Small and medium sized enterprises (SMEs) take up over 98% of the structure of economies and are consequently the biggest creators of new jobs, innovations, economic activity, and greater social inclusion in the European Union. One of the biggest issues that SMEs face is collection of accounts receivable. Late payments in commercial transactions are made not only by private but also public sector, and that public sector entities, i.e. state institutions, are even larger generators of illiquidity compared to private companies. SMEs in BiH have certain, although insufficient, legal solutions available in combating late payment in commercial transactions. However, the fear of losing business partners overcomes their willingness to exercise their rights as creditors.

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)‐induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in the P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1770 patients were included in the analysis of SU efficacy, assessed as the combined outcome of the HbA1c reduction and the prescribed SU daily dose. Sixty‐nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three‐fold higher odds of hypoglycaemia (OR, 2.81; 95% CI, 1.30‐6.09; P = .009) and better response to SU treatment (β, −0.218; SE, 0.074; P = .003) only in patients carrying the POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.

The historical changes in European Black Pine population size across the whole natural distribution in Europe and Asia Minor were analyzed facing the Plio-Pleistocene climatic fluctuations. Thirteen chloroplast SSRs and SNPs markers have been studied under the assumptions of “neutral evolution.” Populations and meta-populations had different histories of migration routes, and they were strongly affected by complex patterns of isolation, fragmentation, speciation, expansion (1.88–4.28 Ma), purification selection (2.09–21.41 Ma) and bottleneck (1.85–21.76 Ma). A significant number of populations (min. 29–41%) were in equilibrium for very long periods. Generally, the bottleneck revealed by chloroplast DNA is weaker than the bottleneck revealed by nuclear DNA. The Ne immediately after the bottleneck reaches between 1820 and 3640 individuals. Generally, the historical effective population sizes shrink significantly for the Tertiary period from 10–15 up to 2.5 Ma in Western Europe (by 82%), followed by Asia Minor (69%) and the Balkan Peninsula (28%), likely resulting from important climatic changes. The rates and frequencies of stepwise westwards migration waves have been not sufficient to prevent isolation between the meta-populations and to suppress “sympatric speciation.” The migration was weak for the Pliocene, but was maximal for the Pleistocene, and finally silent for the present interglacial period, namely the Holocene.

The historical changes in European Black Pine population size across the whole natural distribution in Europe and Asia Minor were analyzed facing the Plio-Pleistocene climatic fluctuations. Thirteen chloroplast SSRs and SNPs markers have been studied under the assumptions of “neutral evolution.” Populations and meta-populations had different histories of migration routes, and they were strongly affected by complex patterns of isolation, fragmentation, speciation, expansion (1.88–4.28 Ma), purification selection (2.09–21.41 Ma) and bottleneck (1.85–21.76 Ma). A significant number of populations (min. 29–41%) were in equilibrium for very long periods. Generally, the bottleneck revealed by chloroplast DNA is weaker than the bottleneck revealed by nuclear DNA. The Ne immediately after the bottleneck reaches between 1820 and 3640 individuals. Generally, the historical effective population sizes shrink significantly for the Tertiary period from 10–15 up to 2.5 Ma in Western Europe (by 82%), followed by Asia Minor (69%) and the Balkan Peninsula (28%), likely resulting from important climatic changes. The rates and frequencies of stepwise westwards migration waves have been not sufficient to prevent isolation between the meta-populations and to suppress “sympatric speciation.” The migration was weak for the Pliocene, but was maximal for the Pleistocene, and finally silent for the present interglacial period, namely the Holocene.

We studied intrinsic resistance switching behaviour in sputter-deposited amorphous silicon suboxide (a-SiOx) films with varying degrees of roughness at the oxide-electrode interface. By combining electrical probing measurements, atomic force microscopy (AFM), and scanning transmission electron microscopy (STEM), we observe that devices with rougher oxide-electrode interfaces exhibit lower electroforming voltages and more reliable switching behaviour. We show that rougher interfaces are consistent with enhanced columnar microstructure in the oxide layer. Our results suggest that columnar microstructure in the oxide will be a key factor to consider for the optimization of future SiOx-based resistance random access memory.

We studied intrinsic resistance switching behaviour in sputter-deposited amorphous silicon suboxide (a-SiOx) films with varying degrees of roughness at the oxide-electrode interface. By combining electrical probing measurements, atomic force microscopy (AFM), and scanning transmission electron microscopy (STEM), we observe that devices with rougher oxide-electrode interfaces exhibit lower electroforming voltages and more reliable switching behaviour. We show that rougher interfaces are consistent with enhanced columnar microstructure in the oxide layer. Our results suggest that columnar microstructure in the oxide will be a key factor to consider for the optimization of future SiOx-based resistance random access memory.

To present the status and development of economies of the countries, a number of macroeconomic indicators is available and used and the most important aggregate in the system of national accounts is the gross domestic product (GDP). An analysis of GDP serves to present the status and trends of the economy of Bosnia and Herzegovina (BiH). We have used the comparison method, in order to establish the status, as well as trends in the economy of BiH in comparison with the neighbouring countries with similar GDP structures and with economies of some developed countries. We note that the structure of gross value added (GVA) in BiH is not primarily oriented towards profitable activities, nor towards activities giving a synergistic effect on the entire economy. The service sector is not sufficiently developed. GDP per capita in 2015 was almost eight times lower than the one recorded in the EU member countries. The relationship between consumption and investment, in addition to the negative balance of trade, are negative determinants of the BiH economy. The global crisis has produced negative effects on the BiH economy. Such trends were imminent even in the developed countries, the only difference is that the developed countries, by size of their GDP per capita, are far stronger and more developed than the BiH economy. The economy is small in its size and growth rates are not sufficient to provide a visible progress, as is the case with developed countries. BiH needs to put maximum efforts into increasing its value added in areas that are fast and strong in contributing to the growth and development.

Our previous in vitro and in vivo studies on standard tumor cell lines: mammary adenocarcinoma 4T1, melanoma B16F10, and squamous cell carcinoma SCCVII have demonstrated that dipotassium-trioxohydroxytetrafluorotriborate, K 2 [B 3 O 3 F 4 OH], affects the growth of cancer cells. Based on indicative results of its anticancer activity, that are comparable to the standard cytostatic 5-fluorouracil, we decided to analyze the antioxidant capacity of K 2 [B 3 O 3 F 4 OH]. In our research, we include two other simpler representatives of the boroxine family compounds: trimethoxyboroxine and t rimethylboroxine , which are commercially available. The study objective is to explore the possibility of similar behavior within the same class of boron compounds, that is, to examine the activity of K 2 [B 3 O 3 F 4 OH] compared to simpler representatives of the same family of compounds. On the one hand, K 2 [B 3 O 3 F 4 OH], theoretically has the ability to exchange electrons in the extinction of reactive radicals, since two boron atoms are sp3-hybridized and use electrons from the inner shell. On the other hand, trimethoxyboroxine, and trimethylboroxine, in theory, should not exchange electrons. However, recent studies indicate the potential for the boron atom to act like carbon and participate in the exchange of protons. The study used the standard laboratory method of 2,2-diphenyl-1-picrylhydrazyl (DPPH) antioxidant assay. The selected boroxines were treated with a DPPH radical at a temperature of 35° C in various concentrations, and with a reaction time of one hour. Results of the DPPH test show an extremely weak antioxidant capacity exists for all investigated boroxines. When K 2 [B 3 O 3 F 4 OH] was tested at high concentrations, instead of decreased color in the DPPH radicals, there was an increase in absorbance readings, which could mean that this compound acts as a pro-oxidant at higher concentrations. Future research is recommended to examine the length of reaction times needed, and whether a change in the reaction conditions would boost the antioxidant capacity of K 2 [B 3 O 3 F 4 OH]. Finally, future research could test the hypothesis that K 2 [B 3 O 3 F 4 OH], in the absence of the expected antioxidant activity, acts as a pro-oxidant.

This chapter describes two unmanned ground vehicles that can help search and rescue teams in their difficult, but life-saving tasks. These robotic assets have been developed within the framework of the European project ICARUS. The large unmanned ground vehicle is intended to be a mobile base station. It is equipped with a powerful manipulator arm and can be used for debris removal, shoring operations, and remote struc- tural operations (cutting, welding, hammering, etc.) on very rough terrain. The smaller unmanned ground vehicle is also equipped with an array of sensors, enabling it to search for victims inside semi-destroyed buildings. Working together with each other and the human search and rescue workers, these robotic assets form a powerful team, increasing the effectiveness of search and rescue operations, as proven by operational validation tests in collaboration with end users.

This chapter describes how the different ICARUS unmanned search and rescue tools have been evaluated and validated using operational benchmarking techniques. Two large‐scale simulated disaster scenarios were organized: a simulated shipwreck and an earthquake response scenario. Next to these simulated response scenarios, where ICARUS tools were deployed in tight interaction with real end users, ICARUS tools also participated to a real relief, embedded in a team of end users for a flood response mission. These validation trials allow us to conclude that the ICARUS tools fulfil the user require‐ ments and goals set up at the beginning of the project.

BackgroundManaged entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available.MethodWe conducted a survey on the implementation of MEAs in CEE between January and March 2017.ResultsSixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC)-L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%).ConclusionsExperience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation.

Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or WCFS1) or placebo for 7 days. To determine whether L. plantarum can enhance immune response, we compared the effects of three stains on systemic and gut mucosal immunity, by among others assessing memory responses against tetanus toxoid (TT)-antigen, and mucosal gene transcription, in human volunteers during induction of mild immune stressor in the intestine, by giving a commonly used enteropathic drug, indomethacin [non-steroidal anti-inflammatory drug (NSAID)]. Systemic effects of the interventions were studies in peripheral blood samples. NSAID was found to induce a reduction in serum CD4+/Foxp3 regulatory cells, which was prevented by L. plantarum TIFN101. T-cell polarization experiments showed L. plantarum TIFN101 to enhance responses against TT-antigen, which indicates stimulation of memory responses by this strain. Cell extracts of the specific L. plantarum strains provoked responses after WCFS1 and TIFN101 consumption, indicating stimulation of immune responses against the specific bacteria. Mucosal immunomodulatory effects were studied in duodenal biopsies. In small intestinal mucosa, TIFN101 upregulated genes associated with maintenance of T- and B-cell function and antigen presentation. Furthermore, L. plantarum TIFN101 and WCFS1 downregulated immunological pathways involved in antigen presentation and shared downregulation of snoRNAs, which may suggest cellular destabilization, but may also be an indicator of tissue repair. Full sequencing of the L. plantarum strains revealed possible gene clusters that might be responsible for the differential biological effects of the bacteria on host immunity. In conclusion, the impact of oral consumption L. plantarum on host immunity is strain dependent and involves responses against bacterial cell components. Some strains may enhance specific responses against pathogens by enhancing antigen presentation and leukocyte maintenance in mucosa. In future studies and clinical settings, caution should be taken in selecting beneficial bacteria as closely related strains can have different effects. Our data show that specific bacterial strains can prevent immune stress induced by commonly consumed painkillers such as NSAID and can have enhancing beneficial effects on immunity of consumers by stimulating antigen presentation and memory responses.

Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The “introduction” of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers.