Showing papers by "University of Graz published in 2017"
TL;DR: This article presents www.prolific.ac and lays out its suitability for recruiting subjects for social and economic science experiments, and traces the platform’s historical development, present its features, and contrast them with requirements for different types of social andEconomic experiments.
1,357 citations
Cornell University1, Paris Descartes University2, University of Massachusetts Medical School3, Spanish National Research Council4, University of Rome Tor Vergata5, Boston Children's Hospital6, University of Pittsburgh7, National Scientific and Technical Research Council8, National University of Cuyo9, Albert Einstein College of Medicine10, University of California, San Francisco11, University of New Mexico12, Goethe University Frankfurt13, University of Split14, University of Helsinki15, University of Salento16, German Cancer Research Center17, Virginia Commonwealth University18, St. Jude Children's Research Hospital19, Discovery Institute20, Harvard University21, University of Tromsø22, Hungarian Academy of Sciences23, Eötvös Loránd University24, New York University25, University of Vienna26, Babraham Institute27, University of South Australia28, Howard Hughes Medical Institute29, University of Texas Southwestern Medical Center30, University of Oviedo31, University of Graz32, National Institutes of Health33, Queens College34, City University of New York35, University of Tokyo36, University of Zurich37, Novartis38, Austrian Academy of Sciences39, University of Groningen40, University of Cambridge41, University of Padua42, University of Oxford43, University of Bern44, University of Oslo45, University of Crete46, Foundation for Research & Technology – Hellas47, Francis Crick Institute48, Osaka University49, Icahn School of Medicine at Mount Sinai50
TL;DR: A panel of leading experts in the field attempts here to define several autophagy‐related terms based on specific biochemical features to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagic research.
Abstract: Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.
1,095 citations
University of Michigan1, Amgen2, University of Florence3, Laval University4, University of Lyon5, University of California, San Francisco6, University of Graz7, University of British Columbia8, University of Bern9, University of Liège10, Paris Descartes University11, Columbia University12, Leiden University Medical Center13
TL;DR: The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years, and serious adverse event rates were generally stable over time.
590 citations
Posted Content•
TL;DR: To allow fast and high‐quality reconstruction of clinical accelerated multi‐coil MR data by learning a variational network that combines the mathematical structure of variational models with deep learning.
Abstract: Purpose: To allow fast and high-quality reconstruction of clinical accelerated multi-coil MR data by learning a variational network that combines the mathematical structure of variational models with deep learning.
Theory and Methods: Generalized compressed sensing reconstruction formulated as a variational model is embedded in an unrolled gradient descent scheme. All parameters of this formulation, including the prior model defined by filter kernels and activation functions as well as the data term weights, are learned during an offline training procedure. The learned model can then be applied online to previously unseen data.
Results: The variational network approach is evaluated on a clinical knee imaging protocol. The variational network reconstructions outperform standard reconstruction algorithms in terms of image quality and residual artifacts for all tested acceleration factors and sampling patterns.
Conclusion: Variational network reconstructions preserve the natural appearance of MR images as well as pathologies that were not included in the training data set. Due to its high computational performance, i.e., reconstruction time of 193 ms on a single graphics card, and the omission of parameter tuning once the network is trained, this new approach to image reconstruction can easily be integrated into clinical workflow.
366 citations
TL;DR: Emphasis is devoted to the integration of PHA-production based on selected raw materials into the holistic patterns of sustainability; this encompasses the choice of new, powerful microbial production strains, non-hazardous, environmentally benign methods for PHA recovery, and reutilization of waste streams from the PHA production process itself.
365 citations
TL;DR: There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking.
349 citations
TL;DR: In this paper, the authors connect three distinct, but complementary, dimensions of strategic management as viewed from the perspective of sustainability in order to encourage the integration of sustainability issues into corporate activities and strategies.
349 citations
TL;DR: In this article, the authors consider the issues of bias correction and make recommendations for research to overcome model biases, and conclude that bias correction cannot overcome major model errors, and naive application might result in ill-informed adaptation decisions.
Abstract: Biases in climate model simulations introduce biases in subsequent impact simulations. Therefore, bias correction methods are operationally used to post-process regional climate projections. However, many problems have been identified, and some researchers question the very basis of the approach. Here we demonstrate that a typical cross-validation is unable to identify improper use of bias correction. Several examples show the limited ability of bias correction to correct and to downscale variability, and demonstrate that bias correction can cause implausible climate change signals. Bias correction cannot overcome major model errors, and naive application might result in ill-informed adaptation decisions. We conclude with a list of recommendations and suggestions for future research to reduce, post-process, and cope with climate model biases. Bias correction methods aim to remove introduced bias for climate model simulations; however, improper use can result in spurious climate signals. This Perspective considers the issues of bias correction and makes recommendations for research to overcome model biases.
341 citations
TL;DR: The extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge.
329 citations
TL;DR: This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid'lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases.
Abstract: Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.
312 citations
TL;DR: In order to directly convert alcohols into carboxylic acids, rational engineering of 5-(hydroxymethyl)furfural oxidase was performed and two active-site residues were exchanged for hydrogen-bond-donating and -accepting amino acids to boost aldehyde-oxidase activity.
Abstract: The oxidation of alcohols to the corresponding carbonyl or carboxyl compounds represents a convenient strategy for the selective introduction of electrophilic carbon centres into carbohydrate-based starting materials. The O₂-dependent oxidation of prim-alcohols by flavin-containing alcohol oxidases often yields mixtures of aldehyde and carboxylic acid, which is due to "over-oxidation" of the aldehyde hydrate intermediate. In order to directly convert alcohols into carboxylic acids, rational engineering of 5-(hydroxymethyl)furfural oxidase was performed. In an attempt to improve the binding of the aldehyde hydrate in the active site to boost aldehyde-oxidase activity, two active-site residues were exchanged for hydrogen-bond-donating and -accepting amino acids. Enhanced over-oxidation was demonstrated and Michaelis-Menten kinetics were performed to corroborate these findings.
Federal University of São Paulo1, University of Illinois at Chicago2, Quinze-Vingts National Eye Hospital3, Queensland University of Technology4, Keio University5, University of Graz6, Duke University7, Ludwig Maximilian University of Munich8, Washington University in St. Louis9, L V Prasad Eye Institute10, Cleveland Clinic11, Aston University12
TL;DR: This report presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries.
Abstract: Dry eye can be caused by a variety of iatrogenic interventions. The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. Preservatives, such as benzalkonium chloride, may further aggravate DED. A variety of systemic drugs can also induce DED secondary to multiple mechanisms. Moreover, the use of contact lens induces or is associated with DED. However, one of the most emblematic situations is DED caused by surgical procedures such as corneal refractive surgery as in laser-assisted in situ keratomileusis (LASIK) and keratoplasty due to mechanisms intrinsic to the procedure (i.e. corneal nerve cutting) or even by the use of postoperative topical drugs. Cataract surgery, lid surgeries, botulinum toxin application and cosmetic procedures are also considered risk factors to iatrogenic DED, which can cause patient dissatisfaction, visual disturbance and poor surgical outcomes. This report also presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries. Novel research into detection of early dry eye prior to surgeries, efforts to establish appropriate therapeutics and a greater attempt to regulate and oversee medications, preservatives and procedures should be considered.
Mariaelisa Graff1, Robert A. Scott2, Anne E. Justice1, Kristin L. Young1 +346 more•Institutions (101)
TL;DR: In additional genome-wide meta-analyses adjusting for PA and interaction with PA, 11 novel adiposity loci are identified, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
TL;DR: PCR-GLOBWB 2 as discussed by the authors is a global hydrology and water resources model with a modular structure, allowing for easier replacement, maintenance, and development of model components.
Abstract: We present PCR-GLOBWB 2, a global hydrology and water resources model. Compared to previous versions of PCR-GLOBWB, this version fully integrates water use. Sector-specific water demand, groundwater and surface water withdrawal, water consumption and return flows are dynamically calculated at every time step and interact directly with the simulated hydrology. PCR-GLOBWB 2 has been fully rewritten in Python and PCRaster-Python and has a modular structure, allowing easier replacement, maintenance, and development of model components. PCR-GLOBWB 2 has been implemented at 5 arc-minute resolution, but a version parameterized at 30 arc-minute resolution is also available. Both versions are available as open source codes on https://github.com/UU-Hydro/PCR-GLOBWB_model . PCR-GLOBWB 2 has its own routines for groundwater dynamics and surface water routing. These relatively simple routines can alternatively be replaced by dynamically coupling PCR-GLOBWB 2 to a global two-layer groundwater model and 1D-2D-hydrodynamic models, respectively. Here, we describe the main components of the model, compare results of the 30 arcminute and the 5 arc-minute versions and evaluate their model performance using GRDC discharge data. Results show that model performance of the 5 arc-minute version is notably better than that of the 30 arc-minute version. Furthermore, we compare simulated time series of total water storage (TWS) of the 5 arc-minute model with those observed with GRACE, showing similar negative trends in areas of prevalent groundwater depletion. Also, we find that simulated water withdrawal, by source and sector, matches reasonably well with reported water withdrawal from AQUASTAT.
TL;DR: This review summarizes the etiology and mechanism of AITD and addresses prevalence of antibodies against thyroid peroxidase, thyroid-stimulating hormone receptor (TSHR), and anti-thyroglobulin and their action outside the thyroid.
Abstract: Autoimmune diseases have a high prevalence in the population and autoimmune thyroid disease (AITD) is one of the most common representatives. Thyroid autoantibodies are frequently detected in patients with AITD but also in subjects without manifest thyroid dysfunction. The high prevalence raises questions regarding a potential role in extra-thyroidal diseases. This review summarizes the etiology and mechanism of AITD and addresses prevalence of antibodies against thyroperoxidase, thyroid stimulating hormone receptor and anti-thyroglobulin and their action outside the thyroid. The main issues limiting the reliability of the conclusions drawn here include problems with different specificities and sensitivities of the antibody detection assays employed, as well as potential confounding effects of altered thyroid hormone levels, and lack of prospective studies. In addition to the well-known effects of thyroid stimulating hormone receptor antibodies on fibroblasts in Graves’ disease, studies speculate on a role of anti-thyroid antibodies in cancer. All antibodies may have a tumor-promoting role in breast cancer carcinogenesis despite anti-thyroperoxidase antibodies having a positive prognostic effect in patients with overt disease. Cross-reactivity with lactoperoxidase leading to induction of chronic inflammation might promote breast cancer, while anti-thyroid antibodies in manifest breast cancer might be an indication for a more active immune system. A better general health condition in older women with anti-thyroperoxidase antibodies might support this hypothesis. The different actions of the anti-thyroid antibodies correspond to differences in cellular location of the antigens, titers of the circulating antibodies, duration of antibody exposure, and immunological mechanisms in Graves’ disease and Hashimoto’s thyroiditis.
Cardiff University1, University of Messina2, Charité3, Monash University4, University of York5, University of Toronto6, University of East London7, University of Southampton8, St Mary's Hospital9, University Hospital Southampton NHS Foundation Trust10, Heidelberg University11, National Institutes of Health12, Eskişehir Osmangazi University13, Erasmus University Rotterdam14, Odense University Hospital15, Bethel University16, Ruhr University Bochum17, Katholieke Universiteit Leuven18, Utrecht University19, Johns Hopkins University20, National and Kapodistrian University of Athens21, University Medical Center Groningen22, University of Groningen23, Nippon Medical School24, University of Milan25, University of Cyprus26, University College London27, University of Graz28, European Union29, Guy's and St Thomas' NHS Foundation Trust30, University of Edinburgh31
TL;DR: A systematic review to assess the effectiveness, cost‐effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis found it to be effective, cost-effective, and safe.
Abstract: Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost-effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis. Methods: We searched nine international biomedical databases for published, in-progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication, and combined symptom and medication scores. Secondary outcomes of interest included cost-effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random-effects meta-analyses. Results: We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD −0.53, 95% CI −0.63, −0.42), medication (SMD −0.37, 95% CI −0.49, −0.26), and combined symptom and medication (SMD −0.49, 95% CI −0.69, −0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post-discontinuation of AIT, suggesting a benefit in relation to symptom scores. Conclusions: AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy.
TL;DR: Therapeutic strategies are warranted, which can be easily used for the management of obese patients with type 2 diabetes to achieve their glycemic and weight loss goals.
Abstract: Obesity is a chronic metabolic disease affecting adults and children worldwide. It has become one of the leading causes of death, as obesity is known to be the main risk factor for a number of non-communicable diseases, in particular type 2 diabetes. This close relationship led to the connotation 'diabesity', highlighting the fact that the majority of individuals with diabetes are overweight or obese. Until today the BMI is still used to classify overweight and obesity. Since reduced muscle mass is highly prevalent throughout the BMI range, the measurement of body composition is strongly recommended. Moreover, it is essential for monitoring the course of weight reduction, which is part of every effective anti-obesity treatment. Weight reduction can be achieved via different weight loss strategies, including lifestyle intervention (diet and exercise), pharmacotherapy, or bariatric surgery. However, not all of these strategies are suitable for all patients, and any further needs should be considered. Besides, attention should also be drawn to concomitant therapies. These therapies may promote additional weight gain and further trigger the deterioration of blood glucose control. Thus, therapeutic strategies are warranted, which can be easily used for the management of obese patients with type 2 diabetes to achieve their glycemic and weight loss goals.
TL;DR: By demonstrating the excitation of both bulk and surface vibrational modes using a single probe, this work represents advances in the detection and visualization of spatially confined surface and bulk phonons in nanostructures.
Abstract: Spatial mapping of optical and acoustic, bulk and surface vibrational modes in magnesium oxide nanocubes is demonstrated using a single electron probe. The vibrational excitations of nanostructures have a fundamental effect on their suitability for various electronic, optical and thermal applications. Maureen Lagos and colleagues probe these excitations, using state-of-the-art electron microscopy to map the vibrational modes both at the surface and within the body of individual nanoparticles. Such information not only contributes to our knowledge of these fundamental vibrational modes, but will also be valuable for the design and optimization of nanostructures for practical use. Imaging of vibrational excitations in and near nanostructures is essential for developing low-loss infrared nanophotonics1, controlling heat transport in thermal nanodevices2,3, inventing new thermoelectric materials4 and understanding nanoscale energy transport. Spatially resolved electron energy loss spectroscopy has previously been used to image plasmonic behaviour in nanostructures in an electron microscope5,6, but hitherto it has not been possible to map vibrational modes directly in a single nanostructure, limiting our understanding of phonon coupling with photons7 and plasmons8. Here we present spatial mapping of optical and acoustic, bulk and surface vibrational modes in magnesium oxide nanocubes using an atom-wide electron beam. We find that the energy and the symmetry of the surface polariton phonon modes depend on the size of the nanocubes, and that they are localized to the surfaces of the nanocube. We also observe a limiting of bulk phonon scattering in the presence of surface phonon modes. Most phonon spectroscopies are selectively sensitive to either surface or bulk excitations; therefore, by demonstrating the excitation of both bulk and surface vibrational modes using a single probe, our work represents advances in the detection and visualization of spatially confined surface and bulk phonons in nanostructures.
TL;DR: It is concluded that functional NST requires adequate substrate supply and cardiac function, but does not depend on ATGL-mediated lipolysis in BAT, suggesting that circulating energy substrates are sufficient to fuel NST.
Queen Mary University of London1, University of Birmingham2, Academic Medical Center3, VU University Medical Center4, King's College London5, University of Graz6, St Thomas' Hospital7, University of Southern Denmark8, University College Dublin9, University of Adelaide10, Technical University of Madrid11, State University of Campinas12, University of North Carolina at Chapel Hill13, University of Antwerp14, Katholieke Universiteit Leuven15, Monash University16, Norwegian School of Sport Sciences17, University of Manitoba18, University of Melbourne19, Alexandria University20, University of Mazandaran21, Oslo University Hospital22, University of Tampere23, University of Western Australia24, University of Modena and Reggio Emilia25, California Polytechnic State University26, Federal University of São Paulo27, Technische Universität München28, University of Copenhagen29, Norwegian University of Science and Technology30, Lund University31, Odense University Hospital32, University of Health Sciences Antigua33, Copenhagen University Hospital34, Keele University35
TL;DR: Diet and lifestyle interventions in pregnancy are clinically effective in reducing GWG irrespective of risk factors, with no effects on composite maternal and fetal outcomes.
Abstract: Background: Diet- and physical activity-based interventions in pregnancy have the potential to alter maternal and child outcomes. Objectives: To assess whether or not the effects of diet and lifestyle interventions vary in subgroups of women, based on maternal body mass index (BMI), age, parity, Caucasian ethnicity and underlying medical condition(s), by undertaking an individual patient data (IPD) meta-analysis. We also evaluated the association of gestational weight gain (GWG) with adverse pregnancy outcomes and assessed the cost-effectiveness of the interventions. Data sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects and Health Technology Assessment database were searched from October 2013 to March 2015 (to update a previous search). Review methods: Researchers from the International Weight Management in Pregnancy Collaborative Network shared the primary data. For each intervention type and outcome, we performed a two-step IPD random-effects meta-analysis, for all women (except underweight) combined and for each subgroup of interest, to obtain summary estimates of effects and 95% confidence intervals (CIs), and synthesised the differences in effects between subgroups. In the first stage, we fitted a linear regression adjusted for baseline (for continuous outcomes) or a logistic regression model (for binary outcomes) in each study separately; estimates were combined across studies using random-effects meta-analysis models. We quantified the relationship between weight gain and complications, and undertook a decision-analytic model-based economic evaluation to assess the cost-effectiveness of the interventions. Results: Diet and lifestyle interventions reduced GWG by an average of 0.70 kg (95% CI-0.92 to-0.48 kg; 33 studies, 9320 women). The effects on composite maternal outcome [summary odds ratio (OR) 0.90, 95% CI 0.79 to 1.03; 24 studies, 8852 women] and composite fetal/neonatal outcome (summary OR 0.94, 95% CI 0.83 to 1.08; 18 studies, 7981 women) were not significant. The effect did not vary with baseline BMI, age, ethnicity, parity or underlying medical conditions for GWG, and composite maternal and fetal outcomes. Lifestyle interventions reduce Caesarean sections (OR 0.91, 95% CI 0.83 to 0.99), but not other individual maternal outcomes such as gestational diabetes mellitus (OR 0.89, 95% CI 0.72 to 1.10), pre-eclampsia or pregnancy-induced hypertension (OR 0.95, 95% CI 0.78 to 1.16) and preterm birth (OR 0.94, 95% CI 0.78 to 1.13). There was no significant effect on fetal outcomes. The interventions were not cost-effective. GWG, including adherence to the Institute of Medicine-recommended targets, was not associated with a reduction in complications. Predictors of GWG were maternal age (summary estimate-0.10 kg, 95% CI-0.14 to-0.06 kg) and multiparity (summary estimate-0.73 kg, 95% CI-1.24 to-0.23 kg). Limitations: The findings were limited by the lack of standardisation in the components of intervention, residual heterogeneity in effects across studies for most analyses and the unavailability of IPD in some studies. Conclusion: Diet and lifestyle interventions in pregnancy are clinically effective in reducing GWG irrespective of risk factors, with no effects on composite maternal and fetal outcomes. Future work: The differential effects of lifestyle interventions on individual pregnancy outcomes need evaluation. Study registration: This study is registered as PROSPERO CRD42013003804.
Stanford University1, Paris Descartes University2, Boston Children's Hospital3, Cincinnati Children's Hospital Medical Center4, Great Ormond Street Hospital5, Vita-Salute San Raffaele University6, University of Toronto7, University of Freiburg8, University of São Paulo9, Marmara University10, University of Ulm11, University of Florence12, Baylor College of Medicine13, French Institute of Health and Medical Research14, University College London15, Ludwig Maximilian University of Munich16, Tokyo Medical and Dental University17, University of Ulsan18, University of Pittsburgh19, Hannover Medical School20, Spanish National Research Council21, Ben-Gurion University of the Negev22, Ghent University Hospital23, University of California, Los Angeles24, Leiden University Medical Center25, Wrocław Medical University26, Université de Montréal27, University of Graz28, Harvard University29, University of California, San Francisco30, University of Alabama at Birmingham31
TL;DR: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long‐term disease‐free survival, and when performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.
Abstract: Background Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant ( P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.
TL;DR: AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study, and further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADVac1.
Abstract: Summary Background Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. Methods We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50–85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198. Findings This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. Interpretation AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. Funding AXON Neuroscience SE.
TL;DR: Patients with PCOS have a lower diversity and an altered phylogenetic profile in their stool microbiome, which is associated with clinical parameters, and these changes may contribute to the clinical phenotype in certain PCOS patients.
Abstract: Background
Polycystic ovary syndrome (PCOS) is a common female endocrinopathy of unclear origin characterized by hyperandrogenism, oligo-/anovulation, and ovarian cysts. Women with PCOS frequently display overweight, insulin resistance, and systemic low-grade inflammation. We hypothesized that endotoxemia resulting from a leaky gut is associated with inflammation, insulin resistance, fat accumulation, and hyperandrogenemia in PCOS. In this pilot study, we compared the stool microbiome, gut permeability, and inflammatory status of women with PCOS and healthy controls.
Methods
16S rRNA gene amplicon sequencing was performed on stool samples from 24 PCOS patients and 19 healthy controls. Data processing and microbiome analysis were conducted in mothur and QIIME using different relative abundance cut-offs. Gut barrier integrity, endotoxemia, and inflammatory status were evaluated using serum and stool markers and associations with reproductive, metabolic, and anthropometric parameters were investigated.
Results
The stool microbiome of PCOS patients showed a lower diversity and an altered phylogenetic composition compared to controls. We did not observe significant differences in any taxa with a relative abundance>1%. When looking at rare taxa, the relative abundance of bacteria from the phylum Tenericutes, the order ML615J-28 (phylum Tenericutes) and the family S24-7 (phylum Bacteroidetes) was significantly lower and associated with reproductive parameters in PCOS patients. Patients showed alterations in some, but not all markers of gut barrier function and endotoxemia.
Conclusion
Patients with PCOS have a lower diversity and an altered phylogenetic profile in their stool microbiome, which is associated with clinical parameters. Gut barrier dysfunction and endotoxemia were not driving factors in this patient cohort, but may contribute to the clinical phenotype in certain PCOS patients.
TL;DR: Details of feasible and useful screening measures for olfactory dysfunction, appropriate clinical evaluation, and patient counseling to avoid harm as well as manage health and quality of life with anosmia are reported and extended.
Abstract: Anosmia and hyposmia, the inability or decreased ability to smell, is estimated to afflict 3-20% of the population. Risk of olfactory dysfunction increases with old age and may also result from chronic sinonasal diseases, severe head trauma, and upper respiratory infections, or neurodegenerative diseases. These disorders impair the ability to sense warning odors in foods and the environment, as well as hinder the quality of life related to social interactions, eating, and feelings of well-being. This article reports and extends on a clinical update commencing at the 2016 Association for Chemoreception Sciences annual meeting. Included were reports from: a patient perspective on losing the sense of smell with information on Fifth Sense, a nonprofit advocacy organization for patients with olfactory disorders; an otolaryngologist's review of clinical evaluation, diagnosis, and management/treatment of anosmia; and researchers' review of recent advances in potential anosmia treatments from fundamental science, in animal, cellular, or genetic models. As limited evidence-based treatments exist for anosmia, dissemination of information on anosmia-related health risks is needed. This could include feasible and useful screening measures for olfactory dysfunction, appropriate clinical evaluation, and patient counseling to avoid harm as well as manage health and quality of life with anosmia.
TL;DR: In this paper, the authors developed a conceptual model, implemented via pair-copula constructions, which allows for the quantification of the risk associated with compound events in present-day and future climate, as well as the uncertainty estimates around such risk.
Abstract: . Compound events (CEs) are multivariate extreme events in which the individual contributing variables may not be extreme themselves, but their joint – dependent – occurrence causes an extreme impact. Conventional univariate statistical analysis cannot give accurate information regarding the multivariate nature of these events. We develop a conceptual model, implemented via pair-copula constructions, which allows for the quantification of the risk associated with compound events in present-day and future climate, as well as the uncertainty estimates around such risk. The model includes predictors, which could represent for instance meteorological processes that provide insight into both the involved physical mechanisms and the temporal variability of compound events. Moreover, this model enables multivariate statistical downscaling of compound events. Downscaling is required to extend the compound events' risk assessment to the past or future climate, where climate models either do not simulate realistic values of the local variables driving the events or do not simulate them at all. Based on the developed model, we study compound floods, i.e. joint storm surge and high river runoff, in Ravenna (Italy). To explicitly quantify the risk, we define the impact of compound floods as a function of sea and river levels. We use meteorological predictors to extend the analysis to the past, and get a more robust risk analysis. We quantify the uncertainties of the risk analysis, observing that they are very large due to the shortness of the available data, though this may also be the case in other studies where they have not been estimated. Ignoring the dependence between sea and river levels would result in an underestimation of risk; in particular, the expected return period of the highest compound flood observed increases from about 20 to 32 years when switching from the dependent to the independent case.
TL;DR: Assessment of toxic metal concentrations in five, nationally popular brands of cig‐a‐like e‐cigarettes found marked variability in nickel and chromium concentration within and between brands, which may come from heating elements.
TL;DR: In this paper, a qualitative, empirical research study conducted in cooperation with 10 Austrian companies in 2014 aims to investigate business models for sustainability in order to better understand how they operate and what the drivers for developing these business models are.
TL;DR: Compared three types of European daily data sets featuring two Pan‐European data sets and a set that combines eight very high‐resolution station‐based regional data sets, it is demonstrated that the differences have the same magnitude as precipitation errors found in regional climate models.
Abstract: Gridded precipitation data sets are frequently used to evaluate climate models or to remove model output biases. Although precipitation data are error prone due to the high spatio-temporal variability of precipitation and due to considerable measurement errors, relatively few attempts have been made to account for observational uncertainty in model evaluation or in bias correction studies. In this study, we compare three types of European daily data sets featuring two Pan-European data sets and a set that combines eight very high-resolution station-based regional data sets. Furthermore, we investigate seven widely used, larger scale global data sets. Our results demonstrate that the differences between these data sets have the same magnitude as precipitation errors found in regional climate models. Therefore, including observational uncertainties is essential for climate studies, climate model evaluation, and statistical post-processing. Following our results, we suggest the following guidelines for regional precipitation assessments. (1) Include multiple observational data sets from different sources (e.g. station, satellite, reanalysis based) to estimate observational uncertainties. (2) Use data sets with high station densities to minimize the effect of precipitation undersampling (may induce about 60% error in data sparse regions). The information content of a gridded data set is mainly related to its underlying station density and not to its grid spacing. (3) Consider undercatch errors of up to 80% in high latitudes and mountainous regions. (4) Analyses of small-scale features and extremes are especially uncertain in gridded data sets. For higher confidence, use climate-mean and larger scale statistics. In conclusion, neglecting observational uncertainties potentially misguides climate model development and can severely affect the results of climate change impact assessments.
TL;DR: In contrast to LDL cholesterol (LDL-C), HDL-C correlates with cardiovascular risk only in healthy individuals and is currently not a valid target for drug therapy.
Abstract: Background
While several lines of evidence prove that elevated concentrations of low-density lipoproteins (LDL) causally contribute to the development of atherosclerosis and its clinical consequences, high-density lipoproteins are still widely believed to exert atheroprotective effects. Hence, HDL cholesterol (HDL-C) is in general still considered as “good cholesterol”. Recent research, however, suggests that this might not always be the case and that a fundamental reassessment of the clinical significance of HDL-C is warranted.
University of Oslo1, Oslo University Hospital2, Bosch3, Université libre de Bruxelles4, Helsinki University Central Hospital5, University of Graz6, National Institute for Health Research7, Sapienza University of Rome8, Marche Polytechnic University9, University College London10, Erasmus University Rotterdam11, University of Hamburg12, Karolinska University Hospital13, The Catholic University of America14
TL;DR: It is recommended that cholangiocarcinoma (CCA) should be suspected in any patient with worsening cholestasis, weight loss, raised serum CA19-9, and/or new or progressive dominant stricture, particularly with an associated enhancing mass lesion.
Abstract: 1 ESGE/EASL recommend that, as the primary diagnostic modality for PSC, magnetic resonance cholangiography (MRC) should be preferred over endoscopic retrograde cholangiopancreatography (ERCP). Moderate quality evidence, strong recommendation. 2 ESGE/EASL suggest that ERCP can be considered if MRC plus liver biopsy is equivocal or contraindicated in patients with persisting clinical suspicion of PSC. The risks of ERCP have to be weighed against the potential benefit with regard to surveillance and treatment recommendations. Low quality evidence, weak recommendation. 6 ESGE/EASL suggest that, in patients with an established diagnosis of PSC, MRC should be considered before therapeutic ERCP. Weak recommendation, low quality evidence. 7 ESGE/EASL suggest performing endoscopic treatment with concomitant ductal sampling (brush cytology, endobiliary biopsies) of suspected significant strictures identified at MRC in PSC patients who present with symptoms likely to improve following endoscopic treatment. Strong recommendation, low quality evidence. 9 ESGE/EASL recommend weighing the anticipated benefits of biliary papillotomy/sphincterotomy against its risks on a case-by-case basis. Strong recommendation, moderate quality evidence. Biliary papillotomy/sphincterotomy should be considered especially after difficult cannulation. Strong recommendation, low quality evidence. 16 ESGE/EASL suggest routine administration of prophylactic antibiotics before ERCP in patients with PSC. Strong recommendation, low quality evidence. 17 EASL/ESGE recommend that cholangiocarcinoma (CCA) should be suspected in any patient with worsening cholestasis, weight loss, raised serum CA19-9, and/or new or progressive dominant stricture, particularly with an associated enhancing mass lesion. Strong recommendation, moderate quality evidence. 19 ESGE/EASL recommend ductal sampling (brush cytology, endobiliary biopsies) as part of the initial investigation for the diagnosis and staging of suspected CCA in patients with PSC. Strong recommendation, high quality evidence.