Manual therapy and exercise for lateral elbow pain.

BACKGROUND: Manual therapy and prescribed exercises are often provided together or separately in contemporary clinical practice to treat people with lateral elbow pain. OBJECTIVES: To assess the benefits and harms of manual therapy, prescribed exercises or both for adults with lateral elbow pain. SEARCH METHODS: We searched the databases CENTRAL, MEDLINE and Embase, and trial registries until 31 January 2024, unrestricted by language or date of publication. SELECTION CRITERIA: We included randomised or quasi-randomised trials. Participants were adults with lateral elbow pain. Interventions were manual therapy, prescribed exercises or both. Primary comparators were placebo or minimal or no intervention. We also included comparisons of manual therapy and prescribed exercises with either intervention alone, with or without glucocorticoid injection. Exclusions were trials testing a single application of an intervention or comparison of different types of manual therapy or prescribed exercises. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted trial characteristics and numerical data, and assessed study risk of bias and certainty of evidence using GRADE. The main comparisons were manual therapy, prescribed exercises or both compared with placebo treatment, and with minimal or no intervention. Major outcomes were pain, disability, heath-related quality of life, participant-reported treatment success, participant withdrawals, adverse events and serious adverse events. The primary endpoint was end of intervention for pain, disability, health-related quality of life and participant-reported treatment success and final time point for adverse events and withdrawals. MAIN RESULTS: Twenty-three trials (1612 participants) met our inclusion criteria (mean age ranged from 38 to 52 years, 47% female, 70% dominant arm affected). One trial (23 participants) compared manual therapy to placebo manual therapy, 12 trials (1124 participants) compared manual therapy, prescribed exercises or both to minimal or no intervention, six trials (228 participants) compared manual therapy and exercise to exercise alone, one trial (60 participants) compared the addition of manual therapy to prescribed exercises and glucocorticoid injection, and four trials (177 participants) assessed the addition of manual therapy, prescribed exercises or both to glucocorticoid injection. Twenty-one trials without placebo control were susceptible to performance and detection bias as participants were not blinded to the intervention. Other biases included selection (nine trials, 39%, including two quasi-randomised), attrition (eight trials, 35%) and selective reporting (15 trials, 65%) biases. We report the results of the main comparisons. Manual therapy versus placebo manual therapy Low-certainty evidence, based upon a single trial (23 participants) and downgraded due to indirectness and imprecision, indicates manual therapy may reduce pain and elbow disability at the end of two to three weeks of treatment. Mean pain at the end of treatment was 4.1 points with placebo (0 to 10 scale) and 2.0 points with manual therapy, MD -2.1 points (95% CI -4.2 to -0.1). Mean disability was 40 points with placebo (0 to 100 scale) and 15 points with manual therapy, MD -25 points (95% CI -43 to -7). There was no follow-up beyond the end of treatment to show if these effects were sustained, and no other major outcomes were reported. Manual therapy, prescribed exercises or both versus minimal intervention Low-certainty evidence indicates manual therapy, prescribed exercises or both may slightly reduce pain and disability at the end of treatment, but the effects were not sustained, and there may be little to no improvement in health-related quality of life or number of participants reporting treatment success. We downgraded the evidence due to increased risk of performance bias and detection bias across all the trials, and indirectness due to the multimodal nature of the interventions included in the trials. At four weeks to three months, mean pain was 5.10 points with minimal treatment and manual therapy, prescribed exercises or both reduced pain by a MD of -0.53 points (95% CI -0.92 to -0.14, I2 = 43%; 12 trials, 1023 participants). At four weeks to three months, mean disability was 63.8 points with minimal or no treatment and manual therapy, prescribed exercises or both reduced disability by a MD of -5.00 points (95% CI -9.22 to -0.77, I2 = 63%; 10 trials, 732 participants). At four weeks to three months, mean quality of life was 73.04 points with minimal treatment on a 0 to 100 scale and prescribed exercises reduced quality of life by a MD of -5.58 points (95% CI -10.29 to -0.99; 2 trials, 113 participants). Treatment success was reported by 42% of participants with minimal or no treatment and 57.1% of participants with manual therapy, prescribed exercises or both, RR 1.36 (95% CI 0.96 to 1.93, I2 = 73%; 6 trials, 770 participants). We are uncertain if manual therapy, prescribed exercises or both results in more withdrawals or adverse events. There were 83/566 participant withdrawals (147 per 1000) from the minimal or no intervention group, and 77/581 (126 per 1000) from the manual therapy, prescribed exercises or both groups, RR 0.86 (95% CI 0.66 to 1.12, I2 = 0%; 12 trials). Adverse events were mild and transient and included pain, bruising and gastrointestinal events, and no serious adverse events were reported. Adverse events were reported by 19/224 (85 per 1000) in the minimal treatment group and 70/233 (313 per 1000) in the manual therapy, prescribed exercises or both groups, RR 3.69 (95% CI 0.98 to 13.97, I2 = 72%; 6 trials). AUTHORS' CONCLUSIONS: Low-certainty evidence from a single trial in people with lateral elbow pain indicates that, compared with placebo, manual therapy may provide a clinically worthwhile benefit in terms of pain and disability at the end of treatment, although the 95% confidence interval also includes both an important improvement and no improvement, and the longer-term outcomes are unknown. Low-certainty evidence from 12 trials indicates that manual therapy and exercise may slightly reduce pain and disability at the end of treatment, but this may not be clinically worthwhile and these benefits are not sustained. While pain after treatment was an adverse event from manual therapy, the number of events was too small to be certain.

Which clinical research questions are the most important? Development and preliminary validation of the Australia & New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network Research Question Importance Tool (ANZMUSC-RQIT).

BACKGROUND AND AIMS: High quality clinical research that addresses important questions requires significant resources. In resource-constrained environments, projects will therefore need to be prioritized. The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network aimed to develop a stakeholder-based, transparent, easily implementable tool that provides a score for the 'importance' of a research question which could be used to rank research projects in order of importance. METHODS: Using a mixed-methods, multi-stage approach that included a Delphi survey, consensus workshop, inter-rater reliability testing, validity testing and calibration using a discrete-choice methodology, the Research Question Importance Tool (ANZMUSC-RQIT) was developed. The tool incorporated broad stakeholder opinion, including consumers, at each stage and is designed for scoring by committee consensus. RESULTS: The ANZMUSC-RQIT tool consists of 5 dimensions (compared to 6 dimensions for an earlier version of RQIT): (1) extent of stakeholder consensus, (2) social burden of health condition, (3) patient burden of health condition, (4) anticipated effectiveness of proposed intervention, and (5) extent to which health equity is addressed by the research. Each dimension is assessed by defining ordered levels of a relevant attribute and by assigning a score to each level. The scores for the dimensions are then summed to obtain an overall ANZMUSC-RQIT score, which represents the importance of the research question. The result is a score on an interval scale with an arbitrary unit, ranging from 0 (minimal importance) to 1000. The ANZMUSC-RQIT dimensions can be reliably ordered by committee consensus (ICC 0.73-0.93) and the overall score is positively associated with citation count (standardised regression coefficient 0.33, p<0.001) and journal impact factor group (OR 6.78, 95% CI 3.17 to 14.50 for 3rd tertile compared to 1st tertile of ANZMUSC-RQIT scores) for 200 published musculoskeletal clinical trials. CONCLUSION: We propose that the ANZMUSC-RQIT is a useful tool for prioritising the importance of a research question.

Barriers and enablers to monitoring and deprescribing opioid analgesics for chronic non-cancer pain: a systematic review with qualitative evidence synthesis using the Theoretical Domains Framework.

BACKGROUND: Understanding barriers and enablers to monitoring and deprescribing opioids will enable the development of tailored interventions to improve both practices. OBJECTIVE: To perform a qualitative evidence synthesis of the barriers and enablers to monitoring ongoing appropriateness and deprescribing of opioids for chronic non-cancer pain (CNCP) and to map the findings to the Theoretical Domains Framework (TDF). METHODS: We included English-language qualitative studies that explored healthcare professional (HCP), patient, carer and the general public's perceptions regarding monitoring and deprescribing opioids for CNCP. We searched MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED) and PsycINFO from inception to August 2020. Two authors independently selected the studies, extracted the data, assessed the methodological quality using the Critical Appraisal Skills Programme, and assessed the confidence in the findings using GRADE CERQual (Grading of Recommendations Assessment, Development, and Evaluation Confidence in the Evidence from Reviews of Qualitative Research). We used an inductive approach to synthesis of qualitative data and mapped identified themes to TDF domains. RESULTS: From 6948 records identified we included 21 studies, involving 209 HCPs and 330 patients. No studies involved carers or the general public. Five barrier themes were identified: limited alternatives to opioids, management of pain is top priority, patient understanding, expectations and experiences, prescriber pressures, and reluctance to change. Four enabler themes were identified: negative effects of opioids and benefits of deprescribing, clear communication and expectations for deprescribing, support for patients, and support for prescribers. 16 barrier and 12 enabler subthemes were identified; most were graded as high (n=15) or moderate (n=9) confidence. The TDF domains 'beliefs about consequences', 'environmental context and resources', 'social influences' and 'emotion' were salient for patients and HCPs. The domains 'skills' and 'beliefs about capabilities' were more salient for HCPs. CONCLUSION: Future implementation interventions aimed at monitoring and deprescribing opioids should target the patient and HCP barriers and enablers identified in this synthesis. PROSPERO REGISTRATION NUMBER: CRD42019140784.

Management of patients presenting with low back pain to a private hospital emergency department in Melbourne, Australia.

OBJECTIVE: Recent studies suggest many patients with non-specific low back pain presenting to public hospital EDs receive low-value care. The primary aim was to describe management of patients presenting with low back pain to the ED of a private hospital in Melbourne, Australia, and received a final ED diagnosis of non-specific low back pain. We also determined predictors of hospital admission. METHODS: Retrospective review of patients who presented with low back pain and received a final ED diagnosis of non-specific low back pain to Cabrini Malvern ED in 2015. Demographics, lumbar spinal imaging, pathology tests and medications were extracted from hospital records. Multivariate logistic regression was used to determine independent predictors of hospital admission. RESULTS: Four hundred and fifty presentations were included (60% female); 238 (52.9%) were admitted to hospital. One hundred and seventy-seven (39.3%) patients received lumbar spine imaging. Two hundred and eighty (62.2%) patients had pathology tests and 391 (86.9%) received medications, which included opioids (n = 298, 66.2%), paracetamol (n = 219, 48.7%), NSAIDs (n = 161, 35.8%), benzodiazepines (n = 118, 26.2%) and pregabalin (n = 26, 5.8%). Predictors of hospital admission included older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02-1.05), arrival by ambulance (OR 2.03, 95% CI 1.06-3.90) and receipt of pathology tests (OR 3.32, 95% CI 2.01-5.49) or computed tomography scans (OR 1.86, 95% CI 1.12-3.11). CONCLUSION: We observed high rates of imaging, pathology tests and hospital admissions compared with previous public hospital studies, while medication use was similar. Implementation of strategies to optimise evidence-based ED care is needed to reduce low-value care and improve patient outcomes.

Enhancing clinician and patient understanding of radiology reports: a scoping review of international guidelines.

Imaging reports are the primary method of communicating diagnostic imaging findings between the radiologist and the referring clinician. Guidelines produced by professional bodies provide guidance on content and format of imaging reports, but the extent to which they consider comprehensibility for referring clinicians and their patients is unclear. The objective of this review was to determine the extent to which radiology reporting guidelines consider comprehensibility of imaging reports for referring clinicians and patients.We performed a scoping review of English-language diagnostic imaging reporting guidelines. We searched electronic databases (OVID MEDLINE, Embase) and websites of radiological professional organisations to identify guidelines. The extent to which the guidelines recommended essential report features such as technical information, content, format and language, as well as features to enhance comprehensibility, such as lay language summaries, was recorded.Six guidelines from professional bodies representing radiologists from the USA, Canada, Australia and New Zealand, Hong Kong, the UK and Europe were identified from the search. Inconsistencies exist between guidelines in their recommendations, and they rarely consider that patients may read the report. No guideline made recommendations about the reporting of results considering the clinical context, and none recommended features preferred by patients such as lay language summaries. This review identifies an opportunity for future radiology reporting guidelines to give greater consideration to referring clinician and patient preferences.

Early development of the Australia and New Zealand Musculoskeletal Clinical Trials Network.

The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network was formed to build capacity and infrastructure for high-quality musculoskeletal clinical trials in our region. The purpose of this paper is to describe the steps taken in its formation to help others interested in establishing similar networks. In particular, we describe the steps taken to form the collaboration and our progress in achieving our vision and mission. Our aim is to focus on trials of highest importance and quality to provide definitive answers to the most pressing questions in our field.

Barriers and enablers to monitoring and deprescribing opioid analgesics for chronic non-cancer pain: protocol for a qualitative evidence synthesis using the Theoretical Domains Framework.

INTRODUCTION: The over-prescription and overuse of opioid analgesics for chronic non-cancer pain (CNCP) is a growing issue. Synthesis of evidence about the barriers and enablers to reducing long-term opioid prescribing and use will enable the development of tailored interventions to address both problems. OBJECTIVE: To synthesise the barriers and enablers to monitoring the ongoing appropriateness of opioid treatment and deprescribing opioids for CNCP from the clinician, patient and general public point of view, and to map the findings to the Theoretical Domains Framework (TDF). METHODS AND ANALYSIS: We will perform a qualitative evidence synthesis using the TDF. We will include qualitative research that has explored clinician, patient and the general public's perceptions regarding barriers and enablers to monitoring and deprescribing opioids for CNCP. Studies will be identified via searches in MEDLINE, EMBASE, CINAHL, AMED and PsycINFO. Databases will be searched from inception to July 2019, and the studies must be published in English. Article selection and data extraction will be completed independently by two review authors. Methodological quality of included studies will be independently assessed by two review authors using the Critical Appraisal Skills Programme quality assessment tool. We will conduct thematic synthesis and then map identified themes and sub-themes to TDF domains. Confidence in synthesis findings will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation Confidence in the Evidence from Reviews of Qualitative Research tool. ETHICS AND DISSEMINATION: Ethical approval is not required to conduct this review. We will publish the results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019140784.

Scoping review of priority setting of research topics for musculoskeletal conditions.

OBJECTIVE: Describe research methods used in priority-setting exercises for musculoskeletal conditions and synthesise the priorities identified. DESIGN: Scoping review. SETTING AND POPULATION: Studies that elicited the research priorities of patients/consumers, clinicians, researchers, policy-makers and/or funders for any musculoskeletal condition were included. METHODS AND ANALYSIS: We searched MEDLINE and EMBASE from inception to November 2017 and the James Lind Alliance top 10 priorities, Cochrane Priority Setting Methods Group, and Cochrane Musculoskeletal and Back Groups review priority lists. The reported methods and research topics/questions identified were extracted, and a descriptive synthesis conducted. RESULTS: Forty-nine articles fulfilled our inclusion criteria. Methodologies and stakeholders varied widely (26 included a mix of clinicians, consumers and others, 16 included only clinicians, 6 included only consumers or patients and in 1 participants were unclear). Only two (4%) reported any explicit inclusion criteria for priorities. We identified 294 broad research priorities from 37 articles and 246 specific research questions from 17 articles, although only four (24%) of the latter listed questions in an actionable format. Research priorities for osteoarthritis were identified most often (n=7), followed by rheumatoid arthritis (n=4), osteoporosis (n=4) and back pain (n=4). Nearly half of both broad and specific research priorities were focused on treatment interventions (n=116 and 111, respectively), while few were economic (n=8, 2.7% broad and n=1, 0.4% specific), implementation (n=6, 2% broad and n=4, 1.6% specific) or health services and systems research (n=15, 5.1% broad and n=9, 3.7% specific) priorities. CONCLUSIONS: While many research priority-setting studies in the musculoskeletal field have been performed, methodological limitations and lack of actionable research questions limit their usefulness. Future studies should ensure they conform to good priority-setting practice to ensure that the generated priorities are of maximum value. PROSPERO REGISTRATION NUMBER: CRD42017059250.

Health literacy profile of recently hospitalised patients in the private hospital setting: a cross sectional survey using the Health Literacy Questionnaire (HLQ).

BACKGROUND: Health service providers should understand and attend to the health literacy needs of their population in view of the known association between low health literacy and poorer health outcomes. This study aimed to determine the health literacy profile of patients treated at a large private hospital in Melbourne, Australia, and any associations between this profile and socio-economic position, health behaviours, health status and use of hospital services. METHODS: A mailed survey was sent to 9173 people aged ≥18 years with a hospital admission between February and October 2014. It included the Health Literacy Questionnaire (HLQ), a multidimensional tool comprising nine independent scales, and socio-demographic and clinical questions. For both respondents and non-respondents, we also extracted residential postcode and admission and follow up details from the Patient Administrative Services database. Differences in demographic, socio-economic and hospital use patterns between respondents and non-respondents were analysed using descriptive statistics. Regression-tests were used to identify differences in health literacy between socio-economic subgroups, with the magnitude of these differences determined using Cohen's d effect sizes. RESULTS: There were 3121 respondents (response rate: 35% excluding 154 returned invitations), the majority born in Australia (74.6%) and living in areas of high socio-economic advantage. Respondents were slightly older than non-respondents (mean (SD) age 65.6 (17.0) versus 60.6 (20.8) years) and included proportionately less females (51.9 versus 59.1%) but were similar with regard to other socio-demographic factors and health service use. Participants who did not speak English at home, reported lower scores across several HLQ scales, including those that measure health provider support and engagement. Those who smoked and reported low physical activity had lower scores for actively managing their health. No relationship was seen between HLQ scale scores and use of hospital services. CONCLUSIONS: Based upon the health literacy profile of a large cohort of patients attending a large private hospital, we found no relationship between HLQ scale scores and use of hospital services. However we did identify significant health literacy needs particularly among patients whose primary language at home was not English and patients needing assistance completing the survey. Identifying ways of addressing these needs may improve patient outcomes.

Differences in health literacy profiles of patients admitted to a public and a private hospital in Melbourne, Australia.

BACKGROUND: Health literacy refers to an individual's ability to find, understand and use health information in order to promote and maintain health. An individual's health literacy may also be influenced by the way health care organisations deliver care. The aim of this study was to investigate the influence of hospital service type (public versus private) on individual health literacy. METHODS: Two cross-sectional surveys were conducted using the Health Literacy Questionnaire (HLQ), a multi-dimensional self-report instrument covering nine health literacy domains. Recently discharged private patients (n = 3121) were sent the survey in English, public patients (n = 384) were sent the survey in English, Arabic, Chinese, Vietnamese, Italian or Greek. Eligibility included hospitalisation ≥24 h in last 30 days, aged ≥18 years, no cognitive impairment. Odds ratios were used to assess differences between hospital sociodemographic and health related variables. ANOVA and Cohen's effect sizes compared HLQ scores between hospitals. Chi square and multiple logistic regression were used to determine whether differences between private and public hospital HLQ scores was independent of hospital population sociodemographic differences. ANOVA was used to review associations between HLQ scores and subgroups of demographic, health behaviour and health conditions and these were then compared across the two hospital populations. RESULTS: Public hospital participants scored lower than private hospital participants on eight of the nine health literacy domains of the HLQ (scores for Active Appraisal did not differ between the two samples). Six domains, five of which in part measure the impact of how care is delivered on health literacy, remained lower among public hospital participants after controlling for age, education, language and income. Across both hospital populations, participants who were smokers, those who had low physical activity, those with depression and/or anxiety and those with 3 or more chronic conditions reported lower scores on some HLQ domains. CONCLUSIONS: Our finding of lower health literacy among patients who had received care at a public hospital in comparison to a private hospital, even after adjustment for sociodemographic and language differences, suggests that private hospitals may possess organisational attributes (environment, structure, values, practices and/or workforce competencies) that result in improved health literacy responsiveness.

Content analysis of consumer information about knee arthroscopy in Australia.

BACKGROUND: Despite the availability of consistent guidelines recommending against arthroscopic treatment for people with symptomatic knee osteoarthritis, Australian data indicate continued use of this treatment modality. A paucity of easy to understand and reliable consumer information about knee arthroscopy may be one explanatory factor. The aim of this study was to determine whether consumer information about knee arthroscopy available in Australia is adequate to inform evidence-based decision-making for people with symptomatic osteoarthritis. METHODS: We performed a content analysis of consumer information about knee arthroscopy for symptomatic osteoarthritis. Information sources were identified from the Australian Commission on Quality and Safety in Health Care and Internet searches conducted 20-28 May 2015. Search terms were 'knee arthroscopy', 'knee pain', 'osteoarthritis knee' and 'meniscal tear', and 'orthopaedic surgeon' linked to each Australian capital city. Two independent reviewers selected documents for inclusion and extracted data. Main outcomes were specific advice regarding use of arthroscopic treatment for people with knee osteoarthritis, mention of guidelines, and/or supporting evidence. RESULTS: Ninety-three documents were analyzed (44 were a paragraph or less). Only eight made a clear recommendation against use of arthroscopy for all/most people with knee osteoarthritis. None included an explicit statement attributed to a guideline, while only six provided any research evidence to support their advice. Wikipedia provided the most valid information but it may be incomprehensible to the average reader. CONCLUSION: Currently available consumer information about knee arthroscopy in Australia may be inadequate to help people with symptomatic knee osteoarthritis make informed decisions about this treatment.

Health literacy of recently hospitalised patients: a cross-sectional survey using the Health Literacy Questionnaire (HLQ).

BACKGROUND: Health literacy is simply defined as an individual's ability to access, understand and use information in ways that promote and maintain good health. Lower health literacy has been found to be associated with increased emergency department presentations and potentially avoidable hospitalisations. This study aimed to determine the health literacy of hospital inpatients, and to examine if associations exist between different dimensions of their health literacy, sociodemographic characteristics and hospital services use. METHODS: A written survey was sent to 3,252 people aged ≥18 years in English, Arabic, Chinese, Vietnamese, Italian or Greek. The survey included demographic and health questions, and the Health Literacy Questionnaire (HLQ). The HLQ is a multidimensional instrument comprising nine independent scales. Use of hospital services was measured by length of stay, number of admissions in 12 months and number of emergency department presentations. Effect size (ES) for standardised differences in means described the magnitude of differences in HLQ scale scores between demographic and socioeconomic groups. RESULTS: 385 questionnaires were returned (13%); mean age 64 years (SD 17), 49% female. Aged ≥65 years (55%), using the Internet < once a month (37%), failure to complete high school (67%), low household income (39%), receiving means-tested government benefits (61%) and being from a culturally and linguistically diverse (CALD) background (24%), were all associated with lower scores in some health literacy scales. Being aged ≥65 years, not currently employed, receiving government benefits, and being from a CALD background were also associated with increased use of some hospital services. There was no association between lower scores on any HLQ scale and greater use of hospital services. CONCLUSION: We found no association between lower health literacy and greater use of hospital health services. However increased age, having a CALD background and not speaking English at home were all associated with having the most health literacy challenges Strategies to address these are needed to reduce health inequalities.

Vascular induction of a disintegrin and metalloprotease 17 by angiotensin II through hypoxia inducible factor 1α.

BACKGROUND: A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS: Cultured vascular smooth muscle cells were stimulated with 100 nM angiotensin II. Mice were infused with 1 µg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter-reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS: In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II-infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS: Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α-dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system.

The scope, funding and publication of musculoskeletal clinical trials performed in Australia.

Musculoskeletal conditions are the leading contributors to disability burden globally and account for 27.4% of total disability burden in Australia. Timely research that addresses important questions relevant to consumers, clinicians and policymakers is critical for reducing the burden associated with these conditions. Clinical trials are particularly important for providing information about whether interventions are effective and safe. They are also needed to test strategies for reducing the sizeable delays in translating evidence into practice. A review of the current scope of musculoskeletal clinical trials in Australia found that National Health and Medical Research Council funding is disproportionally low compared with the burden of these conditions (averaging 5.8 new trials per year through the project grant scheme over the past 5 years, representing 0.8% of all project grants and funding, and 5% of NHMRC clinical trial funding). In the past 2 years, 128 Australian-initiated trials were registered in a trial registry, while about one in 20 randomised trials published in 37 leading general medical and musculoskeletal-specific journals was initiated in Australia. None were implementation trials. Relative to the burden of musculoskeletal conditions in Australia, investment in clinical trials is not ideal. While Australian musculoskeletal trialists are productive and internationally competitive, we may not be addressing the most critical issues. There is an urgent need for Australian researchers, clinicians, policymakers and consumers to work collaboratively to prioritise the most important questions, secure appropriate research funding, and undertake well designed trials to ensure we deliver best evidence-informed care and optimal outcomes for people with musculoskeletal conditions.

ADAM17 silencing by adenovirus encoding miRNA-embedded siRNA revealed essential signal transduction by angiotensin II in vascular smooth muscle cells.

Small interfering RNA (siRNA) mediated gene silencing has been utilized as a powerful molecular tool to study the functional significance of a specific protein. However, due to transient gene silencing and insufficient transfection efficiency, this approach can be problematic in primary cell culture such as vascular smooth muscle cells. To overcome this weakness, we utilized an adenoviral-encoded microRNA (miRNA)-embedded siRNA "mi/siRNA"-based RNA interference. Here, we report the results of silencing a disintegrin and metalloprotease 17 (ADAM17) in cultured rat vascular smooth muscle cells and its functional mechanism in angiotensin II signal transduction. 3 distinct mi/siRNA sequences targeting rat ADAM17 were inserted into pAd/CMV/V5-DEST and adenoviral solutions were obtained. Nearly 90% silencing of ADAM17 was achieved when vascular smooth muscle cells were infected with 100 multiplicity of infection of each ADAM17 mi/siRNA encoding adenovirus for 3days. mi/siRNA-ADAM17 but not mi/siRNA-control inhibited angiotensin II-induced epidermal growth factor receptor trans-activation and subsequent extracellular signal-regulated kinase activation and hypertrophic response in the cells. mi/siRNA-ADAM17 also inhibited angiotensin II-induced heparin-binding epidermal growth factor-like factor shedding. This inhibition was rescued with co-infection of adenovirus encoding mouse ADAM17 but not by its cytosolic domain deletion mutant or cytosolic Y702F mutant. As expected, angiotensin II induced tyrosine phosphorylation of ADAM17 in the cells. In conclusion, ADAM17 activation via its tyrosine phosphorylation contributes to heparin-binding epidermal growth factor-like factor shedding and subsequent growth promoting signals induced by angiotensin II in vascular smooth muscle cells. An artificial mi/siRNA-based adenoviral approach appears to be a reliable gene-silencing strategy for signal transduction research in primary cultured vascular cells.

A repressor protein, Mnt, is a novel negative regulator of vascular smooth muscle cell hypertrophy by angiotensin II and neointimal hyperplasia by arterial injury.

OBJECTIVE: The Max-interacting protein Mnt is a transcriptional repressor that can antagonize the transcriptional and proliferation-related activities of Myc. Here, we tested the hypothesis that Mnt is a negative regulator of pathological vascular remodeling. METHODS: Adenovirus encoding Mnt or control GFP was infected to cultured rat vascular smooth muscle cells (VSMC) and carotid arteries after a balloon angioplasty. RESULTS: In VSMC, adenoviral gene transfer of Mnt suppressed angiotensin II-induced protein expression of early growth response protein-1 (Egr1) and its promoter activation. Mnt adenovirus did not interfere with upstream signaling of angiotensin II. Angiotensin II-induced protein accumulation in VSMC was inhibited by Mnt adenovirus. Mnt adenovirus also inhibited platelet-derived growth factor-induced VSMC proliferation. Moreover, Mnt adenovirus prevented neointima formation in response to arterial injury. The adenoviral Mnt gene transfer also prevented Egr1 induction in neointima. CONCLUSION: These data identify Mnt as a previously unrecognized negative regulator of pathological vascular remodeling.

Constitutive stimulation of vascular smooth muscle cells by angiotensin II derived from an adenovirus encoding a furin-cleavable fusion protein.

BACKGROUND: To fill the gap between acute and chronic stimulation methods of angiotensin II (Ang II) and obtain relevant signaling information, we have made an adenovirus vector encoding a furin-cleavable Ang II fusion protein. METHODS: Vascular smooth muscle cells (VSMCs) were infected with adenovirus to evaluate Ang II production. Also, expression of early growth response-1 (Egr-1) and hypertrophic responses were examined in VSMCs. RESULTS: Acute stimulation of VSMCs with synthetic Ang II showed the peptide had a half-life of less than 1 h. Infection of VSMCs with Ang II adenovirus showed a time-dependent production of Ang II as early as 2 days and up to 7 days postinfection. The Ang II adenovirus induced VSMC hypertrophy, stimulated Egr-1 expression, and suppressed Ang II type 1 receptor mRNA expression. Chronic Ang II infusion in mice for 2 weeks markedly enhanced Egr-1 immunostaining in carotid artery compared with the control saline infusion. CONCLUSION: Application of the Ang II adenovirus vector to cultured cells will be useful to elucidate molecular and signaling mechanisms of cardiovascular diseases associated with enhanced Ang II production.

Home hemodialysis in the remote Canadian north: treatment in Manitoba fly-in communities.

Manitoba has the highest prevalence of ESRD in Canada. Northern Manitoba is a very sparsely settled area with a high proportion of aboriginal ESRD patients. Relocating to urban areas for dialysis is psychosocially and culturally stressful to patients. Delivering dialysis care in a home setting has demonstrated advantages in both clinical, economic, and health related quality of life domains. Establishing home hemodialysis in very remote communities has significant challenges, including poor and inadequate housing, unreliable water supply, limited community medical backup, and poor road access to communities especially for delivery of supplies. These challenges necessitate the development of strong community partnerships, and well documented processes for contingencies. A dedicated interdisciplinary support and training team at the urban hub is essential.

Determination of the exact molecular requirements for type 1 angiotensin receptor epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy.

Major interest surrounds how angiotensin II triggers cardiac hypertrophy via epidermal growth factor receptor transactivation. G protein-mediated transduction, angiotensin type 1 receptor phosphorylation at tyrosine 319, and ß-arrestin-dependent scaffolding have been suggested, yet the mechanism remains controversial. We examined these pathways in the most reductionist model of cardiomyocyte growth, neonatal ventricular cardiomyocytes. Analysis with [(32)P]-labeled cardiomyocytes, wild-type and [Y319A] angiotensin type 1 receptor immunoprecipitation and phosphorimaging, phosphopeptide analysis, and antiphosphotyrosine blotting provided no evidence for tyrosine phosphorylation at Y319 or indeed of the receptor, and mutation of Y319 (to A/F) did not prevent either epidermal growth factor receptor transactivation in COS-7 cells or cardiomyocyte hypertrophy. Instead, we demonstrate that transactivation and cardiomyocyte hypertrophy are completely abrogated by loss of G-protein coupling, whereas a constitutively active angiotensin type 1 receptor mutant was sufficient to trigger transactivation and growth in the absence of ligand. These results were supported by the failure of the ß-arrestin-biased ligand SII angiotensin II to transactivate epidermal growth factor receptor or promote hypertrophy, whereas a ß-arrestin-uncoupled receptor retained these properties. We also found angiotensin II-mediated cardiomyocyte hypertrophy to be attenuated by a disintegrin and metalloprotease inhibition. Thus, G-protein coupling, and not Y319 phosphorylation or ß-arrestin scaffolding, is required for epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy via the angiotensin type 1 receptor.