Ximelagatran: Direct Thrombin Inhibitor

Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with “long-term” use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction

A bulk manifestation of Krylov complexity

There are various definitions of the concept of complexity in Quantum Field Theory as well as for finite quantum systems. For several of them there are conjectured holographic bulk duals. In this work we establish an entry in the AdS/CFT dictionary for one such class of complexity, namely Krylov or K-complexity. For this purpose we work in the double-scaled SYK model which is dual in a certain limit to JT gravity, a theory of gravity in AdS$_2$. In particular, states on the boundary have a clear geometrical definition in the bulk. We use this result to show that Krylov complexity of the infinite-temperature thermofield double state on the boundary of AdS$_2$ has a precise bulk description in JT gravity, namely the length of the two-sided wormhole. We do this by showing that the Krylov basis elements, which are eigenstates of the Krylov complexity operator, are mapped to length eigenstates in the bulk theory by subjecting K-complexity to the bulk-boundary map identifying the bulk/boundary Hilbert spaces. Our result makes extensive use of chord diagram techniques and identifies the Krylov basis of the boundary quantum system with fixed chord number states building the bulk gravitational Hilbert space.Comment: v1: 37 pages + appendices, 12 figures. v2: published versio

A study on scaling up latrine and human excreta management in rural communities of Afghanistan

The overall objective of the study was to identify the trends of scaling up latrine construction and excreta management in rural communities of Afghanistan. A total of 418 households were visited and interviewed and 30 focus group discussions were conducted. The study found that a total of 93.6% of the households had some form of a latrine, of which 47.5% of the latrines were improved and newly constructed since 2010 and only 42% the observed latrines were hygienic or safe. Ninety per cent of the interviewees said that all members of the family are using the latrine all the time. Seventy percent of latrine owners bury excreta nearby lands or yard for awhile and then use it as fertilizer. Trends of latrine scaling up were occurred more in IDPs and returnees settlements

Behavioral reconsolidation interference with episodic memory within-subjects is elusive.

In studies of behavioral reconsolidation interference, reactivation of a consolidated memory using some form of reminder is followed by the presentation of new information that can cause interference with that memory. Under these conditions, the interference not only impairs retrieval by indirect processes such as cue interference, but supposedly disrupts the original memory trace directly. Almost all studies of behavioral reconsolidation interference in episodic memory in humans have employed between-subjects paradigms, and deduced reminder effects from intrusion errors. Such studies might introduce confounds arising, for example, from differences in retrieval strategies engendered by the pre-test treatments. We therefore set out to examine whether behavioral reconsolidation interference in episodic memory might be demonstrated within-subjects and by direct memory strength rather than intrusion errors. In three separate experiments, we attempted to disrupt reconsolidation of episodic object-picture memory using a reminder + retroactive interference manipulation. We applied the manipulation over three consecutive days, using a forced-choice recognition test without intrusions from interfering learning, keeping all other study and test parameters constant. No effects of reminder-potentiated interference were observed for measures of accuracy, response times, subjective expressions of recollection, or levels of confidence, as substantiated by Bayesian analyses. These results highlight the difficulty of observing clear behavioral reconsolidation interference effects within-subjects in human episodic memory, and provide some indications of what might be boundary conditions for its demonstration

The 2010 American college of rheumatology fibromyalgia survey diagnostic criteria and symptom severity scale is a valid and reliable tool in a French speaking fibromyalgia cohort

BACKGROUND: Fibromyalgia (FM) is a pain condition with associated symptoms contributing to distress. The Fibromyalgia Survey Diagnostic Criteria and Severity Scale (FSDC) is a patient-administered questionnaire assessing diagnosis and symptom severity. Locations of body pain measured by the Widespread Pain Index (WPI), and the Symptom Severity scale (SS) measuring fatigue, unrefreshing sleep, cognitive and somatic complaints provide a score (0–31), measuring a composite of polysymptomatic distress. The reliability and validity of the translated French version of the FSDC was evaluated. METHODS: The French FSDC was administered twice to 73 FM patients, and was correlated with measures of symptom status including: Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ), McGill Pain Questionnaire (MPQ), and a visual analogue scale (VAS) for global severity and pain. Test-retest reliability, internal consistency, and construct validity were evaluated. RESULTS: Test-retest reliability was between .600 and .888 for the 25 single items of the FSDC, and .912 for the total FSDC, with all correlations significant (p < 0.0001). There was good internal consistency measured by Cronbach’s alpha (.846 for FSDC assessment 1, and .867 for FSDC assessment 2). Construct validity showed significant correlations between the FSDC and FIQ 0.670, HAQ 0.413, MPQ 0.562, global VAS 0.591, and pain VAS 0.663 (all p<0.001). CONCLUSIONS: The French FSDC is a valid instrument in French FM patients with reliability and construct validity. It is easily completed, simple to score, and has the potential to become the standard for measurement of polysymptomatic distress in FM

Numerical and Analytical Modeling of Aligned Short Fiber Composites including Imperfect Interfaces

Finite element calculations were used to bound the modulus of aligned, short-fiber composites with randomly arranged fibers, including high fiber to matrix modulus ratios and high fiber aspect ratios. The bounds were narrow for low modulus ratio, but far apart for high ratio. These numerical experiments were used to evaluate prior numerical and analytical methods for modeling short-fiber composites. Prior numerical methods based on periodic boundary conditions were revealed as acceptable for low modulus ratio, but degenerate to lower bound modulus at high ratio. Numerical experiments were also compared to an Eshelby analysis and to an new, enhanced shear lag model. Both models could predict modulus for low modulus ratio, but also degenerated to lower bound modulus at high ratio. The new shear lag model accounts for stress transfer on fiber ends and includes imperfect interface effects; it was confirmed as accurate by comparison to finite element calculations.Keywords: Elasticity, Finite element analysis (FEA), Elastic properties, Interface/interphase, Discontinuous reinforcement, Short-fiber compositesKeywords: Elasticity, Finite element analysis (FEA), Elastic properties, Interface/interphase, Discontinuous reinforcement, Short-fiber composite

The Birth and Death of Toxins with Distinct Functions: A Case Study in the Sea Anemone Nematostella

The cnidarian Nematostella vectensis has become an established lab model, providing unique opportunities for venom evolution research. The Nematostella venom system is multimodal: involving both nematocytes and ectodermal gland cells, which produce a toxin mixture whose composition changes throughout the life cycle. Additionally, their modes of interaction with predators and prey vary between eggs, larvae, and adults, which is likely shaped by the dynamics of the venom system. Nv1 is a major component of adult venom, with activity against arthropods (through specific inhibition of sodium channel inactivation) and fish. Nv1 is encoded by a cluster of at least 12 nearly identical genes that were proposed to be undergoing concerted evolution. Surprisingly, we found that Nematostella venom includes several Nv1 paralogs escaping a pattern of general concerted evolution, despite belonging to the Nv1-like family. Here, we show two of these new toxins, Nv4 and Nv5, are lethal for zebrafish larvae but harmless to arthropods, unlike Nv1. Furthermore, unlike Nv1, the newly identified toxins are expressed in early life stages. Using transgenesis and immunostaining, we demonstrate that Nv4 and Nv5 are localized to ectodermal gland cells in larvae. The evolution of Nv4 and Nv5 can be described either as neofunctionalization or as subfunctionalization. Additionally, the Nv1-like family includes several pseudogenes being an example of nonfunctionalization and venom evolution through birth-and-death mechanism. Our findings reveal the evolutionary history for a toxin radiation and point toward the ecological function of the novel toxins constituting a complex cnidarian venom.publishedVersio