Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

Identification and optimization of a novel series of selective PIP5K inhibitors.

Phosphatidyl inositol (4,5)-bisphosphate (PI(4,5)P2) plays several key roles in human biology and the lipid kinase that produces PI(4,5)P2, PIP5K, has been hypothesized to provide a potential therapeutic target of interest in the treatment of cancers. To better understand and explore the role of PIP5K in human cancers there remains an urgent need for potent and specific PIP5K inhibitor molecules. Following a high throughput screen of the AstraZeneca collection, a novel, moderately potent and selective inhibitor of PIP5K, 1, was discovered. Detailed exploration of the SAR for this novel scaffold resulted in the considerable optimization of both potency for PIP5K, and selectivity over the closely related kinase PI3Kα, as well as identifying several opportunities for the continued optimization of drug-like properties. As a result, several high quality in vitro tool compounds were identified (8, 20 and 25) that demonstrate the desired biochemical and cellular profiles required to aid better understanding of this complex area of biology.

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.

Anesthetic Success Using Nitrous Oxide and a Combination of Lidocaine/Clonidine for the Inferior Alveolar Nerve Block and the Effects on Blood Pressure and Pulse in Patients with Symptomatic Irreversible Pulpitis: A Prospective, Randomized, Double-blind Study.

INTRODUCTION: The pulpal anesthetic success rates for an inferior alveolar nerve block (IANB) alone in patients presenting with symptomatic irreversible pulpitis are less than adequate. Nitrous oxide and clonidine have shown increases in IANB success when administered individually, but their success has not been evaluated when used together. The purpose of this prospective, randomized, double-blind study was to determine the effect of nitrous oxide/oxygen plus an IANB using lidocaine/clonidine on the success of the IANB in patients with symptomatic irreversible pulpitis and to evaluate the effect of clonidine on blood pressure and pulse. METHODS: Sixty-two emergency patients experiencing moderate to severe pain and a diagnosis of symptomatic irreversible pulpitis were enrolled. Subjects were randomly divided into 2 groups and received nitrous oxide/oxygen and an IANB using 2% lidocaine with either 27 µg clonidine or 18 µg epinephrine as vasoconstrictors. Blood pressure and pulse were recorded before and during the emergency endodontic treatment. Anesthetic success was defined as no or mild pain upon access and instrumentation of the canals. RESULTS: The pulpal anesthetic success rate in both treatments was 58%, with no significant difference between the groups. There was no statistically significant difference in pulse or systolic blood pressure with the use of clonidine compared with epinephrine. Diastolic blood pressure was significant. CONCLUSIONS: The use of nitrous/oxide plus the addition of lidocaine/clonidine for the IANB in teeth with symptomatic irreversible pulpitis resulted in no statistically significant difference in anesthetic success of the IANB. There were no statistically significant differences in pulse or systolic blood pressure with the use of clonidine compared with epinephrine; diastolic blood pressure was significant.

Estimating retention benchmarks for salvage logging to protect biodiversity.

Forests are increasingly affected by natural disturbances. Subsequent salvage logging, a widespread management practice conducted predominantly to recover economic capital, produces further disturbance and impacts biodiversity worldwide. Hence, naturally disturbed forests are among the most threatened habitats in the world, with consequences for their associated biodiversity. However, there are no evidence-based benchmarks for the proportion of area of naturally disturbed forests to be excluded from salvage logging to conserve biodiversity. We apply a mixed rarefaction/extrapolation approach to a global multi-taxa dataset from disturbed forests, including birds, plants, insects and fungi, to close this gap. We find that 75 ± 7% (mean ± SD) of a naturally disturbed area of a forest needs to be left unlogged to maintain 90% richness of its unique species, whereas retaining 50% of a naturally disturbed forest unlogged maintains 73 ± 12% of its unique species richness. These values do not change with the time elapsed since disturbance but vary considerably among taxonomic groups.

Towards the Development of an Integrative, Evidence-Based Suite of Indicators for the Prediction of Outcome Following Mild Traumatic Brain Injury: Results from a Pilot Study.

BACKGROUND: Persisting post-concussion symptoms (PPCS) is a complex, multifaceted condition in which individuals continue to experience the symptoms of mild traumatic brain injury (mTBI; concussion) beyond the timeframe that it typically takes to recover. Currently, there is no way of knowing which individuals may develop this condition. METHOD: Patients presenting to a hospital emergency department (ED) within 48 h of sustaining a mTBI underwent neuropsychological assessment and demographic, injury-related information and blood samples were collected. Concentrations of blood-based biomarkers neuron specific enolase, neurofilament protein-light, and glial fibrillary acidic protein were assessed, and a subset of patients also underwent diffusion tensor-magnetic resonance imaging; both relative to healthy controls. Individuals were classified as having PPCS if they reported a score of 25 or higher on the Rivermead Postconcussion Symptoms Questionnaire at ~28 days post-injury. Univariate exact logistic regression was performed to identify measures that may be predictive of PPCS. Neuroimaging data were examined for differences in fractional anisotropy (FA) and mean diffusivity in regions of interest. RESULTS: Of n = 36 individuals, three (8.33%) were classified as having PPCS. Increased performance on the Repeatable Battery for the Assessment of Neuropsychological Status Update Total Score (OR = 0.81, 95% CI: 0.61-0.95, p = 0.004), Immediate Memory (OR = 0.79, 95% CI: 0.56-0.94, p = 0.001), and Attention (OR = 0.86, 95% CI: 0.71-0.97, p = 0.007) indices, as well as faster completion of the Trails Making Test B (OR = 1.06, 95% CI: 1.00-1.12, p = 0.032) at ED presentation were associated with a statistically significant decreased odds of an individual being classified as having PPCS. There was no significant association between blood-based biomarkers and PPCS in this small sample, although glial fibrillary acidic protein (GFAP) was significantly increased in individuals with mTBI relative to healthy controls. Furthermore, relative to healthy age and sex-matched controls (n = 8), individuals with mTBI (n = 14) had higher levels of FA within the left inferior frontal occipital fasciculus (t (18.06) = -3.01, p = 0.008). CONCLUSION: Performance on neuropsychological measures may be useful for predicting PPCS, but further investigation is required to elucidate the utility of this and other potential predictors.

Evaluation of RESPOND, a patient-centred program to prevent falls in older people presenting to the emergency department with a fall: A randomised controlled trial.

BACKGROUND: Falls are a leading reason for older people presenting to the emergency department (ED), and many experience further falls. Little evidence exists to guide secondary prevention in this population. This randomised controlled trial (RCT) investigated whether a 6-month telephone-based patient-centred program-RESPOND-had an effect on falls and fall injuries in older people presenting to the ED after a fall. METHODS AND FINDINGS: Community-dwelling people aged 60-90 years presenting to the ED with a fall and planned for discharge home within 72 hours were recruited from two EDs in Australia. Participants were enrolled if they could walk without hands-on assistance, use a telephone, and were free of cognitive impairment (Mini-Mental State Examination > 23). Recruitment occurred between 1 April 2014 and 29 June 2015. Participants were randomised to receive either RESPOND (intervention) or usual care (control). RESPOND comprised (1) home-based risk assessment; (2) 6 months telephone-based education, coaching, goal setting, and support for evidence-based risk factor management; and (3) linkages to existing services. Primary outcomes were falls and fall injuries in the 12-month follow-up. Secondary outcomes included ED presentations, hospital admissions, fractures, death, falls risk, falls efficacy, and quality of life. Assessors blind to group allocation collected outcome data via postal calendars, telephone follow-up, and hospital records. There were 430 people in the primary outcome analysis-217 randomised to RESPOND and 213 to control. The mean age of participants was 73 years; 55% were female. Falls per person-year were 1.15 in the RESPOND group and 1.83 in the control (incidence rate ratio [IRR] 0.65 [95% CI 0.43-0.99]; P = 0.042). There was no significant difference in fall injuries (IRR 0.81 [0.51-1.29]; P = 0.374). The rate of fractures was significantly lower in the RESPOND group compared with the control (0.05 versus 0.12; IRR 0.37 [95% CI 0.15-0.91]; P = 0.03), but there were no significant differences in other secondary outcomes between groups: ED presentations, hospitalisations or falls risk, falls efficacy, and quality of life. There were two deaths in the RESPOND group and one in the control group. No adverse events or unintended harm were reported. Limitations of this study were the high number of dropouts (n = 93); possible underreporting of falls, fall injuries, and hospitalisations across both groups; and the relatively small number of fracture events. CONCLUSIONS: In this study, providing a telephone-based, patient-centred falls prevention program reduced falls but not fall injuries, in older people presenting to the ED with a fall. Among secondary outcomes, only fractures reduced. Adopting patient-centred strategies into routine clinical practice for falls prevention could offer an opportunity to improve outcomes and reduce falls in patients attending the ED. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12614000336684).

An early warning system for emerging drugs of concern in the emergency department: Protocol for the Western Australian Illicit Substance Evaluation (WISE) study.

OBJECTIVE: An ever-increasing number of novel psychoactive substances are being detected worldwide. These emerging drugs have been demonstrated to cause toxicity in clusters, and deaths have been reported. We urgently need to learn more about their effects. We report the protocol for the Western Australian Illicit Substance Evaluation (WISE) study, a research project investigating illicit drug use in the ED. METHODS: Patients can be enrolled if the treating clinician strongly suspects they are currently intoxicated with a stimulant, hallucinogenic or cannabinoid drug; and an i.v. cannula or blood tests are required for routine clinical care. Patients are enrolled under a waiver of consent. A single additional blood tube is collected, de-identified and frozen on site. A temporary link between patient identification number and study identification number is retained for up to 10 business days post-hospital discharge to allow for clinical data collection, before this is destroyed and the patients become permanently de-identified. Samples are transported for external liquid chromatography-mass spectrometry analysis in batches once de-identified. RESULTS: The key outcome will be identification of any psychoactive drugs present in the blood sample, together with their respective concentration. This will be linked to the clinical effects, as well as being compared with the substance the patient believed they had taken. CONCLUSION: We consider the novel approach outlined forms a template for an early warning system for emerging drugs of concern, while also providing vital and comprehensive information on current drugs of abuse, their clinical effects and their impact on the health system.

A randomized-controlled trial of a patient-centred intervention in high-risk discharged older patients.

BACKGROUND: The risk of early reattendance after discharge has been proposed as a performance indicator for emergency departments (EDs), but is not uniform in all patients. Those individuals at the highest risk of reattendance may benefit from an intense intervention to reduce this risk, and our objective was to test this hypothesis in a clinical trial. METHODS: A randomized-controlled trial was conducted in the EDs of two hospitals. Very high-risk adults aged 65 years and older, identified using a validated risk-prediction nomogram and being discharged from ED, were randomized to receive a postdischarge patient-centred intervention or standard care. The intervention focused on identifying and supporting patients to address risk factors for future hospital presentation. The primary outcome measure was any unplanned ED reattendance within 28 days. Secondary outcomes included 28-day and 1-year hospital usage, institutionalization and death. RESULTS: We enrolled 164 patients, 82 in each study arm. There was an 8% absolute (95% confidence interval: -7%-20%) and a 20% relative risk reduction for an intervention patient making an unplanned ED reattendance within 28 days. This difference was not statistically significant (P=0.26). CONCLUSION: This postdischarge intervention was associated with only small and nonsignificant reductions in ED reattendance.

Alcohol-related presentations to the Royal Perth Hospital Emergency Department: A prospective study.

OBJECTIVE: To quantify and describe alcohol-related presentations to our ED, as part of the binational Alcohol Harm in Emergency Departments study. METHODS: A prospective observational study at Royal Perth Hospital of every patient attending ED for the 168-h period commencing 08.00 hours Monday 1 December 2014. Patient presentations were classified as alcohol-related (alcohol-positive) using predefined criteria. These patients were compared to alcohol-negative patients on a range of demographic and clinical descriptors. RESULTS: Two hundred and thirteen (15.2%) of 1403 patients screened were alcohol-positive. Compared with alcohol-negative patients, alcohol-positive patients were more likely to be male (148/213, 69.5% vs 636/1190, 53.4%, P < 0.001) and younger (mean 38 years vs 48 years, P < 0.001). They were more likely to arrive in police custody (OR 3.7, 95% CI 1.3-9.5, P = 0.005), and be admitted to the State Adult Major Trauma Unit (OR 4.2, 95% CI 2.1-8.3, P < 0.001). Forty-two (19.7%) of 213 patients had injuries suspected to be caused by an alcohol-affected third party. The ED length of stay and admission rate were not significantly different between the groups. CONCLUSIONS: 15.2% of patient presentations over the study week were alcohol-related. These patients were more likely to present with injury; one in five having injuries suspected to be caused by a third party affected by alcohol. This is a significant public health problem.

Elevation of oxidative stress indicators in a pilot study of plasma following traumatic brain injury.

Traumatic brain injury (TBI) encompasses a broad range of injury mechanisms and severity. A detailed determination of TBI severity can be a complex challenge, with current clinical tools sometimes insufficient to tailor a clinical response to a spectrum of patient needs. Blood biomarkers of TBI may supplement clinical assessments but currently available biomarkers have limited sensitivity and specificity. While oxidative stress is known to feature in damage mechanisms following TBI, investigation of blood biomarkers of oxidative stress has been limited. This exploratory pilot study of a subset of 18 trauma patients with TBI of varying severity, quantifies circulating concentrations of the structural damage indicators S100b, and myelin basic protein (MBP), and the biomarkers of oxidative stress hydroxynonenal (HNE), malondialdehyde (MDA), carboxy-methyl-lysine (CML), and 8-hydroxy-2'-deoxy-guanosine (8-OHDG). Significant increases in circulating S100b, MBP, and HNE were observed in TBI patient samples compared to 8 uninjured controls, and there was a significant decrease in CML. This small exploratory study supports the current literature on S100b and MBP elevation in TBI, and reveals potential for the use of peripheral oxidative stress markers to assist in determination of TBI severity. Further investigation is required to validate results and confirm trends.

Discovery of potent inhibitors of the lysophospholipase autotaxin.

The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.

Best-practice pain management in the emergency department: A cluster-randomised, controlled, intervention trial.

OBJECTIVES: We aimed to provide 'adequate analgesia' (which decreases the pain score by ≥2 and to <4 [0-10 scale]) and determine the effect on patient satisfaction. METHODS: We undertook a multicentre, cluster-randomised, controlled, intervention trial in nine EDs. Patients with moderate pain (pain score of ≥4) were eligible for inclusion. The intervention was a range of educational activities to encourage staff to provide 'adequate analgesia'. It was introduced into five early intervention EDs between the 0 and 6 months time points and at four late intervention EDs between 3 and 6 months. At 0, 3 and 6 months, data were collected on demographics, pain scores, analgesia provided and pain management satisfaction 48 h post-discharge (6 point scale). RESULTS: Overall, 1317 patients were enrolled. Logistic regression (controlling for site and other confounders) indicated that, between 0 and 3 months, satisfaction increased significantly at the early intervention EDs (OR 2.2, 95% CI 1.5 to 3.4 [P < 0.01]) but was stable at the control EDs (OR 0.8, 95% CI 0.5 to 1.3 [P = 0.35]). Pooling of data from all sites indicated that the proportion of patients very satisfied with their pain management increased from 42.9% immediately pre-intervention to 53.9% after 3 months of intervention (difference in proportions 11.0%, 95% CI 4.2 to 17.8 [P = 0.001]). Logistic regression of all data indicated that 'adequate analgesia' was significantly associated with patient satisfaction (OR 1.4, 95% CI 1.1 to 1.8 [P < 0.01]). CONCLUSIONS: The 'adequate analgesia' intervention significantly improved patient satisfaction. It provides a simple and efficient target in the pursuit of best-practice ED pain management.

Use of a risk nomogram to predict emergency department reattendance in older people after discharge: a validation study.

In older people, revisit to the emergency department (ED) in the short period after discharge is not entirely avoidable, but in a proportion of cases is preventable, and should ideally be minimised. We have previously derived a risk probability nomogram to predict the likelihood of revisit. In this study, we sought to validate the nomogram for use as a general risk stratification tool for use in older people being discharged from ED. We conducted a prospective cohort study, applying the nomogram to consecutive community dwelling discharged patients aged 65 and over. Patients were followed up at 28 days post-discharge to determine whether there had been any unplanned ED revisit in that period. We cross tabulated predicted risk versus revisit rates. In 1143 study subjects, we find the odds of revisit increases progressively with increasing strata of predicted risk, culminating in an OR of 9.7 (95% CI 4.7-19.9) in the highest risk group. The 28-day revisit rates across strata range from 16% through 65%, with the difference between strata being statistically highly significant (p < 0.001). The area under the ROC curve is 0.65. We conclude that the risk nomogram can classify older people discharged from ED into risk strata, and has modest overall predictive value.

Frailty index to measure health status in people with systemic sclerosis.

OBJECTIVE: To develop and validate, as a measure of overall health status, a Frailty Index (FI) for patients (n=1372) in the Canadian Scleroderma Research Group (CSRG) Registry. METHODS: Forty-four items were selected from the CSRG database as health deficits and recoded using FI criteria. To test construct validity, we compared measurement properties of the CSRG-FI to other FI, and related it to measures of damage, age, and time since diagnosis. To test criterion validity, we compared the baseline FI to that at last recorded visit and to mortality. RESULTS: The mean CSRG-FI was 0.33 with a sub-maximal limit of 0.67. In patients with diffuse disease, the mean was 0.38(SD 0.14); in patients with limited disease, the mean was 0.31(SD 0.13). The CSRG-FI was weakly (but significantly) correlated with the Rodnan Skin Score (r=0.28 in people with diffuse disease; 0.18 with limited) and moderately with the Physician Assessment of Damage (r=0.51 for both limited and diffuse). The risk of death increased with higher FI scores and with higher physician ratings of damage. The area under the receiver operating characteristic curve for the baseline FI in relation to death was 0.75, higher than for other measures (range: 0.57-0.67). CONCLUSION: The FI quantifies overall health status in people with scleroderma and predicts mortality. Whether the FI might help with decisions about who might best be served by more aggressive treatment, such as bone marrow transplantation, needs to be evaluated.

Can retention forestry help conserve biodiversity? A meta-analysis.

Industrial forestry typically leads to a simplified forest structure and altered species composition. Retention of trees at harvest was introduced about 25 years ago to mitigate negative impacts on biodiversity, mainly from clearcutting, and is now widely practiced in boreal and temperate regions. Despite numerous studies on response of flora and fauna to retention, no comprehensive review has summarized its effects on biodiversity in comparison to clearcuts as well as un-harvested forests. Using a systematic review protocol, we completed a meta-analysis of 78 studies including 944 comparisons of biodiversity between retention cuts and either clearcuts or un-harvested forests, with the main objective of assessing whether retention forestry helps, at least in the short term, to moderate the negative effects of clearcutting on flora and fauna. Retention cuts supported higher richness and a greater abundance of forest species than clearcuts as well as higher richness and abundance of open-habitat species than un-harvested forests. For all species taken together (i.e. forest species, open-habitat species, generalist species and unclassified species), richness was higher in retention cuts than in clearcuts. Retention cuts had negative impacts on some species compared to un-harvested forest, indicating that certain forest-interior species may not survive in retention cuts. Similarly, retention cuts were less suitable for some open-habitat species compared with clearcuts. Positive effects of retention cuts on richness of forest species increased with proportion of retained trees and time since harvest, but there were not enough data to analyse possible threshold effects, that is, levels at which effects on biodiversity diminish. Spatial arrangement of the trees (aggregated vs. dispersed) had no effect on either forest species or open-habitat species, although limited data may have hindered our capacity to identify responses. Results for different comparisons were largely consistent among taxonomic groups for forest and open-habitat species, respectively. Synthesis and applications. Our meta-analysis provides support for wider use of retention forestry since it moderates negative harvesting impacts on biodiversity. Hence, it is a promising approach for integrating biodiversity conservation and production forestry, although identifying optimal solutions between these two goals may need further attention. Nevertheless, retention forestry will not substitute for conservation actions targeting certain highly specialized species associated with forest-interior or open-habitat conditions. Our meta-analysis provides support for wider use of retention forestry since it moderates negative harvesting impacts on biodiversity. Hence, it is a promising approach for integrating biodiversity conservation and production forestry, although identifying optimal solutions between these two goals may need further attention. Nevertheless, retention forestry will not substitute for conservation actions targeting certain highly specialized species associated with forest-interior or open-habitat conditions.

Diazaheterocycle analogues of tetracene: synthesis and properties of a naphtho-fused cinnoline and a naphtho-fused isoindazole.

The synthesis and characterization of a diethynyl naphtho-fused cinnoline and isoindazole are described. The results show that both electron-accepting and electron-donating molecules can be prepared from a common intermediate.

Current use of Australian snake antivenoms and frequency of immediate-type hypersensitivity reactions and anaphylaxis.

OBJECTIVE: To investigate current use of Australian snake antivenoms and the frequency and severity of immediate-type hypersensitivity reactions. DESIGN: Nested prospective cohort study as part of the Australian Snakebite Project. PATIENTS AND SETTING: Patients receiving snake antivenom in Australian hospitals between 1 January 2002 and 30 November 2007. MAIN OUTCOME MEASURES: The use of CSL Limited antivenom; frequency and severity of hypersensitivity reactions to antivenom; premedication and treatment of these reactions. RESULTS: Snake antivenom was administered to 195 patients, mostly for venom-induced consumption coagulopathy (145 patients, 74%), followed by non-specific systemic effects (12%), neurotoxicity (5%) and myotoxicity (4%). Antivenom was given to nine patients (5%) without evidence of envenoming or who were bitten by a species of snake for which antivenom is not required. The commonest antivenoms used were brown snake (46%), tiger snake (30%) and polyvalent (11%). The median dose was four vials (interquartile range, 2-5 vials), and 24 patients received two different types of antivenom. Immediate-type hypersensitivity reactions occurred in 48 patients (25%); 21 satisfied our definition of anaphylaxis, with 11 moderate and 10 severe cases, including nine in which patients were hypotensive. The remaining 27 reactions were mild (skin only). Adrenaline was used in 26 cases with good effect. The frequency of reactions to tiger snake (41%) and polyvalent (41%) antivenoms was higher than that to brown snake antivenom (10%). Hypersensitivity reactions occurred in 11 of 40 patients receiving any form of premedication (28%) and in 2 of 11 given adrenaline for premedication (18%) versus 20 of 86 not receiving premedication (23%). CONCLUSIONS: Antivenom was used appropriately, and most commonly for coagulopathy. Hypersensitivity reactions were common, but most were not severe. The discretionary use of premedication was not associated with any reduction in reactions.