Showing papers by "University of Glasgow published in 2014"
TL;DR: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure and decreased the symptoms and physical limitations of heart failure.
Abstract: Background We compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results The trial was stopped early, according to prespecified rules, after a median followup of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.)
4,727 citations
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
TL;DR: In this article, a comparative in vivo metabolomic analysis was conducted to identify widely conserved metabolic pathways responsible for mitochondrial reactive oxygen species (ROS) production during ischaemia reperfusion.
Abstract: Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.
1,775 citations
Clinical Trial Service Unit1, University of Glasgow2, Cedars-Sinai Medical Center3, Stanford University4, Boehringer Ingelheim5, Mayo Clinic6, University of Edinburgh7, University of Melbourne8, Florey Institute of Neuroscience and Mental Health9, University of Texas Health Science Center at Houston10, University of Alabama at Birmingham11, Helsinki University Central Hospital12, The George Institute for Global Health13, University of Newcastle14, Sapienza University of Rome15, Karolinska Institutet16, University of Washington17, Heidelberg University18
TL;DR: In this paper, a pre-specifi ed meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control was conducted.
1,773 citations
TL;DR: ConCOCT, a new algorithm that combines sequence composition and coverage across multiple samples, to automatically cluster contigs into genomes is presented, demonstrating high recall and precision on artificial as well as real human gut metagenome data sets.
Abstract: Shotgun sequencing enables the reconstruction of genomes from complex microbial communities, but because assembly does not reconstruct entire genomes, it is necessary to bin genome fragments. Here we present CONCOCT, a new algorithm that combines sequence composition and coverage across multiple samples, to automatically cluster contigs into genomes. We demonstrate high recall and precision on artificial as well as real human gut metagenome data sets.
1,460 citations
TL;DR: The current state of the art in this field is summarized, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and a European consortium of PDX models is introduced.
Abstract: Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. Significance: PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field. Cancer Discov; 4(9); 998–1013. ©2014 AACR .
1,309 citations
TL;DR: The anatomical and physiological distinctions that are observed in the small and large intestines are detailed, and it is suggested how these may account for the diversity in the immune apparatus that is seen throughout the intestine.
Abstract: The intestine represents the largest compartment of the immune system. It is continually exposed to antigens and immunomodulatory agents from the diet and the commensal microbiota, and it is the port of entry for many clinically important pathogens. Intestinal immune processes are also increasingly implicated in controlling disease development elsewhere in the body. In this Review, we detail the anatomical and physiological distinctions that are observed in the small and large intestines, and we suggest how these may account for the diversity in the immune apparatus that is seen throughout the intestine. We describe how the distribution of innate, adaptive and innate-like immune cells varies in different segments of the intestine and discuss the environmental factors that may influence this. Finally, we consider the implications of regional immune specialization for inflammatory disease in the intestine.
1,094 citations
TL;DR: The value of the ratio of branching fractions for the dilepton invariant mass squared range 1 < q(2) < 6 GeV(2)/c(4) is measured to be 0.745(-0.074)(+0.090)(stat) ± 0.036(syst).
Abstract: A measurement of the ratio of the branching fractions of the B+→K+μ+μ− and B+→K+e+e− decays is presented using proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb−1, recorded with the LHCb experiment at center-of-mass energies of 7 and 8 TeV. The value of the ratio of branching fractions for the dilepton invariant mass squared range 1
1,017 citations
TL;DR: This work demonstrates a 32-Gbit’s−1 millimetre-wave link over 2.5 metres with a spectral efficiency of ~16 bit s− 1 Hz−1 using four independent orbital–angular momentum beams on each of two polarizations, and shows an 8-Gbits−1 link containing two orbital angular momentum beams with crosstalk less than −12.5 dB.
Abstract: One property of electromagnetic waves that has been recently explored is the ability to multiplex multiple beams, such that each beam has a unique helical phase front. The amount of phase front ‘twisting’ indicates the orbital angular momentum state number, and beams with different orbital angular momentum are orthogonal. Such orbital angular momentum based multiplexing can potentially increase the system capacity and spectral efficiency of millimetre-wave wireless communication links with a single aperture pair by transmitting multiple coaxial data streams. Here we demonstrate a 32-Gbit s−1 millimetre-wave link over 2.5 metres with a spectral efficiency of ~16 bit s−1 Hz−1 using four independent orbital–angular momentum beams on each of two polarizations. All eight orbital angular momentum channels are recovered with bit-error rates below 3.8 × 10−3. In addition, we demonstrate a millimetre-wave orbital angular momentum mode demultiplexer to demultiplex four orbital angular momentum channels with crosstalk less than −12.5 dB and show an 8-Gbit s−1 link containing two orbital angular momentum beams on each of two polarizations. High speed data transmission using orbital angular momentum beams has been recently demonstrated. Here, Yan et al. demonstrate a 32 Gbit/s millimetre-wave communication link using eight coaxially propagating independent orbital angular momentum beams with four orbital angular momentum states on two orthogonal polarizations.
1,002 citations
SUNY Downstate Medical Center1, McGill University2, University of Connecticut3, Cornell University4, Umeå University5, Wayne State University6, University of Iowa7, University of Miami8, University of Pennsylvania9, Mayo Clinic10, University of Sydney11, University of Buenos Aires12, University of Chicago13, Shanghai Jiao Tong University14, North-West University15, University of Rochester16, University of Glasgow17, Virginia Commonwealth University18, University of Melbourne19
TL;DR: Clinical Practice Guidelines for the Management of Hypertension in the Community as mentioned in this paper A Statement by the American Society of hypertension and the International Society of Hyperpharmension (ISH).
Abstract: Clinical Practice Guidelines for the Management of Hypertension in the Community A Statement by the American Society of Hypertension and the International Society of Hypertension
920 citations
TL;DR: How cell adhesions interact with nanotopography is discussed, and insight is provided as to how materials scientists can exploit these interactions to direct stem cell fate and to understand how the behaviour of stem cells in their niche can be controlled.
Abstract: Stem cells respond to nanoscale surface features, with changes in cell growth and differentiation mediated by alterations in cell adhesion. The interaction of nanotopographical features with integrin receptors in the cells' focal adhesions alters how the cells adhere to materials surfaces, and defines cell fate through changes in both cell biochemistry and cell morphology. In this Review, we discuss how cell adhesions interact with nanotopography, and we provide insight as to how materials scientists can exploit these interactions to direct stem cell fate and to understand how the behaviour of stem cells in their niche can be controlled. We expect knowledge gained from the study of cell-nanotopography interactions to accelerate the development of next-generation stem cell culture materials and implant interfaces, and to fuel discovery of stem cell therapeutics to support regenerative therapies.
TL;DR: It is shown that R2 GLMM can be extended to random slopes models using a simple formula that is straightforward to implement in statistical software and substantially widens the potential application of R2GLMM.
Abstract: Nakagawa & Schielzeth extended the widely used goodness-of-fit statistic R2 to apply to generalized linear mixed models (GLMMs). However, their R2GLMM method is restricted to models with the simplest random effects structure, known as random intercepts models. It is not applicable to another common random effects structure, random slopes models.
I show that R2GLMM can be extended to random slopes models using a simple formula that is straightforward to implement in statistical software. This extension substantially widens the potential application of R2GLMM.
Keywords: coefficient of determination, generalized linear mixed model, random slopes model, random regression
Introduction
The coefficient of determination, R2, is a widely used statistic for assessing the goodness-of-fit, on a scale from 0 to 1, of a linear regression model (LM). It is defined as the proportion of variance in the response variable that is explained by the explanatory variables or, equivalently, the proportional reduction in unexplained variance. Unexplained variance can be viewed as variance in model prediction error, so R2 can also be defined in terms of reduction in prediction error variance. Insofar as it is justifiable to make the leap from ‘prediction’ to ‘understanding’, R2 can be intuitively interpreted as a measure of how much better we understand a system once we have measured and modelled some of its components.
R2 has been extended to apply to generalized linear models (GLMs) (Maddala 1983) and linear mixed effects models (LMMs) (Snijders & Bosker 1994) [reviewed by (Nakagawa & Schielzeth 2013)]. Nakagawa & Schielzeth (2013) proposed a further generalization of R2 to generalized linear mixed effects models (GLMMs), a useful advance given the ubiquity of GLMMs for data analysis in ecology and evolution (Bolker et al. 2009). A function to estimate this R2GLMM statistic, r.squaredGLMM, has been included in the MuMIn package (Barton 2014) for the R statistical software (R Core Team 2014). However, Nakagawa and Schielzeth's R2GLMM formula is applicable to only a subset of GLMMs known as random intercepts models. Random intercepts models are used to model clustered observations, for example, where multiple observations are taken on each of a sample of individuals. Correlations between clustered observations within individuals are accounted for by allowing each subject to have a different intercept representing the deviation of that subject from the global intercept. Random intercepts are typically modelled as being sampled from a normal distribution with mean zero and a variance parameter that is estimated from the data. Although random intercepts are probably the most popular random effects models in ecology and evolution, other random effect specifications are also common, in particular random slopes models, where not only the intercept but also the slope of the regression line is allowed to vary between individuals. Random intercepts and slopes are typically modelled as normally distributed deviations from the global intercept and slope, respectively. For example, random slopes models, under the name of ‘random regression’ models, are used to investigate individual variation in response to different environments (Nussey, Wilson & Brommer 2007). The aim of this article is to show how Nakagawa and Schielzeth's R2GLMM can be further extended to encompass random slopes models.
TL;DR: It is found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period, but these cells did not persist in the intestine of adult mice and were replaced around the time of weaning by the chemokine receptor CCR2–dependent influx of Ly6Chi monocytes that differentiated locally into mature, anti-inflammatory macrophages.
Abstract: The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.
TL;DR: How microbiota development in infants is affected by mode of delivery is addressed, and differences in colonisation patterns to the maturation of a balanced Th1/Th2 immune response are related to.
Abstract: Objective The early intestinal microbiota exerts important stimuli for immune development, and a reduced microbial exposure as well as caesarean section (CS) has been associated with the developmen ...
TL;DR: Key recent developments in theoretical, clinical, and empirical psychological science about the emergence of suicidal thoughts and behaviours are described, and the central importance of psychological factors are emphasised.
university of lille1, University of Copenhagen2, University Medical Center Utrecht3, St George's, University of London4, University of St Andrews5, University of Modena and Reggio Emilia6, VU University Medical Center7, University of Glasgow8, Erasmus University Rotterdam9, Royal Hospital for Sick Children10, University of Edinburgh11
TL;DR: There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation, and the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity is measured.
Abstract: BACKGROUND The measurement of circulating anti-Mullerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood.
University of Paris-Sud1, Tel Aviv University2, University of California, Irvine3, French Institute of Health and Medical Research4, National Institutes of Health5, University of Glasgow6, University of California, Davis7, University of Copenhagen8, University of Milan9, Harvard University10, University of Tokyo11, Kumamoto University12, Merck KGaA13, University of Birmingham14, University of Brescia15, Kindai University16
TL;DR: This work reviews this extended family of chemokine receptors and Chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development and introduces a new nomenclature for atypical chemokin receptors with the stem ACKR (atypicalChemokine receptor).
Abstract: Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.
TL;DR: In this paper, the authors proposed Swarm, a fast, scalable, and input-order independent approach for amplicon clustering that reduces the influence of clustering parameters and produces robust operational taxonomic units.
Abstract: Popular de novo amplicon clustering methods suffer from two fundamental flaws: arbitrary global clustering thresholds, and input-order dependency induced by centroid selection. Swarm was developed to address these issues by first clustering nearly identical amplicons iteratively using a local threshold, and then by using clusters’ internal structure and amplicon abundances to refine its results. This fast, scalable, and input-order independent approach reduces the influence of clustering parameters and produces robust operational taxonomic units.
University of Glasgow1, University of Belgrade2, Karolinska University Hospital3, Mayo Clinic4, University of Verona5, Heidelberg University6, Freeman Hospital7, Trinity College, Dublin8, University of Barcelona9, Technische Universität München10, University of Amsterdam11, Harvard University12, University of Milan13, University of Liverpool14, Kyoto University15, Hospital of the University of Pennsylvania16, Thomas Jefferson University17
TL;DR: Current evidence justifies portomesenteric venous resection in patients with BRPC, and a new classification of extrahepatic mesentericoportal ven Mous resections is proposed by the ISGPS.
TL;DR: In this article, the authors presented a visible light communication (VLC) system based on a single 50-μm gallium nitride light emitting diode (LED) with a 3-dB modulation bandwidth of at least 60 MHz.
Abstract: This letter presents a visible light communication (VLC) system based on a single 50- μm gallium nitride light emitting diode (LED). A device of this size exhibits a 3-dB modulation bandwidth of at least 60 MHz - significantly higher than commercially available white lighting LEDs. Orthogonal frequency division multiplexing is employed as a modulation scheme. This enables the limited modulation bandwidth of the device to be fully used. Pre- and postequalization techniques, as well as adaptive data loading, are successfully applied to achieve a demonstration of wireless communication at speeds exceeding 3 Gb/s. To date, this is the fastest wireless VLC system using a single LED.
TL;DR: Manipulating guard cell transport and metabolism is just as, if not more likely to yield useful benefits as manipulations of their physical and anatomical characteristics, to improve water use efficiency without substantial cost to photosynthetic carbon fixation.
Abstract: The control of gaseous exchange between the leaf and bulk atmosphere by stomata governs CO2 uptake for photosynthesis and transpiration, determining plant productivity and water use efficiency. The balance between these two processes depends on stomatal responses to environmental and internal cues and the synchrony of stomatal behavior relative to mesophyll demands for CO2. Here we examine the rapidity of stomatal responses with attention to their relationship to photosynthetic CO2 uptake and the consequences for water use. We discuss the influence of anatomical characteristics on the velocity of changes in stomatal conductance and explore the potential for manipulating the physical as well as physiological characteristics of stomatal guard cells in order to accelerate stomatal movements in synchrony with mesophyll CO2 demand and to improve water use efficiency without substantial cost to photosynthetic carbon fixation. We conclude that manipulating guard cell transport and metabolism is just as, if not more likely to yield useful benefits as manipulations of their physical and anatomical characteristics. Achieving these benefits should be greatly facilitated by quantitative systems analysis that connects directly the molecular properties of the guard cells to their function in the field.
State University of New York System1, McGill University2, University of Connecticut3, Cornell University4, Umeå University5, Wayne State University6, University of Iowa7, University of Miami8, University of Pennsylvania9, Mayo Clinic10, University of Sydney11, University of Buenos Aires12, University of Chicago13, Shanghai Jiao Tong University14, North-West University15, University of Rochester16, University of Glasgow17, Virginia Commonwealth University18, University of Melbourne19
TL;DR: Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of hypertension as mentioned in this paper, which is based on guidelines from the National Institute of Neurological Disorders and Strochastic Hemorrhage.
Abstract: Clinical practice guidelines for the management of hypertension in the community a statement by the American society of hypertension and the International society of hypertension
TL;DR: Tested interventions are effective at reducing readmissions, but more effective interventions are complex and support patient capacity for self-care.
Abstract: Importance Reducing early ( Objective To synthesize the evidence of the efficacy of interventions to reduce early hospital readmissions and identify intervention features—including their impact on treatment burden and on patients’ capacity to enact postdischarge self-care—that might explain their varying effects. Data Sources We searched PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, and Scopus (1990 until April 1, 2013), contacted experts, and reviewed bibliographies. Study Selection Randomized trials that assessed the effect of interventions on all-cause or unplanned readmissions within 30 days of discharge in adult patients hospitalized for a medical or surgical cause for more than 24 hours and discharged to home. Data Extraction and Synthesis Reviewer pairs extracted trial characteristics and used an activity-based coding strategy to characterize the interventions; fidelity was confirmed with authors. Blinded to trial outcomes, reviewers noted the extent to which interventions placed additional work on patients after discharge or supported their capacity for self-care in accordance with the cumulative complexity model. Main Outcomes and Measures Relative risk of all-cause or unplanned readmission with or without out-of-hospital deaths at 30 days postdischarge. Results In 42 trials, the tested interventions prevented early readmissions (pooled random-effects relative risk, 0.82 [95% CI, 0.73-0.91]; P I 2 = 31%), a finding that was consistent across patient subgroups. Trials published before 2002 reported interventions that were 1.6 times more effective than those tested later (interaction P = .01). In exploratory subgroup analyses, interventions with many components (interaction P = .001), involving more individuals in care delivery (interaction P = .05), and supporting patient capacity for self-care (interaction P = .04) were 1.4, 1.3, and 1.3 times more effective than other interventions, respectively. A post hoc regression model showed incremental value in providing comprehensive, postdischarge support to patients and caregivers. Conclusions and Relevance Tested interventions are effective at reducing readmissions, but more effective interventions are complex and support patient capacity for self-care. Interventions tested more recently are less effective.
TL;DR: Adherence to this principle and enhancement of the reliable practical use of the scale through continuing education of health professionals, standardisation across different settings, and consensus on methods to address confounders will maintain its role in clinical practice and research in the future.
Abstract: Since 1974, the Glasgow Coma Scale has provided a practical method for bedside assessment of impairment of conscious level, the clinical hallmark of acute brain injury. The scale was designed to be easy to use in clinical practice in general and specialist units and to replace previous ill-defined and inconsistent methods. 40 years later, the Glasgow Coma Scale has become an integral part of clinical practice and research worldwide. Findings using the scale have shown strong associations with those obtained by use of other early indices of severity and outcome. However, predictive statements should only be made in combination with other variables in a multivariate model. Individual patients are best described by the three components of the coma scale; whereas the derived total coma score should be used to characterise groups. Adherence to this principle and enhancement of the reliable practical use of the scale through continuing education of health professionals, standardisation across different settings, and consensus on methods to address confounders will maintain its role in clinical practice and research in the future.
University of Milano-Bicocca1, Katholieke Universiteit Leuven2, Gdańsk Medical University3, University of Valencia4, University of Milan5, Ghent University6, Charles University in Prague7, University of Glasgow8, University Medical Center Utrecht9, Linköping University10, University of Birmingham11, University of Oslo12, French Institute of Health and Medical Research13, Lund University14, John Radcliffe Hospital15, Tallinn University of Technology16, University Hospital of Lausanne17, University of Lorraine18
TL;DR: This paper aims to demonstrate the importance of knowing the carrier and removal status of canine coronavirus, as a source of infection for other animals, not necessarily belonging to the same breeds.
Abstract: ABPMambulatory blood pressure monitoringACEangiotensin converting enzymeARBangiotensin receptor blockerA-Vatrio-ventricularBBbeta-blockerBPblood pressureCHDcoronary heart diseaseCKDchronic kidney d...
TL;DR: A Cochrane overview of systematic reviews of interventions provided to improve upper limb function after stroke found moderate-quality evidence showed a beneficial effect of constraint-induced movement therapy, mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions.
Abstract: Background
Improving upper limb function is a core element of stroke rehabilitation needed to maximise patient outcomes and reduce disability. Evidence about effects of individual treatment techniques and modalities is synthesised within many reviews. For selection of effective rehabilitation treatment, the relative effectiveness of interventions must be known. However, a comprehensive overview of systematic reviews in this area is currently lacking.
Objectives
To carry out a Cochrane overview by synthesising systematic reviews of interventions provided to improve upper limb function after stroke.
Methods
Search methods: We comprehensively searched the Cochrane Database of Systematic Reviews; the Database of Reviews of Effects; and PROSPERO (an international prospective register of systematic reviews) (June 2013). We also contacted review authors in an effort to identify further relevant reviews.
Selection criteria: We included Cochrane and non-Cochrane reviews of randomised controlled trials (RCTs) of patients with stroke comparing upper limb interventions with no treatment, usual care or alternative treatments. Our primary outcome of interest was upper limb function; secondary outcomes included motor impairment and performance of activities of daily living. When we identified overlapping reviews, we systematically identified the most up-to-date and comprehensive review and excluded reviews that overlapped with this.
Data collection and analysis: Two overview authors independently applied the selection criteria, excluding reviews that were superseded by more up-to-date reviews including the same (or similar) studies. Two overview authors independently assessed the methodological quality of reviews (using a modified version of the AMSTAR tool) and extracted data. Quality of evidence within each comparison in each review was determined using objective criteria (based on numbers of participants, risk of bias, heterogeneity and review quality) to apply GRADE (Grades of Recommendation, Assessment, Development and Evaluation) levels of evidence. We resolved disagreements through discussion. We systematically tabulated the effects of interventions and used quality of evidence to determine implications for clinical practice and to make recommendations for future research.
Main results
Our searches identified 1840 records, from which we included 40 completed reviews (19 Cochrane; 21 non-Cochrane), covering 18 individual interventions and dose and setting of interventions. The 40 reviews contain 503 studies (18,078 participants). We extracted pooled data from 31 reviews related to 127 comparisons. We judged the quality of evidence to be high for 1/127 comparisons (transcranial direct current stimulation (tDCS) demonstrating no benefit for outcomes of activities of daily living (ADLs)); moderate for 49/127 comparisons (covering seven individual interventions) and low or very low for 77/127 comparisons.
Moderate-quality evidence showed a beneficial effect of constraint-induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions; moderate-quality evidence also indicated that unilateral arm training may be more effective than bilateral arm training. Information was insufficient to reveal the relative effectiveness of different interventions.
Moderate-quality evidence from subgroup analyses comparing greater and lesser doses of mental practice, repetitive task training and virtual reality demonstrates a beneficial effect for the group given the greater dose, although not for the group given the smaller dose; however tests for subgroup differences do not suggest a statistically significant difference between these groups. Future research related to dose is essential.
Specific recommendations for future research are derived from current evidence. These recommendations include but are not limited to adequately powered, high-quality RCTs to confirm the benefit of CIMT, mental practice, mirror therapy, virtual reality and a relatively high dose of repetitive task practice; high-quality RCTs to explore the effects of repetitive transcranial magnetic stimulation (rTMS), tDCS, hands-on therapy, music therapy, pharmacological interventions and interventions for sensory impairment; and up-to-date reviews related to biofeedback, Bobath therapy, electrical stimulation, reach-to-grasp exercise, repetitive task training, strength training and stretching and positioning.
Authors' conclusions
Large numbers of overlapping reviews related to interventions to improve upper limb function following stroke have been identified, and this overview serves to signpost clinicians and policy makers toward relevant systematic reviews to support clinical decisions, providing one accessible, comprehensive document, which should support clinicians and policy makers in clinical decision making for stroke rehabilitation.
Currently, no high-quality evidence can be found for any interventions that are currently used as part of routine practice, and evidence is insufficient to enable comparison of the relative effectiveness of interventions. Effective collaboration is urgently needed to support large, robust RCTs of interventions currently used routinely within clinical practice. Evidence related to dose of interventions is particularly needed, as this information has widespread clinical and research implications.
TL;DR: Strain imaging detects impaired systolic function despite preserved global LVEF inHFpEF that may contribute to the pathophysiology of the HFpEF syndrome.
TL;DR: In this article, the causal role of alcohol consumption in cardiovascular disease was investigated using a Mendelian randomisation meta-analysis of 56 epidemiological studies, including 20 259 coronary heart disease cases and 10 164 stroke events.
Abstract: OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
TL;DR: The proposals introduce new species and genera into both subfamilies, resolve one misclassified species, and improve taxonomic clarity by employing a series of systematic changes.
Abstract: A set of proposals to rationalize and extend the taxonomy of the family Parvoviridae is currently under review by the International Committee on Taxonomy of Viruses (ICTV). Viruses in this family infect a wide range of hosts, as reflected by the longstanding division into two subfamilies: the Parvovirinae, which contains viruses that infect vertebrate hosts, and the Densovirinae, encompassing viruses that infect arthropod hosts. Using a modified definition for classification into the family that no longer demands isolation as long as the biological context is strong, but does require a near-complete DNA sequence, 134 new viruses and virus variants were identified. The proposals introduce new species and genera into both subfamilies, resolve one misclassified species, and improve taxonomic clarity by employing a series of systematic changes. These include identifying a precise level of sequence similarity required for viruses to belong to the same genus and decreasing the level of sequence similarity required for viruses to belong to the same species. These steps will facilitate recognition of the major phylogenetic branches within genera and eliminate the confusion caused by the near-identity of species and viruses. Changes to taxon nomenclature will establish numbered, non-Latinized binomial names for species, indicating genus affiliation and host range rather than recapitulating virus names. Also, affixes will be included in the names of genera to clarify subfamily affiliation and reduce the ambiguity that results from the vernacular use of “parvovirus” and “densovirus” to denote multiple taxon levels.
TL;DR: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.
Abstract: Objective Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with Results More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p Conclusions The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.