TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells.

Rationale: TRPV4 channels are critical regulators of blood vascular function and have been shown to be dysregulated in many disease conditions in association with inflammation and tissue fibrosis. These are key features in the pathophysiology of lymphatic system diseases, including lymphedema and lipedema; however, the role of TRPV4 channels in the lymphatic system remains largely unexplored. TRPV4 channels are calcium permeable, non-selective cation channels that are activated by diverse stimuli, including shear stress, stretch, temperature, and cell metabolites, which may regulate lymphatic contractile function. Objective: To characterize the expression of TRPV4 channels in collecting lymphatic vessels and to determine the extent to which these channels regulate the contractile function of lymphatics. Methods and Results: Pressure myography on intact, isolated, and cannulated lymphatic vessels showed that pharmacological activation of TRPV4 channels with GSK1016790A (GSK101) led to contractile dysregulation. The response to GSK101 was multiphasic and included, 1) initial robust constriction that was sustained for ≥1 minute and in some instances remained for ≥4 minutes; and 2) subsequent vasodilation and partial or complete inhibition of lymphatic contractions associated with release of nitric oxide. The functional response to activation of TRPV4 channels displayed differences across lymphatics from four anatomical regions, but these differences were consistent across different species (mouse, rat, and non-human primate). Importantly, similar responses were observed following activation of TRPV4 channels in arterioles. The initial and sustained constriction was prevented with the COX inhibitor, indomethacin. We generated a controlled and spatially defined single-cell RNA sequencing (scRNAseq) dataset from intact and microdissected collecting lymphatic vessels. Our data uncovered a subset of macrophages displaying the highest expression of Trpv4 compared to other cell types within and surrounding the lymphatic vessel wall. These macrophages displayed a transcriptomic profile consistent with that of tissue-resident macrophages (TRMs), including differential expression of Lyve1 , Cd163 , Folr2 , Mrc1 , Ccl8 , Apoe , Cd209f , Cd209d , and Cd209g ; and at least half of these macrophages also expressed Timd4. This subset of macrophages also highly expressed Txa2s , which encodes the thromboxane A2 (TXA2) synthase. Inhibition of TXA2 receptors (TXA2Rs) prevented TRPV4-mediated contractile dysregulation. TXA2R activation on LMCs caused an increase in mobilization of calcium from intracellular stores through Ip3 receptors which promoted store operated calcium entry and vasoconstriction. Conclusions: Clinical studies have linked cancer-related lymphedema with an increased infiltration of macrophages. While these macrophages have known anti-inflammatory and pro-lymphangiogenic roles, as well as promote tissue repair, our results point to detrimental effects to the pumping capacity of collecting lymphatic vessels mediated by activation of TRPV4 channels in macrophages. Pharmacological targeting of TRPV4 channels in LYVE1-expressing macrophages or pharmacological targeting of TXA2Rs may offer novel therapeutic strategies to improve lymphatic pumping function and lymph transport in lymphedema.

Right ventricular preload and afterload challenge induces contractile dysfunction and arrhythmia in isolated hearts of dystrophin-deficient male mice.

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy due to mutations in the dystrophin gene. Diaphragmatic weakness in DMD causes hypoventilation and elevated afterload on the right ventricle (RV). Thus, RV dysfunction in DMD develops early in disease progression. Herein, we deliver a 30-min sustained RV preload/afterload challenge to isolated hearts of wild-type (Wt) and dystrophic (Dmdmdx-4Cv) mice at both young (2-6 month) and middle-age (8-12 month) to test the hypothesis that the dystrophic RV is susceptible to dysfunction with elevated load. Young dystrophic hearts exhibited greater pressure development than wild type under baseline (Langendorff) conditions, but following RV challenge exhibited similar contractile function as wild type. Following the RV challenge, young dystrophic hearts had an increased incidence of premature ventricular contractions (PVCs) compared to wild type. Hearts of middle-aged wild-type and dystrophic mice had similar contractile function during baseline conditions. After RV challenge, hearts of middle-aged dystrophic mice had severe RV dysfunction and arrhythmias, including ventricular tachycardia. Following the RV load challenge, dystrophic hearts had greater lactate dehydrogenase (LDH) release than wild-type mice indicative of damage. Our data indicate age-dependent changes in RV function with load in dystrophin deficiency, highlighting the need to avoid sustained RV load to forestall dysfunction and arrhythmia.

Adapting an equity-focused implementation process framework with a focus on ethnic health inequities in the Aotearoa New Zealand context.

BACKGROUND: Health intervention implementation in Aotearoa New Zealand (NZ), as in many countries globally, usually varies by ethnicity. Maori (the Indigenous peoples of Aotearoa) and Pacific peoples are less likely to receive interventions than other ethnic groups, despite experiencing persistent health inequities. This study aimed to develop an equity-focused implementation framework, appropriate for the Aotearoa NZ context, to support the planning and delivery of equitable implementation pathways for health interventions, with the intention of achieving equitable outcomes for Maori, as well as people originating from the Pacific Islands. METHODS: A scoping review of the literature to identify existing equity-focused implementation theories, models and frameworks was undertaken. One of these, the Equity-based framework for Implementation Research (EquIR), was selected for adaptation. The adaptation process was undertaken in collaboration with the project's Maori and consumer advisory groups and informed by the expertise of local health equity researchers and stakeholders, as well as the international implementation science literature. RESULTS: The adapted framework's foundation is the principles of Te Tiriti o Waitangi (the written agreement between Maori rangatira (chiefs) and the British Crown), and its focus is whanau (extended family)-centred implementation that meets the health and wellbeing aspirations, priorities and needs of whanau. The implementation pathway comprises four main steps: implementation planning, pathway design, monitoring, and outcomes and evaluation, all with an equity focus. The pathway is underpinned by the core constructs of equitable implementation in Aotearoa NZ: collaborative design, anti-racism, Maori and priority population expertise, cultural safety and values-based. Additionally, the contextual factors impacting implementation, i.e. the social, economic, commercial and political determinants of health, are included. CONCLUSIONS: The framework presented in this study is the first equity-focused process-type implementation framework to be adapted for the Aotearoa NZ context. This framework is intended to support and facilitate equity-focused implementation research and health intervention implementation by mainstream health services.

A scoping review of equity-focused implementation theories, models and frameworks in healthcare and their application in addressing ethnicity-related health inequities.

BACKGROUND: Inequities in implementation contribute to the unequal benefit of health interventions between groups of people with differing levels of advantage in society. Implementation science theories, models and frameworks (TMFs) provide a theoretical basis for understanding the multi-level factors that influence implementation outcomes and are used to guide implementation processes. This study aimed to identify and analyse TMFs that have an equity focus or have been used to implement interventions in populations who experience ethnicity or 'race'-related health inequities. METHODS: A scoping review was conducted to identify the relevant literature published from January 2011 to April 2022 by searching electronic databases (MEDLINE and CINAHL), the Dissemination and Implementation model database, hand-searching key journals and searching the reference lists and citations of studies that met the inclusion criteria. Titles, abstracts and full-text articles were screened independently by at least two researchers. Data were extracted from studies meeting the inclusion criteria, including the study characteristics, TMF description and operationalisation. TMFs were categorised as determinant frameworks, classic theories, implementation theories, process models and evaluation frameworks according to their overarching aim and described with respect to how equity and system-level factors influencing implementation were incorporated. RESULTS: Database searches yielded 610 results, 70 of which were eligible for full-text review, and 18 met the inclusion criteria. A further eight publications were identified from additional sources. In total, 26 papers describing 15 TMFs and their operationalisation were included. Categorisation resulted in four determinant frameworks, one implementation theory, six process models and three evaluation frameworks. One framework included elements of determinant, process and evaluation TMFs and was therefore classified as a 'hybrid' framework. TMFs varied in their equity and systems focus. Twelve TMFs had an equity focus and three were established TMFs applied in an equity context. All TMFs at least partially considered systems-level factors, with five fully considering macro-, meso- and micro-level influences on equity and implementation. CONCLUSIONS: This scoping review identifies and summarises the implementation science TMFs available to support equity-focused implementation. This review may be used as a resource to guide TMF selection and illustrate how TMFs have been utilised in equity-focused implementation activities.

Calcium handling dysfunction and cardiac damage following acute ventricular preload challenge in the dystrophin-deficient mouse heart.

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and is caused by mutations in the dystrophin gene. Dystrophin deficiency is associated with structural and functional changes of the muscle cell sarcolemma and/or stretch-induced ion channel activation. In this investigation, we use mice with transgenic cardiomyocyte-specific expression of the GCaMP6f Ca2+ indicator to test the hypothesis that dystrophin deficiency leads to cardiomyocyte Ca2+ handling abnormalities following preload challenge. α-MHC-MerCreMer-GCaMP6f transgenic mice were developed on both a wild-type (WT) or dystrophic (Dmdmdx-4Cv) background. Isolated hearts of 3-7-mo male mice were perfused in unloaded Langendorff mode (0 mmHg) and working heart mode (preload = 20 mmHg). Following a 30-min preload challenge, hearts were perfused in unloaded Langendorff mode with 40 µM blebbistatin, and GCaMP6f was imaged using confocal fluorescence microscopy. Incidence of premature ventricular complexes (PVCs) was monitored before and following preload elevation at 20 mmHg. Hearts of both wild-type and dystrophic mice exhibited similar left ventricular contractile function. Following preload challenge, dystrophic hearts exhibited a reduction in GCaMP6f-positive cardiomyocytes and an increase in number of cardiomyocytes exhibiting Ca2+ waves/overload. Incidence of cardiac arrhythmias was low in both wild-type and dystrophic hearts during unloaded Langendorff mode. However, after preload elevation to 20-mmHg hearts of dystrophic mice exhibited an increased incidence of PVCs compared with hearts of wild-type mice. In conclusion, these data indicate susceptibility to preload-induced Ca2+ overload, ventricular damage, and ventricular dysfunction in male Dmdmdx-4Cv hearts. Our data support the hypothesis that cardiomyocyte Ca2+ overload underlies cardiac dysfunction in muscular dystrophy.NEW & NOTEWORTHY The mechanisms of cardiac disease progression in muscular dystrophy are complex and poorly understood. Using a transgenic mouse model with cardiomyocyte-specific expression of the GCaMP6f Ca2+ indicator, the present study provides further support for the Ca2+-overload hypothesis of disease progression and ventricular arrhythmogenesis in muscular dystrophy.

Life in a time of COVID: retrospective examination of the association between physical activity and mental well-being in western Australians during and after lockdown.

BACKGROUND: The aim of this study was to examine physical activity and sedentary behaviours during Western Australia's COVID-19 lockdown and their association with mental well-being. METHODS: Participants completed activity related questions approximately two months after a three-month lockdown (which formed part of a larger cross-sectional study from August to October 2020) as part of a 25-minute questionnaire adapted from the Western Australia Health and Well-being Surveillance system. Open-ended questions explored key issues relating to physical activity behaviours. RESULTS: During the lockdown period, 463 participants (female, n = 347; 75.3%) reported lower number of active days (W = 4.47 p < .001), higher non-work-related screen hours per week (W = 11.8 p < .001), and higher levels of sitting time (χ2=28.4 p < .001). Post lockdown body mass index was higher (U = 3.0 p = .003), with obese individuals reporting the highest non-work-related screen hours per week (Wald χ2= 8.9 p = .012). Inverse associations were found for mental well-being where higher lockdown scores of Kessler-10 (p = .011), Dass-21 anxiety (p = .027) and Dass-21 depression (p = .011) were associated with lower physical activity levels. A key qualitative message from participants was wanting to know how to stay healthy during lockdown. CONCLUSIONS: Lockdown was associated with lower physical activity, higher non-work-related screen time and more sitting time compared to post lockdown which also reported higher body mass index. Lower levels of mental well-being were associated with lower physical activity levels during lockdown. Given the known positive affect of physical activity on mental well-being and obesity, and the detrimental associations shown in this study, a key public health message should be considered in an attempt to maintain healthy activity behaviours in future lockdowns and similar emergency situations to promote and maintain positive well-being. Furthermore, consideration should be given to the isolation of a community due to infectious disease outbreaks and to recognise the important role physical activity plays in maintaining weight and supporting good mental health.

Supporting implementation of interventions to address ethnicity-related health inequities: frameworks, facilitators and barriers - a scoping review protocol.

INTRODUCTION: Health inequities are differences in health between groups of people that are avoidable, unfair and unjust. Achieving equitable health outcomes requires approaches that recognise and account for the differences in levels of advantage between groups. Implementation science, which studies how to translate evidence-based interventions into routine practice, is increasingly recognised as an approach to address health inequities by identifying factors and processes that enable equitable implementation of interventions. This article describes the protocol for a scoping review of the literature relating to the equitable implementation of interventions, focusing on ethnicity-related health inequities. The scoping review aims to identify equity-focused implementation science theories, models and frameworks (TMFs) and to synthesise and analyse the evidence relating to the factors that aid or inhibit equitable implementation of health interventions. METHODS AND ANALYSIS: The scoping review is guided by the methodology developed by Arksey and O'Malley and enhanced by Levac and colleagues. Relevant literature will be identified by searching electronic databases, grey literature, hand-searching key journals and searching the reference lists and citations of studies that meet the inclusion criteria. We will focus on literature published from 2011 to the present. Titles, abstracts and full-text articles will be screened independently by two researchers; any disagreements will be resolved through discussion with another researcher. Extracted data will be summarised and analysed to address the scoping review aims. ETHICS AND DISSEMINATION: The scoping review will map the available literature on equity-focused implementation science TMFs and the facilitators and barriers to equitable implementation of interventions. Ethical approval is not required. Dissemination of the results of the review will include publications in peer-review journals and conference and stakeholder presentations. Findings from the review will support those implementing interventions to ensure that the implementation pathway and processes are equitable, thereby improving health outcomes and reducing existing inequities.

"I'm making a positive change in my life": A mixed method evaluation of a well-being tertiary education unit.

ISSUE ADDRESSED: Mental health disorders (MHDs) are prevalent amongst university students with detrimental impacts on individual students, universities and the wider community. There is an urgent need for proactive and preventative strategies to address the mental health crisis in the university population. This study evaluated the efficacy of a 13-week unit developed to directly educate university students about ways to improve and maintain well-being. METHODS: Fifty-eight university students from five disciplines participated in a 13-week elective undergraduate unit "Well-Being Fundamentals for Success" as part of their degree. The Act Belong Commit mental health promotion campaign framework formed the basis of teaching materials. Outcome well-being measures were self-assessed at weeks 1, 6 and 12 using four scales: (1) Warwick-Edinburgh Mental Well-being Scale (WEMWBS); (2) Perceived Stress Scale (PSS); (3) Brief Resilience Scale (BRS) and (4) Mindful Attention Awareness Scale (MAAS). Post-unit group interviews (n = 11) were analysed for key themes. RESULTS: Linear mixed models demonstrated a significant improvement in BRS over the semester; well-being (WEMBS) and mindful attention (MAAS) did increase but not significantly. There was a significant increase in stress (PSS) over the semester. Key themes that emerged from the group interviews were that (1) University life contributes to well-being; (2) University life contributes to stress; (3) The well-being unit helped students see and do things differently; (4) An overall endorsement of the unit. CONCLUSION: University students' resilience increased over the semester following participation in a curriculum focused on well-being which featured a combination of theoretical content and experiential workshops. So what? Incorporating mental well-being curriculum into tertiary education is proactive preventive health strategy which may assist with the increasing prevalence of MHD in Australia.

Does support received for subsequent injuries differ between Maori and non-Maori? Findings from a cohort study of injured New Zealanders.

AIMS: To examine if differences exist between injured Maori and non-Maori in accessing and receiving support from the Accident Compensation Corporation (ACC) for treatment and rehabilitation of subsequent injuries. METHODS: This cohort study utilised participants' self-reported data from the Prospective Outcomes of Injury Study, and ACC claims data. RESULTS: Approximately one-third of Maori (32%) and non-Maori (35%) who self-reported a subsequent injury had no associated ACC claim. Statistically significant differences in this outcome (i.e., self-reported subsequent injury but no ACC claim) were found between Maori and non-Maori when comparing across occupation type and severity of participants' sentinel injuries. Few differences were observed between Maori and non-Maori in the percentages of ACC claims accepted that compensated various treatments and supports; this was similar for average compensation amounts provided. CONCLUSIONS: Maori and non-Maori who received support from ACC for a sentinel injury prior to sustaining another injury appear to have received equitable ACC compensation for the treatment and rehabilitation of the subsequent injury with two potential exceptions. Further research is needed to determine how generalisable these findings are. Establishing routine systems for collecting data about the support needed, treatment pathways and outcomes once accessing ACC support is vital to ensure positive and equitable injury outcomes for Maori.

Examining the barriers and facilitators for Maori accessing injury and rehabilitation services: a scoping review protocol.

INTRODUCTION: Injury accounts for 10% of the global burden of disease. While the literature is scarce, research investigating injury among Indigenous populations has found incidence and prevalence rates are higher, compared with non-Indigenous populations. New Zealand is no exception; Maori have higher rates of injury and disability compared with non-Maori. Given the burden of injury for Maori, this scoping review aims to identify, understand and map available literature related to the barriers and facilitators to accessing injury-related healthcare for Maori in New Zealand. METHODS AND ANALYSIS: A scoping review will be conducted to identify the relevant literature and provide an opportunity to highlight key concepts and research gaps in the literature. This work will be guided by the scoping review framework developed by Arksey and O'Malley and will be underpinned by Kaupapa Maori research principles. The overall project is also be guided by a Maori advisory group. Database searches, for example, MEDLINE (Ovid), Scopus and Embase, will be used to identify empirical literature, and Google, New Zealand government websites and relevant non-government organisations will be used to identify relevant grey literature. ETHICS AND DISSEMINATION: To the best of our knowledge, this scoping review is the first to systematically examine the currently available literature relating to the barriers and facilitators of accessing injury-related healthcare for Maori in New Zealand. Ethical approval was not required for this scoping review. Dissemination will include publication of the scoping review findings in a peer-reviewed journal, as well as presentations at conferences, to the project's advisory group, and staff working in the field of Maori disability and rehabilitation.

Life in a time of COVID: a mixed method study of the changes in lifestyle, mental and psychosocial health during and after lockdown in Western Australians.

BACKGROUND: Since the beginning of the COVID-19 pandemic, the Western Australian government imposed multiple restrictions that impacted daily life activities and the social life. The aim of this study was to examine the effects of COVID-19 lockdown on the community's physical, mental and psychosocial health. METHODS: Approximately 2 months after a three-month lockdown, a cross-sectional study was opened to Western Australian adults for an 8-week period (25th August - 21 October 2020). Participants competed a 25-min questionnaire adapted from the Western Australia Health and Wellbeing Surveillance system. Participants provided information on their socio-demographic status, lifestyle behaviours, mental health, and psychosocial health during and post-lockdown. Open-ended questions explored key issues in greater detail. Changes between the lockdown and post-lockdown period were assessed using Wilcoxon signed rank test and One-Sample Kolmogorov-Smirnov Normal tests as appropriate. Sex differences were examined using the Mann-Whitney U test. A content analysis approach examined responses to the open-ended questions with frequencies and variations in responses determined using Chi-Square tests. RESULTS: A total of 547 complete responses were obtained. Compared to post-lockdown period, lockdown was associated with a significantly lower levels of physical activity, poorer mental well-being and sense of control over one's life, and a higher level of loneliness. Similarly, during lockdown, there was a significantly higher consumption of junk food, soft drinks and alcoholic drinks but no change in fruit and vegetable intake. Participants recalled health campaigns on hand washing and social distancing and there was a retrospective view that more timely and informative campaigns on physical activity, nutrition and mental well-being should have been available during lockdown. CONCLUSIONS: While advice on infection control measures were appropriately provided, there is a need for concurrent health promotional information to help combat the changes in physical, mental and psychosocial well-being observed during quarantine to prevent negative health consequences in the community even if there are minimal effects of the pandemic itself.

"I couldn't even do normal chores": a qualitative study of the impacts of injury for Maori.

AIMS: To investigate the rehabilitation experiences of Maori who were still reporting disability 24 months after an injury resulting in hospitalisation. METHODS: Participants had been hospitalised for an Accident Compensation Corporation (New Zealand's no-fault injury compensation insurer) entitlement claim injury between 2007 and 2009, and were experiencing disability 24 months post-injury. In-depth kanohi ki te kanohi (face-to-face) qualitative interviews with 12 participants aged between 37 and 71 years at the time of interviews were conducted. Interpretive analyses of interview transcripts, focused on the impacts of injury was conducted with the aid of NVivo software. RESULTS: The overarching theme identified during the analysis was "Impact" with four sub-themes of: Impact on daily life; Impact on relationships, Impact on employment; and, long-term or ongoing impacts. CONCLUSIONS: For Maori living with disability 24 months after hospitalisation for injury, adjusting to life after the injury and the rehabilitation process was challenging. Participants discussed frustration with feeling dependent on others, being bored and feeling unfulfilled after their injury, and that many aspects of their lives were impacted on and not always in the expected directions. Many reported longer lasting impacts even after rehabilitation was completed. Implications for rehabilitation programmes e.g., strengthening programmes by taking into account issues discussed by participants, recognising the long-term impacts on both those injured and their whanau (family), and further investigations required are also discussed.IMPLICATIONS FOR REHABILITATIONDisability after injury can have long term impacts for injured Maori and their relationships.Social impacts can be perceived as more debilitating than the physical impacts after injury.Experiences of employment changes and future prospects are often difficult to navigate for Maori returning to work after an injury.

Human Adenovirus 7-Associated Hemophagocytic Lymphohistiocytosis-like Illness: Clinical and Virological Characteristics in a Cluster of Five Pediatric Cases.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation. Children often suffer from primary genetic forms of HLH, which can be triggered by infection. Others suffer from secondary HLH as a complication of infection, malignancy, or rheumatologic disease. Identifying the exact cause of HLH is crucial, as definitive treatment for primary disease is hematopoietic stem cell transplant. Adenoviruses have been associated with HLH but molecular epidemiology data are lacking. METHODS: We describe the clinical and virologic characteristics of 5 children admitted with adenovirus infection during 2018-2019 who developed HLH or HLH-like illness. Detailed virologic studies, including virus isolation and comprehensive molecular typing were performed. RESULTS: All patients recovered; clinical management varied but included immunomodulating and antiviral therapies. A genetic predisposition for HLH was not identified in any patient. Adenovirus isolates were recovered from 4/5 cases; all were identified as genomic variant 7d. Adenovirus type 7 DNA was detected in the fifth case. Phylogenetic analysis of genome sequences identified 2 clusters-1 related to strains implicated in 2016-2017 outbreaks in Pennsylvania and New Jersey, the other related to a 2009 Chinese strain. CONCLUSIONS: It can be challenging to determine whether HLH is the result of an infectious pathogen alone or genetic predisposition triggered by an infection. We describe 5 children from the same center presenting with an HLH-like illness after onset of adenovirus type 7 infection. None of the patients were found to have a genetic predisposition to HLH. These findings suggest that adenovirus 7 infection alone can result in HLH.

Indigenous engagement in health: lessons from Brazil, Chile, Australia and New Zealand.

BACKGROUND: Given the persistence of Indigenous health inequities across national contexts, many countries have adopted strategies to improve the health of Indigenous peoples. Governmental recognition of the unique health needs of Indigenous populations is necessary for the development of targeted programs and policies to achieve universal health coverage. At the same time, the participation of Indigenous peoples in decision-making and program and policy design helps to ensure that barriers to health services are appropriately addressed and promotes the rights of Indigenous peoples to self-determination. Due to similar patterns of Indigenous health and health determinants across borders, there have been calls for greater global collaboration in this field. However, most international studies on Indigenous health policy link Anglo-settler democracies (Canada, Australia, Aotearoa/New Zealand and the United States), despite these countries representing a small fraction of the world's Indigenous people. AIM: This paper examines national-level policy in Australia, Brazil, Chile and New Zealand in relation to governmental recognition of differential Indigenous health needs and engagement with Indigenous peoples in health. The paper aims to examine how Indigenous health needs and engagement are addressed in national policy frameworks within each of the countries in order to contribute to the understanding of how to develop pro-equity policies within national health care systems. METHODS: For each country, a review was undertaken of national policies and legislation to support engagement with, and participation of, Indigenous peoples in the identification of their health needs, development of programs and policies to address these needs and which demonstrate governmental recognition of differential Indigenous health needs. Government websites were searched as well as the following databases: Google, OpenGrey, CAB Direct, PubMed, Web of Science and WorldCat. FINDINGS: Each of the four countries have adopted international agreements regarding the engagement of Indigenous peoples in health. However, there is significant variation in the extent to which the principles laid out in these agreements are reflected in national policy, legislation and practice. Brazil and New Zealand both have established national policies to facilitate engagement. In contrast, national policy to enable engagement is relatively lacking in Australia and Chile. Australia, Brazil and New Zealand each have significant initiatives and policy structures in place to address Indigenous health. However, in Brazil this is not necessarily reflected in practice and although New Zealand has national policies these have been recently reported as insufficient and, in fact, may be contributing to health inequity for Maori. In comparison to the other three countries, Chile has relatively few national initiatives or policies in place to support Indigenous engagement or recognise the distinct health needs of Indigenous communities. CONCLUSIONS: The adoption of international policy frameworks forms an important step in ensuring that Indigenous peoples are able to participate in the formation and implementation of health policy and programs. However, without the relevant principles being reflected in national legislature, international agreements hold little weight. At the same time, while a national legislative framework facilitates the engagement of Indigenous peoples, such policy may not necessarily translate into practice. Developing multi-level approaches that improve cohesion between international policy, national policy and practice in Indigenous engagement in health is therefore vital. Given that each of the four countries demonstrate strengths and weaknesses across this causal chain, cross-country policy examination provides guidance on strengthening these links.

Transient receptor potential vanilloid-4 contributes to stretch-induced hypercontractility and time-dependent dysfunction in the aged heart.

AIMS: Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated transient receptor potential vanilloid-4 (TRPV4) ion channel is expressed in cardiomyocytes of the aged heart. This investigation tests the hypothesis that TRPV4 alters Ca2+ handling and cardiac function in response to increased ventricular preload and cardiomyocyte stretch. METHODS AND RESULTS: Left ventricular maximal pressure (PMax) was monitored in isolated working hearts of Aged (24-27 months) mice following preload elevation from 5 to 20mmHg, with and without TRPV4 antagonist HC067047 (HC, 1 µmol/L). In preload responsive hearts, PMax prior to and immediately following preload elevation (i.e. Frank-Starling response) was similar between Aged and Aged+HC. Within 1 min following preload elevation, Aged hearts demonstrated secondary PMax augmentation (Aged>Aged+HC) suggesting a role for stretch-activated TRPV4 in cardiac hypercontractility. However, after 20 min at 20 mmHg Aged exhibited depressed PMax (Aged

Subsequent injuries experienced by Maori: results from a 24-month prospective study in New Zealand.

AIM: Maori, the indigenous population of New Zealand, experience a disproportionate burden of injury compared to non-Maori. Injury burden can be exacerbated by subsequent injuries (injuries that occur after, but not necessarily because of, an earlier or 'sentinel' injury). Despite obligations under New Zealand's Treaty of Waitangi, it appears no published studies have investigated subsequent injuries among Maori. This study aims to describe subsequent injuries experienced by Maori and reported to New Zealand's no-fault injury Accident Compensation Corporation (ACC), and determine: the number and timing of subsequent injury (SI) claims reported to ACC in 24 months following a sentinel injury; the proportions experiencing ≥1 SI; and the nature of SIs. METHODS: The Subsequent Injury Study analysed interview, ACC and hospital discharge data. SIs were classified as injury events involving an ACC claim within 24 months of a sentinel injury. RESULTS: Of 566 participants, 349 (62%) experienced ≥1 SI in the 24 months post-sentinel injury. Those with moderate/high alcohol use, or cognitive difficulties, before the sentinel injury were more likely to experience SIs. Fewer SIs occurred between 0-3 months after a sentinel injury compared to later periods. Spine dislocations/sprains/strains were the most common SI type. CONCLUSIONS: Despite their descriptive nature, our findings point to both the complexity of SI and the need for a greater research, ACC and health service focus on SI if the burden of injury for Maori is to be truly addressed. That 62% of Maori who had already experienced a profound sentinel injury went on to experience ≥1 SIs reported to ACC within a 24-month period suggests that the burden is considerable, and that preventive opportunities are being missed. Additional analyses are now underway to investigate factors predicting SI, while accounting for potential confounders, in order to assist in the development of SI prevention initiatives for Maori at multiple points in the complex post-injury pathway.

In their own words: A qualitative study exploring influences on the food choices of university students.

ISSUE ADDRESSED: University students generally make independent decisions regarding food choices. Current research about knowledge of Australian Dietary Guidelines (ADG), sources of nutrition information and influences on food choices for this group is scarce. METHODS: Qualitative data were collected from gender-separated focus groups comprising four female (n = 31) and four male (n = 18) to identify: knowledge of ADG; sources of nutrition information; factors that influence food choices; perceived relevant nutrition messages and how best to deliver them. RESULTS: Gaps in knowledge were identified particularly regarding number of serves and serving size for food groups. Social media was the most commonly reported source of knowledge. Social media was also a major influence on food choice due to its impact on body ideals. CONCLUSION: Current health promotion nutrition messages were perceived irrelevant given the focus on long-term health risks. Health and adhering to the ADG were not identified as important. The desire to look a particular way was the major influence on food choices. SO WHAT?: While there is an awareness of ADG, our participants made a deliberate decision not to follow them. This provides a challenge for developing relevant preventive health messages for this target audience.

TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress.

Aims: Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia-reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. Methods and results: TRPV4 protein expression increased in cardiomyocytes of Aged (24-27 months) mice compared with Young (3-6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 µmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4-/-) mice. In Aged, pharmacological inhibition of TRPV4 (1 µmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Conclusions: Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.

Chronic low-intensity exercise attenuates cardiomyocyte contractile dysfunction and impaired adrenergic responsiveness in aortic-banded mini-swine.

Exercise improves clinical outcomes in patients diagnosed with heart failure with reduced ejection fraction (HFrEF), in part via beneficial effects on cardiomyocyte Ca2+ cycling during excitation-contraction coupling (ECC). However, limited data exist regarding the effects of exercise training on cardiomyocyte function in patients diagnosed with heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to investigate cardiomyocyte Ca2+ handling and contractile function following chronic low-intensity exercise training in aortic-banded miniature swine and test the hypothesis that low-intensity exercise improves cardiomyocyte function in a large animal model of pressure overload. Animals were divided into control (CON), aortic-banded sedentary (AB), and aortic-banded low-intensity trained (AB-LIT) groups. Left ventricular cardiomyocytes were electrically stimulated (0.5 Hz) to assess Ca2+ homeostasis (fura-2-AM) and unloaded shortening during ECC under conditions of baseline pacing and pacing with adrenergic stimulation using dobutamine (1 µM). Cardiomyocytes in AB animals exhibited depressed Ca2+ transient amplitude and cardiomyocyte shortening vs. CON under both conditions. Exercise training attenuated AB-induced decreases in cardiomyocyte Ca2+ transient amplitude but did not prevent impaired shortening vs. CON. With dobutamine, AB-LIT exhibited both Ca2+ transient and shortening amplitude similar to CON. Adrenergic sensitivity, assessed as the time to maximum inotropic response following dobutamine treatment, was depressed in the AB group but normal in AB-LIT animals. Taken together, our data suggest exercise training is beneficial for cardiomyocyte function via the effects on Ca2+ homeostasis and adrenergic sensitivity in a large animal model of pressure overload-induced heart failure. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show chronic low-intensity exercise training can prevent cardiomyocyte dysfunction and impaired adrenergic responsiveness in a translational large animal model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

Effect of a health literacy intervention trial on knowledge about cardiovascular disease medications among Indigenous peoples in Australia, Canada and New Zealand.

OBJECTIVES: To assess the effect of a customised, structured cardiovascular disease (CVD) medication health literacy programme on medication knowledge among Indigenous people with, or at high risk of, CVD. DESIGN: Intervention trial with premeasures and postmeasures at multiple time points. SETTING: Indigenous primary care services in Australia, Canada and New Zealand. PARTICIPANTS: 171 Indigenous people aged ≥20 years of age who had at least one clinical diagnosis of a CVD event, or in Canada and Australia had a 5-year CVD risk ≥15%, and were prescribed at least two of the following CVD medication classes: statin, aspirin, ACE inhibitors and beta blockers. INTERVENTION: An education session delivered on three occasions over 1 month by registered nurses or health educators who had received training in health literacy and principles of adult education. An interactive tablet application was used during each session and an information booklet and pill card provided to participants. PRIMARY OUTCOME MEASURES: Knowledge about the CVD medications assessed before and after each session. RESULTS: Knowledge at baseline (presession 1) was low, with the mean per cent correct answers highest for statins (34.0% correct answers), 29.4% for aspirin, 26.0% for beta blockers and 22.7% for ACE inhibitors. Adjusted analyses showed highly significant (P<0.001) increases in knowledge scores between preassessments and postassessments at all three time points for all medication classes. For the four medications, the absolute increases in adjusted per cent correct items from presession 1 to postsession 3 assessments were 60.1% for statins, 76.8% for aspirin, 71.4% for ACE inhibitor and 69.5% for beta blocker. CONCLUSIONS: The intervention was highly effective in contextually diverse Indigenous primary healthcare services in Australia, Canada and New Zealand. The findings from this study have important implications for health services working with populations with low health literacy more generally. TRIAL REGISTRATION NUMBER: ACTRN12612001309875.