Rural community-centred co-planning for sustainable rural health systems.

OBJECTIVE: Sustaining rural healthcare services is challenging because of numerous systemic factors. Rural communities can inform the design of sustainable rural health models; however, further evidence of effective co-design is needed to guide implementation. The study aim was to co-design a series of place-based and evidence-informed rural health models, to improve local health system sustainability. SETTING: A rural region (categorised as Modified Monash Model 5) defined by three adjoining Shires in Central and Northwest Victoria, Australia. PARTICIPANTS: A health executive co-planning network led the co-design, with input and oversight from a broader cross-sector group. Healthcare professionals (n = 44) and consumers and carers (n = 21) participated in interviews, and an online survey was completed by healthcare professionals (n = 11) and consumers and carers (n = 7) to provide feedback on the preliminary results. DESIGN: Community-based participatory action research was applied incorporating co-design methods and systems thinking. Data were collected through qualitative interviews followed by an online feedback survey. Mixed method data analysis (QUAL-quant) was conducted with qualitative directed content analysis of interview transcripts and quantitative descriptive analyses of survey responses to aid prioritisation. RESULTS: Healthcare priorities, strengths and challenges, and proposed rural health models are described. A rural health system sustainability strategy was developed with three integrated pillars: 1. Workforce strengthening, 2. Integrated health services and 3. Innovative models of care. CONCLUSION: Community-centred co-design with rural health stakeholders was effective for generating locally tailored ideas and potential health models that emulate community strengths and resources, and provide a foundation for further planning, implementation and evaluation.

Competition or collaboration in regional Australia? A cross-border and multi-university approach to maximising rural health investments, community health and health workforce outcomes.

AIM: To describe the establishment of a cross-border and multi-university collaboration in rural Australia to mitigate potential competition, maximise Rural Health Multidisciplinary Training (RHMT) Programme investments and regional health workforce outcomes. CONTEXT: Rural Health Multidisciplinary Training programme investments have enabled the establishment of 19 Australian University Departments of Rural Health (UDRH) and 17 Rural Clinical Schools. The importance of these investments is acknowledged. However, in regional settings, due to limited clinical placement and training opportunities, there is potential for heightened competition between universities who are operating within shared geographical footprints. Competition between universities risks focusing RHMT programme activity on individual reporting requirements and activities, in preference to: regional needs; existing community-university relationships; and place-based approaches to health workforce development. PARTICIPANTS: A rural New South Wales and Victorian RHMT-funded departments, collectively known as the Sunraysia Collaboration. APPROACH: Strategic and operational processes, structures and actions underpinning collaboration formation and relationship consolidation will be described. Co-design methodologies employed to collectively define collaboration vision and aims, governance framework and guiding principles, reporting structures and co-contributions to teaching, research and service will be discussed. Collaboration sensitivity to the social, cultural, relationship and economic connectedness within the region and existing health workforce flows will also be explored. CONCLUSION: The Sunraysia collaboration demonstrates one approach towards mitigating potential competition between RHMT Programme funded universities within rural and remote Australia. The collaboration is an exemplar of co-design in action providing an alternative approach to address RHMT Programme parameters and regional needs whilst supporting rural-remote health workforce training and education innovations.

Building a rural workforce through identifying supports for rural, mature-aged nursing and allied health students: A systematic scoping review.

INTRODUCTION: There is a long-standing undersupply of nursing and allied health professionals in rural Australia. Rural, mature-aged people form an untapped section of rural communities that could help to address these workforce needs. There is little understanding of the supports required to assist rural, mature-aged nursing and allied health students to complete their studies and enter the rural health workforce. OBJECTIVE: To scope factors influencing rural, mature-aged nursing and allied health students' ability to access, participate, and succeed in higher education. DESIGN: A scoping review of the international rural nursing and allied health and education literature was undertaken. Five databases (CINAHL Complete, MEDLINE, Education Resources Information Center [ERIC], Embase, and Education Research Complete), key peer-reviewed journals, and Australian grey literature were searched. FINDINGS: Fourteen articles were included in the review. Ten studies described rural, mature-aged nursing and allied health student characteristics, 6 described barriers to students participating and succeeding in higher education, and 4 described student supports. DISCUSSION: This review found limited evidence to guide higher education providers in attracting, supporting and retaining rural, mature-aged nursing and allied health students. In particular, evidence of student supports is required beyond those manifested by students themselves or their family, to include offerings from university and government sources. CONCLUSION: Substantially more research attention is needed to understand the experiences of rural, mature-aged nursing and allied health students, and supports required for this cohort to access, participate and successfully complete higher education.

Rural health services' relationships with patients: An enabler and a barrier to advance care planning.

OBJECTIVE: The barriers and enablers to the uptake of advance care plans has been well documented but more so in metropolitan health services. Rural and regional areas have their own challenges of higher rates of chronic illness and an aging population when considering end of life care. This study aimed to explore the creation of advance care plans in a regional location that has service links to smaller health services. DESIGN: A qualitative study involving thematic analysis of interview data. SETTING: A regional local government area in Victoria, Australia. PARTICIPANTS: Twelve representatives from rural and regional health services, including hospital, private practice and community organisation staff. MAIN OUTCOME MEASURES: Barriers and enablers to the creation of advance care planning documents. RESULTS: The data analysis yielded two main identified themes around Plan creation and communication of patient wishes: system and societal challenges to the creation and communication in advance care planning; and rural communities' expectation of the health service-patient relationship and advance care planning. CONCLUSION: Although barriers to advance care planning are well known, rural and regional practitioners need to be aware of the effect long-term continuity of care from health practitioners and connections with health services has on advance care plan creation, and whether the paucity of written Plans effects end-of-life care. A potential solution was seen in the pending linkages to the national electronic patient record.

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease.

Nearly one-third of deaths in the United States are caused by cardiovascular disease (CVD) each year. In the past, CVD was thought to mainly affect men, leading to the exclusion of women and female animals from clinical studies and preclinical research. In light of sexual dimorphisms in CVD, a need exists to examine baseline cardiac differences in humans and the animals used to model CVD. In humans, sex differences are apparent at every level of cardiovascular physiology from action potential duration and mitochondrial energetics to cardiac myocyte and whole-heart contractile function. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. Although endogenous estrogen is most likely a mediator of the observed functional differences in both health and disease, the signaling mechanisms involved are complex and are not yet fully understood. To investigate how sex modulates CVD development, animal models are essential tools and should be useful in the development of therapeutics. This review will focus on describing the cardiovascular sexual dimorphisms that exist both physiologically and in common animal models of CVD.

Fitness-to-practice concerns in rural undergraduate medical education: a qualitative study.

BACKGROUND: Since July 2010, new reporting requirements have applied to registered Australian health practitioners who have a reasonable belief that a practitioner or student (of any registered discipline) is exhibiting "notifiable conduct". A study of healthcare complaints reported that a small number of practitioners are over-represented in the majority of formal complaints brought against doctors. The impetus for conducting this research was a recognition that identifying and responding to particular behaviours early may prevent issues requiring mandatory reporting later on. As a first step, a better understanding of how fitness-to-practice (FTP) concerns are viewed was sought from stakeholders in a rural medical school. METHODS: This qualitative project used purposive and snowballing sampling. Thirteen participants from an Australian rural medical school were interviewed for the study about FTP concerns. Seven were university staff, including clinical educators, program co-ordinators and academic faculty. Six were medical students in the middle of their final year. Their de-identified interview transcripts were independently coded into themes and emergent data categories were refined through comparative analysis between the authors. Data collection ceased after theoretical saturation was achieved. RESULTS: Although students and faculty staff responded similarly in their recognition of FTP concerns, they varied in their assessment of their frequency, with students indicating that concerns were rare. Students and staff expressed reluctance to formally report students or colleagues with FTP concerns because of the complexity and uncertainty of medical practice. Both groups considered early recognition of problems and implementation of supportive mechanisms as important, but students generally did not want to contact the university about concerns for fear of stigmatisation. CONCLUSION: Education providers need to have clear processes for identifying and responding to FTP concerns in the pre-service years of medical training. Importantly, students need to feel that they can seek help for their own concerns and not be stigmatised in doing so. This is a difficult challenge in a profession that has a perceived culture of strength and a traditional hierarchy. Rural medical schools, with their smaller student groups, are well positioned for early response to issues of concern.

Interferon-γ causes cardiac myocyte atrophy via selective degradation of myosin heavy chain in a model of chronic myocarditis.

Interferon-γ (IFN-γ), a proinflammatory cytokine, has been implicated in the pathogenesis of a number of forms of heart disease including myocarditis and congestive heart failure. In fact, overexpression of IFN-γ in mice causes dilated cardiomyopathy. However, the direct effects of IFN-γ on cardiac myocytes and the mechanism by which it causes cardiac dysfunction have not been described. Here, we present the molecular pathology of IFN-γ exposure and its effect on myofibrillar proteins in isolated neonatal rat ventricular myocytes. Treatment with IFN-γ caused cardiac myocyte atrophy attributable to a specific decrease in myosin heavy chain protein. This selective degradation of myosin heavy chain was not accompanied by a decrease in total protein synthesis or by an increase in total protein degradation. IFN-γ increased both proteasome and immunoproteasome activity in cardiac myocytes and their inhibition blocked myosin heavy chain loss and myocyte atrophy, whereas inhibition of the lysosome or autophagosome did not. Collectively, these results provide a mechanism by which IFN-γ causes cardiac pathology in the setting of chronic inflammatory diseases.

Topographically specific regeneration of sensory axons in the spinal cord.

Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.

Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury.

Dorsal root injury results in substantial and often irreversible loss of sensory functions as a result of the limited regenerative capacity of sensory axons and the inhibitory barriers that prevent both axonal entry into and regeneration in the spinal cord. Here, we describe previously unknown effects of the growth factor artemin after crush injury of the dorsal spinal nerve roots in rats. Artemin not only promoted re-entry of multiple classes of sensory fibers into the spinal cord and re-establishment of synaptic function and simple behavior, but it also, surprisingly, promoted the recovery of complex behavior. These effects occurred after a 2-week schedule of intermittent, systemic administration of artemin and persisted for at least 6 months following treatment, suggesting a substantial translational advantage. Systemic artemin administration produced essentially complete and persistent restoration of nociceptive and sensorimotor functions, and could represent a promising therapy that may effectively promote sensory neuronal regeneration and functional recovery after injury.

An opportunity for remote professional networking to support undergraduate career goals.

Engagement in research as an undergraduate and the availability of mentorship from peers and professionals are effective strategies for improving retention of students in STEM fields. Undergraduates in Molecular, Cellular, and Developmental Biology at the University of Colorado Boulder enroll in one of two large introductory course-based undergraduate research experiences (CUREs) as a requirement of the degree. However, more diverse efforts toward formally supporting students seeking to refine their career goals is needed. We designed a networking-based workshop series aimed at providing access to the current and former students who have been recently successful in achieving relevant educational and career goals. This 5-week series focused on (1) how to convert a resume to a curriculum vitae, (2) careers that are accessible with a bachelor's degree in the life sciences, (3) types of research opportunities as an undergraduate and as a post-graduate, (4) the application process and strategies for successful candidacy in medical school applications, and (5) PhD programs and approaches to producing a competitive application. The workshop connected 52 undergraduates with mentors; the majority of participants requested contact information for continued mentoring. Here, we describe the structure of this remote workshop series and highlight results that emphasized the need for such support that may extend beyond pandemic times.

An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice.

New classes of antibiotics are needed to fight bacterial infections, and repurposing existing drugs as antibiotics may enable rapid deployment of new treatments. Screens for antibacterials have been traditionally performed in standard laboratory media, but bacterial pathogens experience very different environmental conditions during infection, including nutrient limitation. To introduce the next generation of researchers to modern drug discovery methods, we developed a course-based undergraduate research experience (CURE) in which undergraduate students screened a library of FDA-approved drugs for their ability, in a nutrient-poor medium, to prevent the growth of the human Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium. The nine drugs identified all disrupt DNA metabolism in bacteria and eukaryotes. One of the hit compounds, capecitabine, is a well-tolerated oncology drug that is administered orally, a preferred treatment route. We demonstrated that capecitabine is more effective at inhibiting S. Typhimurium growth in nutrient-limited than in standard rich microbiological broth, an explanation for why the antibiotic activity of this compound has not been previously recognized. Capecitabine is enzymatically converted to the active pyrimidine analogue, fluorouracil (5-FU), and Gram-positive bacteria, including Staphylococcus aureus, are significantly more sensitive to 5-FU than Gram-negative bacteria. We therefore tested capecitabine for efficacy in a murine model of S. aureus peritonitis. Oral capecitabine administration reduced the colonization of tissues and increased animal survival in a dose-responsive manner. Since capecitabine is inexpensive, orally available, and relatively safe, it may have utility for treatment of intractable Gram-positive bacterial infections. IMPORTANCE As bacterial infections become increasingly insensitive to antibiotics, whether established, off-patent drugs could treat infections becomes an important question. At the same time, basic research has revealed that during infection, mammals starve pathogens for nutrients and, in response, bacteria dramatically alter their biology. Therefore, it may be fruitful to search for drugs that could be repurposed as antibiotics using bacteria grown with limited nutrients. This approach, executed with undergraduate student researchers, identified nine drugs known to interfere with the production and/or function of DNA. We further explored one of these drugs, capecitabine, a well-tolerated human oncology drug. Oral administration of capecitabine reduced infection with the human pathogen Staphylococcus aureus and increased survival in mice. These data suggest that capecitabine has potential as a therapy for patients with otherwise untreatable bacterial infections.

Blockade of Nogo receptor ligands promotes functional regeneration of sensory axons after dorsal root crush.

A major impediment for regeneration of axons within the CNS is the presence of multiple inhibitory factors associated with myelin. Three of these factors bind to the Nogo receptor, NgR, which is expressed on axons. Administration of exogenous blockers of NgR or NgR ligands promotes the regeneration of descending axonal projections after spinal cord hemisection. A more detailed analysis of CNS regeneration can be made by examining the growth of specific classes of sensory axons into the spinal cord after dorsal root crush injury. In this study, we assessed whether administration of a soluble peptide fragment of the NgR (sNgR) that binds to and blocks all three NgR ligands can promote regeneration after brachial dorsal root crush in adult rats. Intraventricular infusion of sNgR for 1 month results in extensive regrowth of myelinated sensory axons into the white and gray matter of the dorsal spinal cord, but unmyelinated sensory afferents do not regenerate. In concert with the anatomical growth of sensory axons into the cord, there is a gradual restoration of synaptic function in the denervated region, as revealed by extracellular microelectrode recordings from the spinal gray matter in response to stimulation of peripheral nerves. These positive synaptic responses are correlated with substantial improvements in use of the forelimb, as assessed by paw preference, paw withdrawal to tactile stimuli and the ability to grasp. These results suggest that sNgR may be a potential therapy for restoring sensory function after injuries to sensory roots.

The influence of biological sex and sex hormones on bile acid synthesis and cholesterol homeostasis.

Obesity and elevated serum lipids are associated with a threefold increase in the risk of developing atherosclerosis, a condition that underlies stroke, myocardial infarction, and sudden cardiac death. Strategies that aim to reduce serum cholesterol through modulation of liver enzymes have been successful in decreasing the risk of developing atherosclerosis and reducing mortality. Statins, which inhibit cholesterol biosynthesis in the liver, are considered among the most successful compounds developed for the treatment of cardiovascular disease. However, recent debate surrounding their effectiveness and safety prompts consideration of alternative cholesterol-lowering therapies, including increasing cholesterol catabolism through bile acid (BA) synthesis. Targeting the enzymes that convert cholesterol to BAs represents a promising alternative to other cholesterol-lowering approaches that treat atherosclerosis as well as fatty liver diseases and diabetes mellitus. Compounds that modify the activity of these pathways have been developed; however, there remains a lack of consideration of biological sex. This is necessary in light of strong evidence for sexual dimorphisms not only in the incidence and progression of the diseases they influence but also in the expression and activity of the proteins affected and in the manner in which men and women respond to drugs that modify lipid handling in the liver. A thorough understanding of the enzymes involved in cholesterol catabolism and modulation by biological sex is necessary to maximize their therapeutic potential.

Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism.

AIMS: To define the molecular mechanisms of cardiotoxicity induced by Sunitinib and to identify the role of biological sex in modulating toxicity. METHODS AND RESULTS: Exposure of isolated cardiomyocytes to plasma-relevant concentrations of Sunitinib and other tyrosine kinase inhibitors produces a broad spectrum of abnormalities and cell death via apoptosis downstream of sexually dimorphic kinase inhibition. Phosphorylation of protein kinase C and phospholipase γ abrogates these effects for most tyrosine kinase inhibitors tested. Female sex and estradiol cause increased cardiotoxicity, which is mediated by reduced expression of a drug efflux transporter and a metabolic enzyme. Female but not male mice exposed to a 28-day course of oral Sunitinib exhibit similar abnormalities as well as functional deficits and their hearts exhibit differential expression of genes responsible for transport and metabolism of Sunitinib. CONCLUSION: We identify the specific pathways affected by tyrosine kinase inhibitors in mammalian cardiomyocytes, interactions with biological sex, and a role for oestrogen in modulating drug efflux and metabolism. These findings represent a critical step toward reducing the incidence of cardiotoxicity with tyrosine kinase inhibitor chemotherapeutics.

Dietary phytoestrogens present in soy dramatically increase cardiotoxicity in male mice receiving a chemotherapeutic tyrosine kinase inhibitor.

Use of soy supplements to inhibit cancer cell growth is increasing among patients due to the perception that phytoestrogens in soy inhibit carcinogenesis via induction of apoptosis. Genistein, the most prevalent phytoestrogen in soy, is a potent endocrine disruptor and tyrosine kinase inhibitor (TKI) that causes apoptosis in many cells types. Chemotherapeutic TKIs limit cancer cell growth via the same mechanisms. However, TKIs such as Sunitinib cause cardiotoxicity in a significant number of patients. Molecular interactions between Sunitinib and dietary TKIs like genistein have not been examined in cardiomyocytes. Significant lethality occurred in mice treated with Sunitinib and fed a phytoestrogen-supplemented diet. Isolated cardiomyocytes co-treated with genistein and Sunitinib exhibited additive inhibition of signaling molecules important for normal cardiac function and increased apoptosis compared with Sunitinib alone. Thus, dietary soy supplementation should be avoided during administration of Sunitinib due to exacerbated cardiotoxicity, despite evidence for positive effects in cancer.

The python project: a unique model for extending research opportunities to undergraduate students.

Undergraduate science education curricula are traditionally composed of didactic instruction with a small number of laboratory courses that provide introductory training in research techniques. Research on learning methodologies suggests this model is relatively ineffective, whereas participation in independent research projects promotes enhanced knowledge acquisition and improves retention of students in science. However, availability of faculty mentors and limited departmental budgets prevent the majority of students from participating in research. A need therefore exists for this important component in undergraduate education in both small and large university settings. A course was designed to provide students with the opportunity to engage in a research project in a classroom setting. Importantly, the course collaborates with a sponsor's laboratory, producing a symbiotic relationship between the classroom and the laboratory and an evolving course curriculum. Students conduct a novel gene expression study, with their collective data being relevant to the ongoing research project in the sponsor's lab. The success of this course was assessed based on the quality of the data produced by the students, student perception data, student learning gains, and on whether the course promoted interest in and preparation for careers in science. In this paper, we describe the strategies and outcomes of this course, which represents a model for efficiently providing research opportunities to undergraduates.

Estrogens mediate cardiac hypertrophy in a stimulus-dependent manner.

The incidence of cardiac hypertrophy, an established risk factor for heart failure, is generally lower in women compared with men, but this advantage is lost after menopause. Although it is widely believed that estrogens are cardioprotective, there are contradictory reports, including increased cardiac events in postmenopausal women receiving estrogens and enhanced cardiac protection from ischemic injury in female mice without estrogens. We exposed aromatase knockout (ArKO) mice, which produce no estrogens, to both pathologic and physiologic stimuli. This model allows an investigation into the effects of a complete, chronic lack of estrogens in male and female hearts. At baseline, female ArKO mice had normal-sized hearts but decreased cardiac function and paradoxically increased phosphorylation of many progrowth kinases. When challenged with the pathological stimulus, isoproterenol, ArKO females developed 2-fold more hypertrophy than wild-type females. In contrast, exercise-induced physiological hypertrophy was unaffected by the absence of estrogens in either sex, although running performance was blunted in ArKO females. Thus, loss of estrogen signaling in females, but not males, impairs cardiac function and sensitizes the heart to pathological insults through up-regulation of multiple hypertrophic pathways. These findings provide insight into the apparent loss of cardioprotection after menopause and suggest that caution is warranted in the long-term use of aromatase inhibitors in the setting of breast cancer prevention.