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Background: Although education, exercise, and weight loss are recommended for management of knee osteoarthritis, the additional benefits of incorporating weight loss strategies into exercise interventions have not been well investigated. The aim of this study is to compare, in a private health insurance setting, the clinical- and cost-effectiveness of a remotely-delivered, evidence- and theory-informed, behaviour change intervention targeting exercise and self-management (Exercise intervention), with the same intervention plus active weight management (Exercise plus weight management intervention), and with an information-only control group for people with knee osteoarthritis who are overweight or obese., Methods: Three-arm, pragmatic parallel-design randomised controlled trial involving 415 people aged ≥45 and ≤ 80 years, with body mass index ≥28 kg/m 2 and < 41 kg/m 2 and painful knee osteoarthritis. Recruitment is Australia-wide amongst Medibank private health insurance members. All three groups receive access to a bespoke website containing information about osteoarthritis and self-management. Participants in the Exercise group also receive six consultations with a physiotherapist via videoconferencing over 6 months, including prescription of a strengthening exercise and physical activity program, advice about management, and additional educational resources. The Exercise plus weight management group receive six consultations with a dietitian via videoconferencing over 6 months, which include a very low calorie ketogenic diet with meal replacements and resources to support behaviour change, in addition to the interventions of the Exercise group. Outcomes are measured at baseline, 6 and 12 months. Primary outcomes are self-reported knee pain and physical function at 6 months. Secondary outcomes include weight, physical activity levels, quality of life, global rating of change, satisfaction with care, knee surgery and/or appointments with an orthopaedic surgeon, and willingness to undergo surgery. Additional measures include adherence, adverse events, self-efficacy, and perceived usefulness of intervention components. Cost-effectiveness of each intervention will also be assessed., Discussion: This pragmatic study will determine whether a scalable remotely-delivered service combining weight management with exercise is more effective than a service with exercise alone, and with both compared to an information-only control group. Findings will inform development and implementation of future remotely-delivered services for people with knee osteoarthritis., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12618000930280 (01/06/2018).

When calculating sample size or power for stepped wedge or other types of longitudinal cluster randomized trials, it is critical that the planned sampling structure be accurately specified. One common assumption is that participants will provide measurements in each trial period, that is, a closed cohort, and another is that each participant provides only one measurement during the course of the trial. However some studies have an "open cohort" sampling structure, where participants may provide measurements in variable numbers of periods. To date, sample size calculations for longitudinal cluster randomized trials have not accommodated open cohorts. Feldman and McKinlay (1994) provided some guidance, stating that the participant-level autocorrelation could be varied to account for the degree of overlap in different periods of the study, but did not indicate precisely how to do so. We present sample size and power formulas that allow for open cohorts and discuss the impact of the degree of "openness" on sample size and power. We consider designs where the number of participants in each cluster will be maintained throughout the trial, but individual participants may provide differing numbers of measurements. Our results are a unification of closed cohort and repeated cross-sectional sample results of Hooper et al (2016), and indicate precisely how participant autocorrelation of Feldman and McKinlay should be varied to account for an open cohort sampling structure. We discuss different types of open cohort sampling schemes and how open cohort sampling structure impacts on power in the presence of decaying within-cluster correlations and autoregressive participant-level errors., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

Chronic venous leg ulcers are challenging to heal and often recur. This has a significant impact on older individual health and is a financial burden on health care resources. This study aimed to identify factors associated with the healing of venous leg ulcers via secondary examination of data from a previously published prospective randomized controlled trial of elastic and inelastic compression systems. The data from the 45 patients who finished the trial was reanalyzed for a hypothesis generating study. Larger ulcers, higher exudate levels, larger calf circumferences, and longer ulcer duration at baseline were associated with lack of healing at 12 weeks. There was some evidence that NSAID use was associated with an increased likelihood of nonhealing (unadjusted OR for healing, 0.13, 95% CI (0.02, 0.70)). There was no evidence that other variables, including gender and BMI, were associated with healing. The key risk factors for wound healing are largely wound based or inherent to wound development, as these were found to be the factors with the strongest associations in the analysis. Future research should address how and why these factors are associated with wound healing over a longer time frame and explore how NSAIDs may affect wound healing outcomes., (© 2019 by the Wound Healing Society.)

Introduction: This protocol outlines the rationale, design and methods for the process and feasibility evaluations of the primary care management on knee pain and function in patients with knee osteoarthritis (PARTNER) study. PARTNER is a randomised controlled trial to evaluate a new model of service delivery (the PARTNER model) against 'usual care'. PARTNER is designed to encourage greater uptake of key evidence-based non-surgical treatments for knee osteoarthritis (OA) in primary care. The intervention supports general practitioners (GPs) to gain an understanding of the best management options available through online professional development. Their patients receive telephone advice and support for OA management by a centralised, multidisciplinary 'Care Support Team'. We will conduct concurrent process and feasibility evaluations to understand the implementation of this new complex health intervention, identify issues for consideration when interpreting the effectiveness outcomes and develop recommendations for future implementation, cost effectiveness and scalability., Methods and Analysis: The UK Medical Research Council Framework for undertaking a process evaluation of complex interventions and the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) frameworks inform the design of these evaluations. We use a mixed-methods approach including analysis of survey data, administrative records, consultation records and semistructured interviews with GPs and their enrolled patients. The analysis will examine fidelity and dose of the intervention, observations of trial setup and implementation and the quality of the care provided. We will also examine details of 'usual care'. The semistructured interviews will be analysed using thematic and content analysis to draw out themes around implementation and acceptability of the model., Ethics and Dissemination: The primary and substudy protocols have been approved by the Human Research Ethics Committee of The University of Sydney (2016/959 and 2019/503). Our findings will be disseminated to national and international partners and stakeholders, who will also assist with wider dissemination of our results across all levels of healthcare. Specific findings will be disseminated via peer-reviewed journals and conferences, and via training for healthcare professionals delivering OA management programmes. This evaluation is crucial to explaining the PARTNER study results, and will be used to determine the feasibility of rolling-out the intervention in an Australian healthcare context., Trial Registration Number: ACTRN12617001595303; Pre-results., Competing Interests: Competing interests: DJH provides consulting advice to Pfizer, Lilly, Merck Serono and TLC bio. SJB is an employee of Medibank., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria., Methods: A retrospective population-based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re-evaluation from multiple sources. Crude and sex- and serostatus-specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person-years) from 2006 to 2015 were estimated and age-adjusted rates were determined., Results: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52-2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person-years provided an incidence rate of 1.32 (95% CI 1.08-1.61) per 1 000 000 person-years. Age-adjusted prevalence was 1.87 (95% CI 1.56-2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98-1.46) per 1 000 000 person-years., Conclusions: In this first report of a large population-based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations., (© 2019 European Academy of Neurology.)

Background: Attrition due to death and non-attendance are common sources of bias in studies of age-related diseases. A simulation study is presented to compare two methods for estimating the survivor average causal effect (SACE) of a binary exposure (sex-specific dietary iron intake) on a binary outcome (age-related macular degeneration, AMD) in this setting., Methods: A dataset of 10,000 participants was simulated 1200 times under each scenario with outcome data missing dependent on measured and unmeasured covariates and survival. Scenarios differed by the magnitude and direction of effect of an unmeasured confounder on both survival and the outcome, and whether participants who died following a protective exposure would also die if they had not received the exposure (validity of the monotonicity assumption). The performance of a marginal structural model (MSM, weighting for exposure, survival and missing data) was compared to a sensitivity approach for estimating the SACE. As an illustrative example, the SACE of iron intake on AMD was estimated using data from 39,918 participants of the Melbourne Collaborative Cohort Study., Results: The MSM approach tended to underestimate the true magnitude of effect when the unmeasured confounder had opposing directions of effect on survival and the outcome. Overestimation was observed when the unmeasured confounder had the same direction of effect on survival and the outcome. Violation of the monotonicity assumption did not increase bias. The estimates were similar between the MSM approach and the sensitivity approach assessed at the sensitivity parameter of 1 (assuming no survival bias). In the illustrative example, high iron intake was found to be protective of AMD (adjusted OR 0.57, 95% CI 0.40-0.82) using complete case analysis via traditional logistic regression. The adjusted SACE odds ratio did not differ substantially from the complete case estimate, ranging from 0.54 to 0.58 for each of the SACE methods., Conclusions: On average, MSMs with weighting for exposure, missing data and survival produced biased estimates of the SACE in the presence of an unmeasured survival-outcome confounder. The direction and magnitude of effect of unmeasured survival-outcome confounders should be considered when assessing exposure-outcome associations in the presence of attrition due to death.

Trial planning requires making efficient yet practical design choices. In a cluster randomized crossover trial, clusters of subjects cross back and forth between implementing the control and intervention conditions over the course of the trial, with each crossover marking the start of a new period. If it is possible to set up such a trial with more crossovers, a pertinent question is whether there are efficiency gains from clusters crossing over more frequently, and if these gains are substantial enough to justify the added complexity and cost of implementing more crossovers. We seek to determine the optimal number of crossovers for a fixed trial duration, and then identify other highly efficient designs by allowing the total number of clusters to vary and imposing thresholds on maximum cost and minimum statistical power. Our results pertain to trials with continuous recruitment and a continuous primary outcome, with the treatment effect estimated using a linear mixed model. To account for the similarity between subjects' outcomes within a cluster, we assume a correlation structure in which the correlation decays gradually in a continuous manner as the time between subjects' measurements increases. The optimal design is characterized by crossovers between the control and intervention conditions with each successive subject. However, this design is neither practical nor cost-efficient to implement, nor is it necessary: the gains in efficiency increase sharply in moving from a two-period to a four-period trial design, but approach an asymptote for the scenarios considered as the number of crossovers continues to increase., (© 2019 John Wiley & Sons, Ltd.)

Objective: We sought to characterize the relationship between postoperative blood pressure on the day of surgery and metrics of bleeding., Methods: In a preplanned secondary analysis of prospectively collected data from the Limiting IV Chloride to Reduce AKI trial (NCT02020538), univariate and multivariable regression analyses explored the association between peak systolic blood pressure, peak mean arterial pressure, and peak central venous pressure recorded postoperatively on the day of surgery and multiple metrics of bleeding. Patients at increased bleeding risk due to specific criteria were excluded from analysis. The primary outcome was chest tube drainage (milliliters per hour) on the day of surgery. Secondary outcomes included red blood cell transfusion, surgical re-exploration for bleeding, and hospital mortality., Results: The study cohort comprised 793 patients. Mean ± standard deviation peak systolic blood pressure, mean arterial pressure, and central venous pressure were 125 ± 15 mm Hg, 83 ± 9 mm Hg, and 12 ± 4 mm Hg, respectively. Median (interquartile range) chest tube drainage on the day of surgery was 33 mL/hour (interquartile range, 23 mL/hour-51 mL/hour). Adjusted for prespecified variables, there was no positive association between peak systolic blood pressure and bleeding outcomes, including chest tube drainage (-2.2 mL/10 mm Hg; 95% confidence interval, -3.9 to -0.5 mL/h/10 mm Hg; P = .01) or volume of transfusion (-15 mL/10 mm Hg; 95% confidence interval, -29 to -1 mL/h/10 mm Hg; P = .04). Results remained broadly consistent across multiple secondary outcomes and regardless of whether systolic blood pressure or mean arterial pressure was the explanatory variable., Conclusions: The lack of positive association between peak systolic blood pressure or peak mean arterial pressure with metrics of bleeding after cardiac surgery promotes equipoise for testing the influence of higher blood pressure targets during the early postoperative period., (Copyright © 2019 The American Association for Thoracic Surgery. All rights reserved.)

Stepped-wedge cluster randomized trials, which randomize clusters of subjects to treatment sequences in which clusters switch from control to intervention conditions, are being conducted with increasing frequency. Due to the real-world nature of this design, methodological and implementation challenges are ubiquitous. To account for such challenges, more complex statistical models to plan studies and analyze data are required. In this paper, we consider stepped-wedge trials that accommodate treatment effect heterogeneity across clusters, implementation periods during which no data are collected, or both treatment effect heterogeneity and implementation periods. Previous work has shown that the sequence-period cells of a stepped-wedge design contribute unequal amounts of information to the estimation of the treatment effect. In this paper, we extend that work by considering the amount of information available for the estimation of the treatment effect in each sequence-period cell, sequence, and period of stepped-wedge trials with more complex designs and outcome models. When either treatment effect heterogeneity and/or implementation periods are present, the pattern of information content of sequence-period cells tends to be clustered around the times of the switch from control to intervention condition, similarly to when these complexities are absent. However, the presence and degree of treatment effect heterogeneity and the number of implementation periods can influence the information content of periods and sequences markedly., (© 2019 John Wiley & Sons, Ltd.)

Multiple-period cluster randomised trials, such as stepped wedge or cluster cross-over trials, are being conducted with increasing frequency. In the design and analysis of these trials, it is necessary to specify the form of the within-cluster correlation structure, and a common assumption is that the correlation between the outcomes of any pair of subjects within a cluster is identical. More complex models that allow for correlations within a cluster to decay over time have recently been suggested. However, most software packages cannot fit these models. As a result, practitioners may choose a simpler model. We analytically examine the impact of incorrectly omitting a decay in correlation on the variance of the treatment effect estimator and show that misspecification of the within-cluster correlation structure can lead to incorrect conclusions regarding estimated treatment effects for stepped wedge and cluster crossover trials.

Objective: The aim of the study was to evaluate whether a web-based exercise programming system improves adherence to a home exercise program for people with musculoskeletal conditions., Design: Eligible patients with a musculoskeletal condition presenting to a physical therapist in private practice were randomized to the following: (a) control (home exercise prescribed by therapist's usual methods) or (b) intervention (home exercise prescribed using a web-based exercise programming system). The primary outcome was self-rated exercise adherence measured at week 3 via 11-point Numeric Rating Scales. Secondary outcomes were satisfaction with exercise delivery and confidence in ability to undertake prescribed exercise. Process measures were also included., Results: We enrolled 305 participants, with loss to follow-up of 14.5% (22/152) and 13.7% (21/153) in intervention and control groups, respectively. Compared with controls, the intervention group reported higher exercise adherence (mean difference Numeric Rating Scale units (95% confidence intervals): adherence overall -1.0 [-1.6 to -0.3] and regarding number of exercises in session -0.7 [-1.3 to -0.1], number of repetitions -0.8 [-1.4 to -0.2], and number of sessions -1.0 [-1.6 to -0.3]). The intervention group showed greater confidence to exercise than control, with no difference in satisfaction., Conclusions: A web-based exercise programming system improved home exercise adherence and confidence in ability to undertake exercise, although the clinical relevance of the results needs to be established.

Background: Knee osteoarthritis (OA) is a highly prevalent condition. People with knee OA often have other co-morbidities such as obesity. Exercise is advocated in all clinical guidelines for the management of knee OA. It is often undertaken as a home-based program, initially prescribed by a physiotherapist or other qualified health care provider. However, adherence to home-based exercise is often poor, limiting its ability to meaningfully change clinical symptoms of pain and/or physical function. While the efficacy of short message services (SMS) to promote adherence to a range of health behaviours has been demonstrated, its ability to promote home exercise adherence in people with knee OA has not been specifically evaluated. Hence, this trial is investigating whether the addition of an SMS intervention to support adherence to prescribed home-based exercise is more effective than no SMS on self-reported measures of exercise adherence., Methods: We are conducting a two-arm parallel-design, assessor-and participant-blinded randomised controlled trial (ADHERE) in people with knee OA and obesity. The trial is enrolling participants exiting from another randomised controlled trial, the TARGET trial, where participants are prescribed a 12-week home-based exercise program (either weight bearing functional exercise or non-weight bearing quadriceps strengthening exercise) for their knee by a physiotherapist and seen five times over the 12 weeks for monitoring and supervision. Following completion of outcome measures for the TARGET trial, participants are immediately enrolled into the ADHERE trial. Participants are asked to continue their prescribed home exercise program unsupervised three times a week for 24-weeks and are randomly allocated to receive a behaviour change theory-informed SMS intervention to support home exercise adherence or to have no SMS intervention. Outcomes are measured at baseline and 24-weeks. Primary outcomes are self-reported adherence measures. Secondary outcomes include self-reported measures of knee pain, physical function, quality-of-life, physical activity, self-efficacy, kinesiophobia, pain catastrophising, participant-perceived global change and an additional adherence measure., Discussion: Findings will provide new information into the potential of SMS to improve longer-term exercise adherence and ultimately enhance exercise outcomes in knee OA., Trial Registration: Prospectively registered with the Australian New Zealand Clinical Trials Registry. Reference: ACTR N12617001243303 Date/version: August 2019/two.

Introduction: Chronic low back pain (CLBP) is the leading cause of disability worldwide. However, there is no consensus in the literature regarding optimal management. Exercise intervention is the most widely used treatment as it likely influences contributing factors such as physical and psychological. Literature evaluating the effects of exercise on CLBP is often generalised, non-specific and employs inconsistent outcome measures. Moreover, the mechanisms behind exercise-related improvements are poorly understood. Recently, research has emerged identifying associations between neuromuscular-biomechanical impairments and CLBP-related disability. This information can be used as the basis for more specific and, potentially more efficacious exercise interventions for CLBP patients., Methods and Analysis: Ninety-four participants (including both males and females) with CLBP aged 18-65 who present for treatment to a Melbourne-based private physiotherapy practice will be recruited and randomised into one of two treatment groups. Following baseline assessment, participants will be randomly allocated to receive either: (i) strengthening exercises in combination with lumbar force accuracy training exercises or (ii) strengthening exercises alone. Participants will attend exercise sessions twice a week for 12 weeks, with assessments conducted at baseline, midway (ie, 6 weeks into the trial) and at trial completion. All exercise interventions will be supervised by a qualified physiotherapist trained in the intervention protocol. The primary outcome will be functional disability measured using the Oswestry Disability Index. Other psychosocial and mechanistic parameters will also be measured., Ethics and Dissemination: This study was given approval by the University of Melbourne Behavioural and Social Sciences Human Ethics Sub-Committee on 8 August 2017, reference number 1 749 845. Results of the randomised controlled trial will be published in peer-reviewed journals., Trial Registration Number: ACTRN12618000894291., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Knee osteoarthritis (OA) is a prevalent and chronic condition with no known cure. Exercise is advocated in all clinical guidelines due to its positive effects on symptoms. Despite this, exercise participation is often poor in people with knee OA with access to exercise treatments a known barrier. Internet-delivered exercise interventions have the potential to improve access to evidence-based exercise treatments and can benefit OA outcomes, although non-usage and low adherence potentially limit their effectiveness. Short message services (SMS) show promise in facilitating exercise adherence and may be one solution to improve adherence to internet-delivered exercise interventions. The combination of internet-delivered exercise and SMS adherence support has not been specifically evaluated in people with knee OA., Methods: This protocol reports a two-arm parallel-design, assessor- and participant-blinded randomised controlled trial. This trial is recruiting 206 people aged 45 years and older, with a clinical diagnosis of knee OA from the Australian-wide community. Eligible and consenting participants are enrolled and randomised to receive access to either i) 'My Knee Education', an education control website containing OA and exercise information only or ii) a combined intervention that includes a website, 'My Knee Exercise', containing the same educational information as the control, guidance to increase general physical activity, and the prescription of a 24-week self-directed home-based lower-limb strengthening program in addition to a 24-week behaviour change SMS exercise adherence program. Outcome measures are being collected at baseline and 24-weeks. Primary outcomes are self-reported knee pain and physical function. Secondary outcomes include another self-reported measure of knee pain, function in sport and recreation, quality-of-life, physical activity, self-efficacy, participant satisfaction and perceived global change., Discussion: This randomised controlled trial will provide evidence about the effectiveness of a combined intervention of internet-delivered OA and exercise education, physical activity guidance and prescription of a 24-week lower-limb strengthening exercise program supported by a behaviour change SMS program compared to internet delivered OA and exercise education alone., Trial Registration: ACTRN12618001167257/13th July 2018.

Background: Clinical guidelines recommend exercise as a core treatment for individuals with knee osteoarthritis (OA). However, the best type of exercise for clinical benefits is not clear, particularly in different OA subgroups. Obesity is a common co-morbidity in people with knee OA. There is some evidence suggesting that non-weight bearing exercise may be more effective than weight bearing exercise in patients with medial knee OA and obesity., Methods: To compare the efficacy of two different exercise programs (weight bearing functional exercise and non-weight bearing quadriceps strengthening) on pain and physical function for people ≥50 years with painful medial knee OA and obesity (body mass index ≥30 kg/m 2 ) 128 people in Melbourne, Australia will be recruited for a two group parallel-design, assessor- and participant-blinded randomised controlled trial. Participants will be randomly allocated to undertake a program of either weight bearing functional exercise or non-weight bearing quadriceps strengthening exercise. Both groups will attend five individual sessions with a physiotherapist who will teach, monitor and progress the exercise program. Participants will be asked to perform the exercises at home four times per week for 12 weeks. Outcomes will be measured at baseline and 12 weeks. Primary outcomes are self-reported knee pain and physical function. Secondary outcomes include other measures of knee pain, physical function, quality-of-life, participant-perceived global change, physical performance, and lower limb muscle strength., Discussion: This study will compare the efficacy of two different 12-week physiotherapist-prescribed, home-based exercise programs for people with medial knee OA and obesity. Findings will provide valuable information to help inform exercise prescription in this common OA patient subgroup., Trial Registration: Australian New Zealand Clinical Trials Registry reference: ACTRN12617001013358 , 14/7/2017.

Objectives: The aims of the present study were to determine how well physiotherapists implemented person-centred practice principles and behaviour change techniques after a workshop, and to evaluate whether self-audit of performance differed from audits of an experienced training facilitator., Methods: Eight physiotherapists each completed a 2-day workshop followed by two telephone consultations with four patients with knee osteoarthritis. The training facilitator audited audio-recordings of all consultations, and therapists self-audited 50% of consultations using a tool comprising: (a) 10 person-centred practice principles rated on a numerical rating scale of 0 (need to work on this) to 10 (doing really well); and (b) seven behaviour change techniques rated with an ordinal scale (using this technique effectively; need to improve skill level; or need to learn how to apply this technique)., Results: Physiotherapists showed "moderate" fidelity to person-centred principles, with mean scores between 5 and 7 out of 10. For behaviour change techniques, the training facilitator believed that physiotherapists were using three of seven techniques "effectively" during most consultations and "needed to improve skill levels" with most other techniques. Physiotherapists scored themselves significantly lower than the training facilitator for two of 10 person-centred principles, and tended to rate their skills using behaviour change techniques less favourably., Conclusions: Physiotherapists performed moderately well when implementing person-centred practice principles and behaviour change techniques immediately after training, but had room for improvement, particularly for skills relating to providing management options and changing thinking habits. Physiotherapists' self-ratings of performance generally did not differ from expert ratings; however, they underestimated their ability to implement some principles and techniques., (© 2019 John Wiley & Sons, Ltd.)

A requirement for calculating sample sizes for cluster randomized trials (CRTs) conducted over multiple periods of time is the specification of a form for the correlation between outcomes of subjects within the same cluster, encoded via the within-cluster correlation structure. Previously proposed within-cluster correlation structures have made strong assumptions; for example, the usual assumption is that correlations between the outcomes of all pairs of subjects are identical ("uniform correlation"). More recently, structures that allow for a decay in correlation between pairs of outcomes measured in different periods have been suggested. However, these structures are overly simple in settings with continuous recruitment and measurement. We propose a more realistic "continuous-time correlation decay" structure whereby correlations between subjects' outcomes decay as the time between these subjects' measurement times increases. We investigate the use of this structure on trial planning in the context of a primary care diabetes trial, where there is evidence of decaying correlation between pairs of patients' outcomes over time. In particular, for a range of different trial designs, we derive the variance of the treatment effect estimator under continuous-time correlation decay and compare this to the variance obtained under uniform correlation. For stepped wedge and cluster randomized crossover designs, incorrectly assuming uniform correlation will underestimate the required sample size under most trial configurations likely to occur in practice. Planning of CRTs requires consideration of the most appropriate within-cluster correlation structure to obtain a suitable sample size., (© 2019 John Wiley & Sons, Ltd.)

Introduction: Despite the prevalence of low back pain (LBP) worldwide, many people with the condition do not receive evidence-based care or achieve the best possible outcomes. There is a gap in the dissemination of evidence-based information across the globe. The advent of the internet has changed the way people obtain health information. As such, trustworthy, tailored and validated LBP resources may help bridge the gap. This study aims to measure the effectiveness of a new website (MyBackPain) in improving spinal health literacy, treatment preferences and clinical outcomes for people with LBP, in comparison with other online resources., Methods and Analysis: This online, pragmatic, randomised controlled trial will comprise 440 people with non-specific LBP of any duration. In addition to access to publicly available online information (control group), the intervention group will be given access to the MyBackPain.org.au website. Participants and research staff, including the biostatistician, will be blinded to treatment allocation. Data will be collected at baseline, 1, 3 (primary end-point), 6 and 12 months via online surveys and questionnaires. The primary outcome is spinal health literacy. Secondary outcomes include quality of treatment preferences (stated and observed) and LBP clinical outcomes (pain, disability and quality of life). Analyses will be by intention-to-treat and include outcome data on all randomised participants. Descriptive statistics will be presented for demographic and clinical characteristics., Ethics and Dissemination: This trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry and has ethical approval from the University of Queensland Human Research Ethics Committee (2017000995). Trial outcomes will be shared via national and international conference presentations and peer-reviewed journal publications., Trial Registration Number: ACTRN12617001292369; Pre-results., Competing Interests: Competing interests: DJH is on advisory boards for Merck Serono, Tissuegene, TLC Bio and Flexion, outside of the submitted work., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Prostate cancer is the most common cancer in men. Prostatectomy is the most common treatment. Morbidity from prostatectomy is high-80% of men experience urinary incontinence which negatively impacts the quality of life. Postsurgical pelvic floor muscle training is commonly prescribed but recent systematic reviews found no evidence of efficacy. We propose a new treatment that commences preoperatively and targets functional training of specific pelvic floor muscles that contribute to urinary continence. Assessment and biofeedback using transperineal ultrasound imaging assists in training. This will be compared against conventional training (maximal pelvic floor muscle contraction assessed by digital rectal examination) and no training. Embedded physiological studies will allow the investigation of moderation and mediation of the treatment effect on the outcomes., Methods and Analysis: This randomised clinical trial will include 363 men scheduled to undergo radical prostatectomy for prostate cancer. Participants will be randomised into urethral training, conventional training and no training groups. Clinical data will be collected at baseline (1-2 weeks presurgery) and postsurgery after catheter removal, weekly to 3 months (primary endpoint) and monthly to 12 months. Outcomes include 24-hour pad weight test (primary), incontinence, quality of life and cost-effectiveness data. Neuromuscular control measures of pelvic floor muscles will be measured at baseline, postsurgery, 6 weeks, 3 and 12 months. Study assessors and statisticians will be blinded to the group allocation., Ethics and Dissemination: This study is registered with the Australian New Zealand Clinical Trials Registry and has ethical approval from the university and host hospital ethics committees. Trial outcomes will be shared via national/international conference presentations and peer-reviewed journal publications., Trial Registration Number: ACTRN12617000788370; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stepped wedge and cluster randomised crossover trials are examples of cluster randomised designs conducted over multiple time periods that are being used with increasing frequency in health research. Recent systematic reviews of both of these designs indicate that the within-cluster correlation is typically taken account of in the analysis of data using a random intercept mixed model, implying a constant correlation between any two individuals in the same cluster no matter how far apart in time they are measured: within-period and between-period intra-cluster correlations are assumed to be identical. Recently proposed extensions allow the within- and between-period intra-cluster correlations to differ, although these methods require that all between-period intra-cluster correlations are identical, which may not be appropriate in all situations. Motivated by a proposed intensive care cluster randomised trial, we propose an alternative correlation structure for repeated cross-sectional multiple-period cluster randomised trials in which the between-period intra-cluster correlation is allowed to decay depending on the distance between measurements. We present results for the variance of treatment effect estimators for varying amounts of decay, investigating the consequences of the variation in decay on sample size planning for stepped wedge, cluster crossover and multiple-period parallel-arm cluster randomised trials. We also investigate the impact of assuming constant between-period intra-cluster correlations instead of decaying between-period intra-cluster correlations. Our results indicate that in certain design configurations, including the one corresponding to the proposed trial, a correlation decay can have an important impact on variances of treatment effect estimators, and hence on sample size and power. An R Shiny app allows readers to interactively explore the impact of correlation decay.

Stepped wedge and other multiple-period cluster randomized trials, which collect data from multiple clusters across multiple time periods, are being conducted with increasing frequency; statistical research into these designs has not kept apace. In particular, some stepped wedge designs with missing cluster-period "cells" have been proposed without any formal justification. Indeed there are no general guidelines regarding which cells of a stepped wedge design contribute the least information toward estimation of the treatment effect, and correspondingly which may be preferentially omitted. In this article, we define a metric of the information content of cluster-period cells, entire treatment sequences, and entire periods of the standard stepped wedge design as the increase in variance of the estimator of the treatment effect when that cell, sequence, or period is omitted. We show that the most information-rich cells are those that occur immediately before or after treatment switches, but also that there are additional cells that contribute almost as much to the estimation of the treatment effect. However, the information content patterns depend on the assumed correlation structure for the repeated measurements within a cluster., (© 2018, The International Biometric Society.)

Background: Tranexamic acid reduces blood loss and transfusion requirements in cardiac surgery but may increase the risk of coronary graft thrombosis. We previously reported the 30-day results of a trial evaluating tranexamic acid for coronary artery surgery. Here we report the 1-year clinical outcomes., Methods: Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score of less than 8. Secondary outcomes included a composite of myocardial infarction, stroke, and death from any cause through to 1 year after surgery., Results: The rate of death or disability at 1 year was 3.8% in the tranexamic acid group and 4.4% in the placebo group (relative risk, 0.85; 95% confidence interval, 0.64-1.13; P = .27), and this did not significantly differ according to aspirin exposure at the time of surgery (interaction P = .073). The composite rate of myocardial infarction, stroke, and death up to 1 year after surgery was 14.3% in the tranexamic acid group and 16.4% in the placebo group (relative risk, 0.87; 95% CI, 0.76-1.00; P = .053)., Conclusions: In this trial of patients having coronary artery surgery, tranexamic acid did not affect death or severe disability through to 1 year after surgery. Further work should be done to explore possible beneficial effects on late cardiovascular events., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Aspirin may reduce the risk of vascular graft thrombosis after cardiovascular surgery. We previously reported the 30-day results of a trial evaluating aspirin use before coronary artery surgery. Here we report the 1-year outcomes evaluating late thrombotic events and disability-free survival., Methods: Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score < 8. Secondary outcomes included a composite of myocardial infarction, stroke and death from any cause through to 1 year after surgery., Results: Patients were randomly assigned to aspirin (1059 patients) or placebo (1068 patients). The rate of death or severe disability was 4.1% in the aspirin group and 3.5% in the placebo group (relative risk, 1.17; 95% confidence interval, 0.76-1.81; P = .48). There was no significant difference in the rates of myocardial infarction (P = .11), stroke (P = .086), or death (P = .24), or a composite of these cardiovascular end points (P = .68). With the exception of those with a low European System for Cardiac Operative Risk Evaluation score (P = .03), there were no interaction effects on these outcomes with tranexamic acid (all tests of interaction P > .10)., Conclusions: In patients undergoing coronary artery surgery, preoperative aspirin did not reduce death or severe disability, or thrombotic events through to 1 year after surgery., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Higher peak external knee flexion moments (KFM) during running has been observed in healthy people wearing athletic footwear compared to barefoot, which may increase risk of knee pathologies such as patellofemoral pain. Currently, no studies have examined whether stability and neutral style athletic shoes influence the peak KFM differently, or explored the underlying biomechanical mechanisms by which footwear alters peak KFM in young females., Methods: Lower limb biomechanics of sixty girls aged between 10 and 25 years old were collected while running in footwear (both stability and neutral) and barefoot. The external peak KFM, sagittal plane kinematics, sagittal plane knee ground reaction force (GRF) lever arm and sagittal plane resultant GRF magnitude were analysed by repeated measures Analysis of Variance. Linear mixed models were fit to identify predictors of a change in peak KFM, and to determine if the effects of these predictors differed between footwear conditions., Results: The peak KFM was higher wearing both shoe styles compared to barefoot ( p  < 0.001), while no between-shoe differences were found ( p  > 0.05). Both shoes also increased kinematic variables at the hip, knee, and ankle ( p  < 0.05) . When all these variables were entered into the mixed model, only a change in the knee-GRF lever arm was predictive of a change in peak KFM wearing shoes compared to barefoot ( p  < 0.001)., Conclusion: These findings provide evidence that stability and neutral shoes increase peak KFM compared to barefoot, which is associated with a change in the knee-GRF lever arm rather than a change in lower limb kinematics. Future studies may consider manipulating footwear characteristics to reduce the knee-GRF lever arm in an effort to reduce peak KFM and the potential risk of patellofemoral pain., Competing Interests: All participants, together with parents/guardians of those < 18 years of age, signed an informed consent form. Ethics approval was obtained by the University of Melbourne Human Research Ethics Committee (#1442604).Not applicableThis project was conducted in collaboration with our industry partner Asics Oceania. None of the authors receive any financial benefit from the results of this study or from the manufacturer external to this study. All research procedures were conducted independently, without Asics Oceania involvement. We declare that the results of this study are without fabrication, falsification, or inappropriate data manipulation.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Comparing the mortality profiles of dialysis centres is important to ensure that high standards of care are maintained. We compare the performance of dialysis centres in Australia and New Zealand in their treatment of haemodialysis patients, accounting for the competing risks of kidney transplantation and transfer to peritoneal dialysis., Methods: Observational cohort study. We included data from all adult patients (5574 patients) commencing haemodialysis at home or in a facility between 2008 and 2010 across 62 dialysis centres, from the Australia and New Zealand Dialysis and Transplant Registry. Standardised mortality ratios were calculated by estimating mortality probabilities from a pooled random effects logistic regression model, accounting for the competing risk of transplantation using an inverse probability weighting approach. Models were adjusted for patient comorbidities, sex, height, weight, late referral to a nephrologist, age, race, primary kidney disease, smoking status, and serum creatinine (μmol/l)., Results: Two dialysis centres were found to have relatively higher levels of risk-adjusted mortality lying outside the prediction intervals for "usual" performance. Risk adjusted mortality rates were not associated with centres' compliance with guidelines for vascular access and biochemical and haematological targets., Conclusions: We demonstrate that standardised mortality ratios are useful to identify facilities that have statistically outlying mortality risk. Our criterion for determining whether a centre has better or worse performance than expected is statistical, and thus analyses such as ours can serve only as a screening tool, and are only one aspect of assessment of "quality" of performance.

After the publication of this protocol [1], our collaborator Prima Health solutions advised us of their intent to withdraw from the study.

Importance: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes., Objective: To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury., Design, Setting, and Participants: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018., Interventions: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician., Main Outcomes and Measures: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury., Results: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively., Conclusions and Relevance: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury., Trial Registration: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235.

Objective: To compare the effects of a programme of load management education plus exercise, corticosteroid injection use, and no treatment on pain and global improvement in individuals with gluteal tendinopathy., Design: Prospective, three arm, single blinded, randomised clinical trial., Setting: Brisbane and Melbourne, Australia., Participants: Individuals aged 35-70 years, with lateral hip pain for more than 3 months, at least 4/10 on the pain numerical rating scale, and gluteal tendinopathy confirmed by clinical diagnosis and MRI; and with no corticosteroid injection use in previous 12 months, current physiotherapy, total hip replacement, or neurological conditions., Interventions: A physiotherapy led education and exercise programme of 14 sessions over 8 weeks (EDX; n=69), one corticosteroid injection (CSI; n=66), and a wait and see approach (WS; n=69)., Main Outcomes: Primary outcomes were patient reported global rating of change in hip condition (on an 11 point scale, dichotomised to success and non-success) and pain intensity in the past week (0=no pain, 10=worst pain) at 8 weeks, with longer term follow-up at 52 weeks., Results: Of 204 randomised participants (including 167 women; mean age 54.8 years (SD 8.8)), 189 (92.6%) completed 52 week follow-up. Success on the global rating of change was reported at 8 weeks by 51/66 EDX, 38/65 CSI, and 20/68 WS participants. EDX and CSI had better global improvement scores than WS (risk difference 49.1% (95% CI 34.6% to 63.5%), number needed to treat 2.0 (95% CI 1.6 to 2.9); 29.2% (13.2% to 45.2%), 3.4 (2.2 to 7.6); respectively). EDX had better global improvement scores than CSI (19.9% (4.7% to 35.0%); 5.0 (2.9 to 21.1)). At 8 weeks, reported pain on the numerical rating scale was mean score 1.5 (SD 1.5) for EDX, 2.7 (2.4) for CSI, and 3.8 (2.0) for WS. EDX and CSI participants reported less pain than WS (mean difference -2.2 (95% CI -2.89 to -1.54); -1.2 (-1.85 to -0.50); respectively), and EDX participants reported less pain than CSI (-1.04 (-1.72 to -0.37)). Success on the global rating of change was reported at 52 weeks by 51/65 EDX, 36/63 CSI, and 31/60 WS participants; EDX was better than CSI (20.4% (4.9% to 35.9%); 4.9 (2.8 to 20.6)) and WS (26.8% (11.3% to 42.3%); 3.7 (2.4 to 8.8)). Reported pain at 52 weeks was 2.1 (2.2) for EDX, 2.3 (1.9) for CSI, and 3.2 (2.6) for WS; EDX did not differ from CSI (-0.26 (-1.06 to 0.55)), but both treatments did better than WS (1.13 (-1.93 to -0.33); 0.87 (-1.68 to -0.07); respectively)., Conclusions: For gluteal tendinopathy, education plus exercise and corticosteroid injection use resulted in higher rates of patient reported global improvement and lower pain intensity than no treatment at eight weeks. Education plus exercise performed better than corticosteroid injection use. At 52 week follow-up, education plus exercise led to better global improvement than corticosteroid injection use, but no difference in pain intensity. These results support EDX as an effective management approach for gluteal tendinopathy., Trial Registration Number: Prospectively registered at the Australian New Zealand Clinical Trials Registry (ACTRN12612001126808)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

This assessor-, therapist-, and participant-blinded randomised controlled trial evaluated the effects of an automated internet-based pain coping skills training (PCST) program before home exercise for people with clinically diagnosed hip osteoarthritis. One hundred forty-four people were randomised to either the PCST group or the comparator group. In the first 8 weeks, the PCST group received online education and PCST, whereas the comparison group received online education only. From weeks 8 to 24, both groups visited a physiotherapist 5 times for home exercise prescription. Assessments were performed at baseline, 8, 24, and 52 weeks. Primary outcomes were hip pain on walking (11-point numerical rating scale) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) at 24 weeks. Secondary outcomes were other measures of pain, quality-of-life, global change, self-efficacy, pain coping, pain catastrophizing, depression, anxiety, stress, physical activity, and adverse events. Primary outcomes were completed by 137 (95%), 131 (91%), and 127 (88%) participants at 8, 24, and 52 weeks, respectively. There were no significant between-group differences in primary outcomes at week 24 (change in: walking pain [mean difference 0.5 units; 95% confidence interval, -0.3 to 1.3] and function [-0.9 units; 95% confidence interval, -4.8 to 2.9]), with both groups showing clinically relevant improvements. At week 8, the PCST group had greater improvements in function, pain coping, and global improvement than comparison. Greater pain coping improvements persisted at 24 and 52 weeks. In summary, online PCST immediately improved pain coping and function but did not confer additional benefits to a subsequent exercise program, despite sustained pain coping improvements.

Randomised trials with long-term follow-up can provide estimates of the long-term effects of health interventions. However, analysis of long-term outcomes in randomised trials may be complicated by problems with the administration of treatment such as non-adherence, treatment switching and co-intervention, and problems obtaining outcome measurements arising from loss to follow-up and death of participants. Methods for dealing with these issues that involve conditioning on post-randomisation variables are unsatisfactory because they may involve the comparison of non-exchangeable groups and generate estimates that do not have a valid causal interpretation. We describe approaches to analysis that potentially provide estimates of causal effects when such issues arise. Brief descriptions are provided of the use of instrumental variable and propensity score methods in trials with imperfect adherence, marginal structural models and g-estimation in trials with treatment switching, mixed longitudinal models and multiple imputation in trials with loss to follow-up, and a sensitivity analysis that can be used when trial follow-up is truncated by death or other events. Clinical trialists might consider these methods both at the design and analysis stages of randomised trials with long-term follow-up.

Background: Internet-delivered exercise, education, and pain coping skills training is effective for people with knee osteoarthritis, yet it is not clear whether this treatment is better suited to particular subgroups of patients., Objective: The aim was to explore demographic and clinical moderators of the effect of an internet-delivered intervention on changes in pain and physical function in people with knee osteoarthritis., Methods: Exploratory analysis of data from 148 people with knee osteoarthritis who participated in a randomized controlled trial comparing internet-delivered exercise, education, and pain coping skills training to internet-delivered education alone. Primary outcomes were changes in knee pain while walking (11-point Numerical Rating Scale) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index function subscale) at 3 and 9 months. Separate regression models were fit with moderator variables (age, gender, expectations of outcomes, self-efficacy [pain], education, employment status, pain catastrophizing, body mass index) and study group as covariates, including an interaction between the two., Results: Participants in the intervention group who were currently employed had significantly greater reductions in pain at 3 months than similar participants in the control group (between-group difference: mean 2.38, 95% CI 1.52-3.23 Numerical Rating Scale units; interaction P=.02). Additionally, within the intervention group, pain at 3 months reduced by mean 0.53 (95% CI 0.28-0.78) Numerical Rating Scale units per unit increase in baseline self-efficacy for managing pain compared to mean 0.11 Numerical Rating Scale units (95% CI -0.13 to 0.35; interaction P=.02) for the control group., Conclusions: People who were employed and had higher self-efficacy at baseline were more likely to experience greater improvements in pain at 3 months after an internet-delivered exercise, education, and pain coping skills training program. There was no evidence of a difference in the effect across gender, educational level, expectation of treatment outcome, or across age, body mass index, or tendency to catastrophize pain. Findings support the effectiveness of internet-delivered care for a wide range of people with knee osteoarthritis, but future confirmatory research is needed., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12614000243617; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365812&isReview=true (Archived by WebCite at http://www.webcitation.org/6z466oTPs)., (©Belinda J Lawford, Rana S Hinman, Jessica Kasza, Rachel Nelligan, Francis Keefe, Christine Rini, Kim L Bennell. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 09.05.2018.)

Background: To increase the uptake of key clinical recommendations for non-surgical management of knee osteoarthritis (OA) and improve patient outcomes, we developed a new model of service delivery (PARTNER model) and an intervention to implement the model in the Australian primary care setting. We will evaluate the effectiveness and cost-effectiveness of this model compared to usual general practice care., Methods: We will conduct a mixed-methods study, including a two-arm, cluster randomised controlled trial, with quantitative, qualitative and economic evaluations. We will recruit 44 general practices and 572 patients with knee OA in urban and regional practices in Victoria and New South Wales. The interventions will target both general practitioners (GPs) and their patients at the practice level. Practices will be randomised at a 1:1 ratio. Patients will be recruited if they are aged ≥45 years and have experienced knee pain ≥4/10 on a numerical rating scale for more than three months. Outcomes are self-reported, patient-level validated measures with the primary outcomes being change in pain and function at 12 months. Secondary outcomes will be assessed at 6 and 12 months. The implementation intervention will support and provide education to intervention group GPs to deliver effective management for patients with knee OA using tailored online training and electronic medical record support. Participants with knee OA will have an initial GP visit to confirm their diagnosis and receive management according to GP intervention or control group allocation. As part of the intervention group GP management, participants with knee OA will be referred to a centralised multidisciplinary service: the PARTNER Care Support Team (CST). The CST will be trained in behaviour change support and evidence-based knee OA management. They will work with patients to develop a collaborative action plan focussed on key self-management behaviours, and communicate with the patients' GPs. Patients receiving care by intervention group GPs will receive tailored OA educational materials, a leg muscle strengthening program, and access to a weight-loss program as appropriate and agreed. GPs in the control group will receive no additional training and their patients will receive usual care., Discussion: This project aims to address a major evidence-to-practice gap in primary care management of OA by evaluating a new service delivery model implemented with an intervention targeting GP practice behaviours to improve the health of people with knee OA., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12617001595303 , date of registration 1/12/2017.

Background: The Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes., Methods: The POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18-60 years have been enrolled with severe acute traumatic brain injury. The trial intervention of early and sustained prophylactic hypothermia to 33 °C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 °C. The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05., Discussion: Consistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data., Trial Registration: ClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235 . Registered on 3 September 2009.

Objective: To investigate the presence of different trajectories of self-reported adherence to home exercise programs among people with knee osteoarthritis (OA), and to compare baseline characteristics across identified groups., Design: Pooled analysis of data from three randomised controlled trials involving exercise interventions for people aged ≥50 years with clinical knee OA (n = 341). Exercise adherence was self-reported on an 11-point numerical rating scale (NRS; 0 = not at all-10 = completely as instructed). Latent class growth analysis was used to identify distinct trajectories of adherence, at intervals from 12 to 78 weeks from baseline. Baseline characteristics of these groups were compared using chi-squared tests, one-way analysis of variance (ANOVA) and Kruskal Wallis tests where appropriate., Results: Three distinct adherence trajectories were identified: a "Rapidly declining adherence" group (n = 157, 47.4%) whose adherence was 7.7 ± 1.6 (/10) at 12 weeks, declined to 4.2 ± 2.2 by 22 weeks and remained low thereafter; a "Gradually declining adherence" group (n = 153, 45.1%) whose adherence declined from 8.5 ± 1.5 to 7.8 ± 1.5 over the same period, and continued to decline slowly, and a "Low adherence" group (n = 21, 6.3%) whose adherence was 2.2 ± 1.4 at 12 weeks and remained low. At baseline the "Rapidly declining adherence" group reported significantly lower Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (mean difference (95% Confidence Interval (CI)) -0.8 (-1.4, -0.2)) and better WOMAC function compared to the "Gradually declining adherence" group (-3.1 (-5.2, -1.1))., Conclusion: Three trajectories of self-reported adherence to home exercises were found among people with knee OA. Findings highlight the need for close monitoring of adherence from initiation of a home exercise program in order to identify and intervene when low or rapidly declining adherence is identified., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine if an increase in knee extensor strength mediates the effect of a 12-week knee extensor strength training program on pain and physical function improvement in people with knee osteoarthritis (OA)., Design: Secondary analysis from a randomised controlled trial comparing the effects of a 12-week knee extensor strengthening exercise program to a control group with no intervention., Methods: Data from participants with complete data (n = 97) enrolled in a previous clinical trial were analysed. Baseline and 12-week follow-up assessments included peak isometric knee extensor strength, pain and physical function. Peak knee extensor strength (Nm/kg) was assessed on an isokinetic dynamometer and subscales of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index were used to assess pain and physical function. Twelve-week change in pain and physical function were regressed separately, on 12-week change in knee extensor strength and group allocation. Covariates included baseline pain or physical function as appropriate, and baseline knee extensor strength, age, sex and knee alignment (stratification variable)., Results: Improved knee extensor strength mediated the effect of the strengthening program on both pain relief (mediated effect size = 0.69, 95% confidence intervals (CI) 0.05-1.33, P = 0.03), and improved physical function (mediated effect size = 1.86, 95% CI 0.08-3.64, P = 0.04), at 12 weeks., Conclusions: Increased knee extensor strength partially mediates the effect of a knee extensor strength training program on pain and physical function improvement in people with knee OA., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate physical therapists' perceptions of, and willingness to use, telephone- and internet-mediated service models for exercise therapy for people with knee and/or hip osteoarthritis., Methods: This study used an internet-based survey of Australian physical therapists, comprising 3 sections: 1 on demographic information and 2 with 16 positively framed perception statements about delivering exercise via telephone and video over the internet, for people with hip and/or knee osteoarthritis. Levels of agreement with each statement were evaluated. Logistic regression models were used to determine therapist characteristics influencing interest in delivering telerehabilitation., Results: A total of 217 therapists spanning metropolitan, regional, rural, and remote Australia completed the survey. For telephone-delivered care, there was consensus agreement that it would not violate patient privacy (81% agreed/strongly agreed) and would save patient's time (76%), but there was less than majority agreement for 10 statements. There was consensus agreement that video-delivered care would save a patient's time (82%), be convenient for patients (80%), and not violate patient privacy (75%). Most agreed with all other perception statements about video-delivered care, except for liking no physical contact (14%). Low confidence using internet video technologies, and inexperience with telerehabilitation, were significantly associated with reduced interest in delivering telephone and/or video-based services., Conclusion: Physical therapists agree that telerehabilitation offers time-saving and privacy advantages for people with osteoarthritis and perceive video-delivered care more favorably than telephone-delivered services. However, most do not like the lack of physical contact with either service model. These findings may inform the implementation of telerehabilitation osteoarthritis services and the training needs of clinicians involved in delivering care., (© 2017, American College of Rheumatology.)

Background: Gait biomechanics, sex, and obesity can contribute to suboptimal outcomes from primary total knee arthroplasty. The aims of this study were to i) determine if sex and/or obesity influence the amount of change in gait biomechanics from pre-surgery to six months post-surgery and; ii) assess if gait returns to normal in men and women., Methods: Three-dimensional gait analysis was performed on 43 patients undergoing primary total knee arthroplasty for knee osteoarthritis (pre- and six months post-operative) and 40 asymptomatic controls. Mixed linear regression models were fit to assess which factors influenced change in gait biomechanics within the arthroplasty cohort, and interaction terms were included to assess if biomechanics returned to normal following surgery., Findings: Male peak knee adduction moment (p < 0.001) and impulse (p < 0.001) decreased six months following arthroplasty, whilst gait in women remained unchanged after surgery. Obesity did not influence gait changes in men or women. Gait of female arthroplasty participants did not differ from female controls after surgery except for sagittal plane knee range of motion (p = 0.003), whilst men differed from controls for peak knee adduction moment (p = 0.011), knee range of motion (p < 0.001), and peak knee flexion moment (p < 0.001)., Interpretation: Sex, but not obesity, influenced changes in gait biomechanics after arthroplasty. Men retained abnormal gait patterns after surgery, whilst women did not. Further research should determine the long-term implications of gait abnormalities seen in men after arthroplasty., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: This study evaluates whether hip bracing in patients with femoroacetabular impingement (FAI) (a) immediately reduces range of hip internal rotation, flexion, adduction, and pain during functional tasks; and (b) improves patient-reported outcomes when worn daily over 4 weeks., Design: Within-participant design followed by a case series., Methods: Twenty-five adults with symptomatic FAI underwent 3D kinematic assessment with and without a hip brace during single-leg squat, double-leg squat, stair ascent, and stair descent. A subset of this population (n=17) continued to wear the brace daily for 4-weeks. A linear mixed statistical model was used to assess pain and kinematic differences between the braced and unbraced conditions at baseline testing. Patient-reported outcomes (NRS pain, iHot-33 and HAGOS questionnaires) at 4-weeks were compared to baseline using paired t-tests., Results: Bracing resulted in significant but small reductions in peak hip flexion ranging between 5.3° (95% CI 0.8°-9.7°) and 5.6° (95% CI 1.1°-10.0°), internal rotation ranging between 2.5° (95% CI 0.6°-4.4°) and 6.4° (95% CI 4.5°-8.2°), and adduction ranging between 2.2° (95% CI 0.5°-3.8°) and 3.3° (95% CI 1.6°-5.0°) during all tasks, except flexion during single-leg squat, compared with the unbraced condition; pain was not significantly improved with the brace. Bracing over four weeks did not significantly change patient-reported outcomes., Conclusions: Bracing subtly limited impinging hip movements during functional tasks, but did not immediately reduce pain or improve patient-reported clinical outcomes after 4 weeks in a young adult cohort with long-standing FAI., (Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate moderators and biomechanical mediators of effects of unloading shoes on knee pain in people with knee osteoarthritis (OA)., Methods: Exploratory analysis from 164 participants in a clinical trial comparing unloading (ASICS GEL-Melbourne OA) to conventional walking shoes. The primary outcome was 6-month change in knee pain (11-point numerical rating scale (NRS)). Moderators included baseline peak knee adduction moment (KAM), radiographic severity (Kellgren & Lawrence (KL) scale), body mass, foot posture, neuropathic pain and diffuse knee pain. Mediators included change in peak KAM and KAM impulse., Results: Radiographic severity was the only moderator to interact with footwear group (P = 0.02). Participants with KL = 2 experienced greater pain reductions with conventional compared to unloading shoes (mean difference in change in pain -1.64 units, 95% CI -3.07, -0.21), while unloading shoes tended to result in greater pain reductions than conventional shoes in KL = 3 (0.98, 95% CI -0.44, 2.39) and KL = 4 (0.64, 95% CI -0.64, 1.93). No variable showed any significant mediating effect in the entire cohort. However, there was some evidence that unloading shoes may reduce pain through reductions in peak KAM (indirect effect -0.31, 95% CIs -0.65, 0.03; P = 0.07) in people with KL ≥ 3, compared to conventional shoes., Conclusion: Unloading shoes conferred additional symptomatic benefits over conventional shoes in people with moderate to severe knee OA. There was some evidence effects may be mediated by a reduction in peak KAM. However, we were underpowered for subgroup analyses. These patients may represent a subgroup to which biomechanical interventions designed to reduce the KAM may be more effectively targeted., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical guidelines recommend knee muscle strengthening exercises to improve physical function. However, the amount of knee muscle strength increase needed for clinically relevant improvements in physical function is unclear. Understanding how much increase in knee muscle strength is associated with improved physical function could assist clinicians in providing appropriate strength gain targets for their patients in order to optimise outcomes from exercise. The aim of this study was to investigate whether an increase in knee muscle strength is associated with improved self-reported physical function following exercise; and whether the relationship differs according to physical function status at baseline., Methods: Data from 100 participants with medial knee osteoarthritis enrolled in a 12-week randomised controlled trial comparing neuromuscular exercise to quadriceps strengthening exercise were pooled. Participants were categorised as having mild, moderate or severe physical dysfunction at baseline using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Associations between 12-week changes in physical function (dependent variable) and peak isometric knee extensor and flexor strength (independent variables) were evaluated with and without accounting for baseline physical function status and covariates using linear regression models., Results: In covariate-adjusted models without accounting for baseline physical function, every 1-unit (Nm/kg) increase in knee extensor strength was associated with physical function improvement of 17 WOMAC units (95% confidence interval (CI) -29 to -5). When accounting for baseline severity of physical function, every 1-unit increase in knee extensor strength was associated with physical function improvement of 24 WOMAC units (95% CI -42 to -7) in participants with severe physical dysfunction. There were no associations between change in strength and change in physical function in participants with mild or moderate physical dysfunction at baseline. The association between change in knee flexor strength and change in physical function was not significant, irrespective of baseline function status., Conclusions: In patients with severe physical dysfunction, an increase in knee extensor strength and improved physical function were associated., Trial Registration: ANZCTR 12610000660088 . Registered 12 August 2010.

Background: Sex and body mass may influence knee biomechanics associated with poor total knee arthroplasty (TKA) outcomes for knee osteoarthritis (OA). This study aimed to determine if gait differed between men and women, and overweight and class I obese patients with severe knee OA awaiting TKA., Methods: 34 patients with severe knee OA (average age 70.0 (SD 7.2) years, body mass index 30.3 (4.1kg/m 2 )) were recruited from a TKA waiting list. Three-dimensional gait analysis was performed at self-selected walking speed. Comparisons were made between men and women, and overweight (body mass index (BMI) 25.0-29.9kg/m 2 ) and class I obese (BMI 30.0-34.9kg/m 2 ) participants. Biomechanical outcomes included absolute and body size-adjusted peak knee adduction moment (KAM), KAM impulse, peak knee flexion moment, as well as peak knee flexion and varus-valgus angles, peak varus-valgus thrust, and peak vertical ground reaction force (GRF)., Findings: Men had a higher absolute peak KAM, KAM impulse and peak GRF compared to women, and this sex-difference in frontal plane moments remained after adjusting for body size. However, when additionally adjusting for static knee alignment, differences disappeared. Knee biomechanics were similar between obesity groups after adjusting for the greater body weight of those with class I obesity., Interpretation: Men had greater KAM and KAM impulse even after adjustment for body size; however adjustment for their more varus knees removed this difference. Obesity group did not influence knee joint kinematics or moments. This suggests sex- and obesity-differences in these variables may not be associated with TKA outcomes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: There is evidence that end-stage kidney disease patients who are older or with more comorbidity may have a poor trade-off between benefits of dialysis and potential harms. We aimed to develop a tool for predicting patient mortality in the early stages of receiving dialysis., Methods: In 23 658 patients aged 15+ years commencing dialysis between 2000 and 2009 in Australia and New Zealand a point score tool was developed to predict 6-month mortality based on a logistic regression analysis of factors available at dialysis initiation. Temporal validation used 2009-11 data from Australia and New Zealand. External validation used the UK Renal Registry., Results: Within 6 months of commencing dialysis 6.1% of patients had died. A small group (4.7%) of patients had a high predicted mortality risk (>20%), as predicted by the point score tool. Predictive variables were: older age, underweight, chronic lung disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease (particularly for patients <60 years of age), late referral to nephrologist care and underlying cause of renal disease. The new point score tool outperformed existing models, and had an area under the receiver operating characteristic curve of 0.755 on temporal validation with acceptable calibration and 0.713 on external validation with poor calibration., Conclusion: Our point score tool for predicting 6-month mortality in patients at dialysis commencement has sufficient prognostic accuracy to use in Australia and New Zealand for prognosis and identification of high risk patients who may be given appropriate supportive care. Use in other countries requires further study., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objective: To assess whether foot and/or ankle symptoms are associated with an increased risk of worsening of knee pain and radiographic change in people with knee osteoarthritis (OA)., Methods: The presence and laterality of foot/ankle symptoms were recorded at baseline in 1368 participants from the Osteoarthritis Initiative (OAI) with symptomatic radiographic knee OA. Knee pain severity (measured using the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale) and minimum medial tibiofemoral joint space (minJSW) width measured on X-ray were assessed yearly over the subsequent 4 years. Associations between foot/ankle symptoms and worsening of (1) knee pain, and (2) both knee pain and minJSW (i.e., symptomatic radiographic knee OA) were assessed using logistic regression., Results: Foot/ankle symptoms in either foot/ankle significantly increased the odds of knee pain worsening (adjusted OR 1.54, 95% CI 1.25 to 1.91). Laterality analysis showed ipsilateral (adjusted OR 1.50, 95% CI 1.07 to 2.10), contralateral (adjusted OR 1.44, 95% CI 1.02 to 2.06) and bilateral foot/ankle symptoms (adjusted OR 1.61, 95% CI 1.22 to 2.13) were all associated with knee pain worsening in the follow up period. There was no association between foot/ankle symptoms and worsening of symptomatic radiographic knee OA., Conclusion: The presence of foot/ankle symptoms in people with symptomatic radiographic knee OA was associated with increased risk of knee pain worsening, but not worsening of symptomatic radiographic knee OA, over the subsequent 4 years. Future studies should investigate whether treatment of foot/ankle symptoms reduces the risk of knee pain worsening in people with knee OA., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

A critical assumption of causal inference is that of no unmeasured confounding: for estimated exposure effects to have valid causal interpretations, a sufficient set of predictors of exposure and outcome must be adequately measured and correctly included in the respective inference model(s). In an observational study setting, this assumption will often be unsatisfied, and the potential impact of unmeasured confounding on effect estimates should be investigated. The confounding function approach allows the impact of unmeasured confounding on estimates to be assessed, where unmeasured confounding may be due to unmeasured confounders and/or biases such as collider bias or information bias. Although this approach is easy to implement and pertains to the sum of all bias, its use has not been widespread, and discussion has typically been limited to continuous outcomes. In this paper, we consider confounding functions for use with binary outcomes and illustrate the approach with an example. We note that confounding function choice encodes assumptions about effect modification: some choices encode the belief that the true causal effect differs across exposure groups, whereas others imply that any difference between the true causal parameter and the estimate is entirely due to imbalanced risks between exposure groups. The confounding function approach is a useful method for assessing the impact of unmeasured confounding, in particular when alternative approaches, e.g. external adjustment or instrumental variable approaches, cannot be applied. We provide Stata and R code for the implementation of this approach when the causal estimand of interest is an odds or risk ratio., (© The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: We illustrate the effect of survival bias when investigating risk factors for eye disease in elderly populations for whom death is a competing risk. Our investigation focuses on the relationship between smoking and late age-related macular degeneration (AMD) in an observational study impacted by censoring due to death., Methods: Statistical methodology to calculate the survivor average causal effect (SACE) as a sensitivity analysis is described, including example statistical computing code for Stata and R. To demonstrate this method, we examine the causal effect of smoking history at baseline (1990-1994) on the presence of late AMD at the third study wave (2003-2007) using data from the Melbourne Collaborative Cohort Study., Results: Of the 40,506 participants eligible for inclusion, 38,092 (94%) survived until the start of the third study wave, 20,752 (51%) were graded for AMD (60% female, aged 47-85 years, mean 65 ± 8.7 years). Late AMD was detected in 122 participants. Logistic regression showed strong evidence of an increased risk of late AMD for current smokers compared to non-smokers (adjusted naïve odds ratio 2.99, 95% confidence interval, CI, 1.74-5.13). Among participants expected to be alive at the start of follow-up regardless of their smoking status, the estimated SACE odds ratio comparing current smokers to non-smokers was at least 3.42 (95% CI 1.57-5.15)., Conclusions: Survival bias can attenuate associations between harmful exposures and diseases of aging. Estimation of the SACE using a sensitivity analysis approach should be considered when conducting epidemiological research within elderly populations.

Objective: To examine whether change in pain location is associated with clinically-relevant improvements in walking pain severity and physical dysfunction in people with medial tibiofemoral osteoarthritis (OA) using footwear for self-management., Design: We analysed a sub-set of 91 participants pooled from both arms of a 6-month randomised controlled trial of footwear for knee OA. The Photographic Knee Pain Map was self-administered to generate changes in the number of painful zones ('unchanged', 'increased', 'decreased') and anatomical patterns of pain ('unchanged', 'no longer diffuse', 'becoming diffuse', 'other pattern changes'). Improvement in symptoms was determined using the minimum clinically important differences (MCIDs) in pain severity on a numeric rating scale, and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Fisher's exact tests examined differences in symptom improvement across categories of change and odds ratios (ORs, 95% CI) were calculated (adjusted for treatment allocation)., Results: Seventy-four percent (n = 67) of participants reported a change in pain location, and 46-50% (n = 42-45) reported clinically-relevant improvements in pain and function respectively. Fewer participants 'becoming diffuse' reported improved pain (n = 0, 0%) when compared to the other pattern change categories (P = 0.012). Participants with 'no longer diffuse' (OR (95% CI) = 0.3 (0.1-0.9) or 'becoming diffuse' (OR (95% CI) = 0.0 (0.0-0.4) pain patterns had significantly lower odds of improved function than those with 'other pattern changes'., Conclusion: Participants either developing into, or changing from, diffuse pain patterns were less likely to experience improvement in pain and/or function when self-managing with footwear., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)