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Showing papers by "Uppsala University published in 2019"


Journal ArticleDOI
TL;DR: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than amongThose who received placebo, regardless of the presence or absence of diabetes.
Abstract: Background In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-ind...

3,541 citations


Journal ArticleDOI
TL;DR: The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP) resulting in three stages of complexity for intervention.

993 citations


Journal ArticleDOI
TL;DR: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.
Abstract: Rationale This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.

827 citations


Journal ArticleDOI
01 Jun 2019-Brain
TL;DR: A recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE).
Abstract: We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

753 citations


Journal ArticleDOI
TL;DR: It is confirmed that eukaryotes form at least two domains, the loss of monophyly in the Excavata, robust support for the Haptista and Cryptista, and suggested primer sets for DNA sequences from environmental samples that are effective for each clade are provided.
Abstract: This revision of the classification of eukaryotes follows that of Adl et al., 2012 [J. Euk. Microbiol. 59(5)] and retains an emphasis on protists. Changes since have improved the resolution of many ...

750 citations


Journal ArticleDOI
TL;DR: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.
Abstract: Background Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are uncl...

742 citations


Journal ArticleDOI
TL;DR: It is shown how ecosystem service assessments can be expanded to include mental health, and a heuristic, conceptual model for doing so is provided.
Abstract: A growing body of empirical evidence is revealing the value of nature experience for mental health. With rapid urbanization and declines in human contact with nature globally, crucial decisions must be made about how to preserve and enhance opportunities for nature experience. Here, we first provide points of consensus across the natural, social, and health sciences on the impacts of nature experience on cognitive functioning, emotional well-being, and other dimensions of mental health. We then show how ecosystem service assessments can be expanded to include mental health, and provide a heuristic, conceptual model for doing so.

736 citations


Journal ArticleDOI
TL;DR: A range of effective interventions is available to support adequate nutrition and hydration in older persons in order to maintain or improve nutritional status and improve clinical course and quality of life.

700 citations


Journal ArticleDOI
TL;DR: Scientists working on the response of bacteria to antibiotics define antibiotic persistence and provide practical guidance on how to study bacterial persister cells, and provide a guide to measuring persistence.
Abstract: Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.

659 citations


Journal ArticleDOI
Nasim Mavaddat1, Kyriaki Michailidou1, Kyriaki Michailidou2, Joe Dennis1  +307 moreInstitutions (105)
TL;DR: This PRS, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset is developed and empirically validated and is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

653 citations


Journal ArticleDOI
TL;DR: The OpenMolcas environment is described and features unique to simulations of spectroscopic and magnetic phenomena such as the exact semiclassical description of the interaction between light and matter, various X-ray processes, magnetic circular dichroism and properties are described.
Abstract: In this Article we describe the OpenMolcas environment and invite the computational chemistry community to collaborate. The open-source project already includes a large number of new developments realized during the transition from the commercial MOLCAS product to the open-source platform. The paper initially describes the technical details of the new software development platform. This is followed by brief presentations of many new methods, implementations, and features of the OpenMolcas program suite. These developments include novel wave function methods such as stochastic complete active space self-consistent field, density matrix renormalization group (DMRG) methods, and hybrid multiconfigurational wave function and density functional theory models. Some of these implementations include an array of additional options and functionalities. The paper proceeds and describes developments related to explorations of potential energy surfaces. Here we present methods for the optimization of conical intersections, the simulation of adiabatic and nonadiabatic molecular dynamics, and interfaces to tools for semiclassical and quantum mechanical nuclear dynamics. Furthermore, the Article describes features unique to simulations of spectroscopic and magnetic phenomena such as the exact semiclassical description of the interaction between light and matter, various X-ray processes, magnetic circular dichroism, and properties. Finally, the paper describes a number of built-in and add-on features to support the OpenMolcas platform with postcalculation analysis and visualization, a multiscale simulation option using frozen-density embedding theory, and new electronic and muonic basis sets.

Journal ArticleDOI
A. Abada1, Marcello Abbrescia2, Marcello Abbrescia3, Shehu S. AbdusSalam4  +1491 moreInstitutions (239)
TL;DR: In this article, the authors present the second volume of the Future Circular Collider Conceptual Design Report, devoted to the electron-positron collider FCC-ee, and present the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan.
Abstract: In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics.

Journal ArticleDOI
TL;DR: In this article, a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts is described. But despite the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work.
Abstract: This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through online media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focused on the process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come.

Journal ArticleDOI
TL;DR: This research presents a novel probabilistic approach that allows us to assess the importance of knowing the carrier and removal status of canine coronavirus, as a source of infection for other animals.
Abstract: Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limi ...

Journal ArticleDOI
31 Jul 2019-Nature
TL;DR: It is concluded that bacterial infection of the placenta is not a common cause of adverse pregnancy outcome and that the human Placenta does not have a microbiome, but it does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis.
Abstract: We sought to determine whether pre-eclampsia, spontaneous preterm birth or the delivery of infants who are small for gestational age were associated with the presence of bacterial DNA in the human placenta. Here we show that there was no evidence for the presence of bacteria in the large majority of placental samples, from both complicated and uncomplicated pregnancies. Almost all signals were related either to the acquisition of bacteria during labour and delivery, or to contamination of laboratory reagents with bacterial DNA. The exception was Streptococcus agalactiae (group B Streptococcus), for which non-contaminant signals were detected in approximately 5% of samples collected before the onset of labour. We conclude that bacterial infection of the placenta is not a common cause of adverse pregnancy outcome and that the human placenta does not have a microbiome, but it does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis.

Journal ArticleDOI
TL;DR: In this article, key observational indicators of climate change in the Arctic, most spanning a 47-year period (1971-2017) demonstrate fundamental changes among nine key elements of the Arctic system.
Abstract: Key observational indicators of climate change in the Arctic, most spanning a 47 year period (1971–2017) demonstrate fundamental changes among nine key elements of the Arctic system. We find that, coherent with increasing air temperature, there is an intensification of the hydrological cycle, evident from increases in humidity, precipitation, river discharge, glacier equilibrium line altitude and land ice wastage. Downward trends continue in sea ice thickness (and extent) and spring snow cover extent and duration, while near-surface permafrost continues to warm. Several of the climate indicators exhibit a significant statistical correlation with air temperature or precipitation, reinforcing the notion that increasing air temperatures and precipitation are drivers of major changes in various components of the Arctic system. To progress beyond a presentation of the Arctic physical climate changes, we find a correspondence between air temperature and biophysical indicators such as tundra biomass and identify numerous biophysical disruptions with cascading effects throughout the trophic levels. These include: increased delivery of organic matter and nutrients to Arctic near‐coastal zones; condensed flowering and pollination plant species periods; timing mismatch between plant flowering and pollinators; increased plant vulnerability to insect disturbance; increased shrub biomass; increased ignition of wildfires; increased growing season CO2 uptake, with counterbalancing increases in shoulder season and winter CO2 emissions; increased carbon cycling, regulated by local hydrology and permafrost thaw; conversion between terrestrial and aquatic ecosystems; and shifting animal distribution and demographics. The Arctic biophysical system is now clearly trending away from its 20th Century state and into an unprecedented state, with implications not only within but beyond the Arctic. The indicator time series of this study are freely downloadable at AMAP.no.

Journal ArticleDOI
TL;DR: Positive associations between recreational nature contact in the last seven days and self-reported health and well-being were consistent across key groups including older adults and those with long-term health issues.
Abstract: Spending time in natural environments can benefit health and well-being, but exposure-response relationships are under-researched. We examined associations between recreational nature contact in the last seven days and self-reported health and well-being. Participants (n = 19,806) were drawn from the Monitor of Engagement with the Natural Environment Survey (2014/15–2015/16); weighted to be nationally representative. Weekly contact was categorised using 60 min blocks. Analyses controlled for residential greenspace and other neighbourhood and individual factors. Compared to no nature contact last week, the likelihood of reporting good health or high well-being became significantly greater with contact ≥120 mins (e.g. 120–179 mins: ORs [95%CIs]: Health = 1.59 [1.31–1.92]; Well-being = 1.23 [1.08–1.40]). Positive associations peaked between 200–300 mins per week with no further gain. The pattern was consistent across key groups including older adults and those with long-term health issues. It did not matter how 120 mins of contact a week was achieved (e.g. one long vs. several shorter visits/week). Prospective longitudinal and intervention studies are a critical next step in developing possible weekly nature exposure guidelines comparable to those for physical activity.

Journal ArticleDOI
A. Abada1, Marcello Abbrescia2, Marcello Abbrescia3, Shehu S. AbdusSalam4  +1496 moreInstitutions (238)
TL;DR: In this paper, the authors describe the detailed design and preparation of a construction project for a post-LHC circular energy frontier collider in collaboration with national institutes, laboratories and universities worldwide, and enhanced by a strong participation of industrial partners.
Abstract: Particle physics has arrived at an important moment of its history. The discovery of the Higgs boson, with a mass of 125 GeV, completes the matrix of particles and interactions that has constituted the “Standard Model” for several decades. This model is a consistent and predictive theory, which has so far proven successful at describing all phenomena accessible to collider experiments. However, several experimental facts do require the extension of the Standard Model and explanations are needed for observations such as the abundance of matter over antimatter, the striking evidence for dark matter and the non-zero neutrino masses. Theoretical issues such as the hierarchy problem, and, more in general, the dynamical origin of the Higgs mechanism, do likewise point to the existence of physics beyond the Standard Model. This report contains the description of a novel research infrastructure based on a highest-energy hadron collider with a centre-of-mass collision energy of 100 TeV and an integrated luminosity of at least a factor of 5 larger than the HL-LHC. It will extend the current energy frontier by almost an order of magnitude. The mass reach for direct discovery will reach several tens of TeV, and allow, for example, to produce new particles whose existence could be indirectly exposed by precision measurements during the earlier preceding e+e– collider phase. This collider will also precisely measure the Higgs self-coupling and thoroughly explore the dynamics of electroweak symmetry breaking at the TeV scale, to elucidate the nature of the electroweak phase transition. WIMPs as thermal dark matter candidates will be discovered, or ruled out. As a single project, this particle collider infrastructure will serve the world-wide physics community for about 25 years and, in combination with a lepton collider (see FCC conceptual design report volume 2), will provide a research tool until the end of the 21st century. Collision energies beyond 100 TeV can be considered when using high-temperature superconductors. The European Strategy for Particle Physics (ESPP) update 2013 stated “To stay at the forefront of particle physics, Europe needs to be in a position to propose an ambitious post-LHC accelerator project at CERN by the time of the next Strategy update”. The FCC study has implemented the ESPP recommendation by developing a long-term vision for an “accelerator project in a global context”. This document describes the detailed design and preparation of a construction project for a post-LHC circular energy frontier collider “in collaboration with national institutes, laboratories and universities worldwide”, and enhanced by a strong participation of industrial partners. Now, a coordinated preparation effort can be based on a core of an ever-growing consortium of already more than 135 institutes worldwide. The technology for constructing a high-energy circular hadron collider can be brought to the technology readiness level required for constructing within the coming ten years through a focused R&D programme. The FCC-hh concept comprises in the baseline scenario a power-saving, low-temperature superconducting magnet system based on an evolution of the Nb3Sn technology pioneered at the HL-LHC, an energy-efficient cryogenic refrigeration infrastructure based on a neon-helium (Nelium) light gas mixture, a high-reliability and low loss cryogen distribution infrastructure based on Invar, high-power distributed beam transfer using superconducting elements and local magnet energy recovery and re-use technologies that are already gradually introduced at other CERN accelerators. On a longer timescale, high-temperature superconductors can be developed together with industrial partners to achieve an even more energy efficient particle collider or to reach even higher collision energies.The re-use of the LHC and its injector chain, which also serve for a concurrently running physics programme, is an essential lever to come to an overall sustainable research infrastructure at the energy frontier. Strategic R&D for FCC-hh aims at minimising construction cost and energy consumption, while maximising the socio-economic impact. It will mitigate technology-related risks and ensure that industry can benefit from an acceptable utility. Concerning the implementation, a preparatory phase of about eight years is both necessary and adequate to establish the project governance and organisation structures, to build the international machine and experiment consortia, to develop a territorial implantation plan in agreement with the host-states’ requirements, to optimise the disposal of land and underground volumes, and to prepare the civil engineering project. Such a large-scale, international fundamental research infrastructure, tightly involving industrial partners and providing training at all education levels, will be a strong motor of economic and societal development in all participating nations. The FCC study has implemented a set of actions towards a coherent vision for the world-wide high-energy and particle physics community, providing a collaborative framework for topically complementary and geographically well-balanced contributions. This conceptual design report lays the foundation for a subsequent infrastructure preparatory and technical design phase.

Journal ArticleDOI
TL;DR: This paper will demonstrate the performance of the latest TENDL releases for different application fields, as well as new approaches for uncertainty quantification based on Bayesian inference methods and possible differential and integral adjustments.

Journal ArticleDOI
Claire Bridel1, van Wieringen Wn1, Henrik Zetterberg2, Betty M. Tijms1, Charlotte E. Teunissen1, José C. Álvarez-Cermeño, Ulf Andreasson2, Markus Axelsson3, David Bäckström4, Ales Bartos5, Maria Bjerke6, Kaj Blennow3, Kaj Blennow2, A. Boxer7, Lena Brundin8, Joachim Burman9, Tove Christensen10, Lenka Fialová11, Lars Forsgren4, Jette L. Frederiksen12, Magnus Gisslén3, Elizabeth Gray13, Martin Gunnarsson14, Sara Hall15, Oskar Hansson15, Megan K. Herbert3, Joel Jakobsson3, Jessen-Krut J3, Shorena Janelidze15, Gudmundur Johannsson3, Gudmundur Johannsson2, Michael Jonsson3, Ludwig Kappos16, Mohsen Khademi8, Mohsen Khademi17, Michael Khalil18, Jens Kuhle16, Mikael Landén3, Leinonen19, Giancarlo Logroscino20, Lu Ch, Jan Lycke3, Nadia K. Magdalinou21, Andrea Malaspina, Niklas Mattsson15, Lieke H.H. Meeter22, Mehta23, Signe Modvig12, Tomas Olsson8, Tomas Olsson17, Ross W. Paterson21, Pérez-Santiago J24, Fredrik Piehl17, Fredrik Piehl8, Pijnenburg Yal1, Pyykkö Ot19, Ragnarsson O14, Julio C. Rojas7, Romme Christensen J12, Sandberg L4, Carole Scherling25, Jonathan M. Schott21, Finn Sellebjerg12, Isabella Laura Simone20, Tobias Skillbäck3, Stilund M10, Peter Sundström4, Anders Svenningsson8, Rosanna Tortelli20, Carla Tortorella20, Alessandro Trentini26, Troiano M20, Martin R Turner13, van Swieten Jc22, Mattias Vågberg4, Marcel M. Verbeek27, Luisa M. Villar, Pieter Jelle Visser28, Pieter Jelle Visser1, Anders Wallin3, Weiss A29, Carsten Wikkelsö3, Edward J. Wild21 
TL;DR: The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC, and has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
Abstract: Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses. Results: Data were collected for 10059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

Journal ArticleDOI
A. Abada1, Marcello Abbrescia2, Marcello Abbrescia3, Shehu S. AbdusSalam4  +1501 moreInstitutions (239)
TL;DR: In this article, the physics opportunities of the Future Circular Collider (FC) were reviewed, covering its e+e-, pp, ep and heavy ion programs, and the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions.
Abstract: We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics.

Journal ArticleDOI
TL;DR: This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean.
Abstract: Rapid changes in ocean circulation and climate have been observed in marine-sediment and ice cores over the last glacial period and deglaciation, highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. One obstacle hindering progress in our understanding of the interactions between past ocean circulation and climate changes is the difficulty of accurately dating marine cores. Here, we present a set of 92 marine sediment cores from the Atlantic Ocean for which we have established age-depth models that are consistent with the Greenland GICC05 ice core chronology, and computed the associated dating uncertainties, using a new deposition modeling technique. This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean. Moreover, this data set is of direct use in paleoclimate modeling studies.

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TL;DR: The task force of the International Conference of Frailty and Sarcopenia Research developed these clinical practice guidelines to overview the current evidence-base and provide recommendations for the identification and management of frailty in older adults using the GRADE approach.
Abstract: Objective: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. Methods: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

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TL;DR: In this article, a dynamically self-optimized (DSO) NiFe layered double hydroxide (LDH) nanosheets with promising bi-functional performance was reported.
Abstract: Earth-abundant transition metal-based compounds are of high interest as catalysts for sustainable hydrogen fuel generation. The realization of effective electrolysis of water, however, is still limited by the requirement of a high sustainable driving potential above thermodynamic requirements. Here, we report dynamically self-optimized (DSO) NiFe layered double hydroxide (LDH) nanosheets with promising bi-functional performance. Compared with pristine NiFe LDH, DSO NiFe LDH exhibits much lower overpotential for the hydrogen evolution reaction (HER), even outperforming platinum. Under 1 M KOH aqueous electrolyte, the bi-functional DSO catalysts show an overpotential of 184 and −59 mV without iR compensation for oxygen evolution reaction (OER) and HER at 10 mA cm−2. The material system operates at 1.48 V and 1.29 V to reach 10 and 1 mA cm−2 in two-electrode measurements, corresponding to 83% and 95% electricity-to-fuel conversion efficiency with respect to the lower heating value of hydrogen. The material is seen to dynamically reform the active phase of the surface layer during HER and OER, where the pristine and activated catalysts are analyzed with ex situ XPS, SAED and EELS as well as with in situ Raman spectro-electrochemistry. The results show transformation into different active interfacial species during OER and HER, revealing a synergistic interplay between iron and nickel in facilitating water electrolysis.

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TL;DR: This work explains and compares the different methods available to construct a time-evolved matrix-product state, namely theTime-evolving block decimation, the MPO $W^\mathrm{II}$ method, the global Krylov method,The local Krykov method and the one- and two-site time-dependent variational principle.

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TL;DR: There are a number of similarities between the two concepts, the goals for person-centered and patient-centered care differ and there are important differences when the concepts are regarded in light of their different goals.

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TL;DR: This article systematically search, identify and analyze a sample of 89 sources using or attempting to define the term “qualitative,” and formulates and illustrates a definition that tries to capture its core elements.
Abstract: What is qualitative research? If we look for a precise definition of qualitative research, and specifically for one that addresses its distinctive feature of being “qualitative,” the literature is meager. In this article we systematically search, identify and analyze a sample of 89 sources using or attempting to define the term “qualitative.” Then, drawing on ideas we find scattered across existing work, and based on Becker’s classic study of marijuana consumption, we formulate and illustrate a definition that tries to capture its core elements. We define qualitative research as an iterative process in which improved understanding to the scientific community is achieved by making new significant distinctions resulting from getting closer to the phenomenon studied. This formulation is developed as a tool to help improve research designs while stressing that a qualitative dimension is present in quantitative work as well. Additionally, it can facilitate teaching, communication between researchers, diminish the gap between qualitative and quantitative researchers, help to address critiques of qualitative methods, and be used as a standard of evaluation of qualitative research.

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TL;DR: Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

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TL;DR: A series of challenges that PFASs pose to the development of a safe agriculture for future generations are identified and a direct correlation between PFAS concentrations in soil and bioaccumulation in plants is indicated.

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Nick Shrine1, Anna L. Guyatt1, A. Mesut Erzurumluoglu1, Victoria E. Jackson1, Victoria E. Jackson2, Victoria E. Jackson3, Brian D. Hobbs4, Carl A. Melbourne1, Chiara Batini1, Katherine A. Fawcett1, Kijoung Song5, Phuwanat Sakornsakolpat4, Phuwanat Sakornsakolpat6, Xingnan Li7, Ruth Boxall8, Nicola F. Reeve1, Ma'en Obeidat9, Jing Hua Zhao10, Matthias Wielscher11, Stefan Weiss12, Katherine A. Kentistou13, James P. Cook14, Benjamin B. Sun10, Jian Zhou, Jennie Hui15, Stefan Karrasch, Medea Imboden16, Sarah E. Harris13, Jonathan Marten13, Stefan Enroth17, Shona M. Kerr13, Ida Surakka18, Vitart13, Terho Lehtimäki19, Richard J. Allen1, Per Bakke20, Terri H. Beaty21, Eugene R. Bleecker7, Yohan Bossé22, Corry-Anke Brandsma23, Zhengming Chen8, James D. Crapo, John Danesh, Dawn L. DeMeo4, Frank Dudbridge1, Ralf Ewert12, Christian Gieger, Amund Gulsvik20, Anna Hansell1, Ke Hao24, Joshua D. Hoffman5, John E. Hokanson25, Georg Homuth12, Peter K. Joshi13, Philippe Joubert22, Claudia Langenberg10, Liming Li26, Kuang Lin8, Lars Lind27, Nicholas Locantore, Jian'an Luan10, Anubha Mahajan28, Joseph C. Maranville29, Alison Catherine Murray30, David C. Nickle29, Richard Packer1, Margaret M. Parker4, Megan L. Paynton1, David J. Porteous13, Dmitry Prokopenko4, Dandi Qiao4, Rajesh Rawal31, Heiko Runz29, Ian Sayers32, Don D. Sin9, Blair H. Smith33, María Soler Artigas34, David Sparrow35, Ruth Tal-Singer, Timmers Prhj, van den Berge M23, John C. Whittaker, Prescott G. Woodruff36, Laura M Yerges Armstrong5, Olga G. Troyanskaya37, Olli T. Raitakari38, Mika Kähönen19, Ozren Polasek39, Ozren Polasek13, Ulf Gyllensten17, Igor Rudan13, Ian J. Deary13, Nicole Probst-Hensch16, Nicole Probst-Hensch40, Holger Schulz, Alan James41, Alan James15, James F. Wilson13, Beate Stubbe12, Eleftheria Zeggini42, Marjo-Riitta Järvelin, Nicholas J. Wareham10, Edwin K. Silverman4, Caroline Hayward13, Andrew P. Morris14, Andrew P. Morris28, Adam S. Butterworth10, Robert A. Scott, Robin G Walters8, Deborah A. Meyers7, Michael H. Cho4, David P. Strachan43, Ian P. Hall32, Tobin32, Louise V. Wain44, Louise V. Wain1 
TL;DR: In this paper, a genome-wide association study in 400,102 individuals of European ancestry was conducted to define 279 lung function signals, 139 of which are new and the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups.
Abstract: Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.