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Current fertilizer recommendations often neglect nutrient cycling across crop rotations. This study aimed to assess the decay rate and nutrient (N, P, K) release patterns of sorghum, black oat, and corn residues (omitido) in an integrated crop–livestock system. The experiment used factorial treatments based on two sward heights (high and low) and two nitrogen fertilization levels (N-pasture at 200 kg N ha−1 and N-corn at 0 kg N ha−1). Litter bags were collected at various intervals from each crop to measure nutrient release patterns and decomposition rates. The results showed that pasture height and nitrogen fertilization significantly influenced decomposition and nutrient release, affecting the subsequent grain crop phase. Potassium was released rapidly and in high amounts. Nitrogen fertilization during the pasture phase prevented nitrogen and phosphorus immobilization in black oat residue and reduced immobilization in corn residue. These findings highlight the importance of accounting for nutrient cycling and decomposition rates in fertilization strategies to enhance the sustainability of integrated crop–livestock systems.

Venous thromboembolism (VTE) is the leading cause of morbidity and death worldwide, after cancer and cardiovascular diseases. VTE is defined to include pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Approximately 25% of PE patients experience sudden death as an initial symptom of VTE, and between 10% and 30% of patients die within the first month after diagnosis. Currently, the only drugs approved for the treatment of both acute and chronic VTE are vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). However, their effectiveness is limited due to their associated risk of bleeding. Ideally, therapy should be able to treat VTE and limit the risk of VTE recurrence without increasing the risk of bleeding. Several studies have shown that the use of statins during anticoagulation for VTE reduces the risk of death and VTE recurrence. However, to date, there are conflicting data on the impact of statins during anticoagulation for VTE. A biological protective function of statins during anticoagulation has also been reported. Statins affect D-dimer levels; tissue factor (TF) gene expression; and VIII, VII, and Von Willebrand clotting factors—the major clotting factors they are able to affect. However, the usefulness of statins for the treatment and prevention of VTE is currently under debate, and they should not be substituted for guideline-recommended VTE prophylaxis or anticoagulation treatment. In this review of the literature, we illustrate the advances on this topic, including data on the role of statins in primary VTE prevention and secondary VTE prevention, related biological mechanisms, the risk of bleeding during their use, and their ability to reduce the risk of death.

In the present study, we aimed to assess frontal ethmoidal cells by using segmentation 3D software to establish a possible correlation between volume variation and both gender and age, as well as a relationship with Keros classification. Helical computed tomography images were obtained from 71 patients for analysis, in which the agger nasi cell, supra agger cell, supra agger frontal cell, supra bulla frontal cell, supraorbital ethmoidal cell, supra bulla cell, and frontal septal cell were identified and segmented to obtain their volume. Significant differences in volume were found for age and gender regarding agger nasi cells (p-value = 0.017), supra agger cells (p-value < 0.001), and frontal septal cells (p-value = 0.049). In the frontal septal cells, an increase of one year in age reduced the volume by 0.309, on average. According to Keros classification, the mean volumes were 10.07 and 25.64, respectively, for types II and III, both being greater than that of type I. Extracting volumetric data by using segmentation software in agger nasi cells, supra agger cells, and frontal septal cells may be useful for obtaining additional information related to age, in addition to possibly contributing to elucidating the anatomical variations in the region and an identification forensic tool.

The objective was to evaluate the supplementation strategy’s effect on beef cattle during the growing phase and two systems during the finishing phase. One hundred and twenty young bulls were randomly divided in a 2 × 2 factorial design to receive either mineral (ad libitum) or protein + energy (3 g/kg body weight (BW)/day) during the growing phase and pasture plus concentrate supplementation (20 g/kg BW/day) or feedlot (25:75% corn silage:concentrate) during the finishing phase. Feedlot-fed bulls had meat (Longissimus thoracis—LT) with a higher content of lipids and saturated and monounsaturated fatty acids and a greater upregulation of stearoyl-CoA desaturase and sterol regulatory element-binding protein-1c than animals that fed on pasture (p < 0.05). On the other hand, pasture-fed bulls had meat with a higher content of α-linoleic acid, linolenic acid, and n6 and a greater n6:n3 ratio compared to the feedlot-fed group (p < 0.05). In addition, meat from pasture-fed bulls during the finishing phase had 17.6% more isocitrate dehydrogenase enzyme concentration than the feedlot group (p = 0.02). Mineral-fed and pasture-finished bulls showed down-regulation of peroxisome proliferator-activated receptor gamma (p < 0.05), while the bulls fed protein + energy and finished in the feedlot had higher carnitine palmitoyltransferase 2 expression (p ≤ 0.013). In conclusion, mineral or protein + energy supplementation in the growing does not affect the fatty acid composition of intramuscular fat of LT muscle. In the finishing phase, feeding bulls in the feedlot upregulates the lipogenic genes and consequently improves the intramuscular fat content in the meat.

Background: Food waste is a situation that triggers certain controversy, considering that there is still a significant number of people who do not have access to healthy and nutritious food every day. The management of food leftovers from school lunches depends on the creation of measurement mechanisms. Thus, current characteristics of schools should be identified in order to mitigate and better manage these leftovers. This study addresses this gap, that is, it seeks to understand how food waste management is carried out in schools from a circular economy perspective. Methods: Focusing on the management of school lunches in municipal schools, this study aims to build an inductive interpretive theory in order to understand how schools promote food waste management. Results: Loss estimates and their monetization were identified and explained, and alternatives for waste recovery using the ReSOLVE framework were proposed. Conclusions: Therefore, it was assumed that the perspective of circularity is a possible and viable way to manage food waste in school lunches. Stakeholder engagement and awareness raising become necessary premises for success in the food circularity journey.

Domestic herbivores have been closely associated with the historical evolution and development of agriculture systems worldwide as a complementary system for providing milk, meat, wool, leather, and animal power. However, their major role was to enhance and maintain agricultural soil fertility through the recycling of nutrients. In turn, cereal production increased, enabling to feed a progressively increasing human population living in expanding urban areas. Further, digestion of organic matter through the rumen microbiome can also be viewed as enhancing the soil microbiome activity. In particular, when animal droppings are deposited directly in grazing areas or applied to fields as manure, the mineralization–immobilization turnover determines the availability of nitrogen, phosphorus, potassium, and other nutrients in the plant rhizosphere. Recently, this close coupling between livestock production and cereal cropping systems has been disrupted as a consequence of the tremendous use of industrial mineral fertilizers. The intensification of production within these separate and disconnected systems has resulted in huge emissions of nitrogen (N) to the environment and a dramatic deterioration in the quality of soil, air, and ground- and surface water. Consequently, to reduce drastically the dependency of modern and intensified agriculture on the massive use of N and phosphorus (P) fertilizers, we argue that a close reconnection at the local scale, of herbivore livestock production systems with cereal-based cropping systems, would help farmers to maintain and recover the fertility of their soils. This would result in more diverse agricultural landscapes including, besides cereals, grasslands as well as forage and grain crops with a higher proportion of legume species. We developed two examples showing such a beneficial reconnection through (i) an agro-ecological scenario with profound agricultural structural changes on a European scale, and (ii) typical Brazilian integrated crop–livestock systems (ICLS). On the whole, despite domestic herbivores emit methane (CH4), an important greenhouse gas, they participate to nutrient recycling, which can be viewed as a solution to maintaining long-term soil fertility in agro-ecosystems; at a moderate stocking density, ecosystem services provided by ruminants would be greater than the adverse effect of greenhouse gas (GHG).

Microalgae represent a growing innovative source of nutraceuticals such as carotenoids and phenolic compound which are naturally present within these single-celled organisms or can be induced in response to specific growth conditions. The presence of the unfavourable allelic variant in genes involved in the control of oxidative stress, due to one or more SNPs in gene encoding protein involved in the regulation of redox balance, can lead to pathological conditions such as insulin resistance, which, in turn, is directly involved in the pathogenesis of type 2 diabetes mellitus. In this review we provide an overview of the main SNPs in antioxidant genes involved in the promotion of insulin resistance with a focus on the potential role of microalgae-derived antioxidant molecules as novel nutritional tools to mitigate oxidative stress and improve insulin sensitivity.

The assessment of attention in neuropsychological patients could be performed with visual search tests. The Broken Rings enVision Search test (BReViS) here proposed represents a novel open access paper-and-pencil tool in which layout and crowding are varied among four cards. These manipulations allow the assessment of different components of attention: a selective component, the visuo-spatial orientation of attention, and the focal attention, involved in a crowding phenomenon. Our purpose was to determine the characteristics of the BReViS test, provide specific normative data, and assess these components across the lifespan. The test was administered to a sample of 550 participants aged between 20 and 79 years old and to a series of patients. Three indexes targeting different components of visuo-spatial attention (selective attention, strategic orientation of visual attention, focal attention) were obtained by combining execution times and accuracy together with the total errors. The results showed that age, education and gender influenced, in different combinations, the four indexes, for which specific norms were developed. Regression-based norms were provided in percentiles and equivalent scores. All patients showed pathological scores and specific patterns of attentional deficits. The BreViS test proved to be a free and easy valuable tool which can be used in the clinical environment to assess attentional deficits in neuropsychological patients.

The development and implementation of public policies towards renewable energies are crucial in order to address the contemporary challenges faced by humanity. The 3Rs (reduce, reuse, and recycle), as a circular economic practice, are often cited as one of the best solutions for sustainable development. Therefore, this study analyzed public policies for renewable energy from the perspective of the circular economy. Accordingly, a systematic review of the literature was carried out with respect to the beneficiaries and convergences of circularities, with a focus on public policies for renewable energies. The sample had public policies classified into three types (distributive, redistributive, and regulatory policies). The results showed that the first studies began in 1999, with a significant increase in publications during the 2010s, in which Germany was the country with the greatest contribution. The analyses associated with space showed the countries committed to the use of renewable energies and the 3Rs of the circular economy to reduce greenhouse gas emissions. The economic analyses revealed that the circular economy for the generation of renewable energy has a positive economic return in terms of social well-being and the mitigation of environmental degradation. There is a barrier to the circular economy’s development posed by the cost of its implementation in the private sector and the resistance to raising awareness in society, requiring strong public sector engagement in decision making and the constant evaluation of public policies. It is concluded that the circular economy facilitates more efficient, productive structures and public policies, promoting alternatives for energy security and sustainability for the world energy matrix.

Extended-phase anticoagulation with direct oral Xa inhibitors (OAXI) is suggested in patients with cancer-associated venous thromboembolism (CAT). We report on patients enrolled in the MAC (Monitoring AntiCoagulants) Project, given rivaroxaban as extended-phase anticoagulation after CAT. The primary efficacy outcome was the incidence of symptomatic recurrent VTE; the primary safety outcomes were incidence of major and non-major clinically relevant bleeding, adverse events, and all-cause mortality. The mean patients’ follow-up was 19 months (SD 16); 64/604 (11%) had CAT. Recurrent VTE occurred in 9.3% and in 8.1% of patients with and without CAT (OR 1.2, 95% CI 0.5 to 2.9; p = 0.6). Major bleeding occurred in 4.7% and in 2.6%, respectively (OR = 1.8, 95% CI 0.5 to 6.6, p = 0.4), and non-major clinically-relevant bleeding in 4.7% and in 4.1% (OR = 1.2, 95% CI 0.3 to 3.9, p = 0.7). The relative figures for fatal haemorrhage and all-cause death were 1.6% versus 0%, and 1.6% versus 0.4%. Rivaroxaban appears to be effective and safe as extended-phase anticoagulation in patients with CAT. The mean treatment period was 3-times the standard 6-month course.

Venous thromboembolism (VTE) is a major cause of death in the world. After the acute-phase treatment, the optimal duration of anticoagulation is still debatable. The latest guidelines suggest maintaining long-term anticoagulation in patients with cancer-associated thrombosis (CAT) or with unprovoked VTE and a low bleeding risk. Methods: The MAC Project is an ongoing prospective-cohort, multi-center, observational study in Italy. The project aims to collect real-life clinical information in unselected patients given oral anticoagulants for VTE over a 5-year follow-up period. There were no exclusion criteria, except for life expectancy Results: We analyzed 450 consecutive patients treated with rivaroxaban and referred them to the MAC Project database for unprovoked or recurrent VTE. Of these, 267 (55%) were unprovoked VTE, and 377 (87%) were symptomatic. We followed up with the patients for a mean of 22 months (Q1 10.7; Q3 37.4 months). Recurrent VTE occurred in 12 patients on rivaroxaban treatment (IR 1.7 per 100 person-years). Males had more recurrence than women. During the follow-up period, we recorded 13 (2.9%) major bleeding, 12 (2.7%) clinically relevant non-major bleeding, 8 minor bleeding, and no fatal bleeding events. Overall, bleeding events occurred in 33 (7.3%) patients, most occurring within the first 2 years of treatment. In addition, we observed a statistically significant higher incidence of bleeding in patients with a baseline HAS-BLED score of 3 to 4 compared with those with a score of 0 to 2, with most events occurring during the first 3 months of treatment (RR 5.9). Discussion: Rivaroxaban appears to be safe and effective for the long-term treatment of patients with recurrent or unprovoked VTE. Our results match previously published data, and we are confident that the continuation of the follow-up for up to 5 years will confirm these outcomes.

In computer vision, stereoscopy allows the three-dimensional reconstruction of a scene using two 2D images taken from two slightly different points of view, to extract spatial information on the depth of the scene in the form of a map of disparities. In stereophotogrammetry, the disparity map is essential in extracting the digital terrain model (DTM) and thus obtaining a 3D spatial mapping, which is necessary for a better analysis of planetary surfaces. However, the entire reconstruction process performed with the stereo-matching algorithm can be time consuming and can generate many artifacts. Coupled with the lack of adequate stereo coverage, it can pose a significant obstacle to 3D planetary mapping. Recently, many deep learning architectures have been proposed for monocular depth estimation, which aspires to predict the third dimension given a single 2D image, with considerable advantages thanks to the simplification of the reconstruction problem, leading to a significant increase in interest in deep models for the generation of super-resolution images and DTM estimation. In this paper, we combine these last two concepts into a single end-to-end model and introduce a new generative adversarial network solution that estimates the DTM at 4× resolution from a single monocular image, called SRDiNet (super-resolution depth image network). Furthermore, we introduce a sub-network able to apply a refinement using interpolated input images to better enhance the fine details of the final product, and we demonstrate the effectiveness of its benefits through three different versions of the proposal: SRDiNet with GAN approach, SRDiNet without adversarial network, and SRDiNet without the refinement learned network plus GAN approach. The results of Oxia Planum (the landing site of the European Space Agency’s Rosalind Franklin ExoMars rover 2023) are reported, applying the best model along all Oxia Planum tiles and releasing a 3D product enhanced by 4×.

Physiologic fibrinolysis is a localized process in which stable fibrin strands are broken down by plasmin in response to thrombosis. Plasmin activation can also take place separately from the coagulation process, resulting in pathologic fibrinolysis. When plasmin activation exceeds the neutralizing capacity of plasmin inhibitors, severe bleeding can potentially take place. Although the processes which regulate coagulation and fibrinolysis in the blood are well known, it is less clear as to what extent the same processes take place in the body cavities and whether they influence systemic hemostasis. The results of the studies herein cited demonstrate that coagulation followed by fibrinogenolytic/fibrinolytic activity takes place in all kinds of canine ascitic and pleural fluids. Moreover, systemic clotting abnormalities suggesting primary fibrinolysis/primary hyperfibrinolysis (i.e., elevated plasma fibrin/fibrinogen degradation products [FDPs] and normal D-dimer concentrations with fibrinogen concentrations ≤ 100 mg/dL or above this cut-off, respectively) occur in dogs with intracavitary effusion. Enhanced fibrinolytic activity in dogs with intracavitary effusion can also be detected using rotational thromboelastometry (ROTEM), although the degree of agreement between ROTEM and FDPs, D-dimer and fibrinogen concentrations is poor. Finally, contrary to the thrombotic events commonly documented in some humans and cats with cardiac diseases, bleeding tendencies due to primary fibrinolysis/primary hyperfibrinolysis have been documented in dogs with cardiogenic ascites.

In Mediterranean ecosystems, the projected rainfall reduction of up to 30% may alter plant–soil interactions, particularly litter decomposition and Home Field Advantage (HFA). We set up a litter transplant experiment in the three main forests encountered in the northern part of the Medi-terranean Basin (dominated by either Quercus ilex, Quercus pubescens, or Pinus halepensis) equipped with a rain exclusion device, allowing an increase in drought either throughout the year or concentrated in spring and summer. Senescent leaves and needles were collected under two precipitation treatments (natural and amplified drought plots) at their “home” forest and were left to decompose in the forest of origin and in other forests under both drought conditions. MS-based metabolomic analysis of litter extracts combined with multivariate data analysis enabled us to detect modifications in the composition of litter specialized metabolites, following amplified drought treatment. Amplified drought altered litter quality and metabolomes, directly slowed down litter decomposition, and induced a loss of home field (dis)advantage. No indirect effect mediated by a change in litter quality on decomposition was observed. These results may suggest major alterations of plant–soil interactions in Mediterranean forests under amplified drought conditions.

Genetic improvement of native forage species is a sustainable alternative for maximizing livestock production. Paspalum notatum Flügge is the most important forage grass in the native grasslands of southern Brazil, with substantial potential available for further genetic improvement. The objective of this study was to quantify a range of genetic parameters and predict yield gains in a population of P. notatum intraspecific hybrids. Results indicated intraspecific hybrids of P. notatum had high magnitudes of heritability in the broad and average sense of genotype, plus high selective accuracy and genetic variation for all forage characteristics evaluated. This indicated REML/BLUP can contribute useful information for plant selection in future plant breeding programs. The genetic material studied showed high genetic variability for forage production. Analysis indicated hybrids 336, 332, 437, 132 and male parent ‘30N’ should be included in new crosses to increase the dry matter production of P. notatum. Parents need to be selected from different groups in order to maximize genetic variability and heterosis. In addition, these parents must be included in diallel crosses. The results obtained in this study provide important information for the future breeding of improved P. notatum cultivars for commercialization.

Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4–18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02–3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22–5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk.

Extensive urbanization around the world has resulted in the consumption of massive vegetated areas and natural resources. To this end, one strategy for urban development is to consolidate urban areas. In Balneário Camboriú/SC, Brazil, this trend has transformed the city into a vertical built-up area on its coastal strip, accommodating a large amount of buildings both in terms of quantity and number of floors. This research aims to quantify the thermo-hygrometric fluctuation on the waterfront of Balneário Camboriú, in negative radiation balance. To acquire the data on air temperature (Ta) and relative humidity (RH), two mobile transects and measuring at two fixed points were made in a situation of negative radiation balance on 26 August 2019, in the winter period of the Southern Hemisphere. The collection work began at 06:00:00 a.m. (before sunrise, the peak of the negative radiation balance), on Atlântica Avenue (waterfront) and Brasil Avenue (parallel to the waterfront). It was verified that the Ta varied from 16.0 °C to 19.0 °C, and the RH remained over 80% during the entire route. At the meteorological shelters, the temperature presented a variation from 14.4 °C to 17.7 °C, and the RH ranged from 79.6% to 91.3% between the two points. The spatial variability in the Ta and RH along the paths travelled and at the fixed points is directly related to the land cover, represented especially by the buildings’ verticalization and data collection time.

The social wasp Polybia paulista (Hymenoptera, Vespidae) is highly aggressive, being responsible for many medical occurrences. One of the most allergenic components of this venom is Antigen 5 (Poly p 5). The possible modulation of the in vitro immune response induced by antigen 5 from P. paulista venom, expressed recombinantly (rPoly p 5), on BALB/c mice peritoneal macrophages, activated or not with LPS, was assessed. Here, we analyzed cell viability changes, expression of the phosphorylated form of p65 NF-κB subunit, nitric oxide (NO), proinflammatory cytokines production, and co-stimulatory molecules (CD80, CD86). The results suggest that rPoly p 5 does not affect NO production nor the expression of co-stimulatory molecules in mouse peritoneal macrophages. On the other hand, rPoly p 5 induced an increase in IL-1β production in non-activated macrophages and a reduction in the production of TNF-α and MCP-1 cytokines in activated macrophages. rPoly p 5 decreased the in vitro production of the phosphorylated p65 NF-κB subunit in non-activated macrophages. These findings suggest an essential role of this allergen in the polarization of functional M2 macrophage phenotypes, when analyzed in previously activated macrophages. Further investigations, mainly in in vivo studies, should be conducted to elucidate Polybia paulista Ag5 biological role in the macrophage functional profile modulation.

Advances in screening methods and pharmacological treatments are increasing the life expectancy of cancer patients. During recent decades, the community of long-term disease-free cancer survivors (LCS) has grown exponentially, raising the issues related to cancer follow-up. Cancer relapse and other cancer-related diseases, as well as lifestyle, influence cancer survival. Recently, the regulatory role of microRNAs (miRNAs) in gene expression and their involvement in human diseases, including cancer, has been identified. Extracellular circulating miRNAs (ECmiRNAs) have been found in biological fluids and specific ECmiRNAs have been associated with cancer development and progression or with a therapy response. Here, we focus on the pivotal role of ECmiRNAs as biomarkers in cancer diagnosis and prognosis. Then, we discuss the relevance of ECmiRNAs expression in cancer survivors for the identification of specific ECmiRNAs profiles as potential tools to assess cancer outcome and to control LCS follow-up.

PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, p < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients (p < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients’ sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection.

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer’s disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications.

Pattern classification of ingestive behavior in grazing animals has extreme importance in studies related to animal nutrition, growth and health. In this paper, a system to classify chewing patterns of ruminants in in vivo experiments is developed. The proposal is based on data collected by optical fiber Bragg grating sensors (FBG) that are processed by machine learning techniques. The FBG sensors measure the biomechanical strain during jaw movements, and a decision tree is responsible for the classification of the associated chewing pattern. In this study, patterns associated with food intake of dietary supplement, hay and ryegrass were considered. Additionally, two other important events for ingestive behavior were monitored: rumination and idleness. Experimental results show that the proposed approach for pattern classification is capable of differentiating the five patterns involved in the chewing process with an overall accuracy of 94%.

In this work, we have examined the neuromuscular activity of Micrurus laticollaris (Mexican coral snake) venom (MLV) in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations, the MLV induced an irreversible concentration- and time-dependent (1–30 µg/mL) neuromuscular blockade, with 50% blockade occurring between 8 and 30 min. Muscle contractures evoked by exogenous acetylcholine were completely abolished by MLV, whereas those of KCl were also significantly altered (86% ± 11%, 53% ± 11%, 89% ± 5% and 89% ± 7% for one, three, 10 and 30 µg of venom/mL, respectively; n = 4; p < 0.05). In mouse phrenic nerve-diaphragm preparations, MLV (1–10 µg/mL) promoted a slight increase in the amplitude of twitch-tension (3 µg/mL), followed by neuromuscular blockade (n = 4); the highest concentration caused complete inhibition of the twitches (time for 50% blockade = 26 ± 3 min), without exhibiting a previous neuromuscular facilitation. The venom (3 µg/mL) induced a biphasic modulation in the frequency of miniature end-plate potentials (MEPPs)/min, causing a significant increase after 15 min, followed by a decrease after 60 min (from 17 ± 1.4 (basal) to 28 ± 2.5 (t15) and 12 ± 2 (t60)). The membrane resting potential of mouse diaphragm preparations pre-exposed or not to d-tubocurarine (5 µg/mL) was also significantly less negative with MLV (10 µg/mL). Together, these results indicate that M. laticollaris venom induces neuromuscular blockade by a combination of pre- and post-synaptic activities.

MiDCA1, a phospholipase A2 (PLA2) neurotoxin isolated from Micrurus dumerilii carinicauda coral snake venom, inhibited a major component of voltage-activated potassium (Kv) currents (41 ± 3% inhibition with 1 μM toxin) in mouse cultured dorsal root ganglion (DRG) neurons. In addition, the selective Kv2.1 channel blocker guangxitoxin (GxTx-1E) and MiDCA1 competitively inhibited the outward potassium current in DRG neurons. MiDCA1 (1 µM) reversibly inhibited the Kv2.1 current by 55 ± 8.9% in a Xenopus oocyte heterologous system. The toxin showed selectivity for Kv2.1 channels over all the other Kv channels tested in this study. We propose that Kv2.1 channel blockade by MiDCA1 underlies the toxin’s action on acetylcholine release at mammalian neuromuscular junctions.

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.

Guanidine has been used with some success to treat myasthenia gravis and myasthenic syndrome because it increases acetylcholine release at nerve terminals through K+, Na+ and Ca2+ channels-involving mechanisms. Currently, guanidine derivatives have been proposed for treatment of several diseases. Studies aimed at providing new insights to the drug are relevant. Experimentally, guanidine (10 mM) induces on mouse phrenic nerve-diaphragm (PND) preparations neurotransmission facilitation followed by blockade and a greatest secondary facilitation after its removal from bath. Herein, we hypothesized that this peculiar triphasic response may differ in muscles with distinct twitch/metabolic characteristics. Morphological alterations and contractile response of PND, extensor digitorum longus (EDL) and soleus (SOL) preparations incubated with guanidine (10 mM) for 15, 30, 60 min were analyzed. Guanidine concentrations of 5 mM (for PND and EDL) and 1 mM (for EDL) were also tested. Guanidine triphasic effect was only observed on PND regardless the concentration. The morphological alterations in muscle tissue varied along time but did not impede the PND post-wash facilitation. Higher doses (20–25 mM) did not increase EDL or SOL neurotransmission. The data suggest a complex mechanism likely dependent on the metabolic/contractile muscle phenotype; muscle fiber types and density/type of ion channels, sarcoplasmic reticulum and mitochondria organization may have profound impact on the levels and isoform expression pattern of Ca2+ regulatory membrane proteins so reflecting regulation of calcium handling and contractile response in different types of muscle.

Although systemic reactions caused by allergenic proteins present in venoms affect a small part of the world population, Hymenoptera stings are among the main causes of immediate hypersensitivity responses, with risk of anaphylactic shock. In the attempt to obtain therapeutic treatments and prophylaxis to hypersensitivity responses, interest in the molecular characterization of these allergens has grown in the scientific community due to the promising results obtained in immunological and clinical studies. The present review provides an update on the knowledge regarding the immune response and the therapeutic potential of Antigen 5 derived from Hymenoptera venom. The results confirm that the identification and topology of epitopes, associated with molecular regions that interact with antibodies, are crucial to the improvement of hypersensitivity diagnostic methods.

Background/Objectives: Chronic kidney disease and mineral bone disorders (CKD-MBD) are frequently associated with an increased risk of both vascular calcifications (VCs) and bone fractures (BFs). The complex pathogenesis of VCs and BFs involves various factors such as calcium overload, phosphate imbalance, and secondary hyperparathyroidism. Key players, such as the vitamin K-dependent proteins (VKDPs) matrix Gla protein (MGP) and bone Gla protein (BGP), have pivotal roles both for VCs and BFs. The VIKI study highlighted that hemodialysis patients treated with calcimimetics had higher levels of total BGP and MGP compared to those untreated, suggesting a potential protective effect of these drugs on BFs and VCs beyond the beneficial effect of reducing PTH levels. Methods: ETERNITY-ITA is a multi-center, comparative effectiveness, observational, longitudinal study that will enroll 160 hemodialysis patients (80 patients treated with Etelcalcetide and 80 age- and sex-matched patients treated with calcitriol or vitamin D analogs). Nephrologists will tailor the target dose of Etelcalcetide on an individual level to achieve the KDIGO PTH target. In the Etelcalcetide-treated group, the addition of calcitriol will be allowed when required by clinical practice (for correction of hypocalcemia). Conclusions: This study will evaluate the real-world effect of Etelcalcetide on VKDP levels, such as BGP and MGP, at 3, 9, and 18 months from baseline. The resulting preservation of vascular and bone health will be assessed for the first time by examining aortic and iliac artery calcifications and vertebral fractures, respectively.

Background: Opinions in the literature on the impact of cancer on patients with haemophilia are contradictory. There is a lack of data on the clinical presentation and management of cancer in patients with haemophilia (PWH)., Methods: Papers were found following a comprehensive search in PubMed, Google Scholar, and Scopus using the terms "cancer" and "haemophilia" without time limits and using the English language as a filter. The references from all the retrieved original articles and reviews were assessed for additional relevant articles., Results: The emergence of malignancies is one of the important causes of morbidity and mortality in PWH. In the past decade, the literature mainly focused on the epidemiology and outcome of blood-borne cancers in the haemophilia patient group, as the incidence of hepatitis B virus (HBV), hepatitis C (HCV), and HIV infection were high among them. However, with the introduction of recombinant clotting factor concentrates (CFCs), physicians now pay attention to non-virus-related malignancies. Bleeding and thrombotic complications are important causes of morbidity and mortality in critically ill patients with cancer; replacement therapy with factor VIII or IX or others should be maintained during antitumour treatment., Conclusion: Overall, managing cancer in patients with haemophilia requires careful evaluation and individualised planning involving a multidisciplinary team of physicians experienced in haematology, oncology, and surgery.

Background: Portal vein thrombosis (PVT) is a rare disease with an estimated incidence of 2 to 4 cases per 100,000 inhabitants. The most common predisposing conditions for PVT are chronic liver diseases (cirrhosis), primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease, or myeloproliferative disorders. Methods: PVT can be classified on the basis of the anatomical site, the degree of venous occlusion, and the timing and type of presentation. The main differential diagnosis of PVT, both acute and chronic, is malignant portal vein invasion, most frequently by hepatocarcinoma, or constriction (typically by pancreatic cancer or cholangiocarcinoma). Results: The management of PVT is based on anticoagulation and the treatment of predisposing conditions. The aim of anticoagulation in acute thrombosis is to prevent the extension of the clot and enable the recanalization of the vein to avoid the development of complications, such as intestinal infarction and portal hypertension. Conclusions: The treatment with anticoagulant therapy favors the reduction of portal hypertension, and this allows for a decrease in the risk of bleeding, especially in patients with esophageal varices. The anticoagulant treatment is generally recommended for at least three to six months. Prosecution of anticoagulation is advised until recanalization or lifelong if the patient has an underlying permanent pro-coagulant condition that cannot be corrected or if there is thrombosis extending to the mesenteric veins.

Fabry disease (FD) is an X-linked lysosome storage disease that results in the accumulation of globotriaosylceramide (Gb3) throughout the body leading to irreversible target organ damage. As the role of secondary mediators (inflammatory molecules) and their mechanisms has not been fully elucidated, we focused on the interleukin (IL)-6 system in adult FD patients and in matched healthy subjects. To obtain insights into the complex regulation of IL-6 actions, we used a novel approach that integrates information from plasma and exosomes of FD patients (n = 20) and of healthy controls (n = 15). Soluble IL-6 receptor (sIL-6R) levels were measured in plasma with the ELISA method, and membrane-bound IL-6R was quantified in plasma and urinary exosomes using flow cytometry. In FD patients, the levels of soluble IL-6R in plasma were higher than in control subjects (28.0 ± 5.4 ng/mL vs. 18.9 ± 5.4 ng/mL, p < 0.0001); they were also higher in FD subjects with the classical form as compared to those with the late-onset form of the disease (36.0 ± 11.4 ng/mL vs. 26.1 ± 4.5 ng/mL, p < 0.0001). The percentage of urinary exosomes positive for IL-6R was slightly lower in FD (97 ± 1 vs. 100 ± 0% of events positive for IL-6R, p < 0.05); plasma IL-6 levels were not increased. These results suggest a potential role of IL-6 in triggering the inflammatory response in FD. As in FD patients only the levels of sIL-6Rs are consistently higher than in healthy controls, the IL-6 pathogenic signal seems to prevail over the homeostatic one, suggesting a potential mechanism causing multi-systemic damage in FD.

Coagulation factor XI (FXI) promotes fibrin formation and inhibits fibrinolysis. Elevated plasma FXI levels, limited to a single measurement, are associated with a higher thrombotic risk. Our case-control study aimed to identify the effect of persistently increased plasma FXI levels on the risk of deep vein thrombosis (DVT). All patients evaluated between January 2016 and January 2018 for a first episode of proximal DVT of the lower extremity were considered for enrolment. Plasma FXI levels were measured at least 1 month after the discontinuation of anticoagulant treatment (T1). The patients with increased plasma FXI levels (>90th percentile of controls) were tested again 3 months later (T2). Among the 200 enrolled patients (M/F 114/86, age range 26-87 years), 47 patients had increased plasma FXI levels at T1 and16 patients had persistently increased plasma FXI levels at T2. The adjusted odds ratio for DVT was 2.4 (95% CI, 1.3 to 5.5, p < 0.001) for patients with increased FXI levels at T1 and 5.2 (95% CI, 2.3 to 13.2, p < 0.001) for patients with persistently high FXI levels at T2. Elevated FXI levels constitute a risk factor for deep vein thrombosis, and this risk nearly doubled in patients with persistently increased plasma FXI levels. Larger prospective studies are needed to confirm our findings.

Extended-phase anticoagulation with direct oral Xa inhibitors (OAXI) is suggested in patients with cancer-associated venous thromboembolism (CAT). We report on patients enrolled in the MAC (Monitoring AntiCoagulants) Project, given rivaroxaban as extended-phase anticoagulation after CAT. The primary efficacy outcome was the incidence of symptomatic recurrent VTE; the primary safety outcomes were incidence of major and non-major clinically relevant bleeding, adverse events, and all-cause mortality. The mean patients' follow-up was 19 months (SD 16); 64/604 (11%) had CAT. Recurrent VTE occurred in 9.3% and in 8.1% of patients with and without CAT (OR 1.2, 95% CI 0.5 to 2.9; p = 0.6). Major bleeding occurred in 4.7% and in 2.6%, respectively (OR = 1.8, 95% CI 0.5 to 6.6, p = 0.4), and non-major clinically-relevant bleeding in 4.7% and in 4.1% (OR = 1.2, 95% CI 0.3 to 3.9, p = 0.7). The relative figures for fatal haemorrhage and all-cause death were 1.6% versus 0%, and 1.6% versus 0.4%. Rivaroxaban appears to be effective and safe as extended-phase anticoagulation in patients with CAT. The mean treatment period was 3-times the standard 6-month course.

Bleeding is the dominant adverse event of anticoagulation and often discourages many patients and physicians from starting treatment with anticoagulant drugs. The fact that factor (F)XI deficiency is associated with a mild bleeding phenotype and that FXI knockdown or inhibition in different animal models reduced the occurrence of thrombotic events in response to injury suggests that FXI is more important for the coagulation propagation and thrombotic process than for the overall hemostasis. The aim of this review is to summarize clinical pharmacology and evidence from phase 2 clinical trials on efficacy and safety of drugs directed against FXI for the treatment and prevention of thrombosis. Inhibition of FXI or FXIa has been proven to be effective in phase 2 studies at preventing venous thromboembolism (VTE) in patients undergoing total knee arthroplasty, or for prevention of major adverse vascular events in patients with end-stage kidney disease undergoing hemodialysis or as adjuncts to antiplatelet therapy for prevention of recurrent ischemic events in patients with acute myocardial infarction or non-cardioembolic stroke. Should the efficacy of FXI inhibitors as anticoagulant without impairing the hemostasis be proven in phase 3 randomized clinical trials, it would provide an innovative therapeutic option.

Venous thromboembolism (VTE) is a major cause of death in the world. After the acute-phase treatment, the optimal duration of anticoagulation is still debatable. The latest guidelines suggest maintaining long-term anticoagulation in patients with cancer-associated thrombosis (CAT) or with unprovoked VTE and a low bleeding risk. Methods: The MAC Project is an ongoing prospective-cohort, multi-center, observational study in Italy. The project aims to collect real-life clinical information in unselected patients given oral anticoagulants for VTE over a 5-year follow-up period. There were no exclusion criteria, except for life expectancy <6 months and refusal to sign the informed consent form or to attend the planned follow-up visit. All patients were followed-up prospectively with clinical controls scheduled at 3, 6, and 12 months after the index event, and then annually for up to 5 years. The primary efficacy and safety outcomes were symptomatic recurrent VTE and major bleeding. Results: We analyzed 450 consecutive patients treated with rivaroxaban and referred them to the MAC Project database for unprovoked or recurrent VTE. Of these, 267 (55%) were unprovoked VTE, and 377 (87%) were symptomatic. We followed up with the patients for a mean of 22 months (Q1 10.7; Q3 37.4 months). Recurrent VTE occurred in 12 patients on rivaroxaban treatment (IR 1.7 per 100 person-years). Males had more recurrence than women. During the follow-up period, we recorded 13 (2.9%) major bleeding, 12 (2.7%) clinically relevant non-major bleeding, 8 minor bleeding, and no fatal bleeding events. Overall, bleeding events occurred in 33 (7.3%) patients, most occurring within the first 2 years of treatment. In addition, we observed a statistically significant higher incidence of bleeding in patients with a baseline HAS-BLED score of 3 to 4 compared with those with a score of 0 to 2, with most events occurring during the first 3 months of treatment (RR 5.9). Discussion: Rivaroxaban appears to be safe and effective for the long-term treatment of patients with recurrent or unprovoked VTE. Our results match previously published data, and we are confident that the continuation of the follow-up for up to 5 years will confirm these outcomes.

The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments.

Background: Intracranial hemorrhage (ICH) is a highly serious event in patients with haemophilia (PWH) which leads to disability and in some cases to death. ICH occurs among all ages but is particularly frequent in newborns. Aim: The primary aim was to assess the incidence and mortality due to ICH in an Italian population of PWH. Secondary aims were to evaluate the risk factors for ICH, the role of prophylaxis, and the clinical management of patients presenting ICH. Methods: A retrospective-prospective registry was established in the network of the Italian Association of Haemophilia Centers to collect all ICHs in PWH from 2009 to 2019 reporting clinical features, treatments, and outcomes. Results: Forty-six ICHs were collected from 13 Centers. The ICHs occurred in 15 children (10 < 2 years), and in 31 adults, 45.2% of them with mild hemophilia. Overall, 60.9% patients had severe haemophilia (15/15 children). Overall ICH incidence (×1000 person/year) was 0.360 (0.270−0.480 95% CI), higher in children <2 years, 1.995 (1.110−3.442 95% CI). Only 7/46 patients, all with severe haemophilia, had received a prophylactic regimen before the ICH, none with mild. Inhibitors were present in 10.9% of patients. In adult PWHs 17/31 suffered from hypertension; 85.7% of the mild subjects and 29.4% of the moderate/severe ones (p < 0.05). ICH was spontaneous in the 69.6% with lower rate in children (46.7%). Surgery was required in 21/46 patients for cerebral hematoma evacuation. Treatment with coagulation factor concentrates for at least three weeks was needed in 76.7% of cases. ICH was fatal in 30.4% of the cases. Of the survivors, 50.0% became permanently disabled. Only one-third of adult patients received long term prophylaxis after the acute treatment. Conclusion: The results from our Registry confirm the still high incidence of ICH in infants <2 years and in adults, particularly in mild PWHs presenting hypertension and its unfavorable outcomes. The majority of PWHs were treated on-demand before ICH occurred, suggesting the important role of prophylaxis in preventing such life-threatening bleeding.

PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, p < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients ( p < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients' sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection.