Cost-effectiveness analysis of Vaborem in Carbapenem-resistant Enterobacterales (CRE) -Klebsiella pneumoniae infections in Italy

Background: Vaborem is a fixed dose combination of vaborbactam and meropenem with potent activity against target Carbapenem-resistant Enterobacterales (CRE) pathogens, optimally developed for Klebsiella pneumoniae carbapenemase (KPC). The study aims to evaluate the cost-effectiveness of Vaborem versus best available therapy (BAT) for the treatment of patients with CRE-KPC associated infections in the Italian setting. Methods: A cost-effectiveness analysis was conducted based on a decision tree model that simulates the clinical pathway followed by physicians treating patients with a confirmed CRE-KPC infection in a 5-year time horizon. The Italian National Health System perspective was adopted with a 3% discount rate. The clinical inputs were mostly sourced from the phase 3, randomised, clinical trial (TANGO II). Unit costs were retrieved from the Italian official drug pricing list and legislation, while patient resource use was validated by a national expert. Model outcomes included life years (LYs) and quality adjusted life years (QALYs) gained, incremental costs, incremental cost- effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR). Deterministic and probabilistic sensitivity analyses were also performed. Results: Vaborem is expected to decrease the burden associated with treatment failure and reduce the need for chronic renal replacement therapy while costs related to drug acquisition and long-term care (due to higher survival) may increase. Treatment with Vaborem versus BAT leads to a gain of 0.475 LYs, 0.384 QALYs, and incremental costs of €3549, resulting in an ICER and ICUR of €7473/LY and €9246/QALY, respectively. Sensitivity analyses proved the robustness of the model and also revealed that the probability of Vaborem being cost-effective reaches 90% when willingness to pay is €15,850/QALY. Conclusions: In the Italian setting, the introduction of Vaborem will lead to a substantial increase in the quality of life together with a minimal cost impact, therefore Vaborem is expected to be a cost-effective strategy compared to BAT

Assessment and quantification of marginal lands for biomass production in Europe using soil-quality indicators

The cultivation of bioenergy plants in fertile, arable lands increasingly results in new land use conflicts with food production and cannot be considered as sustainable. Marginal lands have been frequently considered as potential alternatives for producing bioenergy from biomass. However, clear definitions and assessment methods for selecting marginal lands and for calculating potentials are still widely missing. The project “SEEMLA” aims at triggering the exploitation of currently underused marginal lands for biomass production for energy purposes. Study sites have been selected in different European countries: Germany, Greece, and Ukraine. The selected sites represent a wide variety of different types of marginal lands. Based on a soil assessment set given by the Muencheberg Soil Quality Rating (SQR) system potentially “marginal” sites have been investigated. The SQR system allows for clearly distinguishing between soils of higher and lower quality. Soils with SQR scores below 40 are regarded as “marginal”. They can be classified into different groups with regard to the importance of soil hazard indicators as evaluated by the SQR approach. The calculated SQR scores correlate significantly with biomass yields of bioenergy plants. Further, the SQR method was adapted for use in a GIS study on marginal-land potentials in Europe. Thus, 46&thinsp;% of the investigated European area could be classified as “marginal” with SQR scores below 40. From that area 22.6&thinsp;% can be considered as potentially suitable for producing renewable resources after eliminating protected sites or other places not suitable for any kind of land use. Taking the ecological demands of selected bioenergy plants into account it is possible to give first preliminary recommendations for regional crop cultivation. It can be concluded that Europe offers a large potential for renewable resources from marginal sites. However, the implementation into practice is often impeded by missing or varying policies and regulations. A proper implementation needs clear regulations and also incentives for farmers at the European level.</p

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia

BACKGROUND: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

3D RECORDING OF UNDERWATER ANTIQUITIES IN THE SOUTH EUBOEAN GULF

An underwater archaeological survey was initiated in 2006 by the Hellenic Institute of Marine Archaeology in collaboration with the Ephorate of Underwater Antiquities of Greece, in the South Euboean Gulf. The survey is being conducted under the direction of the archaeologist Dr G. Koutsouflakis and in the course of the project important shipwrecks of Classical, Roman, and Byzantine periods have been brought to light, adding tangible evidence on ancient seafaring and maritime trade. The South Euboean Gulf archaeological survey has presented many challenges to the documentation team of H.I.M.A, and has served as a case-study for 3D recording applied on ancient wrecks, found at medium depths (22-47m) and under the conditions that are imposed during an archaeological survey of a certain geographical region. This paper focuses on the implementation of photogrammetric and geodetic techniques used for acquisition and processing of collected data, in order to generate 3D models for six different wrecks, resulting in a fast, reliable and cost efficient method to record underwater archaeological sites

SURVEYING THE UNDERWATER ARCAHEOLOGICAL SITE OF CAPE GLAROS AT PAGASETIKOS GULF

The Hellenic Institute of Marine Archaeology (H.I.M.A.)1 has been conducting an underwater archaeological research in the west coast of southern Pagasetikos Gulf, since 2000. Every year the underwater research focuses on specific archaeological targets that have been recovered during previous field campaigns. The current publication elaborates on the comprehensive documentation of the underwater archaeological site at Cape Glaros, during the 2015 field season, under the direction of the archaeologist Elias Spondylis. The 2015 research campaign was conducted within the framework of the ITACA- Innovation Technologies and Applications for Coastal Archaeological sites European Project (FP7/2007-2013, GA No 606805), at two archaeological sites, namely the Cape Glaros and Metohi. It was among the most important challenges of the project to successfully produce the detailed and accurate 3D mapping of the Cape Glaros site that covers an extended area. Four large concentrations of pottery finds and numerous anchors of different typology have been recorded, that can be dated from the late Hellenistic to the Byzantine periods. This challenge was tackled through the simultaneous implementation of three recording methods; photogrammetry, geodesy and conventional architectural mapping. The workflow of the documentation process, including data acquisition, processing and graphic visualization, along with the derived results are presented below. 1The Hellenic Institute of Marine Archaeology (H.I.M.A.) is a private, non-profit organization, founded in 1973, which undertakes maritime archaeological research under the supervision or in collaboration with the Greek Ministry of Culture. It has over 100 members, with diverse academic credentials, all of whom work, mainly, on a voluntary basis. 3D recording of underwater archaeological sites has been applied to numerous projects that have been carried out by the multidisciplinary team of H.I.M.A. in locations of utmost archaeological importance and interest, such as Modi island (Poros) and numerous wreck sites in Pagasetikos and South Euboean (Diamanti, Vlachaki, 2015) Gulfs and others

Endothelial sensing of AHR ligands regulates intestinal homeostasis

Endothelial cells (ECs) line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance, and coordinate angiogenesis/ lymphangiogenesis1,2. In the intestine, dietary and microbial cues are particularly important in the regulation of organ homeostasis. However, whether enteric ECs actively sense and integrate such signals is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR) acts as a critical node for EC-sensing of dietary metabolites in adult mice and human primary ECs. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. Endothelial AHR-deficiency in adult mice resulted in dysregulated inflammatory responses, and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric infection. In human ECs, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling integrates dietary cues to maintain tissue homeostasis by promoting EC quiescence and vascular normalcy