The increase of the particle flux at the HL-LHC with instantaneous luminosities up to L=7.5 × 10 34 cm −2 s −1 will have a severe impact on the ATLAS detector reconstruction and trigger performance. ...The end-cap and forward region where the liquid Argon calorimeter has coarser granularity and the inner tracker has poorer momentum resolution will be particularly affected. A High Granularity Timing Detector will be installed in front of the liquid Argon end-cap calorimeters to help in charged-particle reconstruction and luminosity measurement. This low angle detector is introduced to augment the new all-silicon Inner Tracker in the pseudo-rapidity range from 2.4 to 4.0. Two silicon-sensor double-sided per end-cap will provide precision timing information for minimum-ionizing particles with a resolution as good as 30 ps per track in order to assign each particle to the correct vertex. Readout cells have a size of 1.3 mm × 1.3 mm, leading to a highly granular detector with 3.7 million channels. The Low Gain Avalanche Detectors technology has been chosen as sensor as it provides excellent timing performance. The requirements and overall specifications of the High Granularity Timing Detector are presented as well as the technical design and the project status. The on-going R&D effort carried out to study the sensors, the readout ASIC, and the other components, supported by laboratory and test beam results, are also presented.
VALUE is an open European collaboration to intercompare downscaling approaches for climate change research, focusing on different validation aspects (marginal, temporal, extremes, spatial, ...process‐based, etc.). Here we describe the participating methods and first results from the first experiment, using “perfect” reanalysis (and reanalysis‐driven regional climate model (RCM)) predictors to assess the intrinsic performance of the methods for downscaling precipitation and temperatures over a set of 86 stations representative of the main climatic regions in Europe. This study constitutes the largest and most comprehensive to date intercomparison of statistical downscaling methods, covering the three common downscaling approaches (perfect prognosis, model output statistics—including bias correction—and weather generators) with a total of over 50 downscaling methods representative of the most common techniques.
Overall, most of the downscaling methods greatly improve (reanalysis or RCM) raw model biases and no approach or technique seems to be superior in general, because there is a large method‐to‐method variability. The main factors most influencing the results are the seasonal calibration of the methods (e.g., using a moving window) and their stochastic nature. The particular predictors used also play an important role in cases where the comparison was possible, both for the validation results and for the strength of the predictor–predictand link, indicating the local variability explained. However, the present study cannot give a conclusive assessment of the skill of the methods to simulate regional future climates, and further experiments will be soon performed in the framework of the EURO‐CORDEX initiative (where VALUE activities have merged and follow on).
Finally, research transparency and reproducibility has been a major concern and substantive steps have been taken. In particular, the necessary data to run the experiments are provided at http://www.value‐cost.eu/data and data and validation results are available from the VALUE validation portal for further investigation: http://www.value‐cost.eu/validationportal.
The largest and most comprehensive to date intercomparison of statistical downscaling methods is presented, with a total of over 50 downscaling methods representative of the most common approaches and techniques. Overall, most of the downscaling methods greatly improve raw model biases and no approach is superior in general, due to the large method‐to‐method variability. The main factors influencing the results are the seasonal calibration of the methods and their stochastic nature, for biases in the mean and variance.
The ever increasing size and complexity of data coming from simulations of cosmic structure formation demand equally sophisticated tools for their analysis. During the past decade, the art of object ...finding in these simulations has hence developed into an important discipline itself. A multitude of codes based upon a huge variety of methods and techniques have been spawned yet the question remained as to whether or not they will provide the same (physical) information about the structures of interest. Here we summarize and extent previous work of the 'halo finder comparison project': we investigate in detail the (possible) origin of any deviations across finders. To this extent, we decipher and discuss differences in halo-finding methods, clearly separating them from the disparity in definitions of halo properties. We observe that different codes not only find different numbers of objects leading to a scatter of up to 20 per cent in the halo mass and V
max function, but also that the particulars of those objects that are identified by all finders differ. The strength of the variation, however, depends on the property studied, e.g. the scatter in position, bulk velocity, mass and the peak value of the rotation curve is practically below a few per cent, whereas derived quantities such as spin and shape show larger deviations. Our study indicates that the prime contribution to differences in halo properties across codes stems from the distinct particle collection methods and - to a minor extent - the particular aspects of how the procedure for removing unbound particles is implemented. We close with a discussion of the relevance and implications of the scatter across different codes for other fields such as semi-analytical galaxy formation models, gravitational lensing and observables in general.
There is evidence about the international competitiveness of Small and Medium Enterprises having a close relationship with their absorptive capacity and internationalization networking, and for that ...reason, it is relevant to find out the main trends in this field of knowledge. The objective of this study is to provide a bibliometric analysis of the status of the existing research in the field to recognize main topics and help identify research gaps. This study was done through a review of 1,710 documents published about this relationship from the Scopus and Web of Science databases (1994–2018), using as processing software application that employs two combinations of terms associated with Boolean operators. This was taken into account in order to optimize the accuracy of the search and to facilitate large data capture. The results show that these studies are in a period of high production and concentrated in a few countries and researchers’ networks in the United States, the People’s Republic of China, and some European countries. Moreover, the trend words used by researchers are those which link absorptive capacity with networking, open innovation, and firm performance.
The majority of childhood leukemias are precursor B-cell acute lymphoblastic leukemias (pB-ALLs) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after ...birth. Although genetic predispositions are frequent in children (>1% to 5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. Although infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, by using murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice, even in the absence of infectious stimuli and independent of T cells. By using V4 and full-length 16S ribosomal RNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3983 amplicon sequence variants as proxies for bacterial species. Transplantation of either wild-type (WT) or Pax5+/– hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor genotype–specific manner. Gas chromatography-mass spectrometry (GC-MS) analyses of sera from WT and Pax5+/– mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.
•Genetic predisposition to pB-ALL shapes a distinct gut microbiome.•Microbiome deprivation by antibiotic treatment can trigger leukemia in predisposed genetic carriers in the absence of infectious stimuli.
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Background and purpose
Spain has been one of the countries more heavily stricken by SARS‐CoV‐2, which has had huge implications for stroke care. The aim was to analyse the impact of the COVID‐19 ...epidemic outbreak on reperfusion therapies for acute ischaemic stroke in the northwest of Spain.
Methods
This was a Spanish multicentre retrospective observational study based on data from tertiary hospitals of the NORDICTUS network. All patients receiving reperfusion therapy for ischaemic stroke between 30 December 2019 and 3 May 2020 were recorded, and their baseline, clinical and radiological characteristics, extra‐ and intra‐hospital times of action, Code Stroke activation pathway, COVID‐19 status, reperfusion rate, and short‐term outcome before and after the setting of the emergency state were analysed.
Results
A total of 796 patients received reperfusion therapies for ischaemic stroke. There was a decrease in the number of patients treated per week (46.5 patients per week vs. 39.0 patients per week, P = 0.043) and a delay in out‐of‐hospital (95.0 vs. 110.0 min, P = 0.001) and door‐to‐needle times (51.0 vs. 55.0, P = 0.038). Patients receiving endovascular therapy obtained less successful reperfusion rates (92.9% vs. 86.6%, P = 0.016). COVID‐19 patients had more in‐hospital mortality.
Conclusion
A decrease in the number of patients benefiting from reperfusion therapies was found, with a delay in out‐of‐hospital and door‐to‐needle times and worse reperfusion rates in northwest Spain. COVID‐19 patients had more in‐hospital mortality.
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917).
Virologically-suppressed, HIV-1-positive ...treatment-experienced adults (previous non-darunavir virologic failure VF allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load VL ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis).
Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52–96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis.
Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF.
•Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen.•We present the week 96 analysis of D/C/F/TAF in the Phase 3 EMERALD trial in virologically suppressed HIV-1-positive adults.•Through 96 weeks, D/C/F/TAF had a low rebound rate (3%), high virologic suppression (>90%) with no resistance development.•Bone, renal and lipid safety were consistent with known D/C/F/TAF component profiles.•EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF.
Abstract
Background
Functional mitral regurgitation (FMR) evaluation using effective regurgitant orifice (ERO) by echocardiography remains controversial. Given the morphology of regurgitant jets in ...FMR, determination of ERO using three-dimensional transesophageal echocardiography (3D-TEE) may be more accurate. However, a clear threshold for this parameter has not been defined.
Purpose
Our aim is to evaluate the prognostic value of 3D-ERO in FMR.
Methods
All patients with at least moderate FMR who underwent 3D-TEE in a tertiary center between 2016 and 2020 were retrospectively selected. Echocardiographic variables by transthoracic and transesophageal, as well as demographic and clinical history variables, were collected. A combined event of urgent hospital admission or death was considered. Variables statistically associated with the event were included in multivariate analysis.
Results
112 patients (74 men (66.1%), mean age 72.3±10.9 years) were finally included. The most frequent etiology of FMR was ventricular dysfunction (61.6%), followed by annular dilation (23.2%) and posterior leaflet restriction (15.2%). The mean 3D-ERO was 0.53±0.25 cm2 and mean ejection fraction was 40.7±14.2%. At diagnosis, 49 patients (43.8%) were not receiving diuretics, 63 (56.2%) had atrial fibrillation/flutter, 60.3% permanent. FMR was treated in 54 patients (48.2%), 61,1% percutaneously. During a follow-up of 36 14-54 months, 50 (44,6%) patients were urgently hospitalized (mean 1.9±2.8 admissions) and 49 (43,8%) died, received a heart transplant or LVAD. 3D-ERO was significantly associated with the occurrence of the event (0.55 vs 0.41; p=0.02). Additionally, 3D-ERO was associated with mitral intervention (0.58 vs 0.47 cm2; p=0.01) and had a trend towards death from any cause (0.56 vs 0.5 cm2; p=0.098). The prognostic capacity of 3D-ERO for the combined event was determined using an ROC curve (Figure). An AUC of 0.67 (95% CI 0.55-0.8; p=0.01) and an optimal cutoff value of 0.45 cm2 (sensitivity 0.62, specificity 0.73) were obtained. In univariate analysis, the combined event was also associated with age (73.9 vs. 65.6 years; p=0.01), diabetes (40 vs. 13.6%; p=0.02), chronic kidney disease (42.7 vs. 13.6%; p=0.01), ischemic heart disease (59.6 vs 31,8%, p=0.02) and daily furosemide dose (39.7 vs. 13.6 mg; p<0.01).
In multivariate analysis of the event, age, daily furosemide dose, ischemic heart disease and 3D-ERO were included in the final predictive model (Table).
Conclusions
In patients with FMR, 3D-ERO was significantly associated with the occurrence of events during follow-up, with an optimal prognostic performance cutoff point of 0.45 cm2. Furthermore, it was an independent predictor of mitral intervention and included among the predictors of urgent hospital admission or death. Therefore, 3D-ERO may be useful in risk stratification of FMR.
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