OBJECTIVE: To investigate the association between habitual physical activity levels and brain temporal lobe volumes, and the interaction with the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism. METHODS: This study is a cross-sectional analysis of 114 cognitively healthy men and women aged 60 years and older. Brain volumes quantified by MRI were correlated with self-reported physical activity levels. The effect of the interaction between physical activity and the BDNF Val66Met polymorphism on brain structure volumes was assessed. Post hoc analyses were completed to evaluate the influence of the APOE ε4 allele on any found associations. RESULTS: The BDNF Val66Met polymorphism interacted with physical activity to be associated with hippocampal (β = -0.22, p = 0.02) and temporal lobe (β = -0.28, p = 0.003) volumes. In Val/Val homozygotes, higher levels of physical activity were associated with larger hippocampal and temporal lobe volumes, whereas in Met carriers, higher levels of physical activity were associated with smaller temporal lobe volume. CONCLUSION: The findings from this study support higher physical activity levels in the potential attenuation of age- and disease-related hippocampal and temporal lobe volume loss in Val/Val homozygotes.

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

INTRODUCTION: Frailty is of increasing importance to perioperative and critical care medicine, as the proportion of older patients increases globally. Evidence continues to emerge of the considerable impact frailty has on adverse outcomes from both surgery and critical care, which has led to a proliferation of different frailty measurement tools in recent years. Despite this, there remains a lack of easily implemented, comprehensive frailty assessment tools specific to these complex populations. Development of a frailty index using routinely collected hospital data, able to leverage the automated aspects of an electronic medical record, would aid risk stratification and benefit clinicians and patients alike. METHODS AND ANALYSIS: This is a prospective observational study. 150 intensive care unit (ICU) patients aged ≥50 years and 200 surgical patients aged ≥65 years will be enrolled. The primary objective is to develop a frailty index. Secondary objectives include assessing its ability to predict in-hospital mortality and/or discharge to a new non-home location; the performance of the frailty index in predicting postoperative and ICU complications, as well as health-related quality of life at 6 months; to compare the performance of the frailty index against existing frailty measurement and risk stratification tools; and to assess its modification by patients' health assets. ETHICS AND DISSEMINATION: This study has been approved by the Melbourne Health Human Research Ethics Committee(20 January 2017, HREC/16/MH/321). Dissemination will be via international and national anaesthetic and critical care conferences, and publication in the peer-reviewed literature.

INTRODUCTION: Postoperative pulmonary complications (PPCs) are a common serious complication following upper abdominal surgery leading to significant consequences including increased mortality, hospital costs and prolonged hospitalisation. The primary objective of this study is to detect whether there is a possible signal towards PPC reduction with the use of additional intermittent non-invasive ventilation (NIV) compared with continuous high-flow nasal oxygen therapy alone following high-risk elective upper abdominal surgery. Secondary objectives are to measure feasibility of: (1) trial conduct and design and (2) physiotherapy-led NIV and a high-flow nasal oxygen therapy protocol, safety of NIV and to provide preliminary costs of care information of NIV and high-flow nasal oxygen therapy. METHODS AND ANALYSIS: This is a single-centre, parallel group, assessor blinded, pilot, randomised trial, with 130 high-risk upper abdominal surgery patients randomly assigned via concealed allocation to either (1) usual care of continuous high-flow nasal oxygen therapy for 48 hours following extubation or (2) usual care plus five additional 30 min physiotherapy-led NIV sessions within the first two postoperative days. Both groups receive standardised preoperative physiotherapy and postoperative early ambulation. No additional respiratory physiotherapy is provided to either group. Outcome measures will assess incidence of PPC within the first 14 postoperative days, recruitment ability, physiotherapy-led NIV and high-flow nasal oxygen therapy protocol adherence, adverse events relating to NIV delivery and costs of providing a physiotherapy-led NIV and a high-flow nasal oxygen therapy service following upper abdominal surgery. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the relevant institution and results will be published to inform future multicentre trials. TRIAL REGISTRATION NUMBER: ACTRN12617000269336; Pre-results.

INTRODUCTION: Clinical indicators are used to measure and quantify the safety and quality of patient care. They are also often used as endpoints in clinical trials. Definitions of clinical indicators in common use are extremely heterogeneous, limiting their applicability. As part of the international Standardised Endpoints in Perioperative Medicine initiative, this study will identify clinical indicators by systematically reviewing the anaesthesia and perioperative medicine literature, and will provide consensus, clinically useful definitions for those indicators using a Delphi process. METHODS AND ANALYSIS: An electronic database search will be conducted of Medline (PubMed/OVID), EMBASE and the Cochrane Library in order to meet this review's objectives that are: (1) To identify clinical indicators and their definitions used in randomised controlled trials that assess patient-related quality and safety interventions in perioperative medicine; (2) To select a shortlist of recommended indicators and definitions that are the most suitable for evaluation of quality and safety interventions following an expert-based consensus-gaining process (Delphi method) and (3) To provide a classification scale for each indicator related to its clarity of definition, validity (strength), reliability, feasibility (ease of use) and frequency of use. This systematic review protocol is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidance. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review and Delphi process. The results of this study will be disseminated to the anaesthesia and perioperative medicine clinical and academic community through national and international presentations and through publication in a peer reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42016042102.

Type I interferon (IFN) pathways are significant in SLE pathogenesis. Less is known about the utility of measuring markers of IFN activity in patients, or whether patient subsets with different profiles exist. We explored the longitudinal associations of IFN-induced chemokines with disease activity in a cohort of SLE patients. We calculated a validated composite score (IFN-CK) of three type I IFN-inducible chemokines (CCL2/CXCL10/CCL19) measured in 109 SLE patients (median 7 occasions over 3.2 years). Longitudinal associations of IFN-CK score with disease activity (SLEDAI-2K) and other variables were assessed using general estimating equation (GEE) methods. IFN-CK was detectable in all patients. SLEDAI-2K was significantly associated with IFN-CK, damage score and prednisolone dose. SLEDAI-2K remained significantly associated with IFN-CK over time after adjustment of covariates. Patients with high time-adjusted mean IFN-CK had lower complement and higher time-adjusted disease activity. Concordance between IFN-CK and SLEDAI-2K varied widely among patients, with some individuals having none, others weak, and a subset very high concordance. In summary in our cohort of SLE patients, serum IFN-CK varied over time with disease activity, but with wide variation in concordance. Differing relationships between IFN pathway activation and disease activity may be valuable in assigning patients to emerging IFN-pathway targeting treatments.

OBJECTIVES: To determine factors associated with damage accrual in a prospective cohort of patients with SLE. METHODS: Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. RESULTS: A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non-glucocorticoid related domains of the SDI. CONCLUSIONS: Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with significant impairment of health-related quality of life (HR-QoL). Recently, meeting a definition of a lupus low disease activity state (LLDAS), analogous to low disease activity in rheumatoid arthritis, was preliminarily validated as associated with protection from damage accrual. The LLDAS definition has not been previously evaluated for association with patient-reported outcomes. The objective of this study was to determine whether LLDAS is associated with better HR-QoL, and examine predictors of HR-QoL, in a large multiethnic, multinational cohort of patients with SLE. METHODS: HR-QoL was measured using the Medical Outcomes Study 36-item short form health survey (SF-36v2) in a prospective study of 1422 patients. Disease status was measured using the SLE disease activity index (SLEDAI-2 K), physician global assessment (PGA) and LLDAS. RESULTS: Significant differences in SF-36 domain scores were found between patients stratified by ethnic group, education level and damage score, and with the presence of active musculoskeletal or cutaneous manifestations. In multiple linear regression analysis, Asian ethnicity (p < 0.001), a higher level of education (p < 0.001), younger age (p < 0.001) and shorter disease duration (p < 0.01) remained significantly associated with better physical component scores (PCS). Musculoskeletal disease activity (p < 0.001) was negatively associated with PCS, and cutaneous activity (p = 0.04) was negatively associated with mental component scores (MCS). Patients in LLDAS had better PCS (p < 0.001) and MCS (p < 0.001) scores and significantly better scores in multiple individual SF-36 domain scores. Disease damage was associated with worse PCS (p < 0.001), but not MCS scores. CONCLUSIONS: Ethnicity, education, disease damage and specific organ involvement impacts HR-QoL in SLE. Attainment of LLDAS is associated with better HR-QoL.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic heterogeneous disease with considerable burden from disease activity and damage. A novel clinical treatment target in the form of the lupus low disease activity state (LLDAS) has been recently reported, with retrospective validation showing that time spent in LLDAS translates to reduced damage accrual. The objectives of this study were to describe the frequency and identify the predictors of attaining LLDAS in a large multinational cohort of patients with SLE. METHODS: Data were collected at the recruitment visit in patients with SLE enrolled in a longitudinal study in nine countries. Data were analysed cross-sectionally against the recently published definition of LLDAS, and the frequency and characteristics associated with presence of LLDAS were determined. Stepwise multivariable logistic regression was used to determine predictors of LLDAS. RESULTS: Of the 1846 patients assessed, criteria for LLDAS were met by 44 %. Patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95 % CI 0.19-0.49, p < 0.001). Likewise, patients with a history of discoid rash (OR 0.66, 95 % CI 0.49-0.89, p = 0.006), renal disease (OR 0.60, 95 % CI 0.48-0.75, p < 0.001), elevated double stranded DNA (OR 0.65, 95 % CI 0.53-0.81, p < 0.001) or hypocomplementaemia (OR 0.52, 95 % CI 0.40-0.67, p < 0.001) were less likely to be in LLDAS. When countries were compared, higher national social wealth (OR 1.57, 95 % CI 1.25-1.98, p < 0.001) as measured by the gross domestic product per capita was positively associated with LLDAS, but ethnicity was not. CONCLUSION: The lupus low disease activity state is observed in less than half of patients with SLE at a single point in time. Disease duration and phenotype, and national social wealth, are predictive of LLDAS.

Ethnicity is a key factor impacting on disease severity in SLE, but molecular mechanisms of these associations are unknown. Type I IFN and MIF have each been associated with SLE pathogenesis. We investigated whether increased SLE severity in Asian patients is associated with either MIF or Type I IFN. SLE patients (n = 151) had prospective recording of disease variables. Serum MIF, and a validated composite score of three Type I IFN-inducible chemokines (IFNCK:CCL2, CXCL10, CCL19) were measured. Associations of MIF and IFNCK score with disease activity were assessed, with persistent active disease (PAD) used as a marker of high disease activity over a median 2.6 years follow up. In univariable analysis, MIF, IFNCK score and Asian ethnicity were significantly associated with PAD. Asian ethnicity was associated with higher MIF but not IFNCK score. In multivariable logistic regression analysis, MIF (OR3.62 (95% CI 1.14,11.5), p = 0.03) and Asian ethnicity (OR3.00 (95% CI 1.39,6.46), p < 0.01) but not IFNCK were significantly associated with PAD. These results potentially support an effect of MIF, but not Type I IFN, in heightened SLE disease severity in Asian SLE. The associations of MIF and Asian ethnicity with PAD are at least partly independent.

BACKGROUND: Vitamin D status varies with geographic location and no studies of vitamin D in systemic lupus erythematosus (SLE) have been reported in the Southern Hemisphere. OBJECTIVES: To assess the prevalence of vitamin D deficiency in an Australian SLE cohort, and its relationship with disease activity. METHODS: Data were collected prospectively on 119 consecutive patients with SLE in the Monash Lupus Clinic in Melbourne, Australia, between January 2007 and January 2013. Patients had simultaneous serum 25-hydroxyvitamin D concentration and disease activity (SLEDAI-2K) recorded. Statistical methods were used to determine the correlation of serum vitamin D level and disease activity both at baseline and at a subsequent time point. Adjustments were made for the use of glucocorticoids, immunosuppressants and vitamin D supplementation. RESULTS: Vitamin D deficiency (<40 nmol/L) was detected in 27.7% of patients at baseline. Multiple regression analysis showed a significant inverse correlation of SLEDAI-2K with baseline vitamin D level and with vitamin D supplementation. Over a 12-month period of observation, among the 119 patients, there were 464 serial vitamin D measurements with corresponding SLEDAI-2K, representing 266 time intervals. The median change in vitamin D level was an increase of 25 nmol/L and this corresponded with a decline in SLEDAI-2K of 2 units. In regression analysis, there was a significant association between low vitamin D at a prior time point and a rise in SLEDAI-2K at the subsequent time point (univariable OR 3.3, 95% CI 1.5 to 7.7, p=0.005) or having a high disease activity (SLEDAI-2k>10) at the subsequent time point (univariable OR 3.1, 95% CI 1.4 to 6.8, p=0.004). CONCLUSIONS: In Australian patients with SLE, low vitamin D was associated with a higher disease activity and an increase in serum vitamin D was associated with reduced disease activity over time. The therapeutic effect of vitamin D in SLE should be further assessed in interventional studies.

BACKGROUND: Pulmonary rehabilitation is an effective therapeutic intervention for people with chronic respiratory disease. However, fewer than 5% of eligible individuals receive pulmonary rehabilitation on an annual basis, largely due to limited availability of services and difficulties associated with travel and transport. The Rehabilitation Exercise At Home (REAcH) study is an assessor-blinded, multi-centre, randomised controlled equivalence trial designed to compare the efficacy of home-based telerehabilitation and traditional centre-based pulmonary rehabilitation in people with chronic respiratory disease. METHODS: Participants will undertake an 8-week group-based pulmonary rehabilitation program of twice-weekly supervised exercise training, either in-person at a centre-based pulmonary rehabilitation program or remotely from their home via the Internet. Supervised exercise training sessions will include 30 min of aerobic exercise (cycle and/or walking training). Individualised education and self-management training will be delivered. All participants will be prescribed a home exercise program of walking and strengthening activities. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and 12-months post intervention. The primary outcome is change in dyspnea score as measured by the Chronic Respiratory Questionnaire - dyspnea domain (CRQ-D). Secondary outcomes will evaluate the efficacy of telerehabilitation on 6-min walk distance, endurance cycle time during a constant work rate test, physical activity and quality of life. Adherence to pulmonary rehabilitation between the two models will be compared. A full economic analysis from a societal perspective will be undertaken to determine the cost-effectiveness of telerehabilitation compared to centre-based pulmonary rehabilitation. DISCUSSION: Alternative models of pulmonary rehabilitation are required to improve both equity of access and patient-related outcomes. This trial will establish whether telerehabilitation can achieve equivalent improvement in outcomes compared to traditional centre-based pulmonary rehabilitation. If efficacious and cost-effective, the proposed telerehabilitation model is designed to be rapidly deployed into clinical practice. TRIAL REGISTRATION: Clinical trial registered with the Australian and New Zealand Clinical Trials Register at ( ACTRN12616000360415 ). Registered 21 March 2016.