Allocation of Advertisement Extensions & Formats

This document describes a process of optimizing the selection of a budget-constrained advertiser\u27s formats when allocating the budget of a budget-constrained advertiser. Such optimization is performed by selectively choosing which formats to allocate to this advertiser based on the advertiser\u27s budget. In particular, this document describes allocating formats to budget-constrained advertisers in advertising auctions to create value for the advertisers and an advertiser manager

Far-Infrared Observations of the Very Low Luminosity Embedded Source L1521F-IRS in the Taurus Star-Forming Region

We investigate the environment of the very low luminosity object L1521F-IRS using data from the Taurus Spitzer Legacy Survey. The MIPS 160 μm image shows both extended emission from the Taurus cloud and emission from multiple cold cores over a 1° × 2° region. Analysis shows that the cloud dust temperature is 14.2 ± 0.4 K and the extinction ratio is A_(160)/A_K = 0.010 ± 0.001 up to A_V ~ 4 mag. We find κ_(160) = 0.23 ± 0.046 cm^2 g^(–1) for the specific opacity of the gas-dust mixture. Therefore, for dust in the Taurus cloud we find that the 160 μm opacity is significantly higher than that measured for the diffuse interstellar medium, but not too different from dense cores, even at modest extinction values. Furthermore, the 160 μm image shows features that do not appear in the IRAS 100 μm image. We identify six regions as cold cores, i.e., colder than 14.2 K, all of which have counterparts in extinction maps or C^(18)O maps. Three of the six cores contain embedded young stellar objects, which demonstrates the cores are sites of current star formation. We compare the effects of L1521F-IRS on its natal core and find there is no evidence for dust heating at 160 or 100 μm by the embedded source. From the infrared luminosity L_(TIR) = 0.024 L_⊙ we find L_(bol_int) = 0.034 - 0.046 L_⊙, thus confirming the source's low luminosity. Comparison of L1521F-IRS with theoretical simulations for the very early phases of star formation appears to rule out the first core collapse phase. The evolutionary state appears similar to or younger than the class 0 phase, and the estimated mass is likely to be substellar

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Epidemiology of surgery associated acute kidney injury (EPIS-AKI): a prospective international observational multi-center clinical study

Purpose: The incidence, patient features, risk factors and outcomes of surgery-associated postoperative acute kidney injury (PO-AKI) across different countries and health care systems is unclear. Methods: We conducted an international prospective, observational, multi-center study in 30 countries in patients undergoing major surgery (> 2-h duration and postoperative intensive care unit (ICU) or high dependency unit admission). The primary endpoint was the occurrence of PO-AKI within 72 h of surgery defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included PO-AKI severity and duration, use of renal replacement therapy (RRT), mortality, and ICU and hospital length of stay. Results: We studied 10,568 patients and 1945 (18.4%) developed PO-AKI (1236 (63.5%) KDIGO stage 1500 (25.7%) KDIGO stage 2209 (10.7%) KDIGO stage 3). In 33.8% PO-AKI was persistent, and 170/1945 (8.7%) of patients with PO-AKI received RRT in the ICU. Patients with PO-AKI had greater ICU (6.3% vs. 0.7%) and hospital (8.6% vs. 1.4%) mortality, and longer ICU (median 2 (Q1-Q3, 1-3) days vs. 3 (Q1-Q3, 1-6) days) and hospital length of stay (median 14 (Q1-Q3, 9-24) days vs. 10 (Q1-Q3, 7-17) days). Risk factors for PO-AKI included older age, comorbidities (hypertension, diabetes, chronic kidney disease), type, duration and urgency of surgery as well as intraoperative vasopressors, and aminoglycosides administration. Conclusion: In a comprehensive multinational study, approximately one in five patients develop PO-AKI after major surgery. Increasing severity of PO-AKI is associated with a progressive increase in adverse outcomes. Our findings indicate that PO-AKI represents a significant burden for health care worldwide

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study

ACKNOWLEDGMENTS: The full list of LITMUS investigators is available in Supplemental Table S1, http://links.lww.com/HEP/ H625. FUNDING INFORMATION: The LITMUS project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. Sven Francque holds a senior clinical investigator fellowship from the Research Foundation Flanders (FWO) (1802154N

Utiliser les mélanges fourragers pour s'adapter au changement climatique : opportunités et défis

Ce numéro de la revue Fourrages présente les résultats des travaux du projet Climagie du métaprogramme Adaptation au changement climatique de l'agriculture et de la forêt (ACCAF) de l'InraIn the context of climate change, grasslands will need to be populated with forage species that tolerate drought conditions. Planting forage mixtures is a possible solution, but questions remain regarding the specific varieties to use. Recently, different experiments have shown that both intra- and interspecific diversity could have a positive effect on grassland production under climate change and, more specifically, during droughts. However, to choose which species and genotypes to include, it is necessary to define the rules of assembly. These rules could be based on the choice of certain functional traits. For instance, research suggests that differences in growth-related traits among plants within the community, namely temporal differences in growth periods, have a positive effect. Defining the traits of greatest interest and their relative importance in grassland communities is a major consideration when selecting the plant varieties to include in forage mixtures.Le changement climatique s'accompagne d'un accroissement de la fréquence des sécheresses qui menace la pérennité et la production des prairies. Il est donc nécessaire d'adapter les couverts prairiaux à des conditions hydriques limitantes. Les mélanges offrent des perspectives intéressantes mais posent des questions quant aux critères de sélection des variétésDifférentes expérimentations récentes montrent la plus-value de la diversité spécifique et intraspécifique sur la production des prairies face au changement climatique et en particulier face aux épisodes de sécheresse. Mais le choix des espèces et des génotypes composant cette diversité nécessite de définir correctement les règles d'assemblage. Ces règles pourraient être basées sur des choix de traits (caractères) des espèces et des génotypes. La diversification de traits liés à des stratégies de croissance décalées dans le temps semble avoir un effet positif, contrairement aux traits racinaires. Ainsi, le choix de traits d'intérêt et de la valeur de ces traits dans les couverts prairiaux est à considérer dans les processus de sélection variétale