Showing papers by "University of Milan published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
University of Pennsylvania1, University of Texas Southwestern Medical Center2, University of Oslo3, Boston Children's Hospital4, University of Utah5, Université de Montréal6, Goethe University Frankfurt7, University of Minnesota8, Children's Mercy Hospital9, Emory University10, Ghent University11, Kyoto University12, Stanford University13, Duke University14, Oregon Health & Science University15, University of Michigan16, Medical University of Vienna17, University of Paris18, Royal Children's Hospital19, University of Milan20, University of Toronto21, Novartis22, University of Southern California23
TL;DR: In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects.
Abstract: Background In a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) Methods We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry The rates of event-f
3,237 citations
TL;DR: In this paper, the cosmological parameter results from the final full-mission Planck measurements of the CMB anisotropies were presented, with good consistency with the standard spatially-flat 6-parameter CDM cosmology having a power-law spectrum of adiabatic scalar perturbations from polarization, temperature, and lensing separately and in combination.
Abstract: We present cosmological parameter results from the final full-mission Planck measurements of the CMB anisotropies. We find good consistency with the standard spatially-flat 6-parameter $\Lambda$CDM cosmology having a power-law spectrum of adiabatic scalar perturbations (denoted "base $\Lambda$CDM" in this paper), from polarization, temperature, and lensing, separately and in combination. A combined analysis gives dark matter density $\Omega_c h^2 = 0.120\pm 0.001$, baryon density $\Omega_b h^2 = 0.0224\pm 0.0001$, scalar spectral index $n_s = 0.965\pm 0.004$, and optical depth $\tau = 0.054\pm 0.007$ (in this abstract we quote $68\,\%$ confidence regions on measured parameters and $95\,\%$ on upper limits). The angular acoustic scale is measured to $0.03\,\%$ precision, with $100\theta_*=1.0411\pm 0.0003$. These results are only weakly dependent on the cosmological model and remain stable, with somewhat increased errors, in many commonly considered extensions. Assuming the base-$\Lambda$CDM cosmology, the inferred late-Universe parameters are: Hubble constant $H_0 = (67.4\pm 0.5)$km/s/Mpc; matter density parameter $\Omega_m = 0.315\pm 0.007$; and matter fluctuation amplitude $\sigma_8 = 0.811\pm 0.006$. We find no compelling evidence for extensions to the base-$\Lambda$CDM model. Combining with BAO we constrain the effective extra relativistic degrees of freedom to be $N_{\rm eff} = 2.99\pm 0.17$, and the neutrino mass is tightly constrained to $\sum m_
u< 0.12$eV. The CMB spectra continue to prefer higher lensing amplitudes than predicted in base -$\Lambda$CDM at over $2\,\sigma$, which pulls some parameters that affect the lensing amplitude away from the base-$\Lambda$CDM model; however, this is not supported by the lensing reconstruction or (in models that also change the background geometry) BAO data. (Abridged)
3,077 citations
TL;DR: This analysis expands upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars.
Abstract: On 17 August 2017, the LIGO and Virgo observatories made the first direct detection of gravitational waves from the coalescence of a neutron star binary system. The detection of this gravitational-wave signal, GW170817, offers a novel opportunity to directly probe the properties of matter at the extreme conditions found in the interior of these stars. The initial, minimal-assumption analysis of the LIGO and Virgo data placed constraints on the tidal effects of the coalescing bodies, which were then translated to constraints on neutron star radii. Here, we expand upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars. Our analysis employs two methods: the use of equation-of-state-insensitive relations between various macroscopic properties of the neutron stars and the use of an efficient parametrization of the defining function pðρÞ of the equation of state itself. From the LIGO and Virgo data alone and the first method, we measure the two neutron star radii as R1 ¼ 10.8 þ2.0 −1.7 km for the heavier star and R2 ¼ 10.7 þ2.1 −1.5 km for the lighter star at the 90% credible level. If we additionally require that the equation of state supports neutron stars with masses larger than 1.97 M⊙ as required from electromagnetic observations and employ the equation-of-state parametrization, we further constrain R1 ¼ 11.9 þ1.4 −1.4 km and R2 ¼ 11.9 þ1.4 −1.4 km at the 90% credible level. Finally, we obtain constraints on pðρÞ at supranuclear densities, with pressure at twice nuclear saturation density measured at 3.5 þ2.7 −1.7 × 1034 dyn cm−2 at the 90% level.
1,595 citations
University of Southern California1, Duke University2, Stockholm School of Economics3, University of Virginia4, Center for Open Science5, University of Amsterdam6, University of Pennsylvania7, University of North Carolina at Chapel Hill8, University of Regensburg9, California Institute of Technology10, Research Institute of Industrial Economics11, New York University12, Cardiff University13, Mathematica Policy Research14, Northwestern University15, Ohio State University16, University of Sussex17, Texas A&M University18, Royal Holloway, University of London19, University of Zurich20, University of Melbourne21, University of Wisconsin-Madison22, University of Michigan23, Stanford University24, Rutgers University25, Columbia University26, University of Washington27, University of Edinburgh28, National University of Singapore29, Utrecht University30, Arizona State University31, Princeton University32, University of California, Los Angeles33, Imperial College London34, University of Innsbruck35, Harvard University36, University of Chicago37, University of Pittsburgh38, University of Notre Dame39, University of California, Berkeley40, Johns Hopkins University41, University of Bristol42, University of New South Wales43, Dartmouth College44, Whitman College45, University of Puerto Rico46, University of Milan47, University of California, Irvine48, Paris Dauphine University49, University of British Columbia50, Ludwig Maximilian University of Munich51, Purdue University52, Washington University in St. Louis53, University of California, Davis54, Microsoft55
TL;DR: The default P-value threshold for statistical significance is proposed to be changed from 0.05 to 0.005 for claims of new discoveries in order to reduce uncertainty in the number of discoveries.
Abstract: We propose to change the default P-value threshold for statistical significance from 0.05 to 0.005 for claims of new discoveries.
1,586 citations
University of Milan1, Instituto Português de Oncologia Francisco Gentil2, Curie Institute3, Leiden University Medical Center4, Vienna General Hospital5, University College London6, Leiden University7, Institut Jules Bordet8, Netherlands Cancer Institute9, Turku University Hospital10, University of Oxford11, University of Mannheim12, Ludwig Maximilian University of Munich13, Helsinki University Central Hospital14, The Royal Marsden NHS Foundation Trust15, Institute of Cancer Research16, University Medical Center Groningen17, Radboud University Nijmegen18, Institut Gustave Roussy19, Tel Aviv Sourasky Medical Center20, University Hospital of Lausanne21, University of Bologna22, University of Turin23, Weston Park Hospital24, Aarhus University Hospital25, Katholieke Universiteit Leuven26, Erasmus University Rotterdam27, Oslo University Hospital28, University College Hospital29, Claude Bernard University Lyon 130
1,150 citations
TL;DR: The integration of OCTA in multimodal imaging in the evaluation of retinal vascular occlusive diseases, diabetic retinopathy, uveitis, inherited diseases, age-related macular degeneration, and disorders of the optic nerve is presented.
988 citations
Christina Fitzmaurice1, Christina Fitzmaurice2, Tomi Akinyemiju3, Faris Lami4 +172 more•Institutions (95)
901 citations
Columbia University1, Centre Hospitalier Universitaire de Toulouse2, University of Melbourne3, University of Western Ontario4, Karolinska Institutet5, University of Milan6, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico7, Eli Lilly and Company8, Indiana University9, Avid Radiopharmaceuticals10
TL;DR: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline and the secondary outcomes were considered to be descriptive and are reported without significance testing.
Abstract: Background Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. Methods We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessmen...
679 citations
TL;DR: The status of research into important genetic and epigenetic modifiers of NAFLD progression are discussed and the potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored.
582 citations
TL;DR: The major issues regarding this multi-step process, focussing in particular on challenges of the extraction of radiomic features from data sets provided by computed tomography, positron emission tomographic, and magnetic resonance imaging are summarised.
Abstract: Radiomics is an emerging translational field of research aiming to extract mineable high-dimensional data from clinical images. The radiomic process can be divided into distinct steps with definable inputs and outputs, such as image acquisition and reconstruction, image segmentation, features extraction and qualification, analysis, and model building. Each step needs careful evaluation for the construction of robust and reliable models to be transferred into clinical practice for the purposes of prognosis, non-invasive disease tracking, and evaluation of disease response to treatment. After the definition of texture parameters (shape features; first-, second-, and higher-order features), we briefly discuss the origin of the term radiomics and the methods for selecting the parameters useful for a radiomic approach, including cluster analysis, principal component analysis, random forest, neural network, linear/logistic regression, and other. Reproducibility and clinical value of parameters should be firstly tested with internal cross-validation and then validated on independent external cohorts. This article summarises the major issues regarding this multi-step process, focussing in particular on challenges of the extraction of radiomic features from data sets provided by computed tomography, positron emission tomography, and magnetic resonance imaging.
Princess Margaret Cancer Centre1, Wellcome Trust Sanger Institute2, University of Cambridge3, University of Toronto4, Weizmann Institute of Science5, Ontario Institute for Cancer Research6, International Agency for Research on Cancer7, European Bioinformatics Institute8, University Health Network9, University of East Anglia10, Norwich University11, National and Kapodistrian University of Athens12, University of Milan13, University of Granada14, Cancer Epidemiology Unit15, Prevention Institute16, University of Naples Federico II17, German Cancer Research Center18, Imperial College London19, Utrecht University20, Memorial Sloan Kettering Cancer Center21
TL;DR: Deep sequencing is used to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH, providing proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation.
Abstract: The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4–8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
Princess Margaret Cancer Centre1, University of Aberdeen2, Mount Sinai Hospital3, Cornell University4, Science for Life Laboratory5, University Hospital of Basel6, Brigham and Women's Hospital7, Fudan University8, Taipei Veterans General Hospital9, Seoul National University Bundang Hospital10, University of Pittsburgh11, Harvard University12, New York University13, National Institutes of Health14, University of Tsukuba15, University of Milan16, Memorial Sloan Kettering Cancer Center17, VU University Medical Center18, University of Texas MD Anderson Cancer Center19, Anschutz Medical Campus20
TL;DR: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L 1 immunohistochemical assays.
TL;DR: Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers, but the magnitude of benefit is sex-dependent, and future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women.
Abstract: Summary Background Despite the acknowledged sex-related dimorphism in immune system response, little is known about the effect of patients' sex on the efficacy of immune checkpoint inhibitors as cancer treatments. We did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between men and women. Methods We systematically searched PubMed, MEDLINE, Embase, and Scopus, from database inception to Nov 30, 2017, for randomised controlled trials of immune checkpoint inhibitors (inhibitors of PD-1, CTLA-4, or both) that had available hazard ratios (HRs) for death according to patients' sex. We also reviewed abstracts and presentations from all major conference proceedings. We excluded non-randomised trials and considered only papers published in English. The primary endpoint was to assess the difference in efficacy of immune checkpoint inhibitors between men and women, measured in terms of the difference in overall survival log(HR) reported in male and female study participants. We calculated the pooled overall survival HR and 95% CI in men and women using a random-effects model, and assessed the heterogeneity between the two estimates using an interaction test. Findings Of 7133 studies identified in our search, there were 20 eligible randomised controlled trials of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) that reported overall survival according to patients' sex. Overall, 11 351 patients with advanced or metastatic cancers (7646 [67%] men and 3705 [33%] women) were included in the analysis; the most common types of cancer were melanoma (3632 [32%]) and non-small-cell lung cancer (3482 [31%]). The pooled overall survival HR was 0·72 (95% CI 0·65–0·79) in male patients treated with immune checkpoint inhibitors, compared with men treated in control groups. In women treated with immune checkpoint inhibitors, the pooled overall survival HR compared with control groups was 0·86 (95% CI 0·79–0·93). The difference in efficacy between men and women treated with immune checkpoint inhibitors was significant (p=0·0019). Interpretation Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as melanoma and non-small-cell lung cancer, but the magnitude of benefit is sex-dependent. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women, perhaps exploring different immunotherapeutic approaches in men and women. Funding None.
University of Bern1, Institute of Cancer Research2, Oregon Health & Science University3, Cornell University4, Princess Margaret Cancer Centre5, Yonsei University6, University of Salford7, University of Copenhagen8, Monash University9, University of São Paulo10, Columbia University11, The Royal Marsden NHS Foundation Trust12, University of Texas MD Anderson Cancer Center13, University of California, Davis14, University of Bologna15, University of California, San Francisco16, University of Paris-Sud17, University of British Columbia18, Duke University19, University of Cologne20, Fred Hutchinson Cancer Research Center21, University of Birmingham22, Memorial Sloan Kettering Cancer Center23, University of Tampere24, American University of Beirut25, Medical University of Vienna26, Vanderbilt University27, Tata Memorial Hospital28, Icahn School of Medicine at Mount Sinai29, Ghent University30, University of Washington31, Université de Montréal32, Tulane University33, Tel Aviv University34, Harvard University35, Prostate Cancer Foundation36, Toho University37, University College London38, University of Toronto39, Université catholique de Louvain40, University of Milan41, University of Ulm42
TL;DR: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available.
TL;DR: The DarkSide-20k detector as discussed by the authors is a direct WIMP search detector using a two-phase Liquid Argon Time Projection Chamber (LAr TPC) with an active mass of 23 t (20 t).
Abstract: Building on the successful experience in operating the DarkSide-50 detector, the DarkSide Collaboration is going to construct DarkSide-20k, a direct WIMP search detector using a two-phase Liquid Argon Time Projection Chamber (LAr TPC) with an active (fiducial) mass of 23 t (20 t). This paper describes a preliminary design for the experiment, in which the DarkSide-20k LAr TPC is deployed within a shield/veto with a spherical Liquid Scintillator Veto (LSV) inside a cylindrical Water Cherenkov Veto (WCV). This preliminary design provides a baseline for the experiment to achieve its physics goals, while further development work will lead to the final optimization of the detector parameters and an eventual technical design. Operation of DarkSide-50 demonstrated a major reduction in the dominant 39Ar background when using argon extracted from an underground source, before applying pulse shape analysis. Data from DarkSide-50, in combination with MC simulation and analytical modeling, shows that a rejection factor for discrimination between electron and nuclear recoils of $>3 \times 10^{9}$
is achievable. This, along with the use of the veto system and utilizing silicon photomultipliers in the LAr TPC, are the keys to unlocking the path to large LAr TPC detector masses, while maintaining an experiment in which less than $< 0.1$
events (other than $
u$
-induced nuclear recoils) is expected to occur within the WIMP search region during the planned exposure. DarkSide-20k will have ultra-low backgrounds than can be measured in situ, giving sensitivity to WIMP-nucleon cross sections of $1.2 \times 10^{-47}$
cm2 (
$1.1 \times 10^{-46}$
cm2) for WIMPs of 1 TeV/c2 (10 TeV/c2) mass, to be achieved during a 5 yr run producing an exposure of 100 t yr free from any instrumental background.
University of Pittsburgh1, University of Texas MD Anderson Cancer Center2, Stanford University3, University of Milan4, Institute of Cancer Research5, University of Duisburg-Essen6, University of Chicago7, Institut Gustave Roussy8, University of Michigan9, Emory University10, Harvard University11, University of Zurich12, Kobe University13, Bristol-Myers Squibb14
TL;DR: Nivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up.
TL;DR: The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk.
TL;DR: In this paper, the interpretation of the UV/optical/infrared counterpart of GW170817 with kilonova models, combined with new numerical relativity results, imply a complementary lower bound on the tidal deformability parameter.
Abstract: Gravitational waves detected from the binary neutron star (NS) merger GW170817 constrained the NS equation of state by placing an upper bound on certain parameters describing the binary's tidal interactions. We show that the interpretation of the UV/optical/infrared counterpart of GW170817 with kilonova models, combined with new numerical relativity results, imply a complementary lower bound on the tidal deformability parameter. The joint constraints tentatively rule out both extremely stiff and soft NS equations of state.
TL;DR: In the current analysis, parental food habits and feeding strategies are the most dominant determinants of a child’s eating behaviour and food choices.
Abstract: Relevant factors involved in the creation of some children’s food preferences and eating behaviours have been examined in order to highlight the topic and give paediatricians practical instruments to understand the background behind eating behaviour and to manage children’s nutrition for preventive purposes. Electronic databases were searched to locate and appraise relevant studies. We carried out a search to identify papers published in English on factors that influence children’s feeding behaviours. The family system that surrounds a child’s domestic life will have an active role in establishing and promoting behaviours that will persist throughout his or her life. Early-life experiences with various tastes and flavours have a role in promoting healthy eating in future life. The nature of a narrative review makes it difficult to integrate complex interactions when large sets of studies are involved. In the current analysis, parental food habits and feeding strategies are the most dominant determinants of a child’s eating behaviour and food choices. Parents should expose their offspring to a range of good food choices while acting as positive role models. Prevention programmes should be addressed to them, taking into account socioeconomic aspects and education.
The Heart Research Institute1, Saint Louis University2, Wake Forest University3, University of Maryland, Baltimore4, Heidelberg University5, University of Florida6, University of Milan7, University of Miami8, University of Erlangen-Nuremberg9, Université du Québec à Montréal10, University of Otago11, University of Adelaide12, Agostino Gemelli University Polyclinic13, United States Department of Veterans Affairs14, Tufts University15, Kyung Hee University16, Dalhousie University17, King's College London18, Sichuan University19, The Chinese University of Hong Kong20, University of Western Australia21, National Institutes of Health22, National University of Singapore23, Uppsala University24, University of São Paulo25, Memorial Hospital of South Bend26, Vrije Universiteit Brussel27, Maastricht University28, Universidad Pública de Navarra29, Centre Hospitalier Universitaire de Toulouse30
TL;DR: Evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR) are presented.
Abstract: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefitharm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.
TL;DR: In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented.
Abstract: Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The b jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV).
TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.
University of Southampton1, St Mary's Hospital2, University Hospital Southampton NHS Foundation Trust3, Heidelberg University4, Swiss Institute of Allergy and Asthma Research5, National Institutes of Health6, Erasmus University Rotterdam7, Odense University Hospital8, Nippon Medical School9, University of Cyprus10, University of Edinburgh11, Charité12, University of Messina13, Eskişehir Osmangazi University14, Boston Children's Hospital15, Katholieke Universiteit Leuven16, Utrecht University17, Johns Hopkins University18, Athens State University19, University Medical Center Groningen20, University of Milan21, University College Hospital22, King's College London23, Medical University of Graz24, European Union25, Capital Medical University26, Transylvania University27, Northern General Hospital28, Hospital Clínico San Carlos29, Wrocław Medical University30, University of Amsterdam31, University of Padua32
TL;DR: In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended, and SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit.
Abstract: Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.
University of Milan1, Instituto Português de Oncologia Francisco Gentil2, Paris Descartes University3, Leiden University Medical Center4, Vienna General Hospital5, University College London6, Lund University7, Leiden University8, Institut Jules Bordet9, Netherlands Cancer Institute10, Turku University Hospital11, University of Oxford12, Heidelberg University13, Ludwig Maximilian University of Munich14, Helsinki University Central Hospital15, The Royal Marsden NHS Foundation Trust16, Institute of Cancer Research17, University Medical Center Groningen18, Radboud University Nijmegen19, Institut Gustave Roussy20, Tel Aviv Sourasky Medical Center21, University Hospital of Lausanne22, University of Bologna23, University of Turin24, Weston Park Hospital25, Curie Institute26, Aarhus University27, Katholieke Universiteit Leuven28, Erasmus University Rotterdam29, Oslo University Hospital30, University College Hospital31, Claude Bernard University Lyon 132
TL;DR: Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal; University Hospital Essen, Essen Germany; Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy.
TL;DR: The disulphide breaking activity of NAC also explains its mucolytic activity which is due to its effect in reducing heavily cross-linked mucus glycoproteins and free thiols as well as reduced proteins which have important direct antioxidant activity.
Abstract: The main molecular mechanisms explaining the well-established antioxidant and reducing activity of N-acetylcysteine (NAC), the N-acetyl derivative of the natural amino acid l-cysteine, are summarised and critically reviewed. The antioxidant effect is due to the ability of NAC to act as a reduced glutathione (GSH) precursor; GSH is a well-known direct antioxidant and a substrate of several antioxidant enzymes. Moreover, in some conditions where a significant depletion of endogenous Cys and GSH occurs, NAC can act as a direct antioxidant for some oxidant species such as NO2 and HOX. The antioxidant activity of NAC could also be due to its effect in breaking thiolated proteins, thus releasing free thiols as well as reduced proteins, which in some cases, such as for mercaptoalbumin, have important direct antioxidant activity. As well as being involved in the antioxidant mechanism, the disulphide breaking activity of NAC also explains its mucolytic activity which is due to its effect in reducing heavily cross-linked mucus glycoproteins. Chemical features explaining the efficient disulphide breaking activity of NAC are also explained.
TL;DR: The results of a search for dark matter weakly interacting massive particles (WIMPs) in the mass range below 20 GeV/c^{2} using a target of low-radioactivity argon with a 6786.0 kg d exposure are presented.
Abstract: We present the results of a search for dark matter weakly interacting massive particles (WIMPs) in the mass range below 20 GeV/c2 using a target of low-radioactivity argon with a 6786.0 kg d exposure. The data were obtained using the DarkSide-50 apparatus at Laboratori Nazionali del Gran Sasso. The analysis is based on the ionization signal, for which the DarkSide-50 time projection chamber is fully efficient at 0.1 keVee. The observed rate in the detector at 0.5 keVee is about 1.5 event/keVee/kg/d and is almost entirely accounted for by known background sources. We obtain a 90% C.L. exclusion limit above 1.8 GeV/c2 for the spin-independent cross section of dark matter WIMPs on nucleons, extending the exclusion region for dark matter below previous limits in the range 1.8–6 GeV/c2.
TL;DR: Empicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no proPHylaxis among persons with hemophilia A without inhibitors; more than half of the participants who received prophYLaxis had no treated bleeding events.
Abstract: Background Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostas...
TL;DR: Nivolumab and nivolumsab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer.
Abstract: PurposeMetastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients wit...
TL;DR: Basic definitions of terms such as “machine/deep learning” are provided and the integration of AI into radiology is analyzed, which will allow radiologists to perform more value-added tasks, becoming more visible to patients and playing a vital role in multidisciplinary clinical teams.
Abstract: One of the most promising areas of health innovation is the application of artificial intelligence (AI), primarily in medical imaging. This article provides basic definitions of terms such as “machine/deep learning” and analyses the integration of AI into radiology. Publications on AI have drastically increased from about 100–150 per year in 2007–2008 to 700–800 per year in 2016–2017. Magnetic resonance imaging and computed tomography collectively account for more than 50% of current articles. Neuroradiology appears in about one-third of the papers, followed by musculoskeletal, cardiovascular, breast, urogenital, lung/thorax, and abdomen, each representing 6–9% of articles. With an irreversible increase in the amount of data and the possibility to use AI to identify findings either detectable or not by the human eye, radiology is now moving from a subjective perceptual skill to a more objective science. Radiologists, who were on the forefront of the digital era in medicine, can guide the introduction of AI into healthcare. Yet, they will not be replaced because radiology includes communication of diagnosis, consideration of patient’s values and preferences, medical judgment, quality assurance, education, policy-making, and interventional procedures. The higher efficiency provided by AI will allow radiologists to perform more value-added tasks, becoming more visible to patients and playing a vital role in multidisciplinary clinical teams.