Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A : A nationwide real-world study with 700 person-years

AimFor previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). MethodsFrom the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. ResultsAll 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1years. The mean (SD) annual treatment costs (Europerkg) were 4391Euro (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383448Euro (259085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. ConclusionsEarly high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2years.Peer reviewe

Meson Correlation Function and Screening Mass in Thermal QCD

Analytical results for the spatial dependence of the correlation functions for all meson excitations in perturbative Quantum Chromodynamics, the lowest order, are calculated. The meson screening mass is obtained as a large distance limit of the correlation function. Our analysis leads to a better understanding of the excitations of Quark Gluon Plasma at sufficiently large temperatures and may be of relevance for future numerical calculations with fully interacting Quantum Chromodynamics.Comment: 11 page

A linear programming-based method for job shop scheduling

We present a decomposition heuristic for a large class of job shop scheduling problems. This heuristic utilizes information from the linear programming formulation of the associated optimal timing problem to solve subproblems, can be used for any objective function whose associated optimal timing problem can be expressed as a linear program (LP), and is particularly effective for objectives that include a component that is a function of individual operation completion times. Using the proposed heuristic framework, we address job shop scheduling problems with a variety of objectives where intermediate holding costs need to be explicitly considered. In computational testing, we demonstrate the performance of our proposed solution approach

Mesonic correlation lengths in high-temperature QCD

We consider spatial correlation lengths \xi for various QCD light quark bilinears at temperatures above a few hundred MeV. Some of the correlation lengths (such as that related to baryon density) coincide with what has been measured earlier on from glueball-like states; others do not couple to glueballs, and have a well-known perturbative leading-order expression as well as a computable next-to-leading-order correction. We determine the latter following analogies with the NRQCD effective theory, used for the study of heavy quarkonia at zero temperature: we find (for the quenched case) \xi^{-1} = 2 \pi T + 0.1408 g^2 T, and compare with lattice results. One manifestation of U_A(1) symmetry non-restoration is also pointed out.Comment: 25 pages. v2: small clarifications; published versio

Identification of the Allosteric Regulatory Site of Insulysin

Background: Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Ab peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.Principal Findings: the crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. in addition, changes in the dimer interface suggest a basis for communication between subunits.Conclusions/Significance: Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.United States Public Health ServicesUniv Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USAUniv Kentucky, Struct Biol Ctr, Lexington, KY USAUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, BrazilUnited States Public Health Services: NS38041United States Public Health Services: DA02243United States Public Health Services: DA016176United States Public Health Services: P20 RR20171United States Public Health Services: T32 DA016176Web of Scienc

Female Genitalia Concealment Promotes Intimate Male Courtship in a Water Strider

Violent coercive mating initiation is typical for animals with sexual conflict over mating. In these species, the coevolutionary arms-race between female defenses against coercive mating and male counter-adaptations for increased mating success leads to coevolutionary chases of male and female traits that influence the mating. It has been controversial whether one of the sexes can evolve traits that allow them to “win” this arms race. Here, we use morphological analysis (traditional and scanning electron micrographs), laboratory experiments and comparative methods to show how females of a species characterized by typical coercive mating initiation appear to “win” a particular stage of the sexual conflict by evolving morphology to hide their genitalia from direct, forceful access by males. In an apparent response to the female morphological adaptation, males of this species added to their typically violent coercive mounting of the female new post-mounting, pre-copulatory courtship signals produced by tapping the water's surface with the mid-legs. These courtship signals are intimate in the sense that they are aimed at the female, on whom the male is already mounted. Females respond to the signals by exposing their hidden genitalia for copulatory intromission. Our results indicate that the apparent victory of coevolutionary arms race by one sex in terms of morphology may trigger evolution of a behavioral phenotype in the opposite sex

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder