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Venom-induced consumption coagulopathy (VICC) is one of the most dangerous syndromes caused by snake envenomation and can be caused by several snake species worldwide, including the Australian coastal taipan. Rotational thromboelastometry (ROTEM) provides real-time point-of-care information on all stages of clot formation; however, it has yet to be formally evaluated in the assessment of VICC. We report three cases of Taipan envenomation causing VICC and the associated ROTEM results. The implications for future use of ROTEM in the assessment, management, and further research of VICC are discussed.

Background Lupus anticoagulant (LA) assays are compromised in anticoagulated patients, and existing strategies to overcome the interferences have limitations. The prothrombin-activating Taipan snake venom time (TSVT) screening test and ecarin time (ET) confirmatory test are innately insensitive to vitamin K antagonists (VKA) and direct factor Xa inhibitors (DFXaI). Objectives Validate standardised TSVT/ET reagents for LA detection, in a multi-centre, multi-platform study. Patients/Methods Six centres from four countries analysed samples with TSVT/ET from 81 non-anticoagulated patients with LA, patients with established antiphospholipid syndrome (APS) and proven persistent LA who were either not anticoagulated (n=120) or were anticoagulated with VKAs (n=180) or DFXaIs (n=71). Additionally, 339 non-anticoagulated LA-negative patients, and 575 anticoagulated non-APS patients (172 VKA, 403 DFXaI) were tested. Anticoagulant spiking experiments were performed and 112 samples containing potential interferences (i.e. direct thrombin inhibitors) were tested. Results were evaluated against locally derived cut-offs. Imprecision was evaluated. Results Cut-offs were remarkably similar despite use of different analysers and donor populations. Cut-offs for TSVT ratio, ET ratio, percent correction and normalised TSVT ratio/ET ratio ranged between 1.08-1.10, 1.09-1.12, 9.3%-14.8% and 1.10-1.15 respectively. Coefficients of variation for TSVT and ET ratios were ≤5.0%. TSVT/ET exhibited sensitivity, specificity, negative and positive predictive values of 78.2%/95.0%/86.3%/91.5% respectively with established APS as the LA-positive population, and 86.9%/95.0%/76.8%/97.4% respectively with triple-positive APS. Interference was seen with direct thrombin inhibitors, unfractionated heparin and low molecular weight heparins, but not VKAs or DFXaIs. Conclusions TSVT/ET are validated for LA detection in non-anticoagulated patients and those on VKAs or DFXaIs.

Snakebite is a neglected tropical disease that disproportionately affects the poor. Antivenom is the only specific and effective treatment for snakebite, but its distribution is severely limited by several factors, including the prohibitive cost of some products. Papua New Guinea (PNG) is a snakebite hotspot but the high costs of Australian antivenoms (thousands of dollars per treatment) makes it unaffordable in PNG. A more economical taipan antivenom has recently been developed at the Instituto Clodomiro Picado (ICP) in Costa Rica for PNG and is currently undergoing clinical trials for the treatment of envenomations by coastal taipans (Oxyuranus scutellatus). In addition to potentially having the capacity to neutralise the effects of envenomations of non-PNG taipans, this antivenom may have the capacity to neutralise coagulotoxins in venom from closely related brown snakes (Pseudonaja spp.) also found in PNG. Consequently, we investigated the cross-reactivity of taipan antivenom across the venoms of all Oxyuranus and Pseudonaja species. In addition, to ascertain differences in venom biochemistry that influence variation in antivenom efficacy, we tested for relative cofactor dependence. We found that the new ICP taipan antivenom exhibited high selectivity for Oxyuranus venoms and only low to moderate cross-reactivity with any Pseudonaja venoms. Consistent with this genus level distinction in antivenom efficacy were fundamental differences in the venom biochemistry. Not only were the Pseudonaja venoms significantly more procoagulant, but they were also much less dependent upon the cofactors calcium and phospholipid. There was a strong correlation between antivenom efficacy, clotting time and cofactor dependence. This study sheds light on the structure-function relationships of the procoagulant toxins within these venoms and may have important clinical implications including for the design of next-generation antivenoms.

Coastal taipan (Oxyuranus scutellatus) envenoming causes life-threatening neuromuscular paralysis in humans. We studied the time period during which antivenom remains effective in preventing and arresting in vitro neuromuscular block caused by taipan venom and taipoxin. Venom showed predominant pre-synaptic neurotoxicity at 3 &micro, g/mL and post-synaptic neurotoxicity at 10 &micro, g/mL. Pre-synaptic neurotoxicity was prevented by addition of Australian polyvalent antivenom before the venom and taipoxin and, reversed when antivenom was added 5 min after venom and taipoxin. Antivenom only partially reversed the neurotoxicity when added 15 min after venom and had no significant effect when added 30 min after venom. In contrast, post-synaptic activity was fully reversed when antivenom was added 30 min after venom. The effect of antivenom on pre-synaptic neuromuscular block was reproduced by washing the bath at similar time intervals for 3 &micro, g/mL, but not for 10 &micro, g/mL. We found an approximate 10&ndash, 15 min time window in which antivenom can prevent pre-synaptic neuromuscular block. This time window is likely to be longer in envenomed patients due to the delay in venom absorption. Similar effectiveness of antivenom and washing with 3 &micro, g/mL venom suggests that antivenom most likely acts by neutralizing pre-synaptic toxins before they interfere with neurotransmission inside the motor nerve terminals.

Die Stanford Typ A Aortendissektion zählt aufgrund ihrer hohen Komplikationsrate und damit verbundenen Mortalität zu den herz- und gefäßchirurgischen Notfällen. Neben den klassischen Risikofaktoren, wie z.B. der arteriellen Hypertonie, gilt die Dilatation der Aorta als einziger etablierter morphologischer Risikofaktor. Folglich wird bei einer Dilatation von über 55 mm die Indikation zum prophylaktischen Aortenersatz gestellt. Der prophylaktische Therapieansatz ist bzgl. der Mortalität den notfallmäßigen Therapieverfahren in der Akutsituation deutlich überlegen. Nun wurde jedoch nachgewiesen, dass ein Großteil der TAD-Patienten diesen Grenzwert nicht erreicht. Das Screening der Patienten ist demnach ineffizient. Um eine höhere Sensitivität bei der Indikationsstellung zu erreichen, empfiehlt sich eine Erweiterung der Screening- Parameter. In einer vorangehenden Studie wurde die Aufnahme des Parameters „Elongation der Aorta ascendens“ diskutiert. Die Beteiligung der Elongation an der Entstehung einer Dissektion ist insofern plausibel, als dass der meist vorliegende Intimaeinriss in seinem horizontalen Verlauf physikalisch eine axial wirkende Kraft nahelegt. Ferner wird eine Elongation in disseziierten Aorten klinisch häufig beobachtet. In der erwähnten Studie wurde eine solche Elongation bei den TAD-Patienten in einer zweidimensionalen Bildgebung nachgewiesen. Die vorliegende Arbeit überprüft nun, welche Rolle eine Elongation der Aorta ascendens in disseziierten Aorten spielt und ob die Aufnahme des genannten Parameters zu einer Erhöhung der Test-Sensitivität führt. Dazu wurden drei unabhängige Studiengruppen gebildet, in denen anhand von CTA- Aufnahmen die Aortendimensionen dreidimensional vermessen und analysiert wurden: eine aortengesunde Kontrollgruppe (n = 215), eine präTAD-Gruppe mit Patienten kurz vor Auftreten einer Aortendissektion (n = 15) und eine TAD-Gruppe (n = 150). Neben den Aortendimensionen wurden anthropometrische (Körpergröße, -gewicht, BMI, KOF), demographische (Alter und Geschlecht) und klinische (arterielle Hypertonie) Daten erhoben. In der Studienpopulation wurde eine signifikante Korrelation zwischen dem Patientenalter und den Aortendimensionen nachgewiesen. Dabei fiel eine moderate Korrelation zwischen dem Durchmesser der Aorta ascendens und dem Alter der Patienten auf. Ferner konnte eine signifikante Korrelation des Alters mit der Länge der aufsteigenden Aorta und des distalen Aortenbogens nachgewiesen werden. Die Aortendimensionen korrelierten nicht mit den erhobenen anthropometrischen Daten.Demnach ist eine altersadjustierte Bewertung der Aortendimensionen sinnvoll, eine größen- oder gewichtsabhängige Interpretation jedoch nicht. In der präTAD- und TAD- Gruppe litten signifikant mehr Patienten an einer arteriellen Hypertonie als in der Kontrollgruppe. Da die Hypertoniker jedoch im Durchschnitt 15 Jahre älter waren als die normotensiven Patienten, war es methodisch nicht möglich, den Einfluss des Alters vom Einfluss der Hypertonie auf die Aortenmorphologie zu trennen. Der Durchmesser der Aorta war in der präTAD- und TAD-Gruppe in jedem Messpunkt signifikant höher als in der Kontrollgruppe. Am deutlichsten war der Unterschied in der Aorta ascendens. Hier lag der mediane Durchmesser in den drei Gruppen bei 34,6 mm, 43,2 mm und 50,0 mm. Der signifikante Diameterzuwachs von der präTAD- zur TAD-Gruppe legt eine Dilatation im akuten Prozess der Dissektion nahe. Eine nach der Dissektion diagnostizierte deutliche Dilatation ist also ggf. vor der Dissektion noch nicht indikationsstellend für eine prophylaktische Operation. Den Grenzwert des Aortendurchmessers von 55 mm erreichten 0% der Kontrollgruppe, 7% der präTAD- Gruppe und nur 33% der TAD-Gruppe. Die ROC-Analyse zeigte, dass dieser Grenzwert in unserer Studienpopulation nur mit einer Sensitivität von 6% zwischen der Kontrollgruppe und der präTAD-Gruppe unterschied. Die überwiegende Mehrheit der Patienten wäre folglich mit Hilfe des klassischen Screenings nicht erfasst worden. Die Aorten der präTAD- und TAD-Gruppe waren signifikant länger als die in der Kontrollgruppe. Dies betraf hauptsächlich die Aorta ascendens und den Aortenbogen. Anders als beim Durchmesser der Aorta war kein signifikanter Unterschied zwischen der präTAD- und der TAD-Gruppe nachweisbar; ein Längenzuwachs während der akuten Phase der Dissektion ist also unwahrscheinlich. Als Resultat dieser Ergebnisse wird ein zweidimensionaler Risiko-Score für die Auftrittswahrscheinlichkeit einer TAD zur Indikationsstellung der prophylaktischen operativen Therapie vorgestellt, der neben dem Durchmesser auch die Länge der Aorta ascendens zwischen den leicht zu definierenden anatomischen Landmarken „Aortenklappe“ und „Abgang Truncus brachiocephalicus“ über 120mm berücksichtigt. Eine Erweiterung des prädiktiven TAD-Screenings um diesen Parameter hatte in unserer Studienpopulation eine Steigerung der Test-Sensitivität von 6% auf 27% zur Folge. Die Spezifität blieb dabei unberührt bei 100%. Man könnte unter Einbezug dieser Ergebnisse viermal mehr Patienten mit der risikoärmeren Operation therapieren, ohne dabei die Zahl der falsch-positiven Testungen zu erhöhen.

The phospholipase A2 (PLA2) inhibitors varespladib (LY315920) and its orally available derivative methyl-varespladib (LY333013) have been proposed as potential therapies for the treatment of snakebite envenomings in which toxicity depends on the action of PLA2s. In this study, the ability of LY315920 to abrogate the effect of the potent neurotoxic venom of Oxyuranus scutellatus (taipan) was assessed using the mouse phrenic nerve-diaphragm preparation. LY315920 inhibited the venom when (a) incubated with venom before addition to the medium; (b) added to the medium before addition of venom, and; (c) added to the medium within 30 min after addition of venom, and even after the onset of decline in twitch response. This contrasts with previous results with antivenom using the same experimental model, in which the window of time when antibodies are effective is shorter than 10 min. It is proposed that such differences may depend either on the higher affinity of the inhibitor for PLA2s or on the possibility that LY315920 reaches the cytosol of the nerve terminals, inhibiting neurotoxins that have been internalized. Our findings bear implications on the therapeutic potential of varespladib in neurotoxic snakebite envenomings mediated by presynaptically-acting PLA2s.

Envenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a pro-regenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Papuan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery., Author summary We have taken here a different angle in the search for novel treatments of snake envenomings by focusing of the phase of recovery from the peripheral neuroparalysis caused by neurotoxic snakes. This is a critical period that may require mechanical ventilation and prolonged hospitalization. We have found a drug, dubbed NUCC-390, which accelerates the functional recovery from peripheral neuroparalysis caused by the Taipan venom in mice, by acting on the CXCR4 receptor. In fact, we found here that this receptor is expressed by the motor neuron at the site of damage that, in the case of many snake venoms containing presynaptic PLA2 neurotoxins, consists in the degeneration of the axon terminal. NUCC-390 binds to CXCR4 and acts similarly to its natural agonist the chemokine CXCL12α. The compound is not toxic and can be administered after the snakebite and therefore it has the potential of becoming a non-expensive addition to the currently available antisera treatment whose efficacy is limited by the need of delivery shortly after snakebite.

Lupus anticoagulants (LA) are heterogeneous antibodies and no single assay will detect every LA. Consequently, testing is commonly undertaken with both dilute Russell's viper venom time (dRVVT) and LA-responsive activated partial thromboplastin time (aPTT) to maximize detection rates. Although a huge body of evidence attests to the diagnostic utility of these assays, they have limitations that can render them unreliable in certain circumstances. Other assays are available for detecting LA but unfamiliarity, variable availability and technical concerns expressed in guidelines contribute to less usage than dRVVT and aPTT. However, assays such as Taipan snake venom time and Textarin time are insensitive to anticoagulants that compromise dRVVT and aPTT, and assays such as dilute prothrombin time can detect LA unreactive in dRVVT and aPTT. The pros and cons of alternative assays to dRVVT and APTT for LA detection are discussed.

A previously well man developed acute, marked tender bilateral gynaecomastia two months after confirmed taipan (Oxyuranus scutellatus) envenomation. He had had laboratory evidence of thrombotic microangiopathy (TMA) including microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. Scrotal ultrasound revealed bilateral testicular atrophy, his serum testosterone was repeatedly low, while his luteinising and follicle stimulating hormone were elevated. It is hypothesised that TMA-related testicular ischaemia was responsible for his primary gonadal failure and dramatic clinical presentation.

Ultimate Taipan is a software model checker that combines trace abstraction with abstract interpretation on path programs. In this year’s version, we replaced our abstract interpretation engine and now use a combination of multiple abstraction functions, fixpoint computation, algebraic program analysis, and SMT solving. Our new approach will allow us to integrate new techniques more easily.

TAIPAN is the thermal-neutron instrument located at the reactor face of Australia’s OPAL reactor (ANSTO). TAIPAN hosts two interchangeable secondary spectrometers ; a classic triple-axis spectrometer (TAS) and a beryllium-filter spectrometer, the latter being a high-throughput, low-energy, band-pass filter spectrometer based on the NIST design (Udovic et al., 2008). The TAS option has been operating in the user programme since 2010 whilst the Be-filter is a newer addition, which began operating at the end of 2015. TAIPAN is renowned for its versatility and high neutron flux which has allowed the TAS to measure successfully a broad range of samples including single crystals , powders, thin films, and co-aligned multi-crystal arrays (Danilkin and Yethiraj, 2009; Danilkin et al., 2012, 2007). While the TAS option is used mostly to study structural and magnetic excitations in materials, the Be-filter option is used to measure vibrational density of states from mainly powder samples (Stampfl et al., 2016). TAIPAN has recently undergone some significant upgrades to improve the accessible momentum and energy range of both the TAS and the Be-filter spectrometers. Four key features have been modified to improve performance: the accessible momentum transfer has been increased by re-designing the enclosure and expanding the available instrument range of motion (section A); a new sapphire-filter translation-stage mechanism (Section B) has been installed to allow epithermal neutrons to pass to the two monochromators ; a new Cu-200 double-focussing monochromator has been installed to allow monochromatic selection of neutrons up to 180 meV (Section C); and finally a new tertiary shutter and snout (Section D) have been designed to improve the signal-to-noise ratio and reduced background outside the instrument enclosure. Extensive testing and alignment of all new motion stages were undertaken with reproducibility within ± 0.05 degrees or ± 0.25 mm obtained for both the monochromator rotation angle & sapphire-filter translation.

Introduction A case of life threatening envenoming by a wild specimen of the inland taipan, Oxyuranus microlepidotus , is described. There have been 11 previously well-documented envenomings by O. microlepidotus, but only 2 were inflicted by wild snakes. Envenomed patients have presented predominantly with defibrinating coagulopathy and neurotoxicity. Case report The victim was seeking to observe members of an isolated population of this species and was envenomed while attempting to photograph an approximately 1.5 m specimen. He reported feeling “drowsiness” and blurred vision that progressed to ptosis; he later developed dysphagia and dysarthria. The patient was treated with 1 vial of polyvalent antivenom, which was later followed with an additional two vials of taipan monovalent. He was intubated during retrieval, and recovered after 3 days of intensive care. He had a right ophthalmoplegia that persisted for approximately 1 week post-envenoming. Despite a positive 20-min whole blood clotting test, defibrination coagulopathy was absent, and there was no myotoxicity, or acute kidney injury. Discussion Physicians presented with a patient envenomed by O. microlepidotus should remain cognizant of the possible variability of medically important venom toxins in some populations of this species. Some patients seriously envenomed by this species may develop persistent cranial nerve palsies. When clinically indicated, prompt provision of adequate antivenom is the cornerstone of managing O. microlepidotus envenoming. Rapid application of pressure-bandage immobilization and efficient retrieval of victims envenomed in remote locales, preferably by medically well-equipped aircraft, probably improves the likelihood of a positive outcome.

BackgroundDilute Russell’s viper venom time (dRVVT) is indispensible in lupus anticoagulant (LA) detection yet commercial reagents from different suppliers perform variably, no gold standard assays exist and therapeutic anticoagulation interference is problematic.ObjectiveThe objective of this study was to compare a new formulation dRVVT with two currently available dRVVTs.Materials and methodsLife Diagnostics (LD) dRVVT and Stago PTT-LA were routinely used for lupus anticoagulant detection, plus Taipan snake venom time/ecarin time (TSVT/ET) for patients on warfarin or rivaroxaban. Siemens dRVVT and the new HYPHEN BioMed (HBM) dRVVT were tested with 193 patient samples. Group 1, 59 non-anticoagulated patients (NAPs) LA-positive in LD dRVVT; Group 2, 15 PTT-LA-positive/dRVVT-negative NAPs; Group 3, 24 LA-positive warfarinized patients; Group 4, 13 patients on rivaroxaban; Group 5, 62 LA-negative thrombotic NAPs; Group 6, 20 warfarinized, non-antiphospholipid syndrome patients.ResultsAccepting that the Life Diagnostics reagents were acting as a pseudo-gold standard, Siemens dRVVT detected 56/59, (95%) Group 1 LA and HBM dRVVT 46/59, (76%), one each from Group 2, and Siemens dRVVT detected one in Group 5. The lower HBM dRVVT detection rate mainly concerned weaker LA, where between-reagent concordance is problematic. All Group 3 patients appeared LA-positive in undiluted plasma with Siemens dRVVT, as did 16/24 (67%) with HBM dRVVT but the fewer LA-positives in mixing tests better mapped to clear LA-positives with LD dRVVT. LD and Siemens dRVVTs exhibited 87% and 95% false-positivity for Group 6 whilst HBM dRVVT had none. Increasing the cut-off improved accuracy. Applying higher cut-offs improved accuracy in Group 4 patients.ConclusionHBM dRVVT exhibited improved specificity, mainly due to less interference by anticoagulation, but reduced sensitivity, compared to the other dRVVTs employed.

Alpaca (Vicugna pacos), like all other members of the camelid family, produce a unique heavy chain only IgG subclass. This form of IgG has been proposed as having superior neutralising properties and improved safety as compared with conventional mammalian IgG-based immunotherapeutics. The objective of this study was to investigate the potential of alpaca antibodies to neutralise the lethal and procoagulant properties of several Australian elapid snake venoms. Various experimental antivenoms were produced by immunisation of alpaca (Vicugna pacos) with combinations of five Australian elapid snake venoms: tiger snake (Notechis scutatus), eastern brown snake (Pseudonaja textilis), Papuan taipan (Oxyuranus scutellatus canni), mulga snake (Pseudechis australis) and common death adder (Acanthophis antarcticus). Venoms were emulsified in Freund’s Incomplete Adjuvant and alpaca repeatedly immunised. Having previously shown that such alpaca produce persistent venom-specific antibody responses with minimal physiological impact on the animal, the current report demonstrates that polyvalent alpaca antivenom neutralises the lethal effects of three elapid venoms (tiger, brown and Papuan taipan venoms). Such lethality neutralisation was, however, of generally lower potency, but of the same order of magnitude, when compared with bioCSL monovalent antivenoms (brown, tiger and taipan antivenoms). By contrast, the monovalent alpaca tiger and brown snake antivenom were found to be superior to the equivalent bioCSL monovalent antivenoms when considering the neutralisation of the procoagulant effects of the respective immunising venoms. The bioCSL polyvalent antivenom also less potent, when compared with the alpaca taipan monovalent antivenom, against Papuan taipan venom procoagulant neutralisation. These findings support the potential of camelid immunoglobulin for the development of novel elapid specific antivenoms.

Australian elapid snakes are some of the most venomous snakes in the world and are unique among venomous snakes in having mutated forms of the blood clotting factor X in an activated form (FXa) as a key venom component. In human bite victims, an overdose of this activated clotting enzyme results in the systemic consumption of fibrinogen due to the large amounts of endogenous thrombin generated by the conversion of prothrombin to thrombin by venom FXa. Within Australian elapids, such procoagulant venom is currently known from the tiger snake clade (Hoplocephalus, Notechis, Paroplocephalus, and Tropidechis species), brown/taipan (Oxyuranus and Pseudonaja species) clade, and the red-bellied black snake Pseudechis porphyriacus. We used a STA-R Max coagulation analyser and TEG5000 thromboelastographers to test 47 Australian elapid venoms from 19 genera against human plasma in vitro. In addition to activity being confirmed in the two clades above, FXa-driven potent procoagulant activity was found in four additional genera (Cryptophis, Demansia, Hemiaspis, and Suta). Ontogenetic changes in procoagulant function was also identified as a feature of Suta punctata venom. Phylogenetic analysis of FX sequences confirmed that snake venom FXa toxins evolved only once, that the potency of these toxins against human plasma has increased in a stepwise fashion, and that multiple convergent amplifications of procoagulant activity within Australian elapid snakes have occurred. Cofactor dependence tests revealed all procoagulant venoms in our study, except those of the tiger snake clade, to be highly calcium-dependent, whereas phospholipid dependence was less of a feature but still displayed significant variation between venoms. Antivenom testing using CSL Tiger Snake Antivenom showed broad but differential cross-reactivity against procoagulant venoms, with P. porphyriacus and S. punctata extremely well neutralised but with Cryptophis, Demansia, and Hemiaspis less well-neutralised. The relative variation was not in accordance to genetic relatedness of the species used in antivenom production (Notechis scutatus), which underscores a fundamental principle that the rapid evolution characteristic of venoms results in organismal phylogeny being a poor predictor of antivenom efficacy. Our results have direct and immediate implications for the design of clinical management plans in the event of snakebite by such lesser known Australian elapid snake species that have been revealed in this study to be as potent as the better studied, and proven lethal, species.

Taipans (Oxyuranus spp.) are medically important venomous snakes from Australia and Papua New Guinea. The objective of this study was to describe taipan envenoming in Australian and its response to antivenom.Confirmed taipan bites were recruited from the Australian Snakebite Project. Data were collected prospectively on all snakebites, including patient demographics, bite circumstances, clinical effects, laboratory results, complications and treatment. Blood samples were taken and analysed by venom specific immunoassay to confirm snake species and measure venom concentration pre- and post-antivenom.There were 40 confirmed taipan bites: median age 41 years (2-85 years), 34 were males and 21 were snake handlers. Systemic envenoming occurred in 33 patients with neurotoxicity (26), complete venom induced consumption coagulopathy (VICC) (16), partial VICC (15), acute kidney injury (13), myotoxicity (11) and thrombocytopenia (7). Venom allergy occurred in seven patients, three of which had no evidence of envenoming and one died. Antivenom was given to 34 patients with a median initial dose of one vial (range 1-4), and a median total dose of two vials (range 1-9). A greater total antivenom dose was associated with VICC, neurotoxicity and acute kidney injury. Early antivenom administration was associated with a decreased frequency of neurotoxicity, acute kidney injury, myotoxicity and intubation. There was a shorter median time to discharge of 51 h (19-432 h) in patients given antivenom 4 h post-bite, compared to 175 h (27-1104 h) in those given antivenom 4 h. Median peak venom concentration in 25 patients with systemic envenoming and a sample available was 8.4 ng/L (1-3212 ng/L). No venom was detected in post-antivenom samples, including 20 patients given one vial initially and five patients bitten by inland taipans.Australian taipan envenoming is characterised by neurotoxicity, myotoxicity, coagulopathy, acute kidney injury and thrombocytopenia. One vial of antivenom binds all measurable venom and early antivenom was associated with a favourable outcome.

A chicken-derived antivenom (ChDAv) towards taipan snake (Oxyuranus scutellatus) venom was produced by purifying anti-taipan IgY from egg yolks of hens immunized with taipan venom. The productivity, antivenomic profile, neutralization ability, pharmacokinetic properties and immunogenicity of the ChDAv were compared with those of an antivenom produced in horses (EDAv). We found that 382 eggs are required to produce the mass of anti-taipan antibodies contained in one liter of equine hyperimmune plasma, and that 63 chickens would be needed to generate the amount of anti-taipan antibodies annually produced by one horse. It was estimated that, in Costa Rica, the production of antitaipan antibodies could be 40% cheaper if chickens were used as immunoglobulin source, instead of horses. During antivenomic assessment, ChDAv showed lower ability to immunocapture the a subunit of taipoxin, the most important neurotoxin in the venom. ChDAv showed a lower ability to neutralize the coagulant and lethal activities of taipan venom. ChDAv was more immunogenic in rabbits than EDAv, probably due to the fact that chickens are phylogenetically more distant to rabbits than horses. This finding may explain why clearance from rabbit bloodstream was faster for chicken-IgY than for equineIgG in a pharmacokinetic study. In conclusion, the production of anti-taipan antivenom was less effective when chicken egg yolks were used as source of immunoglobulins instead of horses. Universidad de Costa Rica/[741-B3-017]/UCR/Costa Rica UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)

Alpaca (Vicugna pacos) are domesticated members of the camelid family that have been shown to produce an IgG subclass that is heavy chain only IgG. This camelid-type IgG has been postulated to have improved neutralising properties and reduced immunogenicity, compared with conventional mammalian IgG. This study was undertaken to describe the physiological and antibody responses of alpaca (Vicugna pacos) used for the production of an experimental camelid antivenom. Various antivenom products were developed by immunisation of alpaca with combinations of five Australian elapid snake venoms: common tiger snake (Notechis scutatus), eastern brown snake (Pseudonaja textilis), Papuan taipan (Oxyuranus scutellatus canni), mulga snake (Pseudechis australis) and common death adder (Acanthophis antarcticus) were emulsified with Freund’s Adjuvant and injected monthly using a low dose multi-site approach. Venom specific immune responses were monitored by ELISA. Physiological effects upon alpaca were monitored by clinical examination combined with serial haematology and biochemical profiles. Serum was harvested once immune responses had peaked and the IgG fraction concentrated by ammonium sulphate precipitate of non-IgG proteins. Total serum IgG and total serum protein concentrations increased and decreased in synchrony with boosting specific antibodies. The difference in serum creatinine kinase concentration measured at 24 h after each of the first three immunisations decreased as the alpaca mounted an antibody response to the venom antigens measured by ELISA. In conclusion, alpaca responded to repeated immunisation with various Australian elapid venoms by mounting an increasing antibody response that persisted following prolonged rest with minimal physiological impact on the animal.

Envenomation Envenoming by snake bite is recorded unsystematically. The World Health Organization reports that more than 5 million people are bitten by snakes annually. They estimate that up to 138,000 die of complications, and many victims are left disabled. Stazi et al . developed a mouse model of envenoming by the Papuan taipan ( Oxyuranus scutellatus ). This snake's poison, taipoxin, is a phospholipase A2 neurotoxin akin to tetanus and botulinum toxins. Taipoxin causes the degeneration of motor axon synaptic transport but does not kill the neurons, and a slow recovery occurs if the victim is given respiratory support. Signaling by the G protein–coupled receptor CXCR4 is implicated in this synaptic pathophysiology. The authors studied the effects of a previously identified agonist of CXCR4, NUCC-390, a nontoxic compound in mice that accelerates regeneration of their synapses, and found that it significantly accelerated recovery from paralysis. NUCC-390 thus has the potential to enhance the recovery of patients hospitalized with neuroparalytic snake envenomation. PLOS Negl. Trop. Dis. 14 , e0008547 (2020).

Diseñar la empresa Taipán como opción para la seguridad de los ciclistas, a través de la oferta de un producto de defensa personal idóneo al confort de rodar en bicicleta. El presente trabajo tiene el objetivo de diseñar la empresa Taipán como opción a la seguridad de los ciclistas, a través de la oferta de un producto de defensa personal idóneo al confort de montar en bicicleta. La inmediatez con la que se accederá al producto en el momento del robo aumentará las posibilidades de defensa y reducirá las probabilidades del robo o lesión personal sin que se incurra en ilegalidad. Por otra parte, el producto tiene dos beneficios adicionales ya que también es un soporte horizontal para el apoyo de las manos del ciclista, además de ser posible llevarlo consigo incluso cuando se esté transportando en bicicleta. Cabe resaltar que si la inseguridad del usuario de bicicleta aumenta, la tendencia será el desecho o desuso de éste medio de transporte alternativo que contribuye al medio ambiente, la salud de las personas y la movilidad en las ciudades, afectando la iniciativa del gobierno mediante la Ley 1811 de 2016 que busca incentivar el uso de la bicicleta como medio principal de transporte en todo el territorio nacional. Por lo anterior, en el marco del presente proyecto se realizó un estudio de mercado a través de una encuesta aplicada a 612 personas donde se encontró que el 90.2% utilizarían un elemento de defensa personal y el 40.8% implementaría un gas lacrimógeno para defenderse, pues consideran sentirse nada seguros en un 58.9%. De ahí que Taipán cuente con un respaldo estadístico para su eventual comercialización ya que responde a las necesidades del mercado en Villavicencio.

BackgroundTaipans of the genus Oxyuranus are predominately mammal-eating specialists and a majority of Australian brown snakes of the sister genus Pseudonaja are generalist predators, feeding on mammals, lizards and frogs. In this paper, venom composition of several related mammal-eating species was compared using shotgun proteomics.ResultsVenom of Oxyuranus temporalis consisted predominately of α-neurotoxins (three-finger toxin family) and was deficient in phospholipase A2 neurotoxins. In contrast, PLA2 neurotoxins (taipoxin and paradoxin) were abundant in the venoms of other mammal-eating taipan species – Oxyuranus scutellatus and O. microlepidotus. Variation in neurotoxic PLA2 expression was also recorded in mammal-eating brown snakes, some species having high venom levels of textilotoxin or related homologues, for example Pseudonaja textilis and P. nuchalis, and others, such as P. ingrami, lacking them. Venom prothrombinase proteins (fX and fV) were expressed in most mammalivorous lineages, being particularly abundant in some Pseudonaja species. Notably, Oxyuranus temporalis venom was deficient in venom prothrombinase despite a mammal-based diet. Expression of an α-neurotoxin that is lethal to rodents (pseudonajatoxin b) was profoundly down-regulated in Pseudonaja textilis venom sample from Queensland and highly up-regulated in the sample from South Australia despite a report that the snake feeds on rodents in both regions.ConclusionRelated species of taipans and brown snakes that feed on small mammals express different sets of venom proteins toxic to this vertebrate group. This suggests an involvement of factors other than prey type selection in shaping venom proteome composition.