1,024 research outputs found
Book review: El Sistema: orchestrating Venezuela’s youth, by Geoffrey Baker
No full textBook review of: El Sistema: orchestrating Venezuela’s youth, by Geoffrey Baker.
New York, NY: Oxford University Press, 2014; ISBN: 9780199341559
($35.00)Publisher PD
Supplementary_material - An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of-Concept Study
No full textSupplementary_material for An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of-Concept Study by Deborah P. J., Stephen B. Duffull, James M. Faed, Geoffrey K. Isbister, and Abhishek Gulati in Clinical and Applied Thrombosis/Hemostasis</p
Comments on proteomic investigations of two Pakistani Naja snake venoms species unravel the venom complexity, posttranslational modifications, and presence of extracellular vesicles. toxins 2020, 12, 669
No full textAbstract not availableTheo Tasoulis, Tara L. Pukala and Geoffrey K. Isbiste
Antivenom treatment in arachnidism
No full textEnvenomation by arachnids causes significant medical illness worldwide. Scorpion sting is the most important arachnid envenomation causing adult morbidity and pediatric mortality. Important groups of spiders include the widow spiders (Latrodectus spp.), the recluse spiders (Loxosceles spp.), and two spiders confined to single countries: the Australian funnel web spider (Atrax and Hadronyche spp.) and the armed spider (Phoneutria spp.) from Brazil. There are four widow spider antivenoms available, including the Australian redback spider antivenom and the American black widow antivenom. Despite good in vitro animal work demonstrating effective neutralization with these antivenoms, and cross-reactivity between many species, there continues to be a reluctance to use them in some countries. They are both associated with a relatively low rate of allergic reactions. Redback antivenom is routinely used by the intramuscular route, which may not be as effective as intravenous use based on clinical experience and animal studies. Antivenoms are available for Loxosceles spp., but there is little evidence to support their effectiveness, particularly against local effects. The Australian funnel web spider causes severe neurotoxic envenomation, and antivenom appears to be effective in reported cases. An antivenom exists for the Brazilian armed spider, but is used in only a minority of cases. Many scorpion antivenoms exist worldwide, but there remains significant controversy regarding their efficacy. Animal and human venom level studies demonstrate neutralization of circulating venom in systemic envenomation. Clinical experience in countries where antivenom has been introduced suggests it has reduced pediatric mortality. However, three controlled trials demonstrated that antivenom was not effective, but these included few severe cases. Until controlled trials of antivenom in systemically envenomated patients are undertaken, antivenom use appears justified in severe envenomation. Although envenomation from arthropods is common, no antivenoms exist for these, excepting Lonomia caterpillars in South America, and Ixodes paralysis ticks in Australia.Andis Graudins, Geoffrey K. Isbister, David Warrell and Julian Whit
A Review and Database of Snake Venom Proteomes
No full textAdvances in the last decade combining transcriptomics with established proteomics methods have made possible rapid identification and quantification of protein families in snake venoms. Although over 100 studies have been published, the value of this information is increased when it is collated, allowing rapid assimilation and evaluation of evolutionary trends, geographical variation, and possible medical implications. This review brings together all compositional studies of snake venom proteomes published in the last decade. Compositional studies were identified for 132 snake species: 42 from 360 (12%) Elapidae (elapids), 20 from 101 (20%) Viperinae (true vipers), 65 from 239 (27%) Crotalinae (pit vipers), and five species of non-front-fanged snakes. Approximately 90% of their total venom composition consisted of eight protein families for elapids, 11 protein families for viperines and ten protein families for crotalines. There were four dominant protein families: phospholipase A2s (the most common across all front-fanged snakes), metalloproteases, serine proteases and three-finger toxins. There were six secondary protein families: cysteine-rich secretory proteins, l-amino acid oxidases, kunitz peptides, C-type lectins/snaclecs, disintegrins and natriuretic peptides. Elapid venoms contained mostly three-finger toxins and phospholipase A2s and viper venoms metalloproteases, phospholipase A2s and serine proteases. Although 63 protein families were identified, more than half were present in <5% of snake species studied and always in low abundance. The importance of these minor component proteins remains unknown
Application of pharmacometric methods to understand warfarin dose response
No full textExisting warfarin dosing methods do not accurately predict warfarin maintenance doses for patients in the lower or upper quartile of dose requirements. It was argued that this is related to the use of the international normalised ratio (INR) as a sole marker of anticoagulation for warfarin dose individualisation. The overarching premise of this thesis was that the coagulation proteins are on the causal path from warfarin dose to INR response and that a measure of coagulation protein response in addition to the INR will be helpful in the prediction of future anticoagulant response. The aim of this thesis was to apply pharmacometric methods to understand the coagulation kinetics underpinning the warfarin dose response and to introduce a new perspective to the prediction of anticoagulant response to warfarin.
A joint model was developed to quantify the influence of warfarin on all six vitamin K-dependent coagulation proteins (factors II, VII, IX, X, and proteins C and S) simultaneously. The full correlation structures that exist between parameters at the individual level and between residual errors of different coagulation proteins were accounted for. Of all the coagulation proteins considered, factor VII was found to have the shortest degradation half-life and will therefore be the first to reach a new steady-state following a perturbation introduced by warfarin.
Subsequently, the influence of coagulation proteins and their interactions on the INR was explored based on simulations from a mechanistic coagulation network model. A sensitivity analysis revealed that INR is most sensitive to factor VII and an isobologram analysis demonstrated that the presence of more than one coagulation protein deficiencies is redundant for INR effect. It was proposed that factor VII is the most influential on the INR and that the use of factor VII as a marker of anticoagulation (in addition to the INR) may improve the prediction of the anticoagulant response.
A factor VII-based method for the prediction of anticoagulant response to warfarin was developed based on a heuristic model-order reduction of the coagulation network model. The prediction method was shown to be associated with minimal bias and its use was illustrated using data from one typical simulated patient and two real patients supporting a proof-of-principle.
Finally, a framework for systematic evaluation of model assumptions was developed. In particular, a flowchart was proposed to evaluate assumptions based on the impact and the probability of assumption violation. The assumptions underpinning the pharmacometric analyses presented in this thesis were evaluated and used to illustrate the utility of the proposed framework.
In this thesis, both the top-down and bottom-up pharmacometric analyses were applied to explore the coagulation kinetics underpinning warfarin dose response. Standard methods such as population analysis, model simulations, isobologram analysis, and sensitivity analysis were employed. A heuristic model-order reduction method was experimented and seemed to work well although generalisation of the method to other settings requires prospective testing.
The work conducted in this thesis offered a new perspective on the prediction of anticoagulant response. The next step would be to extend the current method to the prediction of warfarin maintenance dose. This would require setting up and evaluating a dose individualisation algorithm (perhaps Bayesian) that incorporates a factor VII-INR bivariate response variable. Last but not least, a framework for systematic evaluation of assumptions was proposed. An important future step would be to apply the framework to a series of other settings to fully explore the utility and robustness of the framework to different model-building processes and model use settings
Application of pharmacometric methods to understand warfarin dose response
No full textExisting warfarin dosing methods do not accurately predict warfarin maintenance doses for patients in the lower or upper quartile of dose requirements. It was argued that this is related to the use of the international normalised ratio (INR) as a sole marker of anticoagulation for warfarin dose individualisation. The overarching premise of this thesis was that the coagulation proteins are on the causal path from warfarin dose to INR response and that a measure of coagulation protein response in addition to the INR will be helpful in the prediction of future anticoagulant response. The aim of this thesis was to apply pharmacometric methods to understand the coagulation kinetics underpinning the warfarin dose response and to introduce a new perspective to the prediction of anticoagulant response to warfarin.
A joint model was developed to quantify the influence of warfarin on all six vitamin K-dependent coagulation proteins (factors II, VII, IX, X, and proteins C and S) simultaneously. The full correlation structures that exist between parameters at the individual level and between residual errors of different coagulation proteins were accounted for. Of all the coagulation proteins considered, factor VII was found to have the shortest degradation half-life and will therefore be the first to reach a new steady-state following a perturbation introduced by warfarin.
Subsequently, the influence of coagulation proteins and their interactions on the INR was explored based on simulations from a mechanistic coagulation network model. A sensitivity analysis revealed that INR is most sensitive to factor VII and an isobologram analysis demonstrated that the presence of more than one coagulation protein deficiencies is redundant for INR effect. It was proposed that factor VII is the most influential on the INR and that the use of factor VII as a marker of anticoagulation (in addition to the INR) may improve the prediction of the anticoagulant response.
A factor VII-based method for the prediction of anticoagulant response to warfarin was developed based on a heuristic model-order reduction of the coagulation network model. The prediction method was shown to be associated with minimal bias and its use was illustrated using data from one typical simulated patient and two real patients supporting a proof-of-principle.
Finally, a framework for systematic evaluation of model assumptions was developed. In particular, a flowchart was proposed to evaluate assumptions based on the impact and the probability of assumption violation. The assumptions underpinning the pharmacometric analyses presented in this thesis were evaluated and used to illustrate the utility of the proposed framework.
In this thesis, both the top-down and bottom-up pharmacometric analyses were applied to explore the coagulation kinetics underpinning warfarin dose response. Standard methods such as population analysis, model simulations, isobologram analysis, and sensitivity analysis were employed. A heuristic model-order reduction method was experimented and seemed to work well although generalisation of the method to other settings requires prospective testing.
The work conducted in this thesis offered a new perspective on the prediction of anticoagulant response. The next step would be to extend the current method to the prediction of warfarin maintenance dose. This would require setting up and evaluating a dose individualisation algorithm (perhaps Bayesian) that incorporates a factor VII-INR bivariate response variable. Last but not least, a framework for systematic evaluation of assumptions was proposed. An important future step would be to apply the framework to a series of other settings to fully explore the utility and robustness of the framework to different model-building processes and model use settings
Current treatment for venom-induced consumption coagulopathy resulting from snakebite.
No full textVenomous snakebite is considered the single most important cause of human injury from venomous animals worldwide. Coagulopathy is one of the commonest important systemic clinical syndromes and can be complicated by serious and life-threatening haemorrhage. Venom-induced consumption coagulopathy (VICC) is the commonest coagulopathy resulting from snakebite and occurs in envenoming by Viperid snakes, certain elapids, including Australian elapids, and a few Colubrid (rear fang) snakes. Procoagulant toxins activate the clotting pathway, causing a broad range of factor deficiencies depending on the particular procoagulant toxin in the snake venom. Diagnosis and monitoring of coagulopathy is problematic, particularly in resource-poor countries where further research is required to develop more reliable, cheap clotting tests. MEDLINE and EMBASE up to September 2013 were searched to identify clinical studies of snake envenoming with VICC. The UniPort database was searched for coagulant snake toxins. Despite preclinical studies demonstrating antivenom binding toxins (efficacy), there was less evidence to support clinical effectiveness of antivenom for VICC. There were no placebo-controlled trials of antivenom for VICC. There were 25 randomised comparative trials of antivenom for VICC, which compared two different antivenoms (ten studies), three different antivenoms (four), two or three different doses or repeat doses of antivenom (five), heparin treatment and antivenom (five), and intravenous immunoglobulin treatment and antivenom (one). There were 13 studies that compared two groups in which there was no randomisation, including studies with historical controls. There have been numerous observational studies of antivenom in VICC but with no comparison group. Most of the controlled trials were small, did not use the same method for assessing coagulopathy, varied the dose of antivenom, and did not provide complete details of the study design (primary outcomes, randomisation, and allocation concealment). Non-randomised trials including comparison groups without antivenom showed that antivenom was effective for some snakes (e.g., Echis), but not others (e.g., Australasian elapids). Antivenom is the major treatment for VICC, but there is currently little high-quality evidence to support effectiveness. Antivenom is not risk free, and adverse reactions can be quite common and potentially severe. Studies of heparin did not demonstrate it improved outcomes in VICC. Fresh frozen plasma appeared to speed the recovery of coagulopathy and should be considered in bleeding patients
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