Showing papers by "University of Western Ontario published in 2015"

Estimating the reproducibility of psychological science

Abstract: Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.

The PRECIS-2 tool: designing trials that are fit for purpose

Abstract: PRECIS is a tool to help trialists make design decisions consistent with the intended purpose of their trial. This paper gives guidance on how to use an improved, validated version, PRECIS-2, which has been developed with the help of over 80 international trialists, clinicians, and policymakers. Keeping the original simple wheel format, PRECIS-2 has nine domains—eligibility criteria, recruitment, setting, organisation, flexibility (delivery), flexibility (adherence), follow-up, primary outcome, and primary analysis—scored from 1 (very explanatory) to 5 (very pragmatic) to facilitate domain discussion and consensus. It is hoped PRECIS-2 will be valuable in supporting the explicit matching of design decisions to how the trial results are intended to be used

Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

Abstract: Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Does Corporate Social Responsibility Lead to Superior Financial Performance? A Regression Discontinuity Approach

Abstract: This study examines the effect of shareholder proposals related to corporate social responsibility CSR on financial performance. Specifically, I focus on CSR proposals that pass or fail by a small margin of votes. The passage of such "close call" proposals is akin to a random assignment of CSR to companies and hence provides a quasi-experiment to study the effect of CSR on performance. I find that the adoption of close call CSR proposals leads to positive announcement returns and superior accounting performance, implying that these proposals are value enhancing. When I examine the channels through which companies benefit from CSR, I find that labor productivity and sales growth increase after the vote. Finally, I document that close call CSR proposals differ from non-close proposals along several dimensions. Accordingly, although my results imply that adopting close call CSR proposals is beneficial to companies, they do not necessarily imply that CSR proposals are beneficial in general. Data, as supplemental material, are available at http://dx.doi.org/10.1287/mnsc.2014.2038 . This paper was accepted by Wei Jiang, finance.

Automatic deception detection: methods for finding fake news

Abstract: This research surveys the current state-of-the-art technologies that are instrumental in the adoption and development of fake news detection. "Fake news detection" is defined as the task of categorizing news along a continuum of veracity, with an associated measure of certainty. Veracity is compromised by the occurrence of intentional deceptions. The nature of online news publication has changed, such that traditional fact checking and vetting from potential deception is impossible against the flood arising from content generators, as well as various formats and genres. The paper provides a typology of several varieties of veracity assessment methods emerging from two major categories -- linguistic cue approaches (with machine learning), and network analysis approaches. We see promise in an innovative hybrid approach that combines linguistic cue and machine learning, with network-based behavioral data. Although designing a fake news detector is not a straightforward problem, we propose operational guidelines for a feasible fake news detecting system.

Incremental Support Vector Learning for Ordinal Regression

Abstract: Support vector ordinal regression (SVOR) is a popular method to tackle ordinal regression problems. However, until now there were no effective algorithms proposed to address incremental SVOR learning due to the complicated formulations of SVOR. Recently, an interesting accurate on-line algorithm was proposed for training $ u $ -support vector classification ( $ u $ -SVC), which can handle a quadratic formulation with a pair of equality constraints. In this paper, we first present a modified SVOR formulation based on a sum-of-margins strategy. The formulation has multiple constraints, and each constraint includes a mixture of an equality and an inequality. Then, we extend the accurate on-line $ u $ -SVC algorithm to the modified formulation, and propose an effective incremental SVOR algorithm. The algorithm can handle a quadratic formulation with multiple constraints, where each constraint is constituted of an equality and an inequality. More importantly, it tackles the conflicts between the equality and inequality constraints. We also provide the finite convergence analysis for the algorithm. Numerical experiments on the several benchmark and real-world data sets show that the incremental algorithm can converge to the optimal solution in a finite number of steps, and is faster than the existing batch and incremental SVOR algorithms. Meanwhile, the modified formulation has better accuracy than the existing incremental SVOR algorithm, and is as accurate as the sum-of-margins based formulation of Shashua and Levin.

Expanding global access to radiotherapy

Abstract: Summary Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015–35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015–35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries—a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015–35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015–35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015–35 (–$14·9 billion in low-income countries; –$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (–$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.

A Survey on Wireless Security: Technical Challenges, Recent Advances and Future Trends

Abstract: This paper examines the security vulnerabilities and threats imposed by the inherent open nature of wireless communications and to devise efficient defense mechanisms for improving the wireless network security. We first summarize the security requirements of wireless networks, including their authenticity, confidentiality, integrity and availability issues. Next, a comprehensive overview of security attacks encountered in wireless networks is presented in view of the network protocol architecture, where the potential security threats are discussed at each protocol layer. We also provide a survey of the existing security protocols and algorithms that are adopted in the existing wireless network standards, such as the Bluetooth, Wi-Fi, WiMAX, and the long-term evolution (LTE) systems. Then, we discuss the state-of-the-art in physical-layer security, which is an emerging technique of securing the open communications environment against eavesdropping attacks at the physical layer. We also introduce the family of various jamming attacks and their counter-measures, including the constant jammer, intermittent jammer, reactive jammer, adaptive jammer and intelligent jammer. Additionally, we discuss the integration of physical-layer security into existing authentication and cryptography mechanisms for further securing wireless networks. Finally, some technical challenges which remain unresolved at the time of writing are summarized and the future trends in wireless security are discussed.

Response assessment criteria for brain metastases: proposal from the RANO group

Abstract: CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

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.

Uber's Drivers: Information Asymmetries and Control in Dynamic Work

Abstract: This empirical study explores labor in the on-demand economy using the rideshare service Uber as a case study. By conducting sustained monitoring of online driver forums and interviewing Uber drivers, we explore worker experiences within the on-demand economy. We argue that Uber’s digitally and algorithmically mediated system of flexible employment builds new forms of surveillance and control into the experience of using the system, which result in asymmetries around information and power for workers. In Uber’s system, algorithms, CSRs, passengers, semiautomated performance evaluations, and the rating system all act as a combined substitute for direct managerial control over drivers, but distributed responsibility for remote worker management also exacerbates power asymmetries between Uber and its drivers. Our study of the Uber driver experience points to the need for greater attention to the role of platform disintermediation in shaping power relations and communications between employers and workers.

Familial Hypercholesterolaemia in Children and Adolescents: Gaining Decades of Life by Optimizing Detection and Treatment

Abstract: Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is 10 years, or ideally 50% reduction from baseline if 8–10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.

Digital inequalities and why they matter

Abstract: While the field of digital inequality continues to expand in many directions, the relationship between digital inequalities and other forms of inequality has yet to be fully appreciated. This article invites social scientists in and outside the field of digital media studies to attend to digital inequality, both as a substantive problem and as a methodological concern. The authors present current research on multiple aspects of digital inequality, defined expansively in terms of access, usage, skills, and self-perceptions, as well as future lines of research. Each of the contributions makes the case that digital inequality deserves a place alongside more traditional forms of inequality in the twenty-first century pantheon of inequalities. Digital inequality should not be only the preserve of specialists but should make its way into the work of social scientists concerned with a broad range of outcomes connected to life chances and life trajectories. As we argue, the significance of digital inequalities is...

Discovery and spectroscopy of the young Jovian planet 51 Eri b with the Gemini Planet Imager

Abstract: Directly detecting thermal emission from young extrasolar planets allows measurement of their atmospheric compositions and luminosities, which are influenced by their formation mechanisms. Using the Gemini Planet Imager, we discovered a planet orbiting the ~20-million-year-old star 51 Eridani at a projected separation of 13 astronomical units. Near-infrared observations show a spectrum with strong methane and water-vapor absorption. Modeling of the spectra and photometry yields a luminosity (normalized by the luminosity of the Sun) of 1.6 to 4.0 × 10(-6) and an effective temperature of 600 to 750 kelvin. For this age and luminosity, "hot-start" formation models indicate a mass twice that of Jupiter. This planet also has a sufficiently low luminosity to be consistent with the "cold-start" core-accretion process that may have formed Jupiter.

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).

Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study.

Abstract: Purpose An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC) If sentinel node (SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided Patients and Methods In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i+], ≤ 02 mm), were considered positive The optimal SNB identification rate (IR) ≥ 90% and false-negative rate (FNR) ≤ 10% were predetermined Results From March 2009 to December 2012, 153 patients were accrued to the study The SNB IR was 876% (127 of 145; 95% CI, 822% to 930%), and the FNR was 84% (seven of 83; 95% CI, 24% to 144%) If SN ypN0(i+)s had been considered negative, the FNR would have increased to 133% (11 of 83;

Insects in Fluctuating Thermal Environments

Abstract: All climate change scenarios predict an increase in both global temperature means and the magnitude of seasonal and diel temperature variation. The nonlinear relationship between temperature and biological processes means that fluctuating temperatures lead to physiological, life history, and ecological consequences for ectothermic insects that diverge from those predicted from constant temperatures. Fluctuating temperatures that remain within permissive temperature ranges generally improve performance. By contrast, those which extend to stressful temperatures may have either positive impacts, allowing repair of damage accrued during exposure to thermal extremes, or negative impacts from cumulative damage during successive exposures. We discuss the mechanisms underlying these differing effects. Fluctuating temperatures could be used to enhance or weaken insects in applied rearing programs, and any prediction of insect performance in the field—including models of climate change or population performance—mus...

SLC transporters as therapeutic targets: emerging opportunities

Abstract: Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids

Abstract: There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Abstract: Background—Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs ...

Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis

Abstract: Summary Background Among patients with atrial fibrillation, the risk of stroke is highest for those with a history of stroke; however, oral anticoagulants can lower the risk of recurrent stroke by two-thirds. No consensus has been reached about how atrial fibrillation should be investigated in patients with stroke, and its prevalence after a stroke remains uncertain. We did a systematic review and meta-analysis to estimate the proportion of patients newly diagnosed with atrial fibrillation after four sequential phases of cardiac monitoring after a stroke or transient ischaemic attack. Methods We searched PubMed, Embase, and Scopus from 1980 to June 30, 2014. We included studies that provided the number of patients with ischaemic stroke or transient ischaemic attack who were newly diagnosed with atrial fibrillation. We stratified cardiac monitoring methods into four sequential phases of screening: phase 1 (emergency room) consisted of admission electrocardiogram (ECG); phase 2 (in hospital) comprised serial ECG, continuous inpatient ECG monitoring, continuous inpatient cardiac telemetry, and in-hospital Holter monitoring; phase 3 (first ambulatory period) consisted of ambulatory Holter; and phase 4 (second ambulatory period) consisted of mobile cardiac outpatient telemetry, external loop recording, and implantable loop recording. The primary endpoint was the proportion of patients newly diagnosed with atrial fibrillation for each method and each phase, and for the sequential combination of phases. For each method and each phase, we estimated the summary proportion of patients diagnosed with post-stroke atrial fibrillation using random-effects meta-analyses. Findings Our systematic review returned 28 290 studies, of which 50 studies (comprising 11 658 patients) met the criteria for inclusion in the meta-analyses. The summary proportion of patients diagnosed with post-stroke atrial fibrillation was 7·7% (95% CI 5·0–10·8) in phase 1, 5·1% (3·8–6·5) in phase 2, 10·7% (5·6–17·2) in phase 3, and 16·9% (13·0–21·2) in phase 4. The overall atrial fibrillation detection yield after all phases of sequential cardiac monitoring was 23·7% (95% CI 17·2–31·0). Interpretation By sequentially combining cardiac monitoring methods, atrial fibrillation might be newly detected in nearly a quarter of patients with stroke or transient ischaemic attack. The overall proportion of patients with stroke who are known to have atrial fibrillation seems to be higher than previously estimated. Accordingly, more patients could be treated with oral anticoagulants and more stroke recurrences prevented. Funding Heart and Stroke Foundation of Canada, and Natural Science and Engineering Research Council of Canada.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Abstract: Exome sequence analysis of nearly 10,000 people was carried out to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) were associated with disease risk, identifying the key roles of low-density lipoprotein cholesterol and metabolism of triglyceride-rich lipoproteins. Sekar Kathiresan and colleagues use exome sequencing of nearly 10,000 people to probe the contribution of multiple rare mutations within a gene to risk for myocardial infarction at a population level. They find that mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) are associated with disease risk. When compared with non-carriers, LDLR mutation carriers had higher plasma levels of LDL cholesterol, whereas APOA5 mutation carriers had higher plasma levels of triglycerides. As well as confirming that APOA5 is a myocardial infarction gene, this work informs the design and conduct of rare-variant association studies for complex diseases. Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3,4,5,6,7,8, whereas common variants at more than 45 loci have been associated with MI risk in the population9,10,11,12,13,14,15. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.