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We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied. Ministry of Health (MOH) Published version This work is supported by the National Innovation Challenge on Active and Confident Ageing Programme, Ministry of Health of Singapore (Award No.: MOH/NIC/COG06/2017) and the National University of Singapore Society (NUSS) Choir Dementia Research Fund. The funders played no role in the study design, data acquisition, analysis, or manuscript preparation. The views expressed are those of the authors and are not an official view of the institutions or funders.

OBJECTIVE To compare central nervous system (CNS) activation in patients with and without diabetic peripheral neuropathy (DPN) during motor and motor imagery tasks and to correlate activation with functional performance. RESEARCH DESIGN AND METHODS Twenty-six participants (13 with DPN, 13 without DPN) underwent functional MRI during three tasks: ankle dorsi plantar flexion (motor task [MT]) and motor imagery tasks of walking on a smooth surface (SMIT) and rough surface (RMIT). Functional assessment included gait analysis, ankle muscle strength, and ankle range of motion. RESULTS The tasks activated the sensorimotor, motor preparation, visual processing, and decision-making regions. Activation was significantly lower in patients with DPN than in those without DPN during MT and SMIT but not RMIT. Poor functional performance in patients with DPN was associated with greater activation in motor preparation regions. CONCLUSIONS In patients with DPN, CNS responses appear muted compared with patients without DPN, but they remain capable of enhancing CNS activation when tasks are more challenging or when functional deficits are substantial.

Prior research has shown that large interactive displays deployed in public spaces are often underutilized, or even un- noticed, phenomena connected to 'interaction' and 'display blindness', respectively. To better understand how designers can mitigate these issues, we conducted a field experiment that compared how different visual cues impacted engagement with a public display. The deployed interfaces were designed to progressively reveal more information about the display and entice interaction through the use of visual content designed to evoke direct or indirect conation (the mental faculty related to purpose or will to perform an action), and different animation triggers (random or proxemic). Our results show that random triggers were more effective than proxemic triggers at overcoming display and interaction blindness. Our study of conation - the first we are aware of - found that "conceptual" visuals designed to evoke indirect conation were also useful in attracting people's attention.

Objective: Approximately 20% of patients admitted to hospital with drug overdose will require intensive care unit (ICU) admission. An understanding of the characteristics of these patients may assist with their management and identify those patients at risk of multiple hospital presentations due to drug overdose. Our aim was to examine the characteristics of patients admitted to ICU following drug overdoses and identify the predictors of multiple hospital presentations due to drug overdose. Methods: Patients admitted to a metropolitan ICU over a three-year period following drug overdoses were identified using ICU patient databases, and their medical records. Results: There were 254 admissions due to drug overdoses. The majority of overdoses were intentional (82.7%) and included multiple agents (68.1%). Two-thirds of patients had psychiatric diagnosis, and 54% had documented history of substance use disorders. In-hospital mortality was 2.8%. Over half of patients admitted had documented history of prior hospital presentation due to overdoses. Personality disorder and schizophrenia were independent predictors of multiple hospital presentations due to overdoses. Conclusion: Personality disorders or schizophrenia were independent predictors of patients with multiple overdose presentations. Preventative strategies focusing on these patients may reduce the incidence of their hospital presentations and ICU admissions.

1Montreal Heart Institute, Montreal, Quebec; 2CIHR Institute of Circulatory and Respiratory Health, Ottawa, Ontario, Canada Correspondence: Ms Caroline Wong, CIHR Institute of Circulatory and Respiratory Health, 5000 Belanger St – S2580, Montreal, Quebec H1T 1C8, Canada. Telephone 514-593-7433, fax 514-376-7070, e-mail caroline.wong@icm-mhi.org Received for publication October 4, 2014, Accepted October 9, 2014 The Institute of Circulatory and Respiratory Health (ICRH) – 1 of the 13 Institutes of the Canadian Institutes of Health Research (CIHR) – supports research that focuses on cardiovascular health, respiratory health, blood and blood vessels, stroke, critical/intensive care, and sleep/circadian rhythms. Together, the disease areas that are covered under the mandate of the ICRH represent conditions with the largest health, societal, and economic burden of any of the other Institutes within CIHR. This reality and the extraordinary diversity of these medical conditions present a major operational challenge for the ICRH. Despite these difficulties and limited resources, the Institute’s 2013-2016 Strategic Plan1 demonstrates a commitment to ensuring that research excellence, capacity, competitiveness, innovation, and impact are enhanced across all research fields affiliated with the Institute. Moreover, building on previous successes, the ICRH continues to nurture past collaborations and work to establish new meaningful national and international alliances with the research community, partners, and other stakeholders to develop interdisciplinary, integrative health research that reflects Canada’s emerging health needs, gaps, and opportunities. The ICRH also strongly supports partnerships with relevant stakeholders to accelerate the transfer of new knowledge into benefits for Canadians. Notably, patient engagement is an important priority that will serve as 1 of the major building blocks of all clinically related initiatives of the ICRH. Based on identified gaps, opportunities, and feedback received from the International External Review Panel,2 ICRH research communities and partners, and in alignment with the CIHR 2014-2018 Strategic Plan, the ICRH identified 4 research priorities for 2013-2016. The first priority focuses on enhancing capacity, competitiveness, and impact of our communities through networking. This objective is consistent with the importance of aligning with CIHR’s largest comprehensive Roadmap Signature Initiative (RSI) the Strategy for Patient-Oriented Research (SPOR). In 2013, the Institute launched the ICRH Emerging Networks program in 3 gap areas, funding the Canadian Vascular Network, Canadian Respiratory Research Network, and the Canadian Stroke Prevention Intervention Network. In addition, through focused community development programs in critical care, stroke treatment and recovery, sleep and circadian rhythms, blood diseases, and resuscitation clinical research, the ICRH has targeted 5 additional research communities in need of networking. Aligned with CIHR’s Patient Engagement Framework,3 the ICRH will use specific actions and tools to enhance patient engagement in health research, implement patient engagement as a core priority in strategic initiatives, and offer programs that will allow patients to be true partners in research. Finally, the ICRH is continuing its collaboration with the National Heart, Lung, and Blood Institute of the National Institutes of Health in the ongoing support of 2 large Canada-US networks––the Resuscitation Outcomes Consortium and the Cardiothoracic Surgical Network, and will explore other international network opportunities. The second priority of the ICRH targets training, mentoring, and early career development to promote capacity-building––areas with an identified need. Recently, data have shown that the growth of funding within the ICRH’s mandated research areas has been slower than in all other areas at the CIHR, in particular for the cardiovascular and respiratory communities (Fig. 1A). Evidence suggests that this is primarily due to declining numbers of young investigators (Fig. 1B). The development of research capacity related to health systems/services and population/public health has been identified as requiring particular attention. In the upcoming years, the ICRH will work closely with relevant CIHR Institutes and various working groups to address this important and persistent capacity problem, focusing on training/mentoring issues and issues affecting the career success of young investigators. In 2014, the ICRH facilitated the development of the Emerging Research Leaders Initiative, which was launched as a joint initiative between the Heart and Stroke Foundation and the Canadian Lung Association––2 of the ICRH’s key partners. The ICRH will also continue its collaborative work with key stakeholders to develop a comprehensive training and mentoring strategy that will directly align with partner-led programs. A recent national ICRH survey (data not yet published) also confirmed the need for improved mentoring and the ICRH will work with its networks, partners, and the CIHR to improve the quality of mentoring based on current best practices. The third priority of the ICRH focuses on the expansion of clinical research opportunities, health systems/services research, and population health through cohort linkage and data enhancement. This initiative will provide Canadian scientists with a unique opportunity to boost knowledge development and translation at a fraction of the cost of developing new cohorts and will enable Canada to develop better population-based research, and design individualized and community-based prevention and intervention programs. In addition, this initiative will contribute to improving the potential for health and health systems research by creating a pool of population-based data that can be linked to Canada’s uniquely powerful administrative databases. Data enhancement and linkage will also directly assist in gathering and analyzing data related to Canada’s Aboriginal people and other vulnerable populations that are presently lacking. Finally, by helping to address issues such as data storage and access, this initiative will support research on ethics, and increase the use and sustainability of existing cohorts. Along with the CIHR and its other Institutes, the ICRH is helping to coordinate disparate and multidisciplinary communities to bridge gaps and identify ways for harmonizing and sharing population-relevant data sets and their efficient utilization. In the context of the increasing prevalence of cardiovascular and respiratory risk factors, many of which are also risk factors for other serious chronic diseases, this initiative provides a unique opportunity for the ICRH community to link with other research communities in building tools to fuel clinical research and population health, health services, and policy research. Through the Environments and Health Signature Initiative, the ICRH is coleading the Data Platforms component, COMMENTARy

e12540Background: Low serum vitamin D (Vit-D) is associated with an increased risk of breast cancer (BC). Patients with adequate levels of Vit-D/replacement have lower rates of BC incidence. Aims: ...

The effect of uterine artery embolization (UAE) on symptomatic adenomyosis was evaluated in a systematic review and meta-analysis. Four groups were evaluated: short-term (< 12 months) pure adenomyosis, short-term adenomyosis with fibroids (combined adenomyosis), long-term (> 12 months) pure adenomyosis, and long-term combined adenomyosis. Improvement of symptoms occurred in 83.1% (872/1,049) of patients. Reported symptom reduction was 4.8% greater in the short-term combined group (P = .169) and 11.4% greater in the long-term combined group (P = .003). Uterine volume was reduced in all patients at 3 months. The effects of UAE on symptom improvement and uterine volume reduction in patients with adenomyosis are encouraging.

Growth cone response to the bifunctional guidance cue netrin-1 is regulated by the activity of intracellular signaling intermediates such as protein kinase C-alpha (PKCalpha) and adenylyl cyclase. Among the diverse cellular events these enzymes regulate is receptor trafficking. Netrin-1, itself, may govern the activity of these signaling intermediates, thereby regulating axonal responses to itself. Alternatively, other ligands, such as activators of G protein-coupled receptors, may regulate responses to netrin-1 by governing these signaling intermediates. Here, we investigate the mechanisms controlling activation of PKCalpha and the subsequent downstream regulation of cell surface UNC5A receptors. We report that activation of adenosine receptors by adenosine analogs, or activation of the putative netrin-1 receptor, the G protein-coupled receptor adenosine A2b receptor (A2bR) results in PKCalpha-dependent removal of UNC5A from the cell surface. This decrease in cell surface UNC5A reduces the number of growth cones that collapse in response to netrin-1 and converts repulsion to attraction. We show these A2bR-mediated alterations in axonal response are not because of netrin-1 because netrin-1 neither binds A2bR, as assayed by protein overlay, nor stimulates PKCalpha-dependent UNC5A surface loss. Our results demonstrate that netrin-1-independent A2bR signaling governs the responsiveness of a neuron to netrin-1 by regulating the levels of cell surface UNC5A receptor.

Aim: Cardiac amyloidosis is a protein deposition disease that can be difficult to diagnose and has a poor prognosis if diagnosis or treatment are delayed. The two major subtypes are AL and transthyretin (ATTR). Both have vastly different treatments so confirming the correct amyloid subtype is crucial. A tissue biopsy is usually required for the diagnosis of amyloidosis and to distinguish between the subtypes. No blood test, echocardiography or cardiac MRI can reliably distinguish between AL and ATTR. With a cardiac biopsy, distinguishing AL from ATTR can be challenging with immunohistochemistry, and time consuming with mass spectrometry. Recently, Gillmore et al demonstrated bone scintigraphy with 99mTc-DPD tracer can reliably diagnose ATTR, avoiding endomyocardial biopsies to confirm the subtype in most cases. [1] 99mTc-HDP is a tracer similar to 99mTc-DPD and is more readily available in Australian and the USA. We sought to examine the use of 99mTcHDP bone scintigraphy in Australia and determine the accuracy of this tracer to diagnose cardiac amyloidosis and distinguish between the AL and ATTR subtypes. Methods: All patients with confirmed ATTR or AL who had 99mTcHDP bone scintigraphy were analysed. Results were correlated with histology, NT ProBNP, Troponin-T, free light chains, cardiac MRI and echocardiography. Grading was conducted with Perugini scoring.[1] Results: 25 patients with amyloidosis diagnosed by cardiac MRI and/or biopsy, had 99mTcHDP bone scintigraphy. 18 were confirmed ATTR, 7 AL. Two ATTR patients had hereditary disease (Thy60Ala and Gly109Lys), the remainder were wildtype. 17 (94%) patients with ATTR and 2 (29%) AL had positive scans. The negative ATTR patient had localized bladder disease only with a normal echocardiogram and cardiac biomarkers. All ATTR patients with positive scans had Perugini scores of 2 or 3, including the 2 patients with hereditary mutations, while the two positive AL only had scores of 1. All 11 patients with amyloid features on cardiac MRI had positive scans. Mean NTproBNP values for ATTR and AL were 530pmol/L and 1396pmol/L respectively. The two AL amyloidosis patients with positive bone scans had higher NTproBNP values. No ATTR patient had a detectable plasma cell dyscrasia. Conclusion: Bone scintigraphy with 99mTcHDP tracer is an easily accessible, rapid and non-invasive method of diagnosing cardiac amyloidosis. In our small series, all patients with Perugini scores 2 or 3 had ATTR, while those with negative or Perugini score 1 scan either had AL or no cardiac amyloidosis. There was a suggestion that AL patients with higher NTproBNP scores were more likely to have positive scans. This suggests that the 99mTcHDP tracer can be used like 99mTc-DPD to aid in the diagnosis of cardiac amyloidosis, and, as suggested by Gillmore et al, can confirm the ATTR subtype in those with no detectable plasma cell dyscrasia and Perugini score 2 or 3 scans, thus hastening accurate diagnosis and avoiding cardiac biopsies. Reference: Gillmore JD, Maurer MS, Falk RH, Merlini M, Damy T, Dispenzieri A, et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12 Disclosures No relevant conflicts of interest to declare.

Keratinocyte growth factor (KGF or FGF-7) is a member of the heparin binding fibroblast growth factor (FGF) family and is a paracrine mediator of proliferation and differentiation of a wide variety of epithelial cells. To examine the stoichiometry of complexes formed between KGF and its receptor, we have utilized a soluble variant of the extracellular region of the KGF receptor containing two tandem immunoglobulin-like loops, loops II and III (sKGFR). Ligand-receptor complexes were examined by size exclusion chromatography, light scattering, N-terminal protein sequencing, and sedimentation velocity. In the presence of low-molecular mass heparin ( approximately 3 kDa), we demonstrate the formation of complexes containing two molecules of sKGFR and one molecule of KGF. In the absence of heparin, we were unable to detect any KGF-sKGFR complexes using the above techniques, and additional studies in which sedimentation equilibrium was used show that the binding is very weak (Kd >/= 70 microM). Furthermore, using heparin fragments of defined size, we demonstrate that a heparin octamer or decamer can promote formation of a 2:1 complex, while a hexamer does not. Utilizing the highly purified proteins and defined conditions described in this study, we find that heparin is obligatory for formation of a KGF-sKGFR complex. Finally, 32D cells, which appear to lack low-affinity FGF binding sites, were transfected with a KGFR-erythropoeitin receptor chimera and were found to require heparin to achieve maximal KGF stimulation. Our data are consistent with the previously described concept that cell- or matrix-associated heparan sulfate proteoglycans (HSPGs) and FGF ligands participate in a concerted mechanism that facilitates FGFR dimerization and signal transduction in vivo.