Showing papers by "University of Groningen published in 2017"
Theo Vos1, Amanuel Alemu Abajobir, Kalkidan Hassen Abate2, Cristiana Abbafati3 +775 more•Institutions (305)
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016.
10,401 citations
TL;DR: In this paper, the authors used the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to constrain the difference between the speed of gravity and speed of light to be between $-3
Abstract: On 2017 August 17, the gravitational-wave event GW170817 was observed by the Advanced LIGO and Virgo detectors, and the gamma-ray burst (GRB) GRB 170817A was observed independently by the Fermi Gamma-ray Burst Monitor, and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory. The probability of the near-simultaneous temporal and spatial observation of GRB 170817A and GW170817 occurring by chance is $5.0\times {10}^{-8}$. We therefore confirm binary neutron star mergers as a progenitor of short GRBs. The association of GW170817 and GRB 170817A provides new insight into fundamental physics and the origin of short GRBs. We use the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to: (i) constrain the difference between the speed of gravity and the speed of light to be between $-3\times {10}^{-15}$ and $+7\times {10}^{-16}$ times the speed of light, (ii) place new bounds on the violation of Lorentz invariance, (iii) present a new test of the equivalence principle by constraining the Shapiro delay between gravitational and electromagnetic radiation. We also use the time delay to constrain the size and bulk Lorentz factor of the region emitting the gamma-rays. GRB 170817A is the closest short GRB with a known distance, but is between 2 and 6 orders of magnitude less energetic than other bursts with measured redshift. A new generation of gamma-ray detectors, and subthreshold searches in existing detectors, will be essential to detect similar short bursts at greater distances. Finally, we predict a joint detection rate for the Fermi Gamma-ray Burst Monitor and the Advanced LIGO and Virgo detectors of 0.1–1.4 per year during the 2018–2019 observing run and 0.3–1.7 per year at design sensitivity.
2,633 citations
Gregory A. Roth1, Catherine O. Johnson1, Amanuel Alemu Abajobir2, Foad Abd-Allah3 +170 more•Institutions (99)
TL;DR: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden, finding that CVDs remain a major cause of health loss for all regions of the world.
2,525 citations
Stony Brook University1, University of Minnesota2, University of Notre Dame3, University of Vermont4, University of Toronto5, Boston University6, University of Maryland, Baltimore7, Duke University8, University of Kansas9, King's College London10, Columbia University11, Broad Institute12, Purdue University13, University of Iowa14, University of Georgia15, Texas A&M University16, Oklahoma State University–Stillwater17, University of Groningen18, Florida State University19, Uniformed Services University of the Health Sciences20, Bryn Mawr College21, University of North Texas22, University of Otago23, University at Buffalo24, University of Arizona25, University of New South Wales26, Northwestern University27, Emory University28, University of Kentucky29, University of Pittsburgh30, Brown University31
TL;DR: The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies and provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response.
Abstract: The reliability and validity of traditional taxonomies are limited by arbitrary boundaries between psychopathology and normality, often unclear boundaries between disorders, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. These taxonomies went beyond evidence available on the structure of psychopathology and were shaped by a variety of other considerations, which may explain the aforementioned shortcomings. The Hierarchical Taxonomy Of Psychopathology (HiTOP) model has emerged as a research effort to address these problems. It constructs psychopathological syndromes and their components/subtypes based on the observed covariation of symptoms, grouping related symptoms together and thus reducing heterogeneity. It also combines co-occurring syndromes into spectra, thereby mapping out comorbidity. Moreover, it characterizes these phenomena dimensionally, which addresses boundary problems and diagnostic instability. Here, we review the development of the HiTOP and the relevant evidence. The new classification already covers most forms of psychopathology. Dimensional measures have been developed to assess many of the identified components, syndromes, and spectra. Several domains of this model are ready for clinical and research applications. The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies. It also provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response. This can greatly improve the utility of the diagnosis of mental disorders. The new classification remains a work in progress. However, it is developing rapidly and is poised to advance mental health research and care significantly as the relevant science matures. (PsycINFO Database Record
1,635 citations
TL;DR: The InTBIR Participants and Investigators have provided informed consent for the study to take place in Poland.
Abstract: Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Soderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbuchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigators
1,354 citations
TL;DR: In this article, a GW signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13.5%.
Abstract: On 2017 June 8 at 02:01:16.49 UTC, a gravitational-wave (GW) signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13. This system is the lightest black hole binary so far observed, with component masses of ${12}_{-2}^{+7}\,{M}_{\odot }$ and ${7}_{-2}^{+2}\,{M}_{\odot }$ (90% credible intervals). These lie in the range of measured black hole masses in low-mass X-ray binaries, thus allowing us to compare black holes detected through GWs with electromagnetic observations. The source's luminosity distance is ${340}_{-140}^{+140}\,\mathrm{Mpc}$, corresponding to redshift ${0.07}_{-0.03}^{+0.03}$. We verify that the signal waveform is consistent with the predictions of general relativity.
1,268 citations
TL;DR: This work describes an electrochemical neuromorphic organic device (ENODe) operating with a fundamentally different mechanism from existing memristors, opening a path towards extreme interconnectivity comparable to the human brain.
Abstract: A neuromorphic device based on the stable electrochemical fine-tuning of the conductivity of an organic ionic/electronic conductor is realized. These devices show high linearity, low noise and extremely low switching voltage. The brain is capable of massively parallel information processing while consuming only ∼1–100 fJ per synaptic event1,2. Inspired by the efficiency of the brain, CMOS-based neural architectures3 and memristors4,5 are being developed for pattern recognition and machine learning. However, the volatility, design complexity and high supply voltages for CMOS architectures, and the stochastic and energy-costly switching of memristors complicate the path to achieve the interconnectivity, information density, and energy efficiency of the brain using either approach. Here we describe an electrochemical neuromorphic organic device (ENODe) operating with a fundamentally different mechanism from existing memristors. ENODe switches at low voltage and energy ( 500 distinct, non-volatile conductance states within a ∼1 V range, and achieves high classification accuracy when implemented in neural network simulations. Plastic ENODes are also fabricated on flexible substrates enabling the integration of neuromorphic functionality in stretchable electronic systems6,7. Mechanical flexibility makes ENODes compatible with three-dimensional architectures, opening a path towards extreme interconnectivity comparable to the human brain.
1,119 citations
Paris Descartes University1, Cornell University2, University of Massachusetts Medical School3, Spanish National Research Council4, Boston Children's Hospital5, University of Rome Tor Vergata6, University of Pittsburgh7, National University of Cuyo8, National Scientific and Technical Research Council9, Albert Einstein College of Medicine10, University of California, San Francisco11, University of New Mexico12, University of Split13, Goethe University Frankfurt14, 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, University of Texas Southwestern Medical Center29, Howard Hughes Medical Institute30, 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 California, Los Angeles1, University of Utah2, University of South Florida3, University of Helsinki4, Primary Children's Hospital5, University of Groningen6, Norfolk and Norwich University Hospital7, Lund University8, Netherlands Cancer Institute9, University of Michigan10, Wake Forest University11, Ohio State University12, Peter MacCallum Cancer Centre13, University of Zurich14, University of Padua15, Pennsylvania State University16, Saint Louis University17, Tom Baker Cancer Centre18, University of Washington19, University of Lausanne20, Guy's and St Thomas' NHS Foundation Trust21, University of Kiel22, Thomas Jefferson University23, Sunnybrook Research Institute24, Vanderbilt University25, University of Queensland26, Fox Chase Cancer Center27, Greenville Health System28, Stony Brook University29, University Health Network30, Memorial Sloan Kettering Cancer Center31, Roswell Park Cancer Institute32, Northwestern University33, University of Wisconsin-Madison34, Rush University Medical Center35, Tel Aviv Sourasky Medical Center36, Dartmouth College37, Johns Hopkins University38, University of Louisville39, University of Barcelona40, University of Sydney41
TL;DR: Immediate completion lymph‐node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma‐specific survival among patients with melanoma and sentinel‐node metastases.
Abstract: BackgroundSentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. MethodsIn an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. ResultsImmediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in t...
946 citations
TL;DR: It is found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development, which support the use of SnCs as a therapeutic target for treating degenerative joint disease.
Abstract: Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.
929 citations
University of East Anglia1, University of Exeter2, Max Planck Society3, Commonwealth Scientific and Industrial Research Organisation4, Stanford University5, Oak Ridge National Laboratory6, National Oceanic and Atmospheric Administration7, Cooperative Institute for Marine and Atmospheric Studies8, Atlantic Oceanographic and Meteorological Laboratory9, Bjerknes Centre for Climate Research10, Geophysical Institute, University of Bergen11, Met Office12, École Normale Supérieure13, Centre national de la recherche scientifique14, University of Maryland, College Park15, National Institute of Water and Atmospheric Research16, International Institute for Applied Systems Analysis17, Alfred Wegener Institute for Polar and Marine Research18, Woods Hole Oceanographic Institution19, University of New Hampshire20, University of Illinois at Urbana–Champaign21, Karlsruhe Institute of Technology22, University of California, San Diego23, Utrecht University24, Netherlands Environmental Assessment Agency25, Leibniz Institute of Marine Sciences26, University of Paris27, Cooperative Research Centre28, Hobart Corporation29, Oeschger Centre for Climate Change Research30, University of Bern31, National Center for Atmospheric Research32, University of Miami33, Council of Scientific and Industrial Research34, Institute of Arctic and Alpine Research35, National Institute for Environmental Studies36, Spanish National Research Council37, Goddard Space Flight Center38, Montana State University39, Leibniz Institute for Baltic Sea Research40, University of Delaware41, Auburn University42, Food and Agriculture Organization43, Wageningen University and Research Centre44, VU University Amsterdam45, University of Groningen46
TL;DR: In this paper, the authors quantify the five major components of the global carbon budget and their uncertainties, and the resulting carbon budget imbalance (BIM) is a measure of imperfect data and understanding of the contemporary carbon cycle.
Abstract: Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere – the "global carbon budget" – is important to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties. CO2 emissions from fossil fuels and industry (EFF) are based on energy statistics and cement production data, respectively, while emissions from land-use change (ELUC), mainly deforestation, are based on land-cover change data and bookkeeping models. The global atmospheric CO2 concentration is measured directly and its rate of growth (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) and terrestrial CO2 sink (SLAND) are estimated with global process models constrained by observations. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the last decade available (2007–2016), EFF was 9.4 ± 0.5 GtC yr−1, ELUC 1.3 ± 0.7 GtC yr−1, GATM 4.7 ± 0.1 GtC yr−1, SOCEAN 2.4 ± 0.5 GtC yr−1, and SLAND 3.0 ± 0.8 GtC yr−1, with a budget imbalance BIM of 0.6 GtC yr−1 indicating overestimated emissions and/or underestimated sinks. For year 2016 alone, the growth in EFF was approximately zero and emissions remained at 9.9 ± 0.5 GtC yr−1. Also for 2016, ELUC was 1.3 ± 0.7 GtC yr−1, GATM was 6.1 ± 0.2 GtC yr−1, SOCEAN was 2.6 ± 0.5 GtC yr−1, and SLAND was 2.7 ± 1.0 GtC yr−1, with a small BIM of −0.3 GtC. GATM continued to be higher in 2016 compared to the past decade (2007–2016), reflecting in part the high fossil emissions and the small SLAND consistent with El Nino conditions. The global atmospheric CO2 concentration reached 402.8 ± 0.1 ppm averaged over 2016. For 2017, preliminary data for the first 6–9 months indicate a renewed growth in EFF of +2.0 % (range of 0.8 to 3.0 %) based on national emissions projections for China, USA, and India, and projections of gross domestic product (GDP) corrected for recent changes in the carbon intensity of the economy for the rest of the world. This living data update documents changes in the methods and data sets used in this new global carbon budget compared with previous publications of this data set (Le Quere et al., 2016, 2015b, a, 2014, 2013). All results presented here can be downloaded from https://doi.org/10.18160/GCP-2017 (GCP, 2017).
TL;DR: It is suggested that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.
Abstract: Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. Significance: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165–76. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 115
TL;DR: Investigation of the branching phenotype revealed that in branching cells nucleoid organization, divisome formation and peptidoglycan incorporation were disrupted, and Xac with minC deleted exhibited the classic Δmin phenotype observed in other bacteria deleted for min components.
Abstract: Xanthomonas citri (Xac) is the causal agent of citrus canker, a disease that affects citrus crops and causes economic impact worldwide. To further characterize cell division in this plant pathogen, we investigated the role of the protein MinC in cell division, chromosome segregation, and peptidoglycan incorporation by deleting the gene minC using allele exchange. Xac with minC deleted exhibited the classic Δmin phenotype observed in other bacteria deleted for min components: minicells and short filamentation. In addition we noticed the formation of branches, which is similar to what was previously described for Escherichia coli deleted for either min or for several low molecular weight penicillin-binding proteins (PBPs). The branching phenotype was medium dependent and probably linked to gluconeogenic growth. We complemented the minC gene by integrating gfp-minC into the amy locus. Xac complemented strains displayed a wild-type phenotype. In addition, GFP-MinC oscillated from pole to pole, similar to MinCD oscillations observed in E. coli and more recently in Synechococcus elongatus. Further investigation of the branching phenotype revealed that in branching cells nucleoid organization, divisome formation and peptidoglycan incorporation were disrupted.
TL;DR: A direct correlation is found between the density of traps, thedensity of mobile ionic defects, and the degree of hysteresis observed in the current–voltage (J–V) characteristics of perovskite solar cells.
Abstract: Trap-assisted recombination, despite being lower as compared with traditional inorganic solar cells, is still the dominant recombination mechanism in perovskite solar cells (PSCs) and limits their efficiency. We investigate the attributes of the primary trap-assisted recombination channels (grain boundaries and interfaces) and their correlation to defect ions in PSCs. We achieve this by using a validated device model to fit the simulations to the experimental data of efficient vacuum-deposited p–i–n and n–i–p CH3NH3PbI3 solar cells, including the light intensity dependence of the open-circuit voltage and fill factor. We find that, despite the presence of traps at interfaces and grain boundaries (GBs), their neutral (when filled with photogenerated charges) disposition along with the long-lived nature of holes leads to the high performance of PSCs. The sign of the traps (when filled) is of little importance in efficient solar cells with compact morphologies (fused GBs, low trap density). On the other hand,...
Utrecht University1, Alfred Wegener Institute for Polar and Marine Research2, Helmholtz Centre for Environmental Research - UFZ3, Swiss Federal Institute for Forest, Snow and Landscape Research4, University of Paris5, University of Jena6, Imperial College London7, University of Groningen8, Oklahoma State University–Stillwater9, Nanjing University10, Nanjing Agricultural University11, Royal Netherlands Academy of Arts and Sciences12
TL;DR: An ecological overview of the rare microbial biosphere is provided, including causes of rarity and the impacts of rare species on ecosystem functioning, and how rare species can have a preponderant role for local biodiversity and species turnover with rarity potentially bound to phylogenetically conserved features is discussed.
Abstract: Rare species are increasingly recognized as crucial, yet vulnerable components of Earth’s ecosystems. This is also true for microbial communities, which are typically composed of a high number of relatively rare species. Recent studies have demonstrated that rare species can have an over-proportional role in biogeochemical cycles and may be a hidden driver of microbiome function. In this review, we provide an ecological overview of the rare microbial biosphere, including causes of rarity and the impacts of rare species on ecosystem functioning. We discuss how rare species can have a preponderant role for local biodiversity and species turnover with rarity potentially bound to phylogenetically conserved features. Rare microbes may therefore be overlooked keystone species regulating the functioning of host-associated, terrestrial and aquatic environments. We conclude this review with recommendations to guide scientists interested in investigating this rapidly emerging research area.
University of British Columbia1, University of Calgary2, Harvard University3, Johns Hopkins University4, International Society of Nephrology5, Veterans Health Administration6, Merck & Co.7, University of Groningen8, Concord Repatriation General Hospital9, University of Freiburg10, University of Michigan11, Tufts University12, University of Zurich13, University of California, San Diego14, Panamerican University15, University of Alberta16, University of Sydney17, Karolinska Institutet18, University of Washington19, University College London20, University of Erlangen-Nuremberg21
TL;DR: An action plan and performance framework based on ten themes to strengthen CKD surveillance, tackle major risk factors for CKD, and enhance understanding of the genetic causes of CKD is presented.
TL;DR: This work focuses on the control of directional movement, both at the molecular scale and at larger magnitudes, and identifies some key challenges remaining in the field.
Abstract: Motor proteins are nature's solution for directing movement at the molecular level. The field of artificial molecular motors takes inspiration from these tiny but powerful machines. Although directional motion on the nanoscale performed by synthetic molecular machines is a relatively new development, significant advances have been made. In this review an overview is given of the principal designs of artificial molecular motors and their modes of operation. Although synthetic molecular motors have also found widespread application as (multistate) switches, we focus on the control of directional movement, both at the molecular scale and at larger magnitudes. We identify some key challenges remaining in the field.
TL;DR: In this article, a test of lepton universality is performed by measuring the ratio of the branching fractions of the B$0$ → K$*0}$ e$+}$ π$−}$ decays, and the ratio is measured in two regions of the dilepton invariant mass squared.
Abstract: A test of lepton universality, performed by measuring the ratio of the branching fractions of the B$^{0}$ → K$^{*0}$ μ$^{+}$ μ$^{−}$ and B$^{0}$ → K$^{*0}$ e$^{+}$ e$^{−}$ decays, $ {R}_{K^{*0}} $ , is presented. The K$^{*0}$ meson is reconstructed in the final state K$^{+}$ π$^{−}$, which is required to have an invariant mass within 100 MeV/c$^{2}$ of the known K$^{*}$(892)$^{0}$ mass. The analysis is performed using proton-proton collision data, corresponding to an integrated luminosity of about 3 fb$^{−1}$, collected by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The ratio is measured in two regions of the dilepton invariant mass squared, q$^{2}$, to be $ {R}_{K^{*0}}=\left\{\begin{array}{l}{0.66_{-}^{+}}_{0.07}^{0.11}\left(\mathrm{stat}\right)\pm 0.03\left(\mathrm{syst}\right)\kern1em \mathrm{f}\mathrm{o}\mathrm{r}\kern1em 0.045<{q}^2<1.1\kern0.5em {\mathrm{GeV}}^2/{c}^4,\hfill \\ {}{0.69_{-}^{+}}_{0.07}^{0.11}\left(\mathrm{stat}\right)\pm 0.05\left(\mathrm{syst}\right)\kern1em \mathrm{f}\mathrm{o}\mathrm{r}\kern1em 1.1<{q}^2<6.0\kern0.5em {\mathrm{GeV}}^2/{c}^4.\hfill \end{array}\right. $
TL;DR: It is shown that despite the weakness of gravity, the phase evolution induced by the gravitational interaction of two micron size test masses in adjacent matter-wave interferometers can detectably entangle them even when they are placed far apart enough to keep Casimir-Polder forces at bay.
Abstract: Understanding gravity in the framework of quantum mechanics is one of the great challenges in modern physics. However, the lack of empirical evidence has lead to a debate on whether gravity is a quantum entity. Despite varied proposed probes for quantum gravity, it is fair to say that there are no feasible ideas yet to test its quantum coherent behavior directly in a laboratory experiment. Here, we introduce an idea for such a test based on the principle that two objects cannot be entangled without a quantum mediator. We show that despite the weakness of gravity, the phase evolution induced by the gravitational interaction of two micron size test masses in adjacent matter-wave interferometers can detectably entangle them even when they are placed far apart enough to keep Casimir-Polder forces at bay. We provide a prescription for witnessing this entanglement, which certifies gravity as a quantum coherent mediator, through simple spin correlation measurements.
University Hospital of Basel1, University of Paris2, Aarhus University Hospital3, Hochschule Hannover4, Universidade Federal de Minas Gerais5, Shanghai Jiao Tong University6, McMaster University7, University of Rochester8, University of Groningen9, University of Modena and Reggio Emilia10, Capital Medical University11, China-Japan Friendship Hospital12, Medisch Spectrum Twente13, Copenhagen University Hospital14
TL;DR: In this article, a systematic review included individual patient data from 14 randomised controlled trials with a total of 4211 participants and found no increased risk for all-cause mortality or treatment failure when procalcitonin was used to guide initiation and duration of antibiotic treatment in participants with acute respiratory infections compared to control participants.
Abstract: Unnecessary antibiotic use significantly contributes to increasing bacterial resistance, medical costs and the risk of drug-related adverse events. The blood marker procalcitonin increases in bacterial infections and decreases when patients recover from the infection. Hence, procalcitonin may be used to support clinical decision making for the initiation and discontinuation of antibiotic therapy in patients with a clinical suspicion of infection. Randomised controlled trials have demonstrated that such a strategy works, particularly in patients with an infection of the respiratory tract. However, most of these individual studies did not include enough patients to allow for a conclusive assessment about safety (low statistical power). Thus, the risk for mortality and severe complications associated with procalcitonin-guided decision making remained unclear.
This systematic review included individual patient data from 14 randomised controlled trials with a total of 4211 participants. When looking at these combined data, we found no increased risk for all-cause mortality or treatment failure when procalcitonin was used to guide initiation and duration of antibiotic treatment in participants with acute respiratory infections compared to control participants. However, we found a consistent reduction of antibiotic use, mainly due to lower prescription rates in primary care and lower duration of antibiotic courses in emergency department and intensive care unit patients. This analysis is limited to adult patients with respiratory infections excluding patients who were immuno-compromised (i.e. HIV positive, those receiving immuno-suppressive therapies or chemotherapy). Most trials were conducted in Europe and China and similar studies in other countries including the United States are warranted.
TL;DR: Considering the high rates of NPS and PDU in YOD residents and their negative associations with QoL, the findings suggest emphasizing services to manage and reduce NPSAndPDU in nursing home residents with YOD to address specific needs and thereby improveQoL.
Abstract: Aims: The aims of this study are to (1) explore the determinants of quality of life (QoL) in nursing home residents with young-onset dementia (YOD), (2) investigate whether there are differences between dementia subtypes (Alzheimer dementia, vascular/mixed dementia, frontotemporal dementia, other) regarding these determinants, and (3) compare QoL profiles of YOD nursing home residents across dementia subtypes. Methods: This cross-sectional study included 207 nursing home residents. Multilevel modeling was used to determine the relationships between QoL and neuropsychiatric symptoms (NPS), dementia severity, psychotropic drug use (PDU), dementia subtype, age, and gender. Additional multilevel models were used to compare aspects of QoL between dementia subtypes. Results: Residents' QoL was negatively associated with advanced dementia, PDU, and NPS. In general, the relationships between the determinants and QoL were similar across the dementia subtypes. Aspects of QoL differed by dementia subtype. Residents with frontotemporal dementia showed less negative emotions, accepted more help and experienced better quality of relationships with professional caregivers, had a more positive self-image, felt more comfortable in the nursing home environment, and experienced lower quality of social relationships. Conclusions: Considering the high rates of NPS and PDU in YOD residents and their negative associations with QoL, we recommend emphasizing services to manage and reduce NPS and PDU in nursing home residents with YOD. Furthermore, our findings suggest accounting for differences in aspects of QoL by dementia subtype to address specific needs and thereby improve QoL.
Royal College of Surgeons in Ireland1, University of Manchester2, Netherlands Cancer Institute3, Autonomous University of Barcelona4, Katholieke Universiteit Leuven5, University of Glasgow6, University of Cambridge7, Masaryk University8, Utrecht University9, University of Lausanne10, Curie Institute11, University of Paris12, University of Colorado Denver13, Harvard University14, University of Groningen15, University of Oslo16, Catalan Institution for Research and Advanced Studies17, University of Turin18
TL;DR: Patient derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology as mentioned in this paper, and the ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions.
Abstract: Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.
TL;DR: The Nobel Lecture of B. L. Feringa describes the evolution of the field of molecular motors and explains how to program and control molecules by incorporating responsive and adaptive properties.
Abstract: A journey into the nano-world: The ability to design, use and control motor-like functions at the molecular level sets the stage for numerous dynamic molecular systems. In his Nobel Lecture, B. L. Feringa describes the evolution of the field of molecular motors and explains how to program and control molecules by incorporating responsive and adaptive properties.
TL;DR: In this paper, the authors present a systematic review of 157 papers on digital developments and rural development in advanced countries, focusing on the general conclusions, in order to better understand the potential impacts of the coming Next Generation Access revolution.
Seoul National University1, Seoul National University Hospital2, University of Parma3, Samsung Medical Center4, Beckman Research Institute5, Odense University Hospital6, Odense University7, University of Ulsan8, Ludwig Maximilian University of Munich9, University of Groningen10, Princess Margaret Cancer Centre11, Yale Cancer Center12, University of Pennsylvania13, VU University Amsterdam14
TL;DR: Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.
Abstract: PurposeMost crizotinib-treated patients with anaplastic lymphoma kinase gene (ALK)–rearranged non–small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC.Patients and MethodsPatients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point.ResultsOf 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Invest...
TL;DR: In this article, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
Abstract: Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
Queen Mary University of London1, University of Ioannina2, Imperial College London3, National Institute for Health Research4, University of Cambridge5, National Institutes of Health6, University of Liverpool7, Washington University in St. Louis8, University of Bristol9, University College London10, Agency for Science, Technology and Research11, University of Groningen12, Harvard University13, University of Edinburgh14, Bayer HealthCare Pharmaceuticals15, King's College London16, Tulane University17, National University of Singapore18, University of Tartu19, Wellcome Trust Centre for Human Genetics20, University Medical Center Groningen21, University of Glasgow22, Royal College of Surgeons in Ireland23, University of Dundee24, University College Dublin25, Broad Institute26, University of Pennsylvania27, Brigham and Women's Hospital28, Johns Hopkins University School of Medicine29, University of Oxford30, Imperial College Healthcare31, Ealing Hospital32, University of Manchester33, Manchester Academic Health Science Centre34, Glenfield Hospital35, University of Leicester36, Geneva College37
TL;DR: In this paper, the authors report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci.
Abstract: Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.
TL;DR: It is shown that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load, which provides insights into the conformational cycle of Roco proteins and suggests a link between oligomersization and disease-associated mutations in LRRK2.
Abstract: Mutations in LRRK2 are a common cause of genetic Parkinson's disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2.
Broad Institute1, Harvard University2, University of Liège3, University of Oxford4, Wellcome Trust Sanger Institute5, Montreal Heart Institute6, University of Southern Denmark7, Katholieke Universiteit Leuven8, Wellcome Trust Centre for Human Genetics9, John Radcliffe Hospital10, Karolinska Institutet11, Ikerbasque12, Illumina13, University of Kiel14, Örebro University15, Cedars-Sinai Medical Center16, Lancaster University17, University of Western Australia18, Western General Hospital19, Norwegian University of Life Sciences20, Wellcome Trust21, University of Groningen22, University Medical Center Groningen23, University of Pittsburgh24, King's College London25, University of the Witwatersrand26, Université de Montréal27, Yale University28
TL;DR: The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
Abstract: Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
University of Sydney1, St George's Hospital2, Johns Hopkins University3, Population Health Research Institute4, Karolinska Institutet5, Ruijin Hospital6, Brigham and Women's Hospital7, The George Institute for Global Health8, Barts Health NHS Trust9, Boston University10, University of Modena and Reggio Emilia11, National Yang-Ming University12, University Hospital of Basel13, François Rabelais University14, University of Birmingham15, Mayo Clinic16, University of Toronto17, University of Western Australia18, Trinity College, Dublin19, Cornell University20, Lankenau Institute for Medical Research21, The Chinese University of Hong Kong22, Aalborg University23, Edinburgh Napier University24, Duke University25, University of Auckland26, University of Belgrade27, University of Groningen28, University of Alberta29, University of Hong Kong30, University of Copenhagen31, Stanford University32, VA Palo Alto Healthcare System33, University of Göttingen34
TL;DR: A strong case for AF screening now is provided while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.
Abstract: Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.