Showing papers by "Laval University published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: In this article, a new representation learning approach for domain adaptation is proposed, in which data at training and test time come from similar but different distributions, and features that cannot discriminate between the training (source) and test (target) domains are used to promote the emergence of features that are discriminative for the main learning task on the source domain.
Abstract: We introduce a new representation learning approach for domain adaptation, in which data at training and test time come from similar but different distributions. Our approach is directly inspired by the theory on domain adaptation suggesting that, for effective domain transfer to be achieved, predictions must be made based on features that cannot discriminate between the training (source) and test (target) domains.
The approach implements this idea in the context of neural network architectures that are trained on labeled data from the source domain and unlabeled data from the target domain (no labeled target-domain data is necessary). As the training progresses, the approach promotes the emergence of features that are (i) discriminative for the main learning task on the source domain and (ii) indiscriminate with respect to the shift between the domains. We show that this adaptation behaviour can be achieved in almost any feed-forward model by augmenting it with few standard layers and a new gradient reversal layer. The resulting augmented architecture can be trained using standard backpropagation and stochastic gradient descent, and can thus be implemented with little effort using any of the deep learning packages.
We demonstrate the success of our approach for two distinct classification problems (document sentiment analysis and image classification), where state-of-the-art domain adaptation performance on standard benchmarks is achieved. We also validate the approach for descriptor learning task in the context of person re-identification application.
4,862 citations
Columbia University1, Scott & White Hospital2, Cedars-Sinai Medical Center3, Cleveland Clinic4, Emory University5, Stanford University6, University of Pennsylvania7, MedStar Washington Hospital Center8, Hospital Corporation of America9, New York University10, Advocate Lutheran General Hospital11, Mayo Clinic12, Primary Children's Hospital13, Laval University14, University of British Columbia15
TL;DR: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke; surgery resulted in fewer major vascular complications and less paravalvular aorta regurgitation.
Abstract: BackgroundPrevious trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. MethodsWe randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. ResultsThe rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan–Meier event...
3,744 citations
Oregon Health & Science University1, University of Bonn2, Icahn School of Medicine at Mount Sinai3, University of Rochester4, Regeneron5, University of Sheffield6, Northwestern University7, Aarhus University8, Centre Hospitalier Universitaire de Nice9, University of Tartu10, Ludwig Maximilian University of Munich11, Charité12, Laval University13, Sanofi S.A.14
TL;DR: Dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo in two phase 3 trials of identical design.
Abstract: BackgroundDupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. MethodsIn two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. ResultsWe enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who...
1,318 citations
TL;DR: The results shed light on sRNA biogenesis and its dietary regulation during posttesticular sperm maturation, and they also link tRNA fragments to regulation of endogenous retroelements active in the preimplantation embryo.
Abstract: Several recent studies link parental environments to phenotypes in subsequent generations. In this work, we investigate the mechanism by which paternal diet affects offspring metabolism. Protein restriction in mice affects small RNA (sRNA) levels in mature sperm, with decreased let-7 levels and increased amounts of 5′ fragments of glycine transfer RNAs (tRNAs). In testicular sperm, tRNA fragments are scarce but increase in abundance as sperm mature in the epididymis. Epididymosomes (vesicles that fuse with sperm during epididymal transit) carry RNA payloads matching those of mature sperm and can deliver RNAs to immature sperm in vitro. Functionally, tRNA-glycine-GCC fragments repress genes associated with the endogenous retroelement MERVL, in both embryonic stem cells and embryos. Our results shed light on sRNA biogenesis and its dietary regulation during posttesticular sperm maturation, and they also link tRNA fragments to regulation of endogenous retroelements active in the preimplantation embryo.
928 citations
Emory University1, Columbia University Medical Center2, Cedars-Sinai Medical Center3, University of Pennsylvania4, New York University5, University of Texas at Austin6, University of Virginia7, Northwestern University8, Cleveland Clinic9, Mayo Clinic10, Intermountain Medical Center11, St. Paul's Hospital12, Laval University13, Georgetown University14, Scott & White Hospital15, Stanford University16, Wake Forest University17
TL;DR: TAVR with SAPIEN 3 in intermediate-risk patients with severe aortic stenosis is associated with low mortality, strokes, and regurgitation at 1 year after implantation, and a significant superiority for the composite outcome with TAVR compared with surgery is indicated.
840 citations
University of Calgary1, Montreal Heart Institute2, University of Alberta3, Laval University4, University of British Columbia5, McGill University Health Centre6, McGill University7, University of Toronto8, McMaster University9, Robarts Research Institute10, Population Health Research Institute11, University of Ottawa12, Alberta Health Services13
TL;DR: Risk assessment and lipid determination should be considered in individuals older than 40 years of age or in those at increased risk regardless of age, and recommendation for the use of nonstatin medications is provided.
805 citations
Duke University1, Icahn School of Medicine at Mount Sinai2, University of Virginia3, Emory University4, University of Pennsylvania5, Harvard University6, Université de Montréal7, Cleveland Clinic8, Columbia University9, University of Toronto10, Mount Sinai Hospital11, National Institutes of Health12, University of Maryland, Baltimore13, Laval University14
TL;DR: Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias.
Abstract: BackgroundIn a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. MethodsWe randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. ResultsAt 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, −14.1 ml per square meter and −14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-...
772 citations
University of Helsinki1, University of Oulu2, University of Turku3, University of Tampere4, Turku University Hospital5, Hannover Medical School6, University of Cambridge7, Netherlands Cancer Institute8, Institute of Cancer Research9, University of Melbourne10, University of California, Los Angeles11, University of Erlangen-Nuremberg12, University of London13, King's College London14, Wellcome Trust Centre for Human Genetics15, German Cancer Research Center16, Heidelberg University17, French Institute of Health and Medical Research18, University of Copenhagen19, Copenhagen University Hospital20, Beckman Research Institute21, University of California, Irvine22, Technische Universität München23, University of Cologne24, Bosch25, University of Tübingen26, Ruhr University Bochum27, Karolinska Institutet28, University of Eastern Finland29, QIMR Berghofer Medical Research Institute30, Katholieke Universiteit Leuven31, University of Hamburg32, Mayo Clinic33, Cancer Council Victoria34, University of Southern California35, Laval University36, The Breast Cancer Research Foundation37, Oslo University Hospital38, Vanderbilt University39, Oulu University Hospital40, University of Toronto41, Lunenfeld-Tanenbaum Research Institute42, Leiden University Medical Center43, Erasmus University Rotterdam44, Erasmus University Medical Center45, University of Sheffield46, Pontifical Xavierian University47, Pomeranian Medical University48
TL;DR: It is suggested that loss-of-function mutations in RAD 51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
715 citations
03 Mar 2016
TL;DR: The introduction of transcatheter AVR in the past decade has been a transformative therapeutic innovation for patients at high or prohibitive risk for surgical valve replacement, and this new technology might extend to lower-risk patients in the near future.
Abstract: Calcific aortic stenosis (AS) is the most prevalent heart valve disorder in developed countries. It is characterized by progressive fibro-calcific remodelling and thickening of the aortic valve leaflets that, over years, evolve to cause severe obstruction to cardiac outflow. In developed countries, AS is the third-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old. Congenital abnormality (bicuspid valve) and older age are powerful risk factors for calcific AS. Metabolic syndrome and an elevated plasma level of lipoprotein(a) have also been associated with increased risk of calcific AS. The pathobiology of calcific AS is complex and involves genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of cardiac valve interstitial cells and active leaflet calcification. Although no pharmacotherapy has proved to be effective in reducing the progression of AS, promising therapeutic targets include lipoprotein(a), the renin-angiotensin system, receptor activator of NF-κB ligand (RANKL; also known as TNFSF11) and ectonucleotidases. Currently, aortic valve replacement (AVR) remains the only effective treatment for severe AS. The diagnosis and staging of AS are based on the assessment of stenosis severity and left ventricular systolic function by Doppler echocardiography, and the presence of symptoms. The introduction of transcatheter AVR in the past decade has been a transformative therapeutic innovation for patients at high or prohibitive risk for surgical valve replacement, and this new technology might extend to lower-risk patients in the near future.
532 citations
Population Health Research Institute1, McMaster University2, Peking Union Medical College3, St. John's University4, University of Cape Town5, University of the Philippines Manila6, Semmelweis University7, University of Amsterdam8, Uppsala University9, UCSI University10, Technion – Israel Institute of Technology11, Charles University in Prague12, National Academy of Sciences of Ukraine13, University of Leicester14, Glenfield Hospital15, Monash University16, Curtin University17, University of Toronto18, University of Caldas19, Laval University20
TL;DR: Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a doses of 12.5mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease.
Abstract: BackgroundAntihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear. MethodsIn one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years. ResultsThe mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo...
University of Sheffield1, University of Southampton2, University of Manitoba3, University of Lausanne4, Lyon College5, Laval University6, VU University Medical Center7, Kindai University8, McGill University Health Centre9, Lund University10, Uppsala University Hospital11, Deakin University12, Nara Medical University13, The Chinese University of Hong Kong14, University of Gothenburg15, Erasmus University Medical Center16, Osaka Medical College17
TL;DR: The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.
Abstract: Trabecular bone score (TBS) is a grey-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a BMD-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables and outcomes during follow up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% CI: 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR 1.32, 95%CI: 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95%CI: 1.65, 1.87 vs. 1.70, 95%CI: 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. This article is protected by copyright. All rights reserved.
TL;DR: The aim is to present the final template and provide an Explanation and Elaboration Statement to operationalise the 16-item Consensus on Exercise Reporting Template (CERT), which has the potential to increase clinical uptake of effective exercise programmes, enable research replication, reduce research waste and improve patient outcomes.
Abstract: Exercise is effective for prevention and management of acute and chronic health conditions. However, trial descriptions of exercise interventions are often suboptimal, leaving readers unclear about the content of effective programmes. To address this, the 16-item internationally endorsed Consensus on Exercise Reporting Template (CERT) was developed. The aim is to present the final template and provide an Explanation and Elaboration Statement to operationalise the CERT. Development of the CERT was based on the EQUATOR Network methodological framework for developing reporting guidelines. We used a modified Delphi technique to gain consensus of international exercise experts and conducted 3 sequential rounds of anonymous online questionnaires and a Delphi workshop. The 16-item CERT is the minimum data set considered necessary to report exercise interventions. The contents may be included in online supplementary material, published as a protocol or located on websites and other electronic repositories. The Explanation and Elaboration Statement is intended to enhance the use, understanding and dissemination of the CERT and presents the meaning and rationale for each item, together with examples of good reporting. The CERT is designed specifically for the reporting of exercise programmes across all evaluative study designs for exercise research. The CERT can be used by authors to structure intervention reports, by reviewers and editors to assess completeness of exercise descriptions and by readers to facilitate the use of the published information. The CERT has the potential to increase clinical uptake of effective exercise programmes, enable research replication, reduce research waste and improve patient outcomes.
University of Calgary1, McGill University Health Centre2, Université du Québec à Trois-Rivières3, University of British Columbia4, Université de Montréal5, Laval University6, University of Alberta7, University of Toronto8, Ottawa Hospital Research Institute9, Hôpital Maisonneuve-Rosemont10, Memorial University of Newfoundland11, Centre for Addiction and Mental Health12, University of Ottawa13, McGill University14, University Health Network15, University of Western Ontario16, University of Saskatchewan17, University of Manitoba18, Concordia University Wisconsin19, Montreal General Hospital20, Heart and Stroke Foundation of Canada21, Dalhousie University22, Libin Cardiovascular Institute of Alberta23, Université de Sherbrooke24, McMaster University25, Université du Québec à Montréal26, Montreal Heart Institute27, Canadian Stroke Network28, Department of National Defence29, Simon Fraser University30, St George's, University of London31, Centre Hospitalier Universitaire Sainte-Justine32, Children's Hospital of Eastern Ontario33
TL;DR: In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure as mentioned in this paper.
TL;DR: RPA is becoming a molecular tool of choice for the rapid, specific, and cost-effective identification of pathogens and the detection of single nucleotide polymorphisms in human cancers and genetically modified organisms.
Abstract: BACKGROUND: First introduced in 2006, recombinase polymerase amplification (RPA) has stirred great interest, as evidenced by 75 publications as of October 2015, with 56 of them just in the last 2 years. The widespread adoption of this isothermal molecular tool in many diagnostic fields represents an affordable (approximately 4.3 USD per test), simple (few and easy hands-on steps), fast (results within 5–20 min), and sensitive (single target copy number detected) method for the identification of pathogens and the detection of single nucleotide polymorphisms in human cancers and genetically modified organisms.
CONTENT: This review summarizes the current knowledge on RPA. The molecular diagnostics of various RNA/DNA pathogens is discussed while highlighting recent applications in clinical settings with focus on point-of-care (POC) bioassays and on automated fluidic platforms. The strengths and limitations of this isothermal method are also addressed.
SUMMARY: RPA is becoming a molecular tool of choice for the rapid, specific, and cost-effective identification of pathogens. Owing to minimal sample-preparation requirements, low operation temperature (25–42 °C), and commercial availability of freeze-dried reagents, this method has been applied outside laboratory settings, in remote areas, and interestingly, onboard automated sample-to-answer microfluidic devices. RPA is undoubtedly a promising isothermal molecular technique for clinical microbiology laboratories and emergence response in clinical settings.
University of Liège1, Laval University2, Oslo University Hospital3, Leiden University Medical Center4, University of Edinburgh5, University of Cambridge6, French Institute of Health and Medical Research7, Erasmus University Rotterdam8, Medical University of Vienna9, François Rabelais University10, University of São Paulo11, Valparaiso University12, Chinese PLA General Hospital13, Shandong University14, Aix-Marseille University15
TL;DR: The present document provides recommendations for the use of multimodality imaging in the assessment of PHVs.
Abstract: Prosthetic heart valve (PHV) dysfunction is rare but potentially life-threatening. Although often challenging, establishing the exact cause of PHV dysfunction is essential to determine the appropriate treatment strategy. In clinical practice, a comprehensive approach that integrates several parameters of valve morphology and function assessed with 2D/3D transthoracic and transoesophageal echocardiography is a key to appropriately detect and quantitate PHV dysfunction. Cinefluoroscopy, multidetector computed tomography, cardiac magnetic resonance imaging, and to a lesser extent, nuclear imaging are complementary tools for the diagnosis and management of PHV complications. The present document provides recommendations for the use of multimodality imaging in the assessment of PHVs.
Population Health Research Institute1, National University of Ireland, Galway2, Laval University3, Providence Health Care4, Simon Fraser University5, McMaster University6, University of La Frontera7, Cardiovascular Institute of the South8, Centers for Disease Control and Prevention9, Aga Khan University10, St. John's University11, Independent University, Bangladesh12, Universiti Teknologi MARA13, Wrocław Medical University14, Istanbul Medeniyet University15, University of Gothenburg16, Isfahan University of Medical Sciences17, Dubai Health Authority18, North-West University19, College of Health Sciences, Bahrain20, University of Erlangen-Nuremberg21
TL;DR: Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increasedrisk of cardiovascular Events and death is observed in those with or without hypertension.
TL;DR: A systematic literature search on four electronic databases provided a set of key elements making it possible to understand the challenges and opportunities for m-health utilization by healthcare providers.
TL;DR: The successful application of DHAP now leads to nearly defect-free conjugated polymers possessing comparable, if not slightly better, characteristics than their counterparts prepared using classical cross-coupling methods.
Abstract: Direct (hetero)arylation polymerization (DHAP) has recently been established as an environmentally benign method for the preparation of conjugated polymers. This synthetic tool features the formation of C–C bonds between halogenated (hetero)arenes and simple (hetero)arenes with active C–H bonds, thereby circumventing the preparation of organometallic derivatives and decreasing the overall production cost of conjugated polymers. Since its inception, selectivity and reactivity of DHAP procedures have been improved tremendously through the careful scrutinity of polymerization outcomes and the fine-tuning of reaction conditions. A broad range of monomers, from simple arenes to complex functionalized heteroarenes, can now be readily polymerized. The successful application of DHAP now leads to nearly defect-free conjugated polymers possessing comparable, if not slightly better, characteristics than their counterparts prepared using classical cross-coupling methods. This comprehensive review describes the mechan...
TL;DR: The CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases, suggesting that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions.
Abstract: The CB2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role. In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases. In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions. Herein, we review the pharmacology of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation. Finally, we discuss the possible therapies targeting the CB2 receptor and the questions that remain to be addressed to determine whether this receptor could be a potential target to treat inflammatory disease.
Queen Elizabeth II Health Sciences Centre1, University College London2, University of Cambridge3, Toronto Western Hospital4, University of Birmingham5, Hanyang University6, McGill University Health Centre7, University of Calgary8, University of California, Los Angeles9, Oklahoma Medical Research Foundation10, SUNY Downstate Medical Center11, Laval University12, Johns Hopkins University School of Medicine13, Central Manchester University Hospitals NHS Foundation Trust14, University of North Carolina at Chapel Hill15, Northwestern University16, The Feinstein Institute for Medical Research17, University of Alabama at Birmingham18, University of Pittsburgh19, King's College London20, Karolinska Institutet21, Hairmyres Hospital22, University of the Basque Country23, Emory University24, Istanbul University25, University of California, San Diego26, Medical University of South Carolina27, University of Manitoba28, Copenhagen University Hospital29, New York University30
TL;DR: Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life.
Abstract: Objective. To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort.
Methods. Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores.
Results. There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values.
Conclusion. LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.
TL;DR: The result of long-term clinical study and systematic investigation of bone formation mechanism of the biodegradable Mg-5wt%Ca-1wt%Zn alloy implant is reported through simultaneous observation of changes in element composition and crystallinity within degrading interface at hierarchical levels.
Abstract: There has been a tremendous amount of research in the past decade to optimize the mechanical properties and degradation behavior of the biodegradable Mg alloy for orthopedic implant. Despite the feasibility of degrading implant, the lack of fundamental understanding about biocompatibility and underlying bone formation mechanism is currently limiting the use in clinical applications. Herein, we report the result of long-term clinical study and systematic investigation of bone formation mechanism of the biodegradable Mg-5wt%Ca-1wt%Zn alloy implant through simultaneous observation of changes in element composition and crystallinity within degrading interface at hierarchical levels. Controlled degradation of Mg-5wt%Ca-1wt%Zn alloy results in the formation of biomimicking calcification matrix at the degrading interface to initiate the bone formation process. This process facilitates early bone healing and allows the complete replacement of biodegradable Mg implant by the new bone within 1 y of implantation, as demonstrated in 53 cases of successful long-term clinical study.
TL;DR: The 4th International Patellofemoral Research Retreat was held in Manchester, UK, over 3 days (September 2–4th, 2015) and developed a consensus statement addressing different presentation categories, including PFP and factors that influence PFP.
Abstract: Patellofemoral pain (PFP) typically presents as diffuse anterior knee pain, usually with activities such as squatting, running, stair ascent and descent. It is common in active individuals across the lifespan,1–4 and is a frequent cause for presentation at physiotherapy, general practice, orthopaedic and sports medicine clinics in particular.5 ,6 Its impact is profound, often reducing the ability of those with PFP to perform sporting, physical activity and work-related activities pain-free. Increasing evidence suggests that it is a recalcitrant condition, persisting for many years.7–9 In an attempt to share recent innovations, build on the first three successful biennial retreats and define the ‘state of the art’ for this common, impactful condition; the 4th International Patellofemoral Pain Research Retreat was convened.
The 4th International Patellofemoral Research Retreat was held in Manchester, UK, over 3 days (September 2–4th, 2015). After undergoing peer-review for scientific merit and relevance to the retreat, 67 abstracts were accepted for the retreat (50 podium presentations, and 17 short presentations). The podium and short presentations were grouped into five categories; (1) PFP, (2) factors that influence PFP (3) the trunk and lower extremity (4) interventions and (5) systematic analyses. Three keynote speakers were chosen for their scientific contribution in the area of PFP. Professor Andrew Amis spoke on the biomechanics of the patellofemoral joint. Professor David Felson spoke on patellofemoral arthritis,10 and Dr Michael Ratleff's keynote theme was PFP in the adolescent patient.11 As part of the retreat, we held structured, whole-group discussions in order to develop consensus relating to the work presented at the meeting as well as evidence gathered from the literature.
### Consensus development process
In our past three International Patellofemoral Research Retreats, we developed a consensus statement addressing different presentation categories.12–14 In Manchester in 2015, we revised the format. For the exercise and …
University of Oxford1, University of York2, Queen Mary University of London3, Imperial College London4, University of London5, University of Plymouth6, University of Manchester7, University of Exeter8, McGill University9, Østfold University College10, University of Alberta11, Stony Brook University12, Rutgers University13, University of St Andrews14, Nottingham Trent University15, University of Leicester16, Dartmouth College17, University of Oslo18, King's College London19, University College London20, University of Southampton21, Laval University22, University of Wolverhampton23, University of Cape Town24, University of Sydney25, Radboud University Nijmegen26, University of Toronto27, Durham University28, University of Rochester29, Cardiff University30, University of Auckland31, University of Western Ontario32, University of Glasgow33, University of Birmingham34, University of Aberdeen35, Portland State University36, University of Utah37, University of Nottingham38, Bangor University39, University of North Carolina at Chapel Hill40, RAND Corporation41, University of British Columbia42, Karolinska Institutet43, University of Stirling44, Brunel University London45
TL;DR: Seventy six senior academics from 11 countries invite The BMJ ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority.
Abstract: Seventy six senior academics from 11 countries invite The BMJ ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority. They challenge the journal to develop a proactive, scholarly, and pluralist approach to research that aligns with its stated mission
Columbia University Medical Center1, Emory University2, Northwestern University3, University of Virginia4, Mayo Clinic5, New York University6, NorthShore University HealthSystem7, Brigham and Women's Hospital8, Cleveland Clinic9, University of Pennsylvania10, Laval University11, Georgetown University12, St. Paul's Hospital13, Intermountain Medical Center14, Cedars-Sinai Medical Center15, Scott & White Hospital16
TL;DR: The next-generation SAPIEN 3 THV system was associated with low rates of 30-day mortality and major/disabling stroke as well asLow rates of moderate or severe paravalvular regurgitation.
Abstract: Aims Based on randomized trials using first-generation devices, transcatheter aortic valve replacement (TAVR) is well established in the treatment of high-risk (HR) patients with severe aortic stenosis (AS). To date, there is a paucity of adjudicated, prospective data evaluating outcomes with newer generation devices and in lower risk patients. We report early outcomes of a large, multicentre registry of inoperable, HR, and intermediate-risk (IR) patients undergoing treatment with the next-generation SAPIEN 3 transcatheter heart valve (THV).
Methods and results Patients with severe, symptomatic AS (583 high surgical risk or inoperable and 1078 IR) were enrolled in a multicentre, non-randomized registry at 57 sites in the USA and Canada. All patients received TAVR with the SAPIEN 3 system via transfemoral ( n = 1443, 86.9%) and transapical or transaortic ( n = 218, 13.1%) access routes. The rate of 30-day all-cause mortality was 2.2% in HR/inoperable patients [mean Society of Thoracic Surgeons (STS) score 8.7%] and 1.1% in IR patients (mean STS score 5.3%); cardiovascular mortality was 1.4 and 0.9%, respectively. In HR/inoperable patients, the 30-day rate of major/disabling stroke was 0.9%, major bleeding 14.0%, major vascular complications 5.1%, and requirement for permanent pacemaker 13.3%. In IR patients, the 30-day rate of major/disabling stroke was 1.0%, major bleeding 10.6%, major vascular complications 6.1%, and requirement for permanent pacemaker 10.1%. Mean overall Kansas City Cardiomyopathy Questionnaire score increased from 47.8 to 67.8 (HR/inoperable, P < 0.0001) and 54.7 to 74.0 (IR, P < 0.0001). Overall, paravalvular regurgitation at 30 days was none/trace in 55.9% of patients, mild in 40.7%, moderate in 3.4%, and severe in 0.0%. Mean gradients among patients with paired baseline and 30-day or discharge echocardiograms decreased from 45.8 mmHg at baseline to 11.4 mmHg at 30 days, while aortic valve area increased from 0.69 to 1.67 cm2.
Conclusions The SAPIEN 3 THV system was associated with low rates of 30-day mortality and major/disabling stroke as well as low rates of moderate or severe paravalvular regurgitation.
Trial Registration ClinicalTrials.gov #[NCT01314313][1].
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01314313&atom=%2Fehj%2F37%2F28%2F2252.atom
TL;DR: The present review is dedicated to the problematic of IEM fouling phenomena, which includes the methods of fouling visualization and characterization as well as methods allowing investigations of characteristics of the fouled IEMs.
TL;DR: Zn-0.5Mg is the most promising material for stent applications with a good combination of strength, ductility, strain hardening exponent and an appropriate rate of loss of mechanical integrity during degradation.
Abstract: The search for a degradable metal simultaneously showing mechanical properties equal or higher to that of stainless steel and uniform degradation is still an open challenge. Several magnesium-based alloys have been studied, but their degradation rate has proved to be too fast and rarely homogeneous. Fe-based alloys show appropriate mechanical properties but very low degradation rate. In the present work, four novel Zn-Mg and two Zn-Al binary alloys were investigated as potential biodegradable materials for stent applications. The alloys were developed by casting process and homogenized at 350°C for 48h followed by hot extrusion at 250°C. Tube extrusion was performed at 300°C to produce tubes with outer/inner diameter of 4/1.5mm as precursors for biodegradable stents. Corrosion tests were performed using Hanks׳ modified solution. Extruded alloys exhibited slightly superior corrosion resistance and slower degradation rate than those of their cast counterparts, but all had corrosion rates roughly half that of a standard purity Mg control. Hot extrusion of Zn-Mg alloys shifted the corrosion regime from localized pitting to more uniform erosion, mainly due to the refinement of second phase particles. Zn-0.5Mg is the most promising material for stent applications with a good combination of strength, ductility, strain hardening exponent and an appropriate rate of loss of mechanical integrity during degradation. An EBSD analysis in the vicinity of the laser cut Zn-0.5Mg tube found no grain coarsening or texture modification confirming that, after laser cutting, the grain size and texture orientation of the final stent remains unchanged. This work shows the potential for Zn alloys to be considered for stent applications.
TL;DR: In this paper, a complete review of uncertainty modeling approaches for power system studies is presented, making sense about the strengths and weakness of these methods. But, when some of the system uncertain variables are probabilistic and some are possibilistic, neither the conventional pure probability nor pure possibiliistic methods can be implemented.
Abstract: As a direct consequence of power systems restructuring on one hand and unprecedented renewable energy utilization on the other, the uncertainties of power systems are getting more and more attention. This fact intensifies the difficulty of decision making in the power system context; therefore, the uncertainty analysis of the system performance seems necessary. Generally, uncertainties in any engineering system study can be represented probabilistically or possibilistically. When sufficient historical data of the system variables is not available, a probability density function (PDF) might not be defined, they must be represented in another manner i.e. using possibilistic theory. When some of the system uncertain variables are probabilistic and some are possibilistic, neither the conventional pure probabilistic nor pure possibilistic methods can be implemented. Hence, a combined solution is needed. This paper gives a complete review on uncertainty modeling approaches for power system studies making sense about the strengths and weakness of these methods. This work may be used in order to select the most appropriate method for each application.
TL;DR: The measurement properties of commonly used exercise tests in patients with chronic respiratory diseases and published studies on their utilty and/or evaluation obtained from MEDLINE and Cochrane Library searches are reviewed.
Abstract: This document reviews 1) the measurement properties of commonly used exercise tests in patients with chronic respiratory diseases and 2) published studies on their utilty and/or evaluation obtained from MEDLINE and Cochrane Library searches between 1990 and March 2015.Exercise tests are reliable and consistently responsive to rehabilitative and pharmacological interventions. Thresholds for clinically important changes in performance are available for several tests. In pulmonary arterial hypertension, the 6-min walk test (6MWT), peak oxygen uptake and ventilation/carbon dioxide output indices appear to be the variables most responsive to vasodilators. While bronchodilators do not always show clinically relevant effects in chronic obstructive pulmonary disease, high-intensity constant work-rate (endurance) tests (CWRET) are considerably more responsive than incremental exercise tests and 6MWTs. High-intensity CWRETs need to be standardised to reduce interindividual variability. Additional physiological information and responsiveness can be obtained from isotime measurements, particularly of inspiratory capacity and dyspnoea. Less evidence is available for the endurance shuttle walk test. Although the incremental shuttle walk test and 6MWT are reliable and less expensive than cardiopulmonary exercise testing, two repetitions are needed at baseline. All exercise tests are safe when recommended precautions are followed, with evidence suggesting that no test is safer than others.
University of Liège1, Mayo Clinic2, Katholieke Universiteit Leuven3, Icahn School of Medicine at Mount Sinai4, University of Rennes5, Oslo University Hospital6, HealthPartners7, Yonsei University8, Emory University9, University of Toronto10, Laval University11, National Research Council12, Ohio State University13, University of São Paulo14, University of Szeged15
TL;DR: Recommendations for further investigation into the application and performance of stress echocardiography in the evaluation of non-ischaemic heart disease are summarized.
Abstract: A unique and highly versatile technique, stress echocardiography (SE) is increasingly recognized for its utility in the evaluation of non-ischaemic heart disease. SE allows for simultaneous assessment of myocardial function and haemodynamics under physiological or pharmacological conditions. Due to its diagnostic and prognostic value, SE has become widely implemented to assess various conditions other than ischaemic heart disease. It has thus become essential to establish guidance for its applications and performance in the area of non-ischaemic heart disease. This paper summarizes these recommendations.