University General - Research Publications
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ItemProlonged Eyelid Closure Episodes during Sleep Deprivation in Professional Drivers(AMER ACAD SLEEP MEDICINE, 2016)STUDY OBJECTIVES: Real life ocular measures of drowsiness use average blink duration, amplitude and velocity of eyelid movements to reflect drowsiness in drivers. However, averaged data may conceal the variability in duration of eyelid closure episodes, and more prolonged episodes that indicate higher levels of drowsiness. The current study aimed to describe the frequency and duration of prolonged eyelid closure episodes during acute sleep deprivation. METHODS: Twenty male professional drivers (mean age ± standard deviation = 41.9 ± 8.3 years) were recruited from the Transport Workers Union newsletter and newspaper advertisements in Melbourne, Australia. Each participant underwent 24 hours of sleep deprivation and completed a simulated driving task (AusEd), the Psychomotor Vigilance Task, and the Karolinska Sleepiness Scale. Eyelid closure episodes during the driving task were recorded and analyzed manually from digital video recordings. RESULTS: Eyelid closure episodes increased in frequency and duration with a median of zero s/h of eyelid closure after 3 h increasing to 34 s/h after 23 h awake. Eyelid closure episodes were short and infrequent from 3 to 14 h of wakefulness. After 17 h of sleep deprivation, longer and more frequent eyelid closure episodes began to occur. Episodes lasting from 7 seconds up to 18 seconds developed after 20 h of wakefulness. Length of eyelid closure episodes was moderately to highly correlated with the standard deviation of lateral lane position, braking reaction time, crashes, impaired vigilance, and subjective sleepiness. CONCLUSIONS: The frequency and duration of episodes of prolonged eyelid closure increases during acute sleep deprivation, with very prolonged episodes after 17 hours awake. Automated devices that assess drowsiness using averaged measures of eyelid closure episodes need to be able to detect prolonged eyelid closure episodes that occur during more severe sleep deprivation.
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ItemA multilevel study of neighborhood disadvantage, individual socioeconomic position, and body mass index: Exploring cross-level interaction effects(ELSEVIER, 2019-06)This study examined associations between neighborhood disadvantage and body mass index (BMI), and tested whether this differed by level of individual socioeconomic position (SEP). Data were from 9953 residents living in 200 neighborhoods in Brisbane, Australia in 2007. Multilevel linear regression analyses were undertaken by gender to determine associations between neighborhood disadvantage, individual SEP (education, occupation and household income) and BMI (from self-reported height and weight); with cross-level interactions testing whether the relationship between neighborhood disadvantage and BMI differed by level of individual SEP. Both men (Quintile 4, where Quintile 5 is the most disadvantaged β = 0.66 95%CI 0.20, 1.12) and women (Quintile 5 β = 1.32 95%CI 0.76, 1.87) from more disadvantaged neighborhoods had a higher BMI. BMI was significantly higher for those with lower educational attainment (men β = 0.71 95%CI 0.36, 1.07 and women β = 1.66 95%CI 0.78, 1.54), and significantly lower for those in blue collar occupations (men β = -0.67 95%CI -1.09, -0.25 and women β = -0.71 95%CI -1.40, -0.01). Among men, those with a lower income had a significantly lower BMI, while the opposite was found among women. None of the interaction models had a significantly better fit than the random intercept models. The relationship between neighborhood disadvantage and BMI did not differ by level of education, occupation, or household income. This suggests that individual SEP is unlikely to be an effector modifier of the relationship between neighborhood disadvantage and BMI. Further research is required to assist policy-makers to make more informed decisions about where to intervene to counteract BMI-inequalities.
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ItemPrevalence of chlamydia, gonorrhoea, syphilis and trichomonas in Aboriginal and Torres Strait Islander Australians: a systematic review and meta-analysis(CSIRO PUBLISHING, 2016)Higher notification rates of sexually transmissible infections (STIs) are reported among Aboriginal and Torres Strait Islander (Aboriginal) compared with non-Aboriginal people in Australia. The aim of this study is to estimate the pooled prevalence of chlamydia, gonorrhoea, syphilis and trichomonas among Aboriginal people in Australia by sex, age-group, setting (clinic vs population/community-based) and population group [adults, pregnant females, young people (12-29 years) and prisoners]. The databases Medline, PubMed and Web of Science were searched in May 2015. A meta-analysis was conducted to estimate the pooled prevalence of the four STIs in Aboriginal people and if possible, by gender, age-group, setting and population group. A total of 46 studies were included. The pooled prevalence was 11.2% (95%CI: 9.4-13.0%) for chlamydia (36 studies), 12.5% (95%CI: 10.5-14.6%) for gonorrhoea (28 studies), 16.8% (95%CI: 11.0-22.6%) for syphilis (13 studies) and 22.6% (95%CI: 18.5-26.7%) for trichomonas (11 studies); however, there was significant heterogeneity between studies (I(2) <97.5%, P<0.01). In the subgroup analysis, a higher pooled prevalence occurred in females than males for chlamydia (12.7% vs 7.7%) and gonorrhoea (10.7% vs 8.1%). The prevalence of chlamydia was 12.4% in clinic-based compared with 4.3% in population-based studies. The highest pooled prevalence by population group was among pregnant females (16.8%) and young people (16.2%) for chlamydia, pregnant females (25.2%) for trichomonas; and young people for gonorrhoea (11.9%). This review highlights the need to decrease the prevalence of STIs among Aboriginal people through community-based programs that target asymptomatic young people.
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ItemHuman papillomavirus vaccination and genital warts in young Indigenous Australians: national sentinel surveillance data(Australasian Medical Publishing Company, 2017-03-20)OBJECTIVES: To examine the impact of the national human papillomavirus (HPV) vaccination program (available to girls and women [12-26 years] since 2007 and to boys [12-15 years] since 2013) on the number of diagnoses of genital warts in Australian Aboriginal and Torres Strait Islander (Indigenous) people. DESIGN, SETTING, PARTICIPANTS: Analysis of routinely collected data from patients attending 39 sexual health clinics (SHCs) in the Genital Warts Surveillance Network for the first time.Major outcome: The average annual proportion of Indigenous and non-Indigenous SHC patients diagnosed with genital warts during the pre-vaccination (2004-2007) and vaccination periods (2008-2014), stratified by age group and sex. RESULTS: 7.3% of the 215 599 Australian-born patients with known Indigenous status and seen for the first time at participating SHCs during 2004-2014 were Indigenous Australians. The average proportion of female Indigenous patients diagnosed with warts was lower during the vaccination period than during the pre-vaccination period (in those under 21, summary rate ratio [SRR], 0.12; 95% CI, 0.07-0.21; P < 0.001); in 21-30-year olds: SRR, 0.41; 95% CI, 0.27-0.61; P < 0.001); there was no significant difference for women over 30 (SRR, 0.84; 95% CI, 0.51-1.36; P = 0.47). The proportion of male Indigenous heterosexual SHC patients under 21 diagnosed with warts was also lower during the vaccination period (SRR, 0.25; 95% CI, 0.12-0.49; P < 0.001), with no significant changes among older Indigenous men over 30. CONCLUSIONS: There were marked declines in the proportions of diagnoses of genital warts in young Indigenous women and men attending SHCs after the introduction of the HPV vaccination program. If high levels of HPV vaccine coverage are sustained, HPV-related cancer rates should also decline.
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ItemNovel 1-Methyl-1H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity(American Chemical Society, 2019-03-15)A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure–activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.
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ItemStructure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development(AMER CHEMICAL SOC, 2019-01-24)Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
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ItemOptimization of Novel 1-Methyl-1H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm(AMER CHEMICAL SOC, 2018-12-13)A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
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ItemDeguelin exerts potent nematocidal activity via the mitochondrial respiratory chain(WILEY, 2017-10)As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.
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ItemScreening of a small, well-curated natural product-based library identifies two rotenoids with potent nematocidal activity against Haemonchus contortus(ELSEVIER SCIENCE BV, 2017-09-15)The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n=400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to some vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes, and to assess its potential as an anthelmintic candidate.
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ItemAnomalous Behavior Detection in Crowded Scenes Using Clustering and Spatio-Temporal Features(Springer, 2016)important problem in real-life applications. Detection of anomalous behaviors such as people standing statically and loitering around a place are the focus of this paper. In order to detect anomalous events and objects, ViBe was used for background modeling and object detection at first. Then, a Kalman filter and Hungarian cost algorithm were implemented for tracking and generating trajectories of people. Next, spatio-temporal features were extracted and represented. Finally, hyperspherical clustering was used for anomaly detection in an unsupervised manner. We investigate three different approaches to extracting and representing spatio-temporal features, and we demonstrate the effectiveness of our proposed feature representation on a standard benchmark dataset and a real-life video surveillance environment.