A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient

A central challenge in designing and administering effective anticoagulants is achieving the proper therapeutic window and dosage for each patient. The Hill coefficient, nH, which measures the steepness of a dose-response relationship, may be a useful gauge of this therapeutic window. We sought to measure the Hill coefficient of available anticoagulants to gain insight into their therapeutic windows. We used a simple fluorometric in vitro assay to determine clotting activity in platelet poor plasma after exposure to various concentrations of anticoagulants. The Hill coefficient for argatroban was the lowest, at 1.7±0.2 (95% confidence interval, CI), and the Hill coefficient for fondaparinux was the highest, at 4.5±1.3 (95% CI). Thus, doubling the dose of fondaparinux from its IC50 would decrease coagulation activity by nearly a half, whereas doubling the dose of argatroban from its IC50 would decrease coagulation activity by merely one quarter. These results show a significant variation among the Hill coefficients, suggesting a similar variation in therapeutic windows among anticoagulants in our assay

Composite Fermion Metals from Dyon Black Holes and S-Duality

We propose that string theory in the background of dyon black holes in four-dimensional anti-de Sitter spacetime is holographic dual to conformally invariant composite Dirac fermion metal. By utilizing S-duality map, we show that thermodynamic and transport properties of the black hole match with those of composite fermion metal, exhibiting Fermi liquid-like. Built upon Dirac-Schwinger-Zwanziger quantization condition, we argue that turning on magnetic charges to electric black hole along the orbit of Gamma(2) subgroup of SL(2,Z) is equivalent to attaching even unit of statistical flux quanta to constituent fermions. Being at metallic point, the statistical magnetic flux is interlocked to the background magnetic field. We find supporting evidences for proposed holographic duality from study of internal energy of black hole and probe bulk fermion motion in black hole background. They show good agreement with ground-state energy of composite fermion metal in Thomas-Fermi approximation and cyclotron motion of a constituent or composite fermion excitation near Fermi-point.Comment: 30 pages, v2. 1 figure added, minor typos corrected; v3. revised version to be published in JHE

Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: Global survey of the practices of neurologists, neurosurgeons and thrombosis experts

<div><p>Background</p><p>While oral anticoagulants (OACs) are highly effective for ischemic stroke prevention in atrial fibrillation, intracerebral hemorrhage (ICH) remains the most feared complication of OAC. Clinical controversy remains regarding OAC resumption and its timing for ICH survivors with atrial fibrillation because the balance between risks and benefits has not been investigated in randomized trials.</p><p>Aims/Hypothesis</p><p>To survey the practice of stroke neurologists, thrombosis experts and neurosurgeons on OAC re-initiation following OAC-associated ICH.</p><p>Methods</p><p>An online survey was distributed to members of the International Society for Thrombosis and Haemostasis, Canadian Stroke Consortium, NAVIGATE-ESUS trial investigators (Clinicatrials.gov identifier NCT02313909) and American Association of Neurological Surgeons. Demographic factors and 11 clinical scenarios were included.</p><p>Results</p><p>Two hundred twenty-eight participants from 38 countries completed the survey. Majority of participants were affiliated with academic centers, and >20% managed more than 15 OAC-associated ICH patients/year. Proportion of respondents suggesting OAC anticoagulant resumption varied from 30% (for cerebral amyloid angiopathy) to 98% (for traumatic ICH). Within this group, there was wide distribution in response for timing of resumption: 21.4% preferred to re-start OACs after 1–3 weeks of incident ICH, while 25.3% opted to start after 1–3 months. Neurosurgery respondents preferred earlier OAC resumption compared to stroke neurologists or thrombosis experts in 5 scenarios (p<0.05 by Kendall’s tau).</p><p>Conclusions</p><p>Wide variations in current practice exist among management of OAC-associated ICH, with decisions influenced by patient- and provider-related factors. As these variations likely reflect the lack of high quality evidence, randomized trials are direly needed in this population.</p></div

Estimating the role of casual contact from the community in transmission of Bordetella pertussis to young infants

The proportion of infant pertussis cases due to transmission from casual contact in the community has not been estimated since before the introduction of pertussis vaccines in the 1950s. This study aimed to estimate the proportion of pertussis transmission due to casual contact using demographic and clinical data from a study of 95 infant pertussis cases and their close contacts enrolled at 14 hospitals in France, Germany, Canada, and the U.S. between February 2003 and September 2004. A complete case analysis was conducted as well as multiple imputation (MI) to account for missing data for participants and close contacts who did not participate. By considering all possible close contacts, the MI analysis estimated 66% of source cases were close contacts, implying the minimum attributable proportion of infant cases due to transmission from casual contact with community members was 34% (95% CI = 24%, 44%). Estimates from the complete case analysis were comparable but less precise. Results were sensitive to changes in the operational definition of a source case, which broadened the range of MI point estimates of transmission from casual community contact to 20%–47%. We conclude that casual contact appears to be responsible for a substantial proportion of pertussis transmission to young infants

Dronedarone in high-risk permanent atrial fibrillation

BACKGROUND: Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. METHODS: We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. RESULTS: After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P = 0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P = 0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P = 0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P = 0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P = 0.02). CONCLUSIONS: Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.) Copyright © 2011 Massachusetts Medical Society. All rights reserved.published_or_final_versio

Development and psychometric testing of an instrument to compare career choice influences and perceptions of nursing among healthcare students

Background: With the availability of more healthcare courses and an increased intake of nursing students, education institutions are facing challenges to attract school leavers to enter nursing courses. The comparison of career choice influences and perception of nursing among healthcare students can provide information for recruitment strategies. An instrument to compare the influences of healthcare career choice is lacking. The purpose of this study is to develop and evaluate the psychometric properties of an instrument to compare the influences of healthcare career choice with perceptions of nursing as a career choice. Methods: The study was conducted in two phases. In phase one, two sets of scales with parallel items that measure the influences of healthcare career choice and perceptions of nursing as a career choice were developed through an earlier qualitative study, literature review, and expert validation. Phase two involved testing the construct validity, concurrent validity and reliability with a convenience sample of 283 first year healthcare students who were recruited at two education institutions in Singapore. Results: An exploratory factor analysis revealed 35-parallel items in a six-factor solution (personal interest, prior healthcare exposure, self-efficacy, perceived nature of work, job prospects, and social influences) that explained 59 and 64% of the variance for healthcare career choice and nursing as a career choice respectively. A high correlation (r = 0.76, p \u3c 0.001) was obtained with an existing tool, confirming the concurrent validity. The internal consistency was sufficient with Cronbach’s alpha of 0.93 for healthcare career choice and 0.94 for nursing as a career choice. The test-retest reliability was acceptable with an Intraclass Correlation Coefficient of 0.63 for healthcare career choice and 0.60 for nursing as a career choice. Conclusions: The instrument provides opportunities for understanding the differences between influences of healthcare career choice and perceptions of nursing as a career choice. This comparative understanding of career choice influences can guide educator and policy-makers on nursing recruitmen

Protein binding hot spots and the residue-residue pairing preference: a water exclusion perspective

<p>Abstract</p> <p>Background</p> <p>A protein binding hot spot is a small cluster of residues tightly packed at the center of the interface between two interacting proteins. Though a hot spot constitutes a small fraction of the interface, it is vital to the stability of protein complexes. Recently, there are a series of hypotheses proposed to characterize binding hot spots, including the pioneering O-ring theory, the insightful 'coupling' and 'hot region' principle, and our 'double water exclusion' (DWE) hypothesis. As the perspective changes from the O-ring theory to the DWE hypothesis, we examine the physicochemical properties of the binding hot spots under the new hypothesis and compare with those under the O-ring theory.</p> <p>Results</p> <p>The requirements for a cluster of residues to form a hot spot under the DWE hypothesis can be mathematically satisfied by a biclique subgraph if a vertex is used to represent a residue, an edge to indicate a close distance between two residues, and a bipartite graph to represent a pair of interacting proteins. We term these hot spots as DWE bicliques. We identified DWE bicliques from crystal packing contacts, obligate and non-obligate interactions. Our comparative study revealed that there are abundant <it>unique </it>bicliques to the biological interactions, indicating specific biological binding behaviors in contrast to crystal packing. The two sub-types of biological interactions also have their own signature bicliques. In our analysis on residue compositions and residue pairing preferences in DWE bicliques, the focus was on interaction-preferred residues (ipRs) and interaction-preferred residue pairs (ipRPs). It is observed that hydrophobic residues are heavily involved in the ipRs and ipRPs of the obligate interactions; and that aromatic residues are in favor in the ipRs and ipRPs of the biological interactions, especially in those of the non-obligate interactions. In contrast, the ipRs and ipRPs in crystal packing are dominated by hydrophilic residues, and most of the anti-ipRs of crystal packing are the ipRs of the obligate or non-obligate interactions.</p> <p>Conclusions</p> <p>These ipRs and ipRPs in our DWE bicliques describe a diverse binding features among the three types of interactions. They also highlight the specific binding behaviors of the biological interactions, sharply differing from the artifact interfaces in the crystal packing. It can be noted that DWE bicliques, especially the unique bicliques, can capture deep insights into the binding characteristics of protein interfaces.</p