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Several definitions of night-time BP exist for the calculation of nocturnal blood pressure (BP) based on 24-h BP measurements. How much these methods differ regarding the resulting nocturnal blood pressure values, under which circumstances these differences become clinically meaningful, and under which circumstances diary-adjusted measurements should be used preferentially remains uncertain.Data of 512 24-h BP recordings were analysed regarding differences in nocturnal BP based on three alternative definitions of night-time: 2300-0700 h, 0100-0500 h, and diary-adjusted measures.Mean systolic nocturnal BP between 2300-0700 h was 2.5 mmHg higher than between 0100 and 0500 h and 1.6 mmHg higher than diary adjusted estimates. Up to 38.3% of individuals showed BP differences of more than 5 mmHg when comparing temporal definitions of night-time, resulting in significant proportions of individuals being re-classified as hypertensive. When diary-derived sleeping patterns differed by less than 2 h from the 2300 to 0700 h fixed time definition, mean BP discrepancies remained below 3 mmHg. Absolute time discrepancies between diary and 2300-0700 h fixed time definition of 2-4, 4-8 or at least 8 h led to SBP/DBP differences of 4.1/3.1, 6.8/6.1, and 14.5/9.1mmHg, respectively.Average differences of nocturnal BP between varying definitions in study/cohort data are small and would be of limited relevance in many settings. However, substantial differences can be observed in individual cases, which may affect clinical decision-making in specific patients. In patients whose sleeping patterns differs by more than 2 h from defined fixed night-times, diaries should be used for adjustment.

Auditors work in hierarchical teams in which effective upward communication is critical to audit quality. In these teams, subordinates choose both the content, as well as the style, of their communications. We report survey and experimental evidence of the importance of communication style in the context of audit team culture. Our first two studies provide evidence that audit staff perceive assertive upward communication as risky and prefer to communicate passively, especially in less autonomous team cultures. Our third study provides evidence that audit seniors consider more follow-up procedures and rate staff higher when staff communicate assertively, especially in more autonomous team cultures. Combined, these studies indicate a disconnect between audit seniors, who reward and follow up more on assertive communication, and their staff, who prefer passive communication. Our results suggest the potential for audit quality improvements by better alignment of supervisor-subordinate communication-style preferences, especially in more autonomous team cultures. Data Availability: Contact the authors.

Newly expressed proteins in genetically engineered crops are evaluated for potential cross reactivity to known allergens as part of their safety assessment. This assessment uses a weight-of-evidence approach. Two key components of this allergenicity assessment include any history of safe human exposure to the protein and/or the source organism from which it was originally derived, and bioinformatic analysis identifying amino acid sequence relatedness to known allergens. Phosphomannose-isomerase (PMI) has been expressed in commercialized genetically engineered (GE) crops as a selectable marker since 2010 with no known reports of allergy, which supports a history of safe exposure, and GE events expressing the PMI protein have been approved globally based on expert safety analysis. Bioinformatic analyses identified an eight-amino-acid contiguous match between PMI and a frog parvalbumin allergen (CAC83047.1). While short amino acid matches have been shown to be a poor predictor of allergen cross reactivity, most regulatory bodies require such matches be assessed in support of the allergenicity risk assessment. Here, this match is shown to be of negligible risk of conferring cross reactivity with known allergens.

Objective Both grip strength and gait speed can be used as markers of muscle function, however, no previous study has examined them in the same population with respect to risk of falls. Methods In this prospective cohort study, utilising data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and ASPREE-Fracture substudy, we analysed the association of grip strength and gait speed and serious falls in healthy older adults. Grip strength was measured using a handheld dynamometer and gait speed from 3-metre timed walks. Serious falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations with falls. Results Over an average of 4.0±1.3 years, amongst 16,445 participants, 1,533 had at least one serious fall. After adjustment for age, sex, physical activity, body mass index, Short Form 12 (state of health), chronic kidney disease, polypharmacy and aspirin, each standard deviation (SD) lower grip strength was associated with 27% (HR 1.27, 95% CI 1.17–1.38) higher risk of falls. The results remained the same for males and females. There was a dose-response relationship in the association between grip strength and falls risk. The higher risk of falls was observed in males in all body mass index (BMI) categories, but only in obese females. The association between gait speed and falls risk was weaker than the association between grip strength and falls risk. Conclusions All males and only obese females with low grip strength appear to be at the greatest risk of serious falls. These findings may assist in early identification of falls.

Capillaries are equipped to sense neurovascular coupling agents released onto the outer wall of a capillary, translating these external signals into electrical/Ca 2+ changes that play a crucial role in blood flow regulation and ensuring that neuronal demands are met. However, control mechanisms attributable to forces imposed onto the lumen are less clear. Here, we show that Piezo1 channels act as mechanosensors in central nervous system capillaries. Electrophysiological analyses confirmed expression and function of Piezo1 channels in brain cortical and retinal capillaries. Activation of Piezo1 channels evoked currents that were sensitive to endothelial cell–specific Piezo1 deletion. Using genetically encoded Ca 2+ indicator mice and an ex vivo pressurized retina preparation, we found that activation of Piezo1 channels by mechanical forces triggered Ca 2+ signals in capillary endothelial cells. Collectively, these findings indicate that Piezo1 channels are capillary mechanosensors that initiate crucial Ca 2+ signals and could, therefore, have a profound impact on central nervous system blood flow control.

The dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuron- and glial-derived compounds that enhance regional and global cerebral perfusion. The membrane potential ( V M ) of vascular cells serves as the physiological bridge that translates brain activity into vascular function. In other beds, the ATP-sensitive K + (K ATP ) channel regulates V M in vascular smooth muscle, which is absent in the capillary network. Here, with transgenic mice that expressed a dominant-negative mutant of the pore-forming Kir6.1 subunit specifically in brain cECs or pericytes, we demonstrated that K ATP channels were present in both cell types and robustly controlled V M . We further showed that the signaling nucleotide adenosine acted through A 2A receptors and the Gα s /cAMP/PKA pathway to activate capillary K ATP channels. Moreover, K ATP channel stimulation in vivo increased cerebral blood flow (CBF), an effect that was blunted by expression of the dominant-negative Kir6.1 mutant in either capillary cell type. These findings establish an important role for K ATP channels in cECs and pericytes in the regulation of CBF.

Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the seventh decade, after which concentrations increase and are restored to those of reproductive-aged women early in the eighth decade. We aimed to establish the association between the concentration of testosterone in the blood and risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women.SHOW was a prospective cohort substudy of the longitudinal randomised ASPREE trial. Eligible participants were women aged at least 70 years from Australia with unimpaired cognition, no previous MACE, and a life expectancy of at least 5 years. Participants who were receiving hormonal or steroid therapy were ineligible for inclusion. We measured serum concentrations of sex steroids with liquid chromatography-tandem mass spectrometry and of SHBG with immunoassay. We compared lower concentrations of sex hormones with higher concentrations using four quartiles. Primary endpoints were risk of MACE and all-cause mortality, the associations of which with sex steroid concentrations were assessed using Cox proportional hazards regression that included age, body-mass index, smoking status, alcohol consumption, diabetes, hypertension, dyslipidaemia, impaired renal function, and treatment allocation in the ASPREE trial (aspirinOf the 9180 women recruited to the ASPREE trial between March 10, 2010, and Dec 31 2014, 6358 participants provided sufficient biobank samples at baseline and 5535 were included in the final analysis. Median age at entry was 74·0 years (IQR 71·7-77·7). During a median 4·4 years of follow-up (24 553 person-years), 144 (2·6%) women had a first MACE (incidence 5·9 per 1000 person-years). During a median 4·6 years of follow-up (3·8-5·6), 200 women died (7·9 per 1000 person-years). In the fully adjusted models, higher concentrations of testosterone were associated with a lower incidence of MACE (quartile 4Blood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with a reduced risk of a first-ever MACE. Given that the physiological effects of DHEA are mediated through its steroid metabolites, if the current findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischaemic cardiovascular disease events in older women would be warranted.The National Health and Medical Research Council of Australia, US National Institute on Aging, the Victorian Cancer Agency, the Commonwealth Scientific and Industrial Research Organisation, and Monash University.

Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K+) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles. We hypothesized that TBI causes widespread disruption of electrical signaling from capillaries-to-arterioles through impairment of Kir2.1 channel function. We randomized mice to TBI or control groups and allowed them to recover for 4 to 7 days post-injury. We measured in vivo cerebral hemodynamics and arteriolar responses to local stimulation of capillaries with 10 mM K+ using multiphoton laser scanning microscopy through a cranial window under urethane and α-chloralose anesthesia. Capillary angio-architecture was not significantly affected following injury. However, K+-induced hyperemia was significantly impaired. Electrophysiology recordings in freshly isolated capillary endothelial cells revealed diminished Ba2+-sensitive Kir2.1 currents, consistent with a reduction in channel function. In pressurized cerebral arteries isolated from TBI mice, K+ failed to elicit the vasodilation seen in controls. We conclude that disruption of endothelial Kir2.1 channel function impairs capillary-to-arteriole electrical signaling, contributing to altered cerebral hemodynamics after TBI.

Significance Phosphatidylinositol 4,5-bisphosphate (PIP 2 ), a plasma membrane lipid, is hydrolyzed by G q -protein–coupled receptor (G q PCR) signaling into inositol 1,4,5-trisphosphate and diacylglycerol—extensively studied second messengers with profound regulatory effects in the vasculature. However, there is extensive evidence that PIP 2 directly regulates ion channels, a finding with significant implications for vascular function. Beyond providing a previously unexplored perspective on how vascular G q PCR signaling influences vascular function, the concept of PIP 2 -mediated ion channel regulation helps to explain how vascular cell excitability is coordinated to support cerebral blood flow control mechanisms. Importantly, the link between the metabolic state of vascular cells and PIP 2 content may provide insight into how metabolism affects vascular ion channel activity and, ultimately, vascular function in health and disease.

RATIONALE, AIMS AND OBJECTIVES: Applying traditional industrial quality improvement (QI) methodologies to primary care is often inappropriate because primary care and its relationship to the healthcare macrosystem has many features of a complex adaptive system (CAS) that is particularly responsive to bottom-up rather than top-down management approaches. We report on a demonstration case study of improvements made in the Family Health Center (FHC) of the JPS Health Network in a refugee patient population that illustrate features of QI in a CAS framework as opposed to a traditional QI approach. METHODS: We report on changes in health system utilization by new refugee patients of the FHC from 2016 to 2017. We review the literature and summarize relevant theoretical understandings of quality management in complex adaptive systems as it applies to this case example. RESULTS: Applying CAS principles in the FHC, utilization of the Emergency Department and Urgent Care Center by newly arrived refugee patients before their first clinic visit was reduced by more than half (total visits decreased from 31%-14% of the refugee patients). Our review of the literature demonstrates that traditional algorithmic top-down QI processes are most often unsuccessful in improving even a few single-disease metrics, and increases clinician burnout and penalizes clinicians who care for vulnerable patients. Improvement in a CAS occurs when front-line clinicians identify care gaps and are given the flexibility to learn and self-organize to enable new care processes to emerge, which are created from bottom-up leadership that utilize existing interdependencies and interact with the top levels of the organization through intelligent top-down causation. We give examples of early adapters who are better applying the principles of CAS change to their QI efforts. CONCLUSIONS: Meaningful improvement in primary care is more likely achieved when the impetus to implement change shifts from top-down to bottom-up.

Objectives Determine if outpatient physiotherapy care via telerehabilitation is as effective as in-person physiotherapy care after total hip replacement. Design Randomised, single-blind, controlled, non-inferiority clinical trial. Setting QEII Jubilee Hospital, Brisbane, Australia. Participants Seventy patients receiving a total hip replacement entered the study, sixty-nine completed the study. Interventions The control group (n = 35; x ¯ age 67; female 60%) received in-person outpatient physiotherapy and a paper-based home exercise programme. The intervention group (n = 35; x ¯ age 62; female 66%) received remotely delivered telerehabilitation directly into their homes and a technology-based home exercise program using an iPad application. Main outcome measures The primary outcome was the quality of life subscale of the Hip disability and Osteoarthritis Outcome Score measured at six weeks post-operatively. Secondary outcomes included objective strength and balance outcomes, self-reported function and satisfaction outcomes, and home exercise program compliance. Results No between group difference was detected in the Hip disability and Osteoarthritis Outcome Score quality of life subscale at the primary end point of six weeks (P = 0.970). Strength, balance and self-reported function showed no between group differences. Overall satisfaction was high across both groups, with the intervention group scoring higher for ease of attending appointments (intervention 95 (10), control 86 (18), mean difference 9 (95% CI 2 to 16), P = 0.017. The intervention group were more compliant with their home exercise programme (intervention 86% (20%), control 74% (26%), mean difference 12% (95% CI 1% to 23%), P = 0.048). Conclusions Telerehabilitation programmes can be delivered to total hip replacement patients in their own homes, using readily available technology while maintaining high levels of satisfaction. More importantly, telerehabilitation patients appear to achieve non-inferior physical and functional outcomes as those receiving in-person rehabilitation programmes. Trial Registration : ACTRN12615000824561. (Australian New Zealand Clinical Trials Registry).

Background and aims Among treatment-naive individuals with chronic hepatitis C viral (HCV) infection and without cirrhosis, glecaprevir/pibrentasvir for 8 weeks is recommended. The aim of this analysis was to evaluate the efficacy of glecaprevir/pibrentasvir for 6 weeks in people with acute and recent HCV infection. Approach and results In this open-label, single-arm, multicenter, international pilot study, adults with recent HCV (duration of infection 10 × upper limit of normal) or anti-HCV antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months of enrollment and evidence of prior spontaneous or treatment-induced clearance. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Thirty men (median age 43 years, 90% men who have sex with men) received treatment, of whom 77% (n = 23) were human immunodeficiency virus-positive, 47% (n = 14) had ever injected drugs, and 13% (n = 4) had HCV reinfection. The majority had HCV genotype 1 (83%, n = 25), followed by genotype 4 (10%, n = 3) and genotype 3 (7%, n = 2). At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention-to-treat and per-protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively. There was one case of relapse, and there were two cases of nonvirological failure (death, n = 1; loss to follow-up, n = 1). No treatment-related serious adverse events were seen. Conclusions Glecaprevir/pibrentasvir for 6 weeks was highly effective among people with acute and recent HCV infection, supporting further evaluation of shortened-duration pan-genotypic therapy in this setting.

This paper summarizes the overall results of the VIII World Engineering Education Forum, X Global Engineering Deans Council, XIV Global Student Forum, held in November 2018 in Albuquerque, NM USA, and discusses the emerging global collaboration for Peace Engineering (PEng) and Peace Engineering education. The theme of this first ever global conference on Peace Engineering was in tune with global events and developments. Participants were a confluence of practitioners, researchers, policy makers and educators from all over world, encompassing academia, multinational industry, US national labs and multilateral organizations. Results from a formal survey show that participants rated the conference as very good or excellent in all aspects and asked for more coverage of the topic of Peace Engineering and teaching material and strategies that embody Peace Engineering learning and teaching. The Conference succeeded in catalyzing conversations and idea exchanges for concrete plans for the next steps to advance a movement for Peace Engineering education, including • A Global Peace Engineering minor • Peace Engineering Certificate program • Master of Science in Peace Engineering • Database of Peace Engineering case studies • Workshops and other forums to promote discussion and planning for Peace Engineering programs and curricula • Data models, metrics, analytics and simulations: fine grain to large grain • Development of Peace Engineering as the new global engineering mindset Participants were engaged and enthusiastic about the concept and a Peace Engineering movement was born, along with the idea of creating a Peace Engineering Consortium.

The creation of the Peace Engineering Consortium is an outcome of the First Global Peace Engineering Conference, held November 2018 in Albuquerque NM, USA (www.weef-gedc2018.org). A team of conference participants are collaborating to develop the Peace Engineering Consortium. That is, to define and implement its charter, identify initiatives and preliminary activities, and continue to identify definitions of what Peace Engineering (PEng) – or Engineering for Peace – is. PEng is a call for action, in a new mindset not only for engineering, but for all existing and future disciplines to address global challenges. Current activities are: • Curricula and content – Members are collaborating to define, create and share curricula for undergraduate minors, professional certificate programs and graduate work; Creating experiential laboratories with industry and practitioner partners; Facilitating information exchange and the symmetry of information/knowledge through globally accessible digital libraries; Incorporating engineering diplomacy, diversity and cultural awareness (including the arts, music and language) into the practice for peacebuilding, peacemaking and peacekeeping. • Research and Development - The group is focused on collaborations, both domestic and international, and internal initiatives that advance the state of Peace Engineering. Key areas of focus have been developing metrics, data models, analytics, visualization and prediction. Some key initiatives include developing a modelling and visualizing conflict, Peace Data Standard, and pollution mitigation. • Entrepreneurial and Economic Development – The consortium is pursuing entrepreneurial activities in peace technology. It has been invited to produce a special edition on Peace Engineering and Innovation in the high impact Technological Forecasting and Social Change journal. • Events – In its charter year, the consortium organized a summer institute at The Hague and Peace Engineering workshops in Colombia – both models for future global workshops. • Case Studies – Members are compiling and publishing case studies and collaborating with US National Laboratories, industry, and governments to create scalable Peace Engineering case studies.

Background: The use of a polygenic risk score (PRS) to improve risk prediction of coronary heart disease (CHD) events has been demonstrated to have clinical utility in the general adult population. However, the prognostic value of a PRS for CHD has not been examined specifically in older populations of individuals aged ≥70 years, who comprise a distinct high-risk subgroup. The objective of this study was to evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of older individuals without a history of cardiovascular events. Methods: We used data from 12 792 genotyped, healthy older individuals enrolled into the ASPREE trial (Aspirin in Reducing Events in the Elderly), a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. Participants had no previous history of diagnosed atherothrombotic cardiovascular events, dementia, or persistent physical disability at enrollment. We calculated a PRS (meta-genomic risk score) consisting of 1.7 million genetic variants. The primary outcome was a composite of incident myocardial infarction or CHD death over 5 years. Results: At baseline, the median population age was 73.9 years, and 54.9% were female. In total, 254 incident CHD events occurred. When the PRS was added to conventional risk factors, it was independently associated with CHD (hazard ratio, 1.24 [95% CI, 1.08–1.42], P =0.002). The area under the curve of the conventional model was 70.53 (95% CI, 67.00–74.06), and after inclusion of the PRS increased to 71.78 (95% CI, 68.32–75.24, P =0.019), demonstrating improved prediction. Reclassification was also improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.15–0.28). Conclusion: A PRS for CHD performs well in older people and improves prediction over conventional cardiovascular risk factors. Our study provides evidence that genomic risk prediction for CHD has clinical utility in individuals aged 70 years and older. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01038583

Clinical Trial Networks in which trialists work collaboratively enable multi-site, large-scale, high-quality clinical trials to be efficiently run. Although the benefits of Clinical Trial Networks are largely known, establishing a Clinical Trial Network can be complex. There are many factors for clinicians and researchers to consider, and there is currently a paucity of information on how to form a Clinical Trial Network. This article provides a suggested roadmap on how to establish a Clinical Trial Network. The Australian Clinical Trials Alliance (ACTA) is the peak body for Clinical Trial Networks, Coordinating Centres and Registries in Australia, and has produced several resources to support the effective and efficient running of clinical trials. This guide has come about through discussions with members of the ACTA Clinical Trial Network Sector Expansion Reference Group consisting of clinical trialists, clinicians, researchers, and consumers.

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 μM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly ( P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly ( P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly ( P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.

Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but may cause secondary, deleterious effects such as excessive bleeding. Here, we demonstrate that suramin—a widely available polyanionic drug—completely neutralizes the toxic effects of histones. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sub-lethal doses of histones in vivo. Suramin also prevented lung edema, intra-alveolar hemorrhage and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.Significance StatementPathologic levels of circulating histones cause acute endotheliopathy, characterized by widespread disruption of critical endothelial functions and thromboinflammation. We discovered that suramin binds histones and prevents histone-induced endothelial dysfunction, thrombin generation, lung injury, and death. Histone binding is a novel mechanism of action for suramin, considered among the safest and most effective drugs by the World Health Organization. These results support the use of suramin for protection of blood vessels in conditions exacerbated by circulating histones including trauma and sepsis.

Health-related quality of life (QoL) is poor after stroke, but may be improved with comprehensive care plans. We aimed to determine the effects of an individualized management program on QoL in people with stroke or transient ischemic attack (TIA), describe changes in QoL over time, and identify variables associated with QoL.This was a multicenter, cluster randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients with stroke or TIA aged ≥ 18 years were randomized by general practice to receive usual care or an intervention comprising a tailored chronic disease management plan and education. QoL was assessed at baseline and 3, 12, and 24 months after baseline using the Assessment of Quality of Life instrument. Patient responses were converted to utility scores ranging from - 0.04 (worse than death) to 1.00 (good health). Mixed-effects models were used for analyses.Among 563 participants recruited (mean age 68.4 years, 64.5% male), median utility scores ranged from 0.700 to 0.772 at different time points, with no difference observed between intervention and usual care groups. QoL improved significantly from baseline to 3 months (ß = 0.019; P = 0.015) and 12 months (ß = 0.033; P 0.001), but not from baseline to 24 months (ß = 0.013; P = 0.140) in both groups combined. Older age, females, lower educational attainment, greater handicap, anxiety and depression were longitudinally associated with poor QoL.An individualized management program did not improve QoL over 24 months. Those who are older, female, with lower educational attainment, greater anxiety, depression and handicap may require greater support.https://www.anzctr.org.au . Unique identifier: ACTRN12608000166370.