Peoples' Friendship University of Russia

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).

Understanding and quantifying the global methane (CH4) budget is important for assessing realistic pathways to mitigate climate change. Atmospheric emissions and concentrations of CH4 continue to increase, making CH4 the second most important human-influenced greenhouse gas in terms of climate forcing, after carbon dioxide (CO2). The relative importance of CH4 compared to CO2 depends on its shorter atmospheric\nlifetime, stronger warming potential, and variations in atmospheric growth rate over the past decade, the causes of which are still debated. Two major challenges in reducing uncertainties in the atmospheric growth rate arise from the variety of geographically overlapping CH4 sources and from the destruction of CH4 by short-lived hydroxyl radicals (OH). To address these challenges, we have established a consortium of multidisciplinary scientists under the umbrella of the Global Carbon Project to synthesize and stimulate new research aimed at improving and regularly updating the global methane budget. Following Saunois et al. (2016), we present here the second version of the living review paper dedicated to the decadal methane budget, integrating results of top-down studies (atmospheric observations within an atmospheric inverse-modelling framework) and bottom-up estimates (including process-based models for estimating land surface emissions and atmospheric chemistry, inventories of anthropogenic emissions, and data-driven extrapolations).\nFor the 2008–2017 decade, global methane emissions are estimated by atmospheric inversions (a top-down approach) to be 576 TgCH4 yr-1 (range 550–594, corresponding to the minimum and maximum estimates of the model ensemble). Of this total, 359 TgCH4 yr-1 or 60% is attributed to anthropogenic sources, that is emissions caused by direct human activity (i.e. anthropogenic emissions; range 336–376 TgCH4 yr-1 or 50 %–65 %). The mean annual total emission for the new decade (2008–2017) is 29 TgCH4 yr-1 larger than our estimate for the previous decade (2000–2009), and 24 TgCH4 yr-1 larger than the one reported in the previous budget for 2003–2012 (Saunois et al., 2016). Since 2012, global CH4 emissions have been tracking the warmest scenarios assessed by the Intergovernmental Panel on Climate Change. Bottom-up methods suggest almost 30% larger global emissions (737 TgCH4 yr-1, range 594–881) than top-down inversion methods. Indeed, bottom-up estimates for natural sources such as natural wetlands, other inland water systems, and geological sources are higher than top-down estimates. The atmospheric constraints on the top-down budget suggest that at least some of these bottom-up emissions are overestimated. The latitudinal distribution of atmospheric observation-based emissions indicates a predominance of tropical emissions (∼65% of the global budget, <30◦N) compared to mid-latitudes (∼30 %, 30–60◦ N) and high northern latitudes (∼4 %, 60–90◦N). The most important source of uncertainty in the methane budget is attributable to natural emissions, especially those from wetlands and other inland waters.\nSome of our global source estimates are smaller than those in previously published budgets (Saunois et al., 2016; Kirschke et al., 2013). In particular wetland emissions are about 35 TgCH4 yr-1 lower due to improved partition wetlands and other inland waters. Emissions from geological sources and wild animals are also found to be smaller by 7 TgCH4 yr-1 by 8 TgCH4 yr-1, respectively. However, the overall discrepancy between bottom-up and top-down estimates has been reduced by only 5% compared to Saunois et al. (2016), due to a higher estimate of emissions from inland waters, highlighting the need for more detailed research on emissions factors. Priorities for improving the methane budget include (i) a global, high-resolution map of water-saturated soils and inundated areas emitting methane based on a robust classification of different types of emitting habitats; (ii) further development of process-based models for inland-water emissions; (iii) intensification of methane observations at local scales (e.g., FLUXNET-CH4 measurements) and urban-scale monitoring to constrain bottom-up land surface models, and at regional scales (surface networks and satellites) to constrain atmospheric inversions; (iv) improvements of transport models and the representation of photochemical sinks in top-down inversions; and (v) development of a 3D variational inversion system using isotopic and/or co-emitted species such as ethane to improve source partitioning.\nThe data presented here can be downloaded from https://doi.org/10.18160/GCP-CH4-2019 (Saunois et al.,\n2020) and from the Global Carbon Project

The ‘4 per mille Soils for Food Security and Climate’ was launched at the COP21 with an aspiration to increase global soil organic matter stocks by 4 per 1000 (or 0.4 %) per year as a compensation for the global emissions of greenhouse gases by anthropogenic sources. This paper surveyed the soil organic carbon (SOC) stock estimates and sequestration potentials from 20 regions in the world (New Zealand, Chile, South Africa, Australia, Tanzania, Indonesia, Kenya, Nigeria, India, China Taiwan, South Korea, China Mainland, United States of America, France, Canada, Belgium, England & Wales, Ireland, Scotland, and Russia). We asked whether the 4 per mille initiative is feasible for the region. The outcomes highlight region specific efforts and scopes for soil carbon sequestration. Reported soil C sequestration rates globally show that under best management practices, 4 per mille or even higher sequestration rates can be accomplished. High C sequestration rates (up to 10 per mille) can be achieved for soils with low initial SOC stock (topsoil less than 30 t C ha− 1), and at the first twenty years after implementation of best management practices. In addition, areas which have reached equilibrium will not be able to further increase their sequestration. We found that most studies on SOC sequestration only consider topsoil (up to 0.3 m depth), as it is considered to be most affected by management techniques. The 4 per mille number was based on a blanket calculation of the whole global soil profile C stock, however the potential to increase SOC is mostly on managed agricultural lands. If we consider 4 per mille in the top 1m of global agricultural soils, SOC sequestration is between 2-3 Gt C year− 1, which effectively offset 20–35% of global anthropogenic greenhouse gas emissions. As a strategy for climate change mitigation, soil carbon sequestration buys time over the next ten to twenty years while other effective sequestration and low carbon technologies become viable. The challenge for cropping farmers is to find disruptive technologies that will further improve soil condition and deliver increased soil carbon. Progress in 4 per mille requires collaboration and communication between scientists, farmers, policy makers, and marketeers.

Microbial composition and functions in the rhizosphere-an important microbial hotspot-are among the most fascinating yet elusive topics in microbial ecology. We used 557 pairs of published 16S rDNA amplicon sequences from the bulk soils and rhizosphere in different ecosystems around the world to generalize bacterial characteristics with respect to community diversity, composition, and functions. The rhizosphere selects microorganisms from bulk soil to function as a seed bank, reducing microbial diversity. The rhizosphere is enriched in Bacteroidetes, Proteobacteria, and other copiotrophs. Highly modular but unstable bacterial networks in the rhizosphere (common for r-strategists) reflect the interactions and adaptations of microorganisms to dynamic conditions. Dormancy strategies in the rhizosphere are dominated by toxin-antitoxin systems, while sporulation is common in bulk soils. Functional predictions showed that genes involved in organic compound conversion, nitrogen fixation, and denitrification were strongly enriched in the rhizosphere (11-182%), while genes involved in nitrification were strongly depleted.

Photocatalysis is a green technology which converts abundantly available photonic energy into useful chemical energy. With a rapid rise of flow photoreactors in the last decade, the design and development of novel semiconductor photocatalysts is happening at a blistering rate. Currently, developed synthetic approaches have allowed the design of diverse modified/unmodified semiconductor materials exhibiting enhanced performances in heterogeneous photocatalysis. In this review, we have classified the so far reported highly efficient modified/unmodified semiconductor photocatalysts into four different categories based on the elemental composition, band gap engineering and charge carrier migration mechanism in composite photocatalysts. The recent synthetic developments are reported for each novel semiconductor photocatalyst within the four different categories, namely: pure semiconductors, solid solutions, type-II heterojunction nanocomposites and Z-scheme. The motivation behind the synthetic upgrading of modified/unmodified (pure) semiconductor photocatalysts along with their particular photochemical applications and photoreactor systems have been thoroughly reviewed.

Furans represent one of the most important classes of intermediates in the conversion of non-edible lignocellulosic biomass into bio-based chemicals and fuels. At present, bio-furan derivatives are generally obtained from cellulose and hemicellulose fractions of biomass via the acid-catalyzed dehydration of their relative C6-C5 sugars and then converted into a wide range of products. Furfural (FUR) and 5-hydroxymethylfurfural (HMF) are surely the most used furan-based feedstocks since their chemical structure allows the preparation of various high-value-added chemicals. Among several well-established catalytic approaches, hydrogenation and oxygenation processes have been efficiently adopted for upgrading furans; however, harsh reaction conditions are generally required. In this review, we aim to discuss the conversion of biomass derived FUR and HMF through unconventional (transfer hydrogenation, photocatalytic and electrocatalytic) catalytic processes promoted by heterogeneous catalytic systems. The reaction conditions adopted, the chemical nature and the physico-chemical properties of the most employed heterogeneous systems in enhancing the catalytic activity and in driving the selectivity to desired products are presented and compared. At the same time, the latest results in the production of FUR and HMF through novel environmental friendly processes starting from lignocellulose as well as from wastes and by-products obtained in the processing of biomass are also overviewed.

Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

AIMS: To evaluate the safety and efficacy of levosimendan in patients with left ventricular failure complicating acute myocardial infarction. METHODS AND RESULTS: Levosimendan at different doses (0.1-0.4 microg x kg(-1) x min(-1)) or placebo were administered intravenously for 6h to 504 patients in a randomised, placebo-controlled, double-blind study. The primary end-point was hypotension or myocardial ischaemia of clinical significance adjudicated by an independent Safety Committee. Secondary end-points included risk of death and worsening heart failure, symptoms of heart failure and all-cause mortality. The incidence of ischaemia and/or hypotension was similar in all treatment groups (P=0.319). A higher frequency of ischaemia and/or hypotension was only seen in the highest levosimendan dose group. Levosimendan-treated patients experienced lower risk of death and worsening heart failure than patients receiving placebo, during both the 6h infusion (2.0% vs 5.9%; P=0.033) and over 24h (4.0% vs 8.8%; P=0.044). Mortality was lower with levosimendan compared with placebo at 14 days (11.7% vs 19.6%; hazard ratio 0.56 [95% CI 0.33-0.95];P =0.031) and the reduction was maintained at the 180-day retrospective follow-up (22.6% vs 31.4%; 0.67 [0.45-1.00],P =0.053). CONCLUSION: s Levosimendan at doses 0.1-0.2 microg x kg(-1) x min(-1) did not induce hypotension or ischaemia and reduced the risk of worsening heart failure and death in patients with left ventricular failure complicating acute myocardial infarction.

A number of studies have reported that zinc plays a substantial role in the development of metabolic syndrome, taking part in the regulation of cytokine expression, suppressing inflammation, and is also required to activate antioxidant enzymes that scavenge reactive oxygen species, reducing oxidative stress. Zinc also plays a role in the correct functioning of lipid and glucose metabolism, regulating and forming the expression of insulin. In numerous studies, zinc supplementation has been found to improve blood pressure, glucose, and LDL cholesterol serum level. Deeper knowledge of zinc's properties may help in treating metabolic syndrome, thus protecting against stroke and angina pectoris, and ultimately against death.

‘Borders’ will be in the twenty-first century what ‘frontiers’ where in the nineteenth. Frontiers were conceived as the line indicating the last point in the relentless march of civilization. On the one side of the frontiers was civilization; on the other, nothing; just barbarism or emptiness. The march of civilization and the idea of the frontiers created a geographic and bodygraphic divide. Certain areas of the planet were designated as the location of the barbarians, and since the eighteenth century, of the primitives. In one stroke, bodies were classified and assigned a given place on the planet. But who had the authority to enact such a classification, and what was the logic of that classification? Furthermore, the classification of the world by region, and the link established between regions and people inhabiting them, was parallel to the march of civilization and companions of it: on the other side of the epistemic frontiers, people do not think or theorize; hence, one of the reasons they were considered barbarians.

Chalcogen bonding is a type of noncovalent interaction in which a covalently bonded chalcogen atom (O, S, Se or Te) acts as an electrophilic species towards a nucleophilic (negative) region(s) in another or in the same molecule. In general, this interaction is strengthened by the presence of an electron-withdrawing group on the electron-acceptor chalcogen atom and upon moving down in the periodic table of elements, from O to Te. Following a short discussion of the phenomenon of chalcogen bonding, this Perspective presents some demonstrative experimental observations in which this bonding is crucial for synthetic transformations, crystal engineering, catalysis and design of materials as synthons/tectons.

Abstract Forests are a substantial terrestrial carbon sink, but anthropogenic changes in land use and climate have considerably reduced the scale of this system 1 . Remote-sensing estimates to quantify carbon losses from global forests 2–5 are characterized by considerable uncertainty and we lack a comprehensive ground-sourced evaluation to benchmark these estimates. Here we combine several ground-sourced 6 and satellite-derived approaches 2,7,8 to evaluate the scale of the global forest carbon potential outside agricultural and urban lands. Despite regional variation, the predictions demonstrated remarkable consistency at a global scale, with only a 12% difference between the ground-sourced and satellite-derived estimates. At present, global forest carbon storage is markedly under the natural potential, with a total deficit of 226 Gt (model range = 151–363 Gt) in areas with low human footprint. Most (61%, 139 Gt C) of this potential is in areas with existing forests, in which ecosystem protection can allow forests to recover to maturity. The remaining 39% (87 Gt C) of potential lies in regions in which forests have been removed or fragmented. Although forests cannot be a substitute for emissions reductions, our results support the idea 2,3,9 that the conservation, restoration and sustainable management of diverse forests offer valuable contributions to meeting global climate and biodiversity targets.

Spiroindolines and spiroindoles are an important class of spirocyclic compounds present in a wide range of pharmaceuticals and biologically important natural alkaloids. Various spiroindolines and spiroindoles possess versatile reactivity which enables them to act as precursors for other privileged heterocycles. In view of the importance of this scaffold, many researchers focused their efforts to develop facile and mild synthetic methods for spirocyclization of indoles. However, the synthesis of spiroindolines and spiroindoles is known to be difficult due to rapid 1,2-migration to restore aromaticity. This review aims to briefly discuss the latest developments to access highly functionalized spiroindolines and spiroindoles to stimulate further research in the field to find new and efficient methodologies for accessing new spiroindolines and spiroindoles.

On-line platforms foster the communication capabilities of the Internet to develop large-scale influence networks in which the quality of the interactions can be evaluated based on trust and reputation. So far, this technology is well known for building trust and harnessing cooperation in on-line marketplaces, such as Amazon (www.amazon.com) and eBay (www.ebay.es). However, these mechanisms are poised to have a broader impact on a wide range of scenarios, from large scale decision making procedures, such as the ones implied in e-democracy, to trust based recommendations on e-health context or influence and performance assessment in e-marketing and e-learning systems. This contribution surveys the progress in understanding the new possibilities and challenges that trust and reputation systems pose. To do so, it discusses trust, reputation and influence which are important measures in networked based communication mechanisms to support the worthiness of information, products, services opinions and recommendations. The existent mechanisms to estimate and propagate trust and reputation, in distributed networked scenarios, and how these measures can be integrated in decision making to reach consensus among the agents are analysed. Furthermore, it also provides an overview of the relevant work in opinion dynamics and influence assessment, as part of social networks. Finally, it identifies challenges and research opportunities on how the so called trust based network can be leveraged as an influence measure to foster decision making processes and recommendation mechanisms in complex social networks scenarios with uncertain knowledge, like the mentioned in e-health and e-marketing frameworks.

INTRODUCTION: Metabolic syndrome (MetS) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in MetS has not been completely clarified. AIM: To systematically analyse the relationship between androgen levels and MetS we performed a review and meta-analyses of available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was also performed. METHODS: An extensive Medline search was performed including the following words "testosterone,""metabolic syndrome," and "males". MAIN OUTCOME MEASURES: Out of 323 retrieved articles, 302 articles were excluded for different reasons. Among the 20 published studies included, 13, 3, and 4 were cross-sectional, longitudinal, and RCTs, respectively. Another unpublished RCT was retrieved on http://www.clinicaltrials.gov. RESULTS: MetS patients showed significantly lower T plasma levels, as compared with healthy individuals. Similar results were obtained when MetS subjects with and without erectile dysfunction were analyzed separately or when NCEP-ATPIII MetS criteria were compared with other definitions. Meta-regression analysis demonstrated that type 2 diabetes (T2DM) increased the MetS-associated T fall. In a multiple regression model, after adjusting for age and BMI, both T2DM and MetS independently predicted low testosterone (adj. r = -0.752; P < 0.001 and -0.271; P < 0.05, respectively). Analysis of longitudinal studies demonstrated that baseline testosterone was significantly lower among patients with incident MetS in comparison with controls (2.17 [-2.41;-1.94] nmol/L; P < 0.0001). Combining the results of RCTs, TRT was associated with a significant reduction of fasting plasma glucose, homeostatic model assessment index, triglycerides, and waist circumference. In addition, an increase of high-density lipoprotein cholesterol was also observed. CONCLUSIONS: The meta-analysis of the available cross-sectional data suggests that MetS can be considered an independent association of male hypogonadism. Although only few RCTs have been reported, TRT seems to improve metabolic control, as well as central obesity.

Abstract The WKB approach for finding quasinormal modes of black holes, suggested in Schutz and Will (1985 Astrophys. J. Lett . 291 L33–6) by Schutz and Will at the first order and later developed to higher orders (Iyer and Will 1987 Phys. Rev . D 35 3621; Konoplya 2003 Phys. Rev . D 68 024018; Matyjasek and Opala 2017 Phys. Rev . D 96 024011), became popular during the past decades, because, unlike more sophisticated numerical approaches, it is automatic for different effective potentials and mostly provides sufficient accuracy. At the same time, the seeming simplicity of the WKB approach resulted in appearance of a big number of partially misleading papers, where the WKB formula was used beyond its scope of applicability. Here we review various situations in which the WKB formula can or cannot bring us to reliable conclusions. As the WKB series converges only asymptotically, there is no mathematically strict criterium for evaluation of an error. Therefore, here we are trying to introduce a number of practical recipes instead and summarize cases in which higher WKB orders improve accuracy. We show that averaging of the Padé approximations, suggested first by Matyjasek and Opala (2017 Phys. Rev . D 96 024011), leads to much higher accuracy of the WKB approach, estimate the error and present the automatic code (The Mathematica ® package with the WKB formula of 13th order and Padé approximations ready for calculation of the quasinormal modes and grey-body factors, as well as examples of such calculations for the Schwarzschild black hole are publicly available to download from https://goo.gl/nykYGL ) which computes quasinormal modes and grey-body factors.

The waste-to-wealth concept aims to promote a future sustainable lifestyle where waste valorization is seen not only for its intrinsic benefits to the environment but also to develop new technologies, livelihoods and jobs. Based on the concept of waste valorization and circular economy, this review aims to provide an overview of present trends and future potential in the conversion of residues from different food sectors into valuable bio(nano)materials.

Polyphenols are plant-derived compounds with known biological activities and potential health benefits. Over the past decade, there are an increasing number of studies have investigated the application of polyphenols and polyphenol-rich additives in aquaculture as functional feed additives. There are several types of polyphenolic compounds such as flavonoids, phenolic acids, lignans, and stilbenes of widely known beneficial influences on the overall performances and immunity of fish, and thereby improving the health status and production of fish farms. This review discusses the beneficial applications, optimum recommended dose, and potential side effects of these natural compounds on the growth performance, proximate body composition, immune responses, disease resistance, reproductive performance, and fillet quality of different fish species. Also, it points out that the biological functions and mechanisms associated with the polyphenolic compounds involved in the pathways of antioxidant and pro-oxidant activities, as well as the modulation of gene expression and different immune parameters. The output of this review article provided overwhelming evidence to support the claim that natural polyphenols can be considered as relatively safe and viable alternatives to synthetic chemical compounds that not only to improve the fish health status but also to enhance the fish quality, productivity, and food safety while reducing the use of chemicals and antibiotics in the aquatic eco-systems.

We consider a simple spherical model consisting of a Schwarzschild black hole of mass $M$ and a dark matter of mass $\Delta M$ around it. The general formula for the radius of black-hole shadow has been derived in this case. It is shown that the change of the shadow is not negligible, once the effective radius of the dark matter halo is of order $\sim \sqrt{3 M \Delta M}$. For this to happen, for example, for the galactic black hole, the dark matter must be concentrated near the black hole. For small deviations from the Schwarzschild limit, the dominant contribution into the size of a shadow is due to the dark matter under the photon sphere, but at larger deviations, the matter outside the photon sphere cannot be ignored.

AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02661217.