Deciding the First Levels of the Modal mu Alternation Hierarchy by Formula Construction

We construct, for any sentence of the modal mu calculus Psi, derived sentences in the modal fragment and the fragment without least fixpoints of the modal mu calculus such that Psi is equivalent to a formula in these fragments if and only if it is equivalent to these formulas. The formula without greatest fixpoints that Psi is equivalent to if and only if it is equivalent to any formula without greatest fixpoint is obtained by duality. This yields a constructive proof of decidability of the first levels of the modal mu alternation hierarchy. The blow-up incurred by turning Psi into the modal formula is shown to be necessary: there are modal formulas that can be expressed sub-exponentially more efficiently with the use of fixpoints. For the fragments with only greatest or least fixpoints however, as long as formulas are in disjunctive form, the transformation into a formula syntactically in these fragments does not increase the size of the formula

Permeability of a one-dimensional potential barrier

Permeability of one dimensional potential barrie

Estimating capacity and resource allocation in healthcare settings using business process modelling and simulation

Healthcare involves complex decision making from planning to resource management. Resources in hospitals are usually allocated by experienced managers,however, due to an inherent process complexity, decisions are surrounded by uncertainties, variabilities, and constraints. Information Systems must be robust enough to provide support to stakeholders, capable of controlling and support work flows. The present work explores the required synergy when combining business processes with discrete event simulation. The objective is to estimate performance indices and address capacity management of a surgical center as a case study.Postprin

Transfinite Extension of the Mu-Calculus

In [1] Bradfield found a link between finite differences formed by Sigma(2)(0) sets and the mu-arithmetic introduced by Lubarski [7]. We extend this approach into the transfinite: in allowing countable disjunctions we show that this kind of extended mu-calculus matches neatly to the transfinite difference hierarchy of E-2(0) sets. The difference hierarchy is intimately related to parity games. When passing to infinitely many priorities, it might not longer be true that there is a positional winning strategy. However, if such games are derived from the difference hierarchy, this property still holds true

Persistence of Middle Stone Age technology to the Pleistocene/Holocene transition supports a complex hominin evolutionary scenario in West Africa

The evolutionary origins of Homo sapiens and associated behavioural changes are increasingly seen as complex processes, involving multiple regions of Africa. In West Africa, Terminal Pleistocene/Holocene aged human fossils, demonstrating the late continuity of archaic morphological features in the region have been linked to models of surprisingly recent admixture processes between late archaic hominins and H. sapiens. However, the limited chronological resolution of the archaeological record has prevented evaluation of how these biological records relate to patterns of behaviour. Here, we provide a preliminary report of the first excavated and dated Stone Age site in northern Senegal which features the youngest Middle Stone Age (MSA) technology yet documented in Africa. Ndiayène Pendao features classic MSA core axes, basally thinned flakes, Levallois points and denticulates mostly made from chert. Similar technological features characterise several, larger surface sites in the vicinity. From this, it is postulated that populations using ‘anachronistic’ technologies in the Lower Senegal Valley around the transition to the Holocene may have been widespread, in sharp contrast to other areas of Senegal and West Africa. The chronology and technology of Ndiayène Pendao provides the first cultural evidence to support a complex evolutionary history in West Africa. This is consistent with a persistently high degree of Pleistocene population substructure in Africa and the spatially and temporally complex character of behavioural and biological evolution

CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+\u2009ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+\u2009ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6,809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes

Objectives: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- A nd older-onset patients are still incompletely understood. Methods: We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results: A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Conclusion: Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA