Virtual Care Initiatives for Older Adults in Australia: Scoping Review.

BACKGROUND: There has been a rapid shift toward the adoption of virtual health care services in Australia. It is unknown how widely virtual care has been implemented or evaluated for the care of older adults in Australia. OBJECTIVE: We aimed to review the literature evaluating virtual care initiatives for older adults across a wide range of health conditions and modalities and identify key challenges and opportunities for wider adoption at both patient and system levels in Australia. METHODS: A scoping review of the literature was conducted. We searched MEDLINE, Embase, PsycINFO, CINAHL, AgeLine, and gray literature (January 1, 2011, to March 8, 2021) to identify virtual care initiatives for older Australians (aged ≥65 years). The results were reported according to the World Health Organization's digital health evaluation framework. RESULTS: Among the 6296 documents in the search results, we identified 94 that reported 80 unique virtual care initiatives. Most (69/80, 89%) were at the pilot stage and targeted community-dwelling older adults (64/79, 81%) with chronic diseases (52/80, 65%). The modes of delivery included videoconference, telephone, apps, device or monitoring systems, and web-based technologies. Most initiatives showed either similar or better health and behavioral outcomes compared with in-person care. The key barriers for wider adoption were physical, cognitive, or sensory impairment in older adults and staffing issues, legislative issues, and a lack of motivation among providers. CONCLUSIONS: Virtual care is a viable model of care to address a wide range of health conditions among older adults in Australia. More embedded and integrative evaluations are needed to ensure that virtually enabled care can be used more widely by older Australians and health care providers.

Use of General Practitioner Telehealth Services During the COVID-19 Pandemic in Regional Victoria, Australia: Retrospective Analysis.

BACKGROUND: In March 2020, the Australian Government expanded general practitioner (GP) telehealth services in response to the COVID-19 pandemic. OBJECTIVE: This study sought to assess use patterns of GP telehealth services in response to changing circumstances (before and during the COVID-19 pandemic and with or without a lockdown) in regional Victoria, Australia. METHODS: We conducted a secondary analysis of monthly Medicare claims data from July 2019 to June 2021 from 140 regional GP practices in Western Victoria. The longitudinal patterns of proportion of GP telehealth consultations stratified by type of consultation (ie, videoconference vs telephone) and by geographical, consumer, and consultation characteristics were analyzed. RESULTS: Telehealth comprised 25.8% (522,932/2,025,615) of GP consultations over the 2-year period. After the introduction of the Australian telehealth expansion policy in March 2020, there was a rapid uptake in GP telehealth services (including telephone and video services), from 0% before COVID-19 to 15% (11,854/80,922) of all consultations in March 2020, peaking at 55% (50,828/92,139) in August 2020. Thereafter, the use of telehealth declined steadily to 31% (23,941/77,344) in January 2021 and tapered off to 28% (29,263/103,798) in June 2021. Telephone services and shorter consultations were the most dominant form, and those aged 15-64 years had higher telehealth use rates than younger or older age groups. The proportion of video consultations was higher during periods with government-imposed lockdowns and higher in the most socioeconomically advantaged areas compared to less socioeconomically advantaged areas. CONCLUSIONS: Our findings support the continuation of telehealth use in rural and regional Australia post pandemic. Future policy must identify mechanisms to reduce existing equity gaps in video consultations and consider patient- and system-level implications of the dominant use of short telephone consultations.

The Preventable Productivity Burden of Kidney Disease in Australia.

BACKGROUND: Kidney disease is associated with impaired work productivity. However, the collective effect of missed work days, reduced output at work, and early withdrawal from the workforce is rarely considered in health-economic evaluations. METHODS: To determine the effect on work productivity of preventing incident cases of kidney disease, using the novel measure "productivity-adjusted life year" (PALY), we constructed a dynamic life table model for the Australian working-age population (aged 15-69 years) over 10 years (2020-2029), stratified by kidney-disease status. Input data, including productivity estimates, were sourced from the literature. We ascribed a financial value to the PALY metric in terms of gross domestic product (GDP) per equivalent full-time worker and assessed the total number of years lived, total PALYs, and broader economic costs (GDP per PALY). We repeated the model simulation, assuming a reduced kidney-disease incidence; the differences reflected the effects of preventing new kidney-disease cases. Outcomes were discounted by 5% annually. RESULTS: Our projections indicate that, from 2020 to 2029, the estimated number of new kidney-disease cases will exceed 161,000. Preventing 10% of new cases of kidney disease during this period would result in >300 premature deaths averted and approximately 550 years of life and 7600 PALYs saved-equivalent to a savings of US$1.1 billion in GDP or US$67,000 per new case avoided. CONCLUSIONS: Pursuing a relatively modest target for preventing kidney disease in Australia may prolong years of life lived and increase productive life years, resulting in substantial economic benefit. Our findings highlight the need for investment in preventive measures to reduce future cases of kidney disease.

The role of dihydrosphingolipids in disease.

Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3-ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1-phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10-15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest.

Inhibition of Apoptosis Signal-Regulating Kinase 1 Attenuates Myocyte Hypertrophy and Fibroblast Collagen Synthesis.

BACKGROUND: Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. METHODS: Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2hours before stimulated with 100nM angiotensin II (AngII), 10µM indoxyl sulphate (IS) or 10ng/ml transforming growth factor ß1 (TGFß1) for 48hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2hours before being stimulated with 100nM AngII for 60hours, 10µM IS, 10ng/ml interleukin 1ß (IL-1ß) or tumour necrosis factor α (TNFα) for 48hours. 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. RESULTS: Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1ß- and TNFα-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFß1-stimulated NCF collagen synthesis and AngII- and TGFß1-stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. CONCLUSIONS: Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles.

Investigating consumer preferences and experiences of telehealth services in Australian allied health practice: a study protocol.

INTRODUCTION: Telehealth service provision and uptake has rapidly increased since the COVID-19 pandemic, allowing healthcare to be delivered safely and reducing non-essential face-to-face (F2F) contact. In Australia, the expansion of subsidisation of telehealth during COVID has led to its permanent installation within Australian primary care in 2022. However, little is known about consumer preferences and experiences with these services, particularly in relation to allied health practice (AHP). Previous studies on telehealth services have focused on general practice rather than allied health (AH) and broader primary care. Given that AH professionals make up a large proportion of the Australian healthcare workforce, the purpose of this study is to explore consumer preferences and experiences with telehealth AHP healthcare. METHODS AND ANALYSIS: This study uses a mixed methods research design that incorporates three independent but interrelated phases. Phase 2 of the study will use a focus group methodology to discuss consumer attitudes and experiences via a semistructured interview format. Phase 3 involves a discrete choice experiment (DCE) involving a large online survey conducted across the general population. The DCE will be informed by the qualitative findings from phases 1 and 2. The experiment aims to elicit consumer preferences in relation to AH services delivered through telehealth or F2F consultations, based on several hypothetical scenarios and preferences over several different dimensions. ETHICS AND DISSEMINATION: Ethics approval has been obtained from La Trobe University (approval number HEC23404). Findings will be disseminated as reports, presentations and peer-reviewed journal articles.

Perspectives on telehealth implementation in Australia: An exploratory qualitative study with practice managers and general practitioners.

BACKGROUND: There is a lack of understanding regarding the impact of telehealth on clinical delivery and the feasibility of sustained implementation by health services. The COVID-19 pandemic provided an ideal opportunity to identify factors related to the implementation of telehealth. This study assessed factors that influenced telehealth implementation during COVID-19 in the Western region of Victoria, Australia, from the perspectives of practice managers and general practitioners (GPs). METHODS: Employing a qualitative approach, we conducted semi-structured interviews with 14 GPs and 11 practice managers across metropolitan and rural settings in the Western region of Victoria, Australia. Interviews were conducted between December 2021 to June 2022, which included periods during and beyond the peak of the COVID-19 pandemic. Themes were synthesised using the Consolidated Framework for Implementation Research, which comprised five domains: innovation, inner setting, outer setting, individuals and implementation process. An additional domain related to billing and finances was added. RESULTS: The innovation domain revealed that telehealth was identified by both stakeholder groups as a critical tool for improving healthcare access for vulnerable patients. GPs highlighted the role of telehealth in follow-up care and the need for extended telephone consultation services. For the implementation process, both stakeholder groups identified a shift in attitudes among GPs from reluctance to acceptance of telehealth. In terms of outer setting, constant changes in regulations posed challenges to administrative staff. Practice managers faced difficulties in acquiring information on changes, but those with robust professional networks were well supported. Initial loss of incentive funding and government-imposed billing methods posed hurdles for clinics. Both stakeholder groups highlighted the need for education around videoconference and a standardised telehealth platform. CONCLUSION: Evolving telehealth regulations during the emergence of COVID-19 posed financial, operational and administrative challenges to primary care clinics. To ensure sustainability, policymakers should improve stakeholder communication, set interoperability standards, and ensure sustainable funding for telehealth.

Digital Health Literacy and Its Association With Sociodemographic Characteristics, Health Resource Use, and Health Outcomes: Rapid Review.

BACKGROUND: Digital health literacy has emerged as a critical skill set to navigate the digital age. OBJECTIVE: This review sought to broadly summarize the literature on associations between digital health literacy and (1) sociodemographic characteristics, (2) health resource use, and (3) health outcomes in the general population, patient groups, or parent or caregiver groups. METHODS: A rapid review of literature published between January 2016 and May 2022 was conducted through a search of 4 web-based databases. Articles were included on the basis of the following keywords: "measured digital health literacy," "digital literacy," "ehealth literacy," "e-health literacy," "electronic health literacy," or "internet health literacy" in adult populations; participants were from countries where English was the primary language; studies had to be cross-sectional, longitudinal, prospective, or retrospective, and published in English. RESULTS: Thirty-six articles met the inclusion criteria. Evidence on the associations between digital health literacy and sociodemographic characteristics varied (27/36, 75% included studies), with higher education (16/21, 76.2% studies that examined the association) and younger age (12/21, 57.1% studies) tending to predict higher digital health literacy; however, other studies found no associations. No differences between genders were found across the majority of studies. Evidence across ethnic groups was too limited to draw conclusions; some studies showed that those from racial and ethnic minority groups had higher digital health literacy than White individuals, while other studies showed no associations. Higher digital health literacy was associated with digital health resource use in the majority of studies (20/36, 55.6%) that examined this relationship. In addition, higher digital health literacy was also associated with health outcomes across 3 areas (psychosocial outcomes; chronic disease and health management behaviors; and physical outcomes) across 17 included studies (17/36, 47.2%) that explored these relationships. However, not all studies on the relationship among digital health literacy and health resource use and health outcomes were in the expected direction. CONCLUSIONS: The review presents mixed results regarding the relationship between digital health literacy and sociodemographic characteristics, although studies broadly found that increased digital health literacy was positively associated with improved health outcomes and behaviors. Further investigations of digital health literacy on chronic disease outcomes are needed, particularly across diverse groups. Empowering individuals with the skills to critically access and appraise reliable health information on digital platforms and devices is critical, given emerging evidence that suggests that those with low digital health literacy seek health information from unreliable sources. Identifying cost-effective strategies to rapidly assess and enhance digital health literacy capacities across community settings thus warrants continued investigation.

The digital divide in rural and regional communities: a survey on the use of digital health technology and implications for supporting technology use.

OBJECTIVE: A digital divide exists for people from rural and regional areas where they are less likely and confident to engage in digital health technologies. The aim of this study was to evaluate the digital health literacy and engagement of people from rural and regional communities, with a focus on identifying barriers and facilitators to using technology. RESULTS: Forty adults living in rural/regional areas completed a survey consisting of the eHealth Literacy Scale (eHEALS) with additional items surveying participants' experience with a range of digital health technologies. All participants had used at least one digital health technology. Most (80%) participants had an eHEALS score of 26 or above indicating confidence in online health information. Commonly reported barriers to digital health technology use centred on product complexity and reliability, awareness of resources, lack of trust, and cost. Effective digital health technology use is becoming increasingly important, there may be a need to prioritise and support people with lower levels of digital health literacy. We present opportunities to support community members in using and accessing digital health technology.

Consumer preferences for telehealth in Australia: A discrete choice experiment.

This study aims to elicit consumer preferences regarding telehealth and face-to-face consultations in Australia. It used a discrete choice experiment, presenting participants with a series of hypothetical choices, and based on their responses, infer what is most important to them. Data were analysed using conditional logit regression and latent class analysis. A total of 1,025 participants completed the survey, considering four different clinical scenarios. Face-to-face contacts were, on average, preferred to either telephone or video services. However, telehealth was identified as an attractive option if it prevents significant travel and can be conducted with a familiar doctor. Participants were strongly driven by cost, particularly greater than $30. Telehealth was least preferred for situations involving a new and unknown physical symptom, and relatively more preferred for surgical follow-up. The latent class analysis demonstrates only 15.9% of participants appeared unwilling to consider telehealth. The findings of this study suggest that meeting the needs of the Australian population requires a blended approach to service delivery, with telehealth being valued in a range of clinical scenarios. Price sensitivity was evident, therefore if telehealth services can be delivered with lower patient cost, then they are likely to be attractive.

Evaluation of the priority primary care centre program to reduce emergency department burden in regional Victoria, Australia: a mixed-method study.

INTRODUCTION: In Australia, the Victorian State Government has established a number of priority primary care centres (PPCCs) across the state to address the increasing demand for emergency departments (EDs). PPCCs are general practitioner-led, free-of-charge services that aim to provide care for conditions that require urgent attention but do not require the high-acuity care of an ED. This study aims to evaluate the implementation processes, outcomes and the impact of the PPCC on reducing ED demand within Barwon, Warrnambool and Grampians Health Services in the Western region of Victoria, Australia. METHODS AND ANALYSIS: This is a convergent mixed-method study. Qualitative data collection will be undertaken through semistructured interviews to understand the experiences of PPCC patients, PPCC clinical staff, PPCC managerial and administrative staff and ED clinical staff. A documentary analysis will be conducted on the materials relating to the implementation of the PPCC. The quantitative component will involve interrupted time series analysis of de-identified administrative data, comprising ED presentation records and PPCC clinical records. Implementation science frameworks will be integrated throughout the study. The RE-AIM framework is a guide used for the planning and evaluation of programmes through five outcomes: reach, effectiveness, adoption, implementation and maintenance. The Consolidated Framework for Implementation Research will be integrated. ETHICS AND DISSEMINATION: This study has received ethical approval from Deakin University HREC (Ref No. 2023-046) and Barwon Health HREC (Ref No. 94374). Findings will be disseminated as reports, presentations and peer-reviewed journal articles.

Knowledge, attitudes and practices of COVID-19 in rural Bangladesh: a cross-sectional study.

OBJECTIVES: Understanding the knowledge, attitudes and practices (KAP) of COVID-19 within distinct populations may aid further public health messaging. This study's aims were to explore KAP towards COVID-19 in rural Bangladesh and identify any potential links to sociodemographics, existing clinical conditions and sources of information. DESIGN: Cross-sectional community-based study. SETTING: Participants were recruited from 18 villages using multistage cluster random sampling. METHODS: Data were collected through face-to-face interviews, from June to November 2021, using a structured questionnaire. Data included sociodemographics, clinical conditions, sources of information and KAP of COVID-19 questions. Χ2 test, multiple logistic regression and correlation analyses were performed. RESULTS: A total of 1603 participants were included with mean ages of 42.3±14.2 years, ranging from 18 to 60 years. Of these, 51% were male, 42.2% had secondary education and 45% had comorbidities. Television was the main source of COVID-19 information (55.8%). The overall correct response rate of KAP questions was 90%, 78% and 59%, respectively. In stepwise multiple logistic regression, good knowledge was associated with higher education (adjusted OR (AOR): 4.61, 95% CI: 2.40 to 8.85, p<0.001), employment, high body mass index (overweight and obese) and trust in the sources of information. Being female (AOR: 1.48, 95% CI: 1.19 to 1.85, p<0.001), having depression (AOR: 1.80, 95% CI: 1.34 to 2.43, p<0.001), being a past smoker and sources of information (family members/friends/relatives/neighbours) were associated with positive attitudes. Good practices were associated with older age (AOR: 1.52, 95% CI: 1.10 to 2.11, p=0.01), higher education (AOR: 2.78, 95% CI: 1.58 to 4.89, p<0.001) and having anxiety, while current smokers and fully vaccinated people were less likely to be engaged in good practices. Positive significant correlations between domains of KAP were observed as well as between past vaccination KAP and COVID-19 KAP. CONCLUSION: This study uncovered gaps in understanding and practices, and identified targeted intervention especially for young and less educated people using mass media to promote updated knowledge regarding COVID-19 and the efficacy of preventive practices.

Evaluation of COVID-19 vaccine acceptance and uptake in rural Bangladesh: a cross-sectional study.

OBJECTIVE: The objective of this study was to evaluate the acceptance and uptake of COVID-19 vaccines in rural Bangladesh. DESIGN: This was a cross-sectional study conducted between June and November 2021. SETTING: This study was conducted in rural Bangladesh. PARTICIPANTS: People older than 18 years of age, not pregnant and no history of surgery for the last 3 months were eligible to participate. PRIMARY AND SECONDARY OUTCOMES: The primary outcomes were proportions of COVID-19 vaccine acceptance and roll-out participation among the rural population. The secondary outcome was identification of correlates which contributed to COVID-19 vaccine acceptance and roll-out participation. Χ2 tests and multivariable logistic regression analyses were performed to identify relevant correlates such as sociodemographic factors, clinical conditions and COVID-19-related factors. RESULTS: A total of 1603 participants were enrolled. The overall COVID-19 vaccine acceptance was very high (1521/1601, 95%), and half of the participants received at least one dose of the COVID-19 vaccine. Majority of participants wanted to keep others safe (89%) and agreed to the benefits of COVID-19 vaccines (88%). To fulfil the requirement of online registration for the vaccine at the time, 62% of participants had to visit an internet café and only 31% downloaded the app. Over half (54%) of participants were unaware of countries they knew and trust to produce the COVID-19 vaccine. Increased age, being housewives, underweight and undergraduate education level were associated with vaccine acceptance, while being female, increased age and being overweight/obese were associated with vaccine uptake. Trust in the health department and practical knowledge regarding COVID-19 vaccines were positively associated with both vaccine acceptance and uptake. CONCLUSION: This study found a very high COVID-19 vaccine acceptance in rural Bangladesh. Policymakers should support interventions aimed at increasing vaccine and general health literacy and ensure ongoing vaccine supply and improvement of infrastructure in rural areas.

Cost-effectiveness of dapagliflozin in chronic heart failure: an analysis from the Australian healthcare perspective.

AIM: To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure and reduced ejection fraction. METHODS: A Markov model was constructed based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial to assess the clinical outcomes and costs of 1000 hypothetical subjects with established heart failure and reduced ejection fraction. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for heart failure' and 'dead'. Costs and utilities were estimated from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. An Australian public healthcare perspective was employed. All outcomes and costs were discounted at a rate of 5% annually. RESULTS: Over a lifetime horizon, the addition of dapagliflozin to standard care in patients with heart failure and reduced ejection fraction prevented 88 acute heart failure hospitalisations (including readmissions) and yielded an additional 416 years of life and 288 quality-adjusted life-years (discounted) at an additional cost of A$3,692,440 (discounted). This equated to an incremental cost-effectiveness ratio of A$12,482 per quality-adjusted life-year gained, well below the Australian willingness-to-pay threshold of A$50,000 per quality-adjusted life-year gained. Subanalyses in subjects with and without diabetes resulted in similar incremental cost-effectiveness ratios of A$13,234 and A$12,386 per quality-adjusted life-year gained, respectively. CONCLUSION: Dapagliflozin is likely to be cost-effective when used as an adjunct therapy to standard care compared with standard care alone for the treatment of chronic heart failure and reduced ejection fraction.

The impact of coronary heart disease prevention on work productivity: a 10-year analysis.

AIMS: To determine the impact of preventing new (incident) cases of coronary heart disease (CHD) on years of life and productivity, using the novel measure 'productivity-adjusted life year' (PALY), over the next 10 years. METHODS AND RESULTS: A dynamic life table model was constructed for the total Australian working-age population (15-69 years) over 10 years (2020-2029), separated by CHD status. Productivity estimates were sourced from the literature. The PALY was ascribed a financial value in terms of gross domestic product (GDP) per equivalent full-time worker. The total number of years lived, PALYs, and economic burden (in terms of GDP per PALY) were estimated. The model simulation was repeated assuming incidence was reduced, and the differences represented the impact of CHD prevention. All outcomes were discounted by 5% per annum. Over 10 years, the total projected years lived and PALYs in the Australian working-age population (with and without CHD) were 133 million and 83 million, respectively, amounting to A$17.2 trillion in GDP. We predicted more than 290 000 new (incident) CHD cases over the next 10 years. If all new cases of CHD could be prevented during this period, a total of 4 000 deaths could be averted, resulting in more than 8 000 years of life saved and 104 000 PALYs gained, equivalent to a gain of nearly A$21.8 billion (US$14.8 billion) in GDP. CONCLUSION: Prevention of CHD will prolong years of life lived and productive life years, resulting in substantial economic benefit. Policy makers and employers are encouraged to engage in preventive measures addressing CHD.

Dihydrosphingosine driven enrichment of sphingolipids attenuates TGFß induced collagen synthesis in cardiac fibroblasts.

The sphingolipid de novo synthesis pathway, encompassing the sphingolipids, the enzymes and the cell membrane receptors, are being investigated for their role in diseases and as potential therapeutic targets. The intermediate sphingolipids such as dihydrosphingosine (dhSph) and sphingosine (Sph) have not been investigated due to them being thought of as precursors to other more active lipids such as ceramide (Cer) and sphingosine 1 phosphate (S1P). Here we investigated their effects in terms of collagen synthesis in primary rat neonatal cardiac fibroblasts (NCFs). Our results in NCFs showed that both dhSph and Sph did not induce collagen synthesis, whilst dhSph reduced collagen synthesis induced by transforming growth factor ß (TGFß). The mechanisms of these inhibitory effects were associated with the increased activation of the de novo synthesis pathway that led to increased dihydrosphingosine 1 phosphate (dhS1P). Subsequently, through a negative feedback mechanism that may involve substrate-enzyme receptor interactions, S1P receptor 1 expression (S1PR1) was reduced.

The effect of dihydroceramide desaturase 1 inhibition on endothelial impairment induced by indoxyl sulfate.

Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 µM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 µM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects.

Attenuating PI3K/Akt- mTOR pathway reduces dihydrosphingosine 1 phosphate mediated collagen synthesis and hypertrophy in primary cardiac cells.

Cardiac fibrosis and myocyte hypertrophy play contributory roles in the progression of diseases such as heart Failure (HF) through what is collectively termed cardiac remodelling. The phosphoinositide 3- kinase (PI3K), protein kinase B (Akt) and mammalian target for rapamycin (mTOR) signalling pathway (PI3K/Akt- mTOR) is an important pathway in protein synthesis, cell growth, cell proliferation, and lipid metabolism. The sphingolipid, dihydrosphingosine 1 phosphate (dhS1P) has been shown to bind to high density lipids in plasma. Unlike its analog, spingosine 1 phosphate (S1P), the role of dhS1P in cardiac fibrosis is still being deciphered. This study was conducted to investigate the effect of dhS1P on PI3K/Akt signalling in primary cardiac fibroblasts and myocytes. Our findings demonstrate that inhibiting PI3K reduced collagen synthesis in neonatal cardiac fibroblasts (NCFs), and hypertrophy in neonatal cardiac myocytes (NCMs) induced by dhS1P, in vitro. Reduced activation of the PI3K/Akt- mTOR signalling pathway led to impaired translation of fibrotic proteins such as collagen 1 (Coll1) and transforming growth factor ß (TGFß) and inhibited the transcription and translation of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). PI3K inhibition also affected the gene expression of S1P receptors and enzymes such as the dihydroceramide delta 4 desaturase (DEGS1) and sphingosine kinase 1 (SK1) in the de novo sphingolipid pathway. While in myocytes, PI3K inhibition reduced myocyte hypertrophy induced by dhS1P by reducing skeletal muscle α- actin (αSKA) mRNA expression, and protein translation due to increased glycogen synthase kinase 3ß (GSK3ß) mRNA expression. Our findings show a relationship between the PI3K/Akt- mTOR signalling cascade and exogenous dhS1P induced collagen synthesis and myocyte hypertrophy in primary neonatal cardiac cells.

Apoptosis signal-regulating kinase 1 inhibition reverses deleterious indoxyl sulfate-mediated endothelial effects.

AIMS: Indoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS. MAIN METHODS: IS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes. KEY FINDINGS: IS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor ß receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression. SIGNIFICANCE: ASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.