Showing papers by "University of Alberta published in 2015"

Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke

Abstract: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. Methods We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). Results The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P = 0.75). Conclusions Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.)

MetaboAnalyst 3.0—making metabolomics more meaningful

Abstract: MetaboAnalyst (www.metaboanalyst.ca) is a web server designed to permit comprehensive metabolomic data analysis, visualization and interpretation. It supports a wide range of complex statistical calculations and high quality graphical rendering functions that require significant computational resources. First introduced in 2009, MetaboAnalyst has experienced more than a 50X growth in user traffic (>50 000 jobs processed each month). In order to keep up with the rapidly increasing computational demands and a growing number of requests to support translational and systems biology applications, we performed a substantial rewrite and major feature upgrade of the server. The result is MetaboAnalyst 3.0. By completely re-implementing the MetaboAnalyst suite using the latest web framework technologies, we have been able substantially improve its performance, capacity and user interactivity. Three new modules have also been added including: (i) a module for biomarker analysis based on the calculation of receiver operating characteristic curves; (ii) a module for sample size estimation and power analysis for improved planning of metabolomics studies and (iii) a module to support integrative pathway analysis for both genes and metabolites. In addition, popular features found in existing modules have been significantly enhanced by upgrading the graphical output, expanding the compound libraries and by adding support for more diverse organisms.

Climate change and the permafrost carbon feedback

Abstract: Large quantities of organic carbon are stored in frozen soils (permafrost) within Arctic and sub-Arctic regions. A warming climate can induce environmental changes that accelerate the microbial breakdown of organic carbon and the release of the greenhouse gases carbon dioxide and methane. This feedback can accelerate climate change, but the magnitude and timing of greenhouse gas emission from these regions and their impact on climate change remain uncertain. Here we find that current evidence suggests a gradual and prolonged release of greenhouse gas emissions in a warming climate and present a research strategy with which to target poorly understood aspects of permafrost carbon dynamics.

Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes

Abstract: Background Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. Methods In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Results During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P Conclusions Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study

Abstract: Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients. The Acute Kidney Injury–Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge. A total of 1032 ICU patients out of 1802 [57.3 %; 95 % confidence interval (CI) 55.0–59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95 % CI 0.890–3.169; p = 0.109), stage 2 = 2.945 (95 % CI 1.382–6.276; p = 0.005), and stage 3 = 6.884 (95 % CI 3.876–12.228; p < 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m2 in 47.7 % (95 % CI 43.6–51.7) versus 14.8 % (95 % CI 11.9–18.2) in those without AKI, p < 0.001. This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.

Elevation-dependent warming in mountain regions of the world

Abstract: There is growing evidence that the rate of warming is amplified with elevation, such that high-mountain environments experience more rapid changes in temperature than environments at lower elevations. Elevation-dependent warming (EDW) can accelerate the rate of change in mountain ecosystems, cryospheric systems, hydrological regimes and biodiversity. Here we review important mechanisms that contribute towards EDW: snow albedo and surface-based feedbacks; water vapour changes and latent heat release; surface water vapour and radiative flux changes; surface heat loss and temperature change; and aerosols. All lead to enhanced warming with elevation (or at a critical elevation), and it is believed that combinations of these mechanisms may account for contrasting regional patterns of EDW. We discuss future needs to increase knowledge of mountain temperature trends and their controlling mechanisms through improved observations, satellite-based remote sensing and model simulations.

Combined Measurement of the Higgs Boson Mass in pp Collisions at √s=7 and 8 TeV with the ATLAS and CMS Experiments

Abstract: A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4l decay channels. The results are obtained from a simultaneous fit to the reconstructed invariant mass peaks in the two channels and for the two experiments. The measured masses from the individual channels and the two experiments are found to be consistent among themselves. The combined measured mass of the Higgs boson is mH=125.09±0.21 (stat)±0.11 (syst) GeV.

Early infancy microbial and metabolic alterations affect risk of childhood asthma

Abstract: Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.

Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response

Abstract: Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity

The Institutional Logics Perspective

Abstract: This essay discusses a new approach to institutional analysis—the institutional logics perspective (ILP). This perspective is a meta-theory useful for integrating and augmenting a variety of social science theories to better understand the effects of cultural institutions on individuals, organizations, and societies. We describe the history of the development of the ILP, define its core concepts and mechanisms, and review and discuss foundational and cutting-edge research. Prior overviews emphasize the mechanisms, variety of substantive contexts, and the cross-level effects. We take a different approach by organizing the literature review by institutional orders. This meta-analysis reveals a pattern of institutional change—the weakening of the professions and the spread of the market logic in many domains. We discuss implications of this finding and suggest future research. Keywords: institutional theory; institutional logics; institutional orders; institutional fields; institutional change

Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus

Abstract: This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.

Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

Abstract: Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

REVIEW: Wildlife camera trapping: a review and recommendations for linking surveys to ecological processes

Abstract: Summary Reliable assessment of animal populations is a long-standing challenge in wildlife ecology. Technological advances have led to widespread adoption of camera traps (CTs) to survey wildlife distribution, abundance and behaviour. As for any wildlife survey method, camera trapping must contend with sources of sampling error such as imperfect detection. Early applications focused on density estimation of naturally marked species, but there is growing interest in broad-scale CT surveys of unmarked populations and communities. Nevertheless, inferences based on detection indices are controversial, and the suitability of alternatives such as occupancy estimation is debatable. We reviewed 266 CT studies published between 2008 and 2013. We recorded study objectives and methodologies, evaluating the consistency of CT protocols and sampling designs, the extent to which CT surveys considered sampling error, and the linkages between analytical assumptions and species ecology. Nearly two-thirds of studies surveyed more than one species, and a majority used response variables that ignored imperfect detection (e.g. presence–absence, relative abundance). Many studies used opportunistic sampling and did not explicitly report details of sampling design and camera deployment that could affect conclusions. Most studies estimating density used capture–recapture methods on marked species, with spatially explicit methods becoming more prominent. Few studies estimated density for unmarked species, focusing instead on occupancy modelling or measures of relative abundance. While occupancy studies estimated detectability, most did not explicitly define key components of the modelling framework (e.g. a site) or discuss potential violations of model assumptions (e.g. site closure). Studies using relative abundance relied on assumptions of equal detectability, and most did not explicitly define expected relationships between measured responses and underlying ecological processes (e.g. animal abundance and movement). Synthesis and applications. The rapid adoption of camera traps represents an exciting transition in wildlife survey methodology. We remain optimistic about the technology's promise, but call for more explicit consideration of underlying processes of animal abundance, movement and detection by cameras, including more thorough reporting of methodological details and assumptions. Such transparency will facilitate efforts to evaluate and improve the reliability of camera trap surveys, ultimately leading to stronger inferences and helping to meet modern needs for effective ecological inquiry and biodiversity monitoring.

Overview of Power Management Strategies of Hybrid AC/DC Microgrid

Abstract: Today, conventional power systems are evolving to modern smart grids, where interconnected microgrids may dominate the distribution system with high penetration of renewable energy and energy storage systems. The hybrid ac/dc systems with dc and ac sources/loads are considered to be the most possible future distribution or even transmission structures. For such hybrid ac/dc microgrids, power management strategies are one of the most critical operation aspects. This paper presents an overview of power management strategies for a hybrid ac/dc microgrid system, which includes different system structures (ac-coupled, dc-coupled, and ac–dc-coupled hybrid microgrids), different operation modes, a thorough study of various power management and control schemes in both steady state and transient conditions, and examples of power management and control strategies. Finally, discussion and recommendations of power management strategies for the further research are presented.

Peanut shell hybrid sodium ion capacitor with extreme energy–power rivals lithium ion capacitors

Abstract: This is the first report of a hybrid sodium ion capacitor (NIC) with the active materials in both the anode and the cathode being derived entirely from a single precursor: peanut shells, which are a green and highly economical waste globally generated at over 6 million tons per year. The electrodes push the envelope of performance, delivering among the most promising sodiation capacity–rate capability–cycling retention combinations reported in the literature for each materials class. Hence the resultant NIC also offers a state-of-the-art cyclically stable combination of energy and power, not only in respect to previously but also as compared to Li ion capacitors (LICs). The ion adsorption cathode based on Peanut Shell Nanosheet Carbon (PSNC) displays a hierarchically porous architecture, a sheet-like morphology down to 15 nm in thickness, a surface area on par with graphene materials (up to 2396 m2 g−1) and high levels of oxygen doping (up to 13.51 wt%). Scanned from 1.5–4.2 V vs. Na/Na+ PSNC delivers a specific capacity of 161 mA h g−1 at 0.1 A g−1 and 73 mA h g−1 at 25.6 A g−1. A low surface area Peanut Shell Ordered Carbon (PSOC) is employed as an ion intercalation anode. PSOC delivers a total capacity of 315 mA h g−1 with a flat plateau of 181 mA h g−1 occurring below 0.1 V (tested at 0.1 A g−1), and is stable at 10 000 cycles (tested at 3.2 A g−1). The assembled NIC operates within a wide temperature range (0–65 °C), yielding at room temperature (by active mass) 201, 76 and 50 W h kg−1 at 285, 8500 and 16 500 W kg−1, respectively. At 1.5–3.5 V, the hybrid device achieved 72% capacity retention after 10 000 cycles tested at 6.4 A g−1, and 88% after 100 000 cycles at 51.2 A g−1.

Towards a more comprehensive concept for prebiotics

Abstract: The essential role of the gut microbiota for health has generated tremendous interest in modulating its composition and metabolic function. One of these strategies is prebiotics, which typically refer to selectively fermented nondigestible food ingredients or substances that specifically support the growth and/or activity of health-promoting bacteria that colonize the gastrointestinal tract. In this Perspective, we argue that advances in our understanding of diet-microbiome-host interactions challenge important aspects of the current concept of prebiotics, and especially the requirement for effects to be 'selective' or 'specific'. We propose to revise this concept in an effort to shift the focus towards ecological and functional features of the microbiota more likely to be relevant for host physiology. This revision would provide a more rational basis for the identification of prebiotic compounds, and a framework by which the therapeutic potential of modulating the gut microbiota could be more fully materialized.

Minimum Information about a Biosynthetic Gene cluster.

Abstract: A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

Abstract: The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010–2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.

Tackling Grand Challenges Pragmatically: Robust Action Revisited

Abstract: In this article, we theorize a novel approach to addressing the world’s grand challenges based on the philosophical tradition of American pragmatism and the sociological concept of robust action. Grounded in prior empirical organizational research, we identify three robust strategies that organizations can employ in tackling issues such as climate change and poverty alleviation: participatory architecture, multivocal inscriptions and distributed experimentation. We demonstrate how these strategies operate, the manner in which they are linked, the outcomes they generate, and why they are applicable for resolving grand challenges. We conclude by discussing our contributions to research on robust action and grand challenges, as well as some implications for research on stakeholder theory, institutional theory and theories of valuation.

Exercise programs for people with dementia

Abstract: Background This is an update of our previous 2013 review. Several recent trials and systematic reviews of the impact of exercise on people with dementia are reporting promising findings. Objectives Primary objective Do exercise programs for older people with dementia improve their cognition, activities of daily living (ADLs), neuropsychiatric symptoms, depression, and mortality? Secondary objectives Do exercise programs for older people with dementia have an indirect impact on family caregivers’ burden, quality of life, and mortality? Do exercise programs for older people with dementia reduce the use of healthcare services (e.g. visits to the emergency department) by participants and their family caregivers? Search methods We identified trials for inclusion in the review by searching ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register, on 4 September 2011, on 13 August 2012, and again on 3 October 2013. Selection criteria In this review, we included randomized controlled trials in which older people, diagnosed with dementia, were allocated either to exercise programs or to control groups (usual care or social contact/activities) with the aim of improving cognition, ADLs, neuropsychiatric symptoms, depression, and mortality. Secondary outcomes related to the family caregiver(s) and included caregiver burden, quality of life, mortality, and use of healthcare services. Data collection and analysis Independently, at least two authors assessed the retrieved articles for inclusion, assessed methodological quality, and extracted data. We analysed data for summary effects. We calculated mean differences or standardized mean difference (SMD) for continuous data, and synthesized data for each outcome using a fixed-effect model, unless there was substantial heterogeneity between studies, when we used a random-effects model. We planned to explore heterogeneity in relation to severity and type of dementia, and type, frequency, and duration of exercise program. We also evaluated adverse events. Main results Seventeen trials with 1067 participants met the inclusion criteria. However, the required data from three included trials and some of the data from a fourth trial were not published and not made available. The included trials were highly heterogeneous in terms of subtype and severity of participants' dementia, and type, duration, and frequency of exercise. Only two trials included participants living at home. Our meta-analysis revealed that there was no clear evidence of benefit from exercise on cognitive functioning. The estimated standardized mean difference between exercise and control groups was 0.43 (95% CI -0.05 to 0.92, P value 0.08; 9 studies, 409 participants). There was very substantial heterogeneity in this analysis (I² value 80%), most of which we were unable to explain, and we rated the quality of this evidence as very low. We found a benefit of exercise programs on the ability of people with dementia to perform ADLs in six trials with 289 participants. The estimated standardized mean difference between exercise and control groups was 0.68 (95% CI 0.08 to 1.27, P value 0.02). However, again we observed considerable unexplained heterogeneity (I² value 77%) in this meta-analysis, and we rated the quality of this evidence as very low. This means that there is a need for caution in interpreting these findings. In further analyses, in one trial we found that the burden experienced by informal caregivers providing care in the home may be reduced when they supervise the participation of the family member with dementia in an exercise program. The mean difference between exercise and control groups was -15.30 (95% CI -24.73 to -5.87; 1 trial, 40 participants; P value 0.001). There was no apparent risk of bias in this study. In addition, there was no clear evidence of benefit from exercise on neuropsychiatric symptoms (MD -0.60, 95% CI -4.22 to 3.02; 1 trial, 110 participants; P value .0.75), or depression (SMD 0.14, 95% CI -0.07 to 0.36; 5 trials, 341 participants; P value 0.16). We could not examine the remaining outcomes, quality of life, mortality, and healthcare costs, as either the appropriate data were not reported, or we did not retrieve trials that examined these outcomes. Authors' conclusions There is promising evidence that exercise programs may improve the ability to perform ADLs in people with dementia, although some caution is advised in interpreting these findings. The review revealed no evidence of benefit from exercise on cognition, neuropsychiatric symptoms, or depression. There was little or no evidence regarding the remaining outcomes of interest (i.e., mortality, caregiver burden, caregiver quality of life, caregiver mortality, and use of healthcare services).

Diagnostic Criteria for the Classification of Cancer-Associated Weight Loss

Abstract: Purpose Existing definitions of clinically important weight loss (WL) in patients with cancer are unclear and heterogeneous and do not consider current trends toward obesity. Methods Canadian and European patients with cancer (n = 8,160) formed a population-based data set. Body mass index (BMI) and percent WL (%WL) were recorded, and patients were observed prospectively until death. Data were entered into a multivariable analysis controlling for age, sex, cancer site, stage, and performance status. Relationships for BMI and %WL to overall survival were examined to develop a grading system. Results Mean overall %WL was −9.7% ± 8.4% and BMI was 24.4 ± 5.1 kg/m2, and both %WL and BMI independently predicted survival (P < .01). Differences in survival were observed across five categories of BMI (< 20.0, 20.0 to 21.9, 22.0 to 24.9, 25.0 to 27.9, and ≥ 28.0 kg/m2; P < .001) and five categories of %WL (−2.5% to −5.9%, −6.0% to −10.9%, −11.0% to −14.9%, ≥ −15.0%, and weight stable (± 2.4%); P < .001). A 5 × 5 mat...

Hierarchical Density Estimates for Data Clustering, Visualization, and Outlier Detection

Abstract: An integrated framework for density-based cluster analysis, outlier detection, and data visualization is introduced in this article. The main module consists of an algorithm to compute hierarchical estimates of the level sets of a density, following Hartigan’s classic model of density-contour clusters and trees. Such an algorithm generalizes and improves existing density-based clustering techniques with respect to different aspects. It provides as a result a complete clustering hierarchy composed of all possible density-based clusters following the nonparametric model adopted, for an infinite range of density thresholds. The resulting hierarchy can be easily processed so as to provide multiple ways for data visualization and exploration. It can also be further postprocessed so that: (i) a normalized score of “outlierness” can be assigned to each data object, which unifies both the global and local perspectives of outliers into a single definition; and (ii) a “flat” (i.e., nonhierarchical) clustering solution composed of clusters extracted from local cuts through the cluster tree (possibly corresponding to different density thresholds) can be obtained, either in an unsupervised or in a semisupervised way. In the unsupervised scenario, the algorithm corresponding to this postprocessing module provides a global, optimal solution to the formal problem of maximizing the overall stability of the extracted clusters. If partially labeled objects or instance-level constraints are provided by the user, the algorithm can solve the problem by considering both constraints violations/satisfactions and cluster stability criteria. An asymptotic complexity analysis, both in terms of running time and memory space, is described. Experiments are reported that involve a variety of synthetic and real datasets, including comparisons with state-of-the-art, density-based clustering and (global and local) outlier detection methods.

Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research

Abstract: This article reviews current evidence for autism spectrum disorder (ASD) interventions for children aged <3 years, based on peer-reviewed articles published up to December 2013. Several groups have adapted treatments initially designed for older, preschool-aged children with ASD, integrating best practice in behavioral teaching methods into a developmental framework based on current scientific understanding of how infants and toddlers learn. The central role of parents has been emphasized, and interventions are designed to incorporate learning opportunities into everyday activities, capitalize on "teachable moments," and facilitate the generalization of skills beyond the familiar home setting. Our review identified several comprehensive and targeted treatment models with evidence of clear benefits. Although some trials were limited to 8- to 12-week outcome data, enhanced outcomes associated with some interventions were evaluated over periods as long as 2 years. Based on this review, recommendations are proposed for clinical practice and future research.

A combined maximum-likelihood analysis of the high-energy astrophysical neutrino flux measured with icecube

Abstract: Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for neutrino events with deposited energies greater than or similar to 30 TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, nu(mu)-induced tracks from the Northern Hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle, and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index -2.50 +/- 0.09 and a flux at 100 TeV of (6.7(-1.2)(+1.1)) x 10(-18) GeV-1 s(-1) sr(-1) cm(-2). Under the same assumptions, an unbroken power law with index -2 is disfavored with a significance of 3.8 sigma (p = 0.0066%) with respect to the best fit. This significance is reduced to 2.1 sigma (p = 1.7%) if instead we compare the best fit to a spectrum with index -2 that has an exponential cut-off at high energies. Allowing the electron-neutrino flux to deviate from the other two flavors, we find a nu(e) fraction of 0.18 +/- 0.11 at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay-dominated sources, is rejected with a significance of 3.6 sigma ( p = 0.014%).

Phospholipid synthesis and transport in mammalian cells.

Abstract: Membranes of mammalian subcellular organelles contain defined amounts of specific phospholipids that are required for normal functioning of proteins in the membrane. Despite the wide distribution of most phospholipid classes throughout organelle membranes, the site of synthesis of each phospholipid class is usually restricted to one organelle, commonly the endoplasmic reticulum (ER). Thus, phospholipids must be transported from their sites of synthesis to the membranes of other organelles. In this article, pathways and subcellular sites of phospholipid synthesis in mammalian cells are summarized. A single, unifying mechanism does not explain the inter-organelle transport of all phospholipids. Thus, mechanisms of phospholipid transport between organelles of mammalian cells via spontaneous membrane diffusion, via cytosolic phospholipid transfer proteins, via vesicles and via membrane contact sites are discussed. As an example of the latter mechanism, phosphatidylserine (PS) is synthesized on a region of the ER (mitochondria-associated membranes, MAM) and decarboxylated to phosphatidylethanolamine in mitochondria. Some evidence is presented suggesting that PS import into mitochondria occurs via membrane contact sites between MAM and mitochondria. Recent studies suggest that protein complexes can form tethers that link two types of organelles thereby promoting lipid transfer. However, many questions remain about mechanisms of inter-organelle phospholipid transport in mammalian cells.