Hungary election: Viktor Orbán tightens his grip with a super-majority

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Brexit and the Balkans: Implications for Future EU Enlargement

The UK’s withdrawal from the European Union has the potential to impact EU enlargement to the Western Balkans in a multitude of ways, writes Eamonn Butler. He argues that, while EU leaders have reaffirmed their commitment to enlargement, accessions are likely to be pushed back several years and the remaining EU may itself seem a less attractive, although still necessary, prospect for the Balkan states

Pipeline politics and energy (in)security in Central and South-Eastern Europe

No abstract available

Pipeline politics and energy (in)security in Central and South-Eastern Europe

No abstract available

Pipeline politics and energy (in)security in Central and South-Eastern Europe

This essay concerns energy security, or more specifically energy insecurity, in Central and South-Eastern Europe. Insecurity can be defined as a situation in which vulnerability from a particular danger or threat is perceived to exist. Threats generally come from external sources, but can also come from within, and usually have an existential quality. Energy is existential in that it underpins modern life—we use it to provide power, heat and light to our homes, workplaces and cities; to fuel our cars and other forms of transport; to help produce and power technology; and even to help us grow and process the food we eat. Energy is a critical resource and as such it is a commodity of significant strategic importance, particularly with regard to access. The main concern that has driven the rise of energy insecurity has been ‘security of supply’. This refers to the ability of states and other users to guarantee sources of affordable energy, sufficient to meet their needs across all economic and business, societal and even politico-military activities. Energy insecurity exists when internal actions, those by third parties, or even natural disasters, threaten to, or actually do, disrupt the supply or affordability of energy

Extending pharmacy services to the point of discharge

Aim: The aim of this study was to determine the impact of introducing a clinical pharmacist led discharge service on medication safety at the point of discharge and its acceptability to healthcare staff. Methods: A retrospective chart review to identify medication discrepancies was undertaken before and after the introduction of a pharmacist led discharge service. An evaluation was undertaken by means of a questionnaire to community pharmacists, GPs and hospital clinicians. Results: The pharmacist led discharge service significantly reduced errors from 50% (n=17) to 7% (n=2) of patients (p<0.001) and 10% (n=22) to 1% (n=2) of medication orders (p=0.001). The evaluation revealed that the majority of clinicians found the service useful, had the potential to reduce errors and improve communication. Conclusion: Pharmacist involvement at the point of discharge had a significant impact on medication safety. Crucially, in this project, we show the service was received well by medical personnel and improved communication between primary and secondary care, enhancing implementation potential

On the performance of access control policy evaluation

There is growing awareness of the need to protect digital resources and services in both corporate and home ICT scenarios. Meanwhile, communication tools tailored for corporations are blurring the line between communication mech- anisms and (near) real-time resource sharing. The resulting requirement for near real-time policy-based access control is technically challenging. In a corporate domain, such access control mechanisms must be unobtrusive and comply with strict security objectives. Thus policy evaluation performance needs to be considered while addressing traditional security concerns. This paper discusses policy system design principles that motivate a novel Policy Decision Point (PDP) implementation and associated policy language. These principles are consistent with recent web development techniques designed to improve performance and scalability. Given a modern web development stack comprising a language (Javascript), a framework (Node.js) and a database management system (Redis), the proposition is that significant performance gains can be made. Our performance experiments suggest this is the case when, through various design iterations, our prototype PDP implementation is compared with an estab- lished, Java/XACML-based access control PDP implementation. The experiments presented in this paper suggest that newer technologies offer better performance. The analysis suggests that this is because they offer a more efficient data representation and make better use of computing resources

Inverse agonism at the P2Y₁₂ receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor

Ticagrelor is a potent antagonist of the P2Y(12) receptor (P2Y(12)R) and consequently an inhibitor of platelet activity effective in the treatment of atherothrombosis. Here, we sought to further characterize its molecular mechanism of action. Initial studies showed that ticagrelor promoted a greater inhibition of adenosine 5′-diphosphate (ADP)–induced Ca(2+) release in washed platelets vs other P2Y(12)R antagonists. This additional effect of ticagrelor beyond P2Y(12)R antagonism was in part as a consequence of ticagrelor inhibiting the equilibrative nucleoside transporter 1 (ENT1) on platelets, leading to accumulation of extracellular adenosine and activation of G(s)-coupled adenosine A(2A) receptors. This contributed to an increase in basal cyclic adenosine monophosphate (cAMP) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P). In addition, ticagrelor increased platelet cAMP and VASP-P in the absence of ADP in an adenosine receptor–independent manner. We hypothesized that this increase originated from a direct effect on basal agonist-independent P2Y(12)R signaling, and this was validated in 1321N1 cells stably transfected with human P2Y(12)R. In these cells, ticagrelor blocked the constitutive agonist-independent activity of the P2Y(12)R, limiting basal G(i)-coupled signaling and thereby increasing cAMP levels. These data suggest that ticagrelor has the pharmacological profile of an inverse agonist. Based on our results showing insurmountable inhibition of ADP-induced Ca(2+) release and forskolin-induced cAMP, the mode of antagonism of ticagrelor also appears noncompetitive, at least functionally. In summary, our studies describe 2 novel modes of action of ticagrelor, inhibition of platelet ENT1 and inverse agonism at the P2Y(12)R that contribute to its effective inhibition of platelet activation

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity