignments for HOOBr and HOBrO and to assist in future identification of the as yet unobserved HBr(O)O isomer. Optimized geometries of the HOOBr, HOBrO, and HBr(O)O isomers and the transition states connecting them were obtained at the CCSD(T)/O, H: aug-cc-pVTZ, Br: aug-cc-pVTZ-PP level of theory. The corresponding harmonic vibrational frequencies for the HOOBr, HOBrO, and HBr(O)O isomers are reported for all isotopologues considered in the experimental measurements, i.e., those involving hydrogen, deuterium, $$^{79}$$ Br, $$^{81}$$ Br, $$^{16}$$ O, and $$^{18}$$ O. The relative energetics of the stationary point geometries were determined through extrapolation of energies to the complete basis set limit. To explain the photodestruction observed experimentally for HOOBr and HOBrO, the three lowest low-lying singlet and triplet excited electronic states for each of the three isomers were computed using the equation-of-motion coupled-cluster with inclusion of single and double excitations (EOM-CCSD) and time-dependent density functional theory (TD-B3LYP and TD-CAM-B3LYP) approaches; all utilizing the all-electron aug-cc-pVTZ basis sets for all atoms. Multi-reference configuration interaction (MRCI)/aug-cc-pVTZ computations were carried out for the lowest singlet and lowest two triplet excited states. The vertical excitation energies for the low-lying excited states of the most stable isomer (HOOBr) are reported for the first time. The vibrational frequencies for the $$\hbox{HBrO}_{2}$$ isomers are used along with new anharmonic vibrational frequency computations (at the PBE0/aug-cc-pVTZ level of theory) and vertical excitation energies (at the TD-B3LYP/aug-cc-pVTZ, TD-CAMB3LYP/aug-cc-pVTZ, and EOM-CCSD/aug-cc-pVTZ levels of theory) for the $$\hbox {HBrO}_{3}$$ isomers, HOOOBr and HOOBrO, to determine that previously unassigned peaks in the experimental spectrum generated from HBr/O $$_{2}$$ photolysis in a Ne matrix belong to HOOOBr.

Background The disparities in health and life expectancy of Aboriginal and Torres Strait Islander peoples compared to non-Indigenous Australians are well documented. Chronic diseases are a leading contributor to these disparities. We aimed to determine the feasibility, acceptability and appropriateness of a case management approach to chronic disease care integrated within an urban Aboriginal and Torres Strait Islander primary health care service. Methods The Home-based, Outreach case Management of chronic disease Exploratory (HOME) Study provided holistic, patient centred multidisciplinary care for Aboriginal and Torres Strait Islander people with chronic disease. A developmental evaluation approach supported the implementation and ongoing adaptations in the delivery of the model of care, and ensured its alignment with Aboriginal and Torres Strait Islander peoples’ understandings of, and approaches to, health and wellbeing. In-depth, semi-structured interviews were conducted with nine patient participants (one interview also included a participant’s spouse) and 15 health service staff and key themes were identified through an iterative reflective process. Quantitative data were collected directly from patient participants and from their medical records at baseline, 3 and 6 months. Patient participants’ baseline characteristics were described using frequencies and percentages. Attrition and patterns of missing values over time were evaluated using binomial generalized estimating equation (GEE) models and mean differences in key clinical outcomes were determined using normal GEE models. Results Forty-one patients were recruited and nine withdrew over the 6 month period. There was no evidence of differential attrition. All participants (patients and health service staff) were very positive about the model of care. Patient participants became more involved in their health care, depression rates significantly decreased (p = 0.03), and significant improvements in systolic blood pressure (p

We present a computational study on two flavonols that were recently isolated from Loranthaceae family plant extracts: kaempferol 3-O-α-L-arabinofuranosyl-(1 → 3)-α-L-rhamnoside and quercetin 3-O-α-L-arabinofuranosyl-(1 → 3)-α-L-rhamnoside. Their structures and energetics have been investigated at the density functional level of theory, up to B3LYP/6-31+G(d,p), incorporating solvent effects with polarizable continuum models. In addition, their potential antioxidant activities were probed through the computation of the (i) bond dissociation enthalpies (BDEs), which are related to the hydrogen-atom transfer mechanism (HAT), and (ii) ionization potentials (IPs), which are related to the single-electron transfer mechanism (SET). The BDEs were determined in water to be 83.23 kcal/mol for kaempferol 3-O-α-L-arabinofuranosyl-(1 → 3)-α-L-rhamnoside and 77.49 kcal/mol for quercetin 3-O-α-L-arabinofuranosyl-(1 → 3)-α-L-rhamnoside. The corresponding IPs were obtained for both compounds as 133.38 and 130.99 kcal/mol, respectively. The BDEs and IPs are comparable to those probed for their parental molecules kaempferol and quercetin; this is in marked contrast to previous studies where glycosylation at the 3-position increases the corresponding BDEs, and, hence, decreases subsequent antioxidant activity. The BDEs and IPs obtained suggest both compounds are promising for antioxidant activity and thus further experimental tests are encouraged.

Populations of small pelagic fish support important fisheries in Spanish Mediterranean waters, particularly sardine (Sardina pilchardus) and anchovy (Engraulis encrasicolus), and are distributed along the entire length of the Spanish continental shelf. Using annual acoustic survey data for the years 2003–2005, a GIS-based environmental modelling approach was used to investigate the distribution and abundance of small pelagic fish in relation to environmental variables. Multivariate analysis was applied to provide a preliminary picture of relationships between fish and environmental conditions, followed by application of Generalised Additive Models (GAMs). GAMs showed the presence/absence of fish to be related to bathymetry, sea surface chlorophyll-a concentration and sea surface temperature (SST). The strength and significance of these relationships varied spatially and temporally. High resolution Essential Fish Habitat (EFH) maps were generated for sardine and anchovy, based on the predicted probability of presence of each species. Substantial inter-annual variability in the distribution and quality of EFH was observed, particularly for anchovy. Identification of EFH is of great importance to assess and manage sardine and anchovy resources as it provides a natural link between population dynamics features and geographical scenarios. 2

Background The increasing prevalence of chronic disease faced by both developed and developing countries is of considerable concern to a number of international organisations. Many of the interventions to address this concern within primary healthcare settings are based on the chronic care model (CCM). The implementation of complex interventions such as CCMs requires careful consideration and planning. Success depends on a number of factors at the healthcare provider, team, organisation and system levels. Methods The aim of this systematic review was to systematically examine the scientific literature in order to understand the facilitators and barriers to implementing CCMs within a primary healthcare setting. This review focused on both quantitative and qualitative studies which included patients with chronic disease (cardiovascular disease, chronic kidney disease, chronic respiratory disease, type 2 diabetes mellitus, depression and HIV/AIDS) receiving care in primary healthcare settings, as well as primary healthcare providers such as doctors, nurses and administrators. Papers were limited to those published in English between 1998 and 2013. Results The search returned 3492 articles. The majority of these studies were subsequently excluded based on their title or abstract because they clearly did not meet the inclusion criteria for this review. A total of 226 full text articles were obtained and a further 188 were excluded as they did not meet the criteria. Thirty eight published peer-reviewed articles were ultimately included in this review. Five primary themes emerged. In addition to ensuring appropriate resources to support implementation and sustainability, the acceptability of the intervention for both patients and healthcare providers contributed to the success of the intervention. There was also a need to prepare healthcare providers for the implementation of a CCM, and to support patients as the way in which they receive care changes. Conclusion This systematic review demonstrated the importance of considering human factors including the influence that different stakeholders have on the success or otherwise of the implementing a CCM. Electronic supplementary material The online version of this article (doi:10.1186/s12875-015-0319-5) contains supplementary material, which is available to authorized users.

Background There is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function. However, differences in body build and body composition between Indigenous and non-Indigenous Australians suggest that creatinine-based estimates of glomerular filtration rate derived for European populations may not be appropriate for Indigenous Australians. The burden of kidney disease is borne disproportionately by Indigenous Australians in central and northern Australia, and there is significant heterogeneity in body build and composition within and amongst these groups. This heterogeneity might differentially affect the accuracy of estimation of glomerular filtration rate between different Indigenous groups. By assessing kidney function in Indigenous Australians from Northern Queensland, Northern Territory and Western Australia, we aim to determine a validated and practical measure of glomerular filtration rate suitable for use in all Indigenous Australians. Methods/Design A cross-sectional study of Indigenous Australian adults (target n = 600, 50% male) across 4 sites: Top End, Northern Territory; Central Australia; Far North Queensland and Western Australia. The reference measure of glomerular filtration rate was the plasma disappearance rate of iohexol over 4 hours. We will compare the accuracy of the following glomerular filtration rate measures with the reference measure: Modification of Diet in Renal Disease 4-variable formula, Chronic Kidney Disease Epidemiology Collaboration equation, Cockcroft-Gault formula and cystatin C- derived estimates. Detailed assessment of body build and composition was performed using anthropometric measurements, skinfold thicknesses, bioelectrical impedance and a sub-study used dual-energy X-ray absorptiometry. A questionnaire was performed for socio-economic status and medical history. Discussion We have successfully managed several operational challenges within this multi-centre complex clinical research project performed across remote North, Western and Central Australia. It seems unlikely that a single correction factor (similar to that for African-Americans) to the equation for estimated glomerular filtration rate will prove appropriate or practical for Indigenous Australians. However, it may be that a modification of the equation in Indigenous Australians would be to include a measure of fat-free mass.

Phospholipid-mediated signaling pathways control a myriad of physiological processes including various aspects of brain function. Among the phospholipid enzyme families, phospholipase D (PLD) is emerging as a key player in regulating phospholipid metabolism, and a newly appreciated therapeutic target for Alzheimer's disease (AD), stroke, and other brain disorders (Oliveira and Di Paolo, 2010). PLD catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid and choline. Two mammalian isoforms of conventional PLDs have been identified, PLD1 and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Previous research relied on the overexpression of either catalytically active or inactive forms of either PLD1 or PLD2 in cells, or employed siRNA for the individual isoforms in an effort to discern discrete roles for PLD1 and PLD2 in brain disorders (Oliveira and Di Paolo, 2010). In 2010, PLD1−/− and PLD2−/− mice developed via gene targeting were reported, clearly defining, nonoverlapping roles, and therapeutic potential for both PLD1 and PLD2 in the pathogenesis of AD. From overexpression and biochemical studies, it has been shown that PLD1 (but not PLD2) regulates the trafficking of APP and the assembly of the γ-secretase complex via a direct interaction with PS1 (Cai et al, 2006). In 2010, PLD2−/− mice provided the first in vivo evidence implicating PLD in AD. Here, PLD2 was shown to be required for the synaptotoxic action of Aβ, and that PLD2 ablation rescues memory deficits and engenders synaptic protection in SwAPP mice, despite a high Aβ load (Oliveira et al, 2010). Also in 2010, PLD1−/− mice were shown to display impaired αIIbβ3 intergrin activation and defective glycoprotein 1b-dependent aggregate formation, leading to protection from thrombosis and ischemic brain injury without increasing bleeding time (Elvers et al, 2010). Historically, few small molecule tools existed to study PLD function, and none of the inhibitors displayed PLD isoform-selective inhibition. The classical biochemical approach relies on n-butanol, a small molecule that is not a PLD inhibitor, rather n-butanol blocks PLD-catalyzed phosphatidic acid production by competing with water as a nucleophile, thereby generating phosphatidylbutanol in a competitive transphosphatidylation reaction. A renaissance in the PLD inhibitor field began in 2007 when halopemide (1), a psychotropic agent discovered in the late 1970s, was shown to be a dual PLD1/2 inhibitor (Scott et al, 2009). More importantly, 1 has been in humans in five clinical trials and was shown to be safe and effective; thus inhibition of PLD with a small molecule is a viable therapeutic approach, a finding also noted in the PLD KO mice. Using 1 as a lead, a diversity-oriented synthesis campaign was pursued by the Brown and Lindsley labs, where ∼1000 analogs of 1 were synthesized and evaluated in cell-based and biochemical PLD1 and PLD2 assays (Scott et al, 2009). From this effort, isoform-selective PLD1 (2) and PLD2 (3) inhibitors were developed with low nanomolar potencies, unprecedented PLD isoform selectivity and DMPK profiles to allow in vivo target validation studies to be pursued (Lavieri et al, 2010; Figure 1). Figure 1 Evolution of small molecule, isoform-selective PLD inhibitors.

Metabolomics reveals new insights into the mechanism of an antimicrobial agent and folate metabolism.