Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study

Background and Purposes—This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods—The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P=0.10) for major bleedings. Results—The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P=0.009) for ischemic outcome events and 0.407 (0.275–0.540; P=0.14) for hemorrhagic outcome events. Conclusions—In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings

LIME -- a gas TPC prototype for directional Dark Matter search for the CYGNO experiment

The CYGNO experiment aims at the development of a large gaseous TPC with GEM-based amplification and an optical readout by means of PMTs and scientific CMOS cameras for 3D tracking down to O(keV) energies, for the directional detection of rare events such as low mass Dark Matter and solar neutrino interactions. The largest prototype built so far towards the realisation of the CYGNO experiment demonstrator is the 50 L active volume LIME, with 4 PMTs and a single sCMOS imaging a 33$\times$33 cm\textsuperscript{2} area for 50 cm drift, that has been installed in underground Laboratori Nazionali del Gran Sasso in February 2022. We will illustrate LIME performances as evaluated overground in Laboratori Nazionali di Frascati by means of radioactive X-ray sources, and in particular the detector stability, energy response and energy resolution. We will discuss the MC simulation developed to reproduce the detector response and show the comparison with actual data. We will furthermore examine the background simulation worked out for LIME underground data taking and illustrate the foreseen expected measurement and results in terms of natural and materials intrinsic radioactivity characterisation and measurement of the LNGS underground natural neutron flux. The results that will be obtained by underground LIME installation will be paramount in the optimisation of the CYGNO demonstrator, since this is foreseen to be composed by multiple modules with the same LIME dimensions and characteristics

Technical Design Report - TDR CYGNO-04/INITIUM

The aim of this Technical Design Report is to illustrate the technological choices foreseen to be implemented in the construction of the CYGNO-04 demonstrator, motivate them against the experiment physics goals of CYGNO-30 and demonstrate the financial sustainability of the project. CYGNO-04 represents PHASE 1 of the long term CYGNO roadmap, towards the development of large high precision tracking gaseous Time Projection Chamber (TPC) for directional Dark Matter searches and solar neutrino spectroscopy. The CYGNO project1 peculiarities reside in the optical readout of the light produced during the amplification of the primary ionization electrons in a stack of triple Gas Electron Multipliers (GEMs), thanks to the nice scintillation properties of the chosen He:CF4 gas mixture. To this aim, CYGNO is exploiting the fast progress in commercial scientific Active Pixel Sensors (APS) development for highly performing sCMOS cameras, whose high granularity and sensitivity allow to significantly boost tracking, improve particle identification and lower the energy threshold. The X-Y track project obtained from the reconstruction of the sCMOS images is combined with a PMT measurement to obtain a full 3D track reconstruction. In addition, several synergic R&Ds based on the CYGNO experimental approach are under development in the CYGNO collaboration (see Sec 2) to further enhance the light yield by means of electro luminescence after the amplification stage, to improve the tracking performances by exploiting negative ion drift operation within the INITIUM ERC Consolidator Grant, and to boost the sensitivity to O(GeV) Dark Matter masses by employing hydrogen rich target towards the development of PHASE 2 (see Sec. 1.2). While still under optimization and subject to possible significant improvements, the CYGNO experimental approach performances and capabilities demonstrated so far with prototypes allow to foresee the development of an O(30) m3 experiment by 2026 for a cost of O(10) MEUROs. A CYGNO-30 experiment would be able to give a significant contribution to the search and study of Dark Matter with masses below 10 GeV/c2 for both SI and SD coupling. In case of a Dark Matter observation claim by other experiments, the information provided by a directional detector such as CYGNO would be fundamental to positively confirm the galactic origin of the allegedly detected Dark Matter signal. CYGNO-30 could furthermore provide the first directional measurement of solar neutrinos from the pp chain, possibly extending to lower energies the Borexino measurement2. In order to reach this goal, the CYGNO project is proceeding through a staged approach. The PHASE 0 50 L detector (LIME, recently installed underground LNGS) will validate the full performances of the optical readout via APS commercial cameras and PMTs and the Montecarlo simulation of the expected backgrounds. The full CYGNO-04 demonstrator will be realized with all the technological and material choices foreseen for CYGNO-30, to demonstrate the scalability of the experimental approach and the potentialities of the large PHASE 2 detector to reach the expected physics goals. The first PHASE 1 design anticipated a 1 m3 active volume detector with two back-to-back TPCs with a central cathode and 500 mm drift length. Each 1 m2 readout area would have been composed by 9 + 9 readout modules having the LIME PHASE 0 dimensions and layout. Time (end of INITIUM project by March 2025) and current space availability at underground LNGS (only Hall F) forced the rescaling of the PHASE 1 active volume and design to a 0.4 m3, hence CYGNO-04. CYGNO-04 will keep the back-to-back double TPC layout with 500 mm drift length each, but with an 800 x 500 mm2 readout area covered by a 2 + 2 modules based on LIME design. The reduction of the detector volume has no impact on the technological objectives of PHASE 1, since the modular design with central cathode, detector materials and shieldings and auxiliary systems are independent of the total volume. The physics reach (which is a byproduct of PHASE 1 and NOT an explicit goal) will be only very partially reduced (less than a factor 2 overall) since a smaller detector volume implies also a reduced background from internal materials radioactivity. In addition, the cost reduction of CYGNO-04 of about 1⁄3 with respect to CYGNO-1 illustrated in the CDR effectively makes the overall project more financially sustainable (see CBS in the last section). In summary this document will explain: the physical motivation of the CYGNO project and the technical motivations of the downscale of the PHASE 1 to CYGNO-04, 400 liters of active volume, with respect to the demonstrator presented in the CDR; the results of R&D and the Montecarlo expectations for PHASE 0; the technical choices, procedures and the executive drawings of CYGNO-04 in the Hall F of the LNGS; safety evaluations and the interference/request to the LNGS services; Project management, WBS/WBC, WP, GANTT, ec

Nuclear Reprogramming: Kinetics of Cell Cycle and Metabolic Progression as Determinants of Success

Establishment of totipotency after somatic cell nuclear transfer (NT) requires not only reprogramming of gene expression, but also conversion of the cell cycle from quiescence to the precisely timed sequence of embryonic cleavage. Inadequate adaptation of the somatic nucleus to the embryonic cell cycle regime may lay the foundation for NT embryo failure and their reported lower cell counts. We combined bright field and fluorescence imaging of histone H2b-GFP expressing mouse embryos, to record cell divisions up to the blastocyst stage. This allowed us to quantitatively analyze cleavage kinetics of cloned embryos and revealed an extended and inconstant duration of the second and third cell cycles compared to fertilized controls generated by intracytoplasmic sperm injection (ICSI). Compared to fertilized embryos, slow and fast cleaving NT embryos presented similar rates of errors in M phase, but were considerably less tolerant to mitotic errors and underwent cleavage arrest. Although NT embryos vary substantially in their speed of cell cycle progression, transcriptome analysis did not detect systematic differences between fast and slow NT embryos. Profiling of amino acid turnover during pre-implantation development revealed that NT embryos consume lower amounts of amino acids, in particular arginine, than fertilized embryos until morula stage. An increased arginine supplementation enhanced development to blastocyst and increased embryo cell numbers. We conclude that a cell cycle delay, which is independent of pluripotency marker reactivation, and metabolic restraints reduce cell counts of NT embryos and impede their development

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes

Background: The aim of this study in patients with acute posterior ischemic stroke (PS) and atrial fibrillation (AF) were to evaluate the risks of recurrent ischemic event and severe bleeding and these risks in relation with oral anticoagulant therapy (OAT) and its timing. Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of: stroke recurrence, TIA, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results: A total of 2,470 patients were available for the analysis: 473 (19.1%) with PS and 1,997 (80.9%) AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80). Conclusions: Patients with posterior or anterior stroke and AF appear to have similar risks of ischemic or hemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT

Hemorrhagic transformation in acute ischemic stroke patients and atrial fibrillation: time to initiation of anticoagulants and outcome

Background: In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation (HT). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT, (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results: HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT. Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3–8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0–6.0) of those without HT; 53.1% of patients with HT were deceased or disabled compared with 35.8% of those without HT. On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24–2.35). Conclusions: In patients with HT, anticoagulation was initiated about 12 days later than patients without HT. This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Measurements of the Higgs boson production and decay rates and coupling strengths using pp collision data at √S=7 and 8 TeV in the ATLAS experiment

Combined analyses of the Higgs boson production and decay rates as well as its coupling strengths to vector bosons and fermions are presented. The combinations include the results of the analyses of the H -> gamma gamma, ZZ*, WW*, Z gamma, b (b) over bar, tau tau and mu mu decay modes, and the constraints on the associated production with a pair of top quarks and on the off-shell coupling strengths of the Higgs boson. The results are based on the LHC proton-proton collision datasets, with integrated luminosities of up to 4.7 fb(-1) at root s = 7 TeV and 20.3 fb(-1) at root s = 8 TeV, recorded by the ATLAS detector in 2011 and 2012. Combining all production modes and decay channels, the measured signal yield, normalised to the Standard Model expectation, is 1.18(-0.14)(+0.15). The observed Higgs boson production and decay rates are interpreted in a leading-order coupling framework, exploring a wide range of benchmark coupling models both with and without assumptions on the Higgs boson width and on the Standard Model particle content in loop processes. The data are found to be compatible with the Standard Model expectations for a Higgs boson at a mass of 125.36 GeV for all models considered

The CYGNO Experiment

The search for a novel technology able to detect and reconstruct nuclear and electron recoil events with the energy of a few keV has become more and more important now that large regions of high-mass dark matter (DM) candidates have been excluded. Moreover, a detector sensitive to incoming particle direction will be crucial in the case of DM discovery to open the possibility of studying its properties. Gaseous time projection chambers (TPC) with optical readout are very promising detectors combining the detailed event information provided by the TPC technique with the high sensitivity and granularity of latest-generation scientific light sensors. The CYGNO experiment (a CYGNus module with Optical readout) aims to exploit the optical readout approach of multiple-GEM structures in large volume TPCs for the study of rare events as interactions of low-mass DM or solar neutrinos. The combined use of high-granularity sCMOS cameras and fast light sensors allows the reconstruction of the 3D direction of the tracks, offering good energy resolution and very high sensitivity in the few keV energy range, together with a very good particle identification useful for distinguishing nuclear recoils from electronic recoils. This experiment is part of the CYGNUS proto-collaboration, which aims at constructing a network of underground observatories for directional DM search. A one cubic meter demonstrator is expected to be built in 2022/23 aiming at a larger scale apparatus (30 m$^3$--100 m$^3$) at a later stage

Anticoagulation After Stroke in Patients With Atrial Fibrillation : To Bridge or Not With Low-Molecular-Weight Heparin?

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.Peer reviewe