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Item Emerging infectious uveitis: Chikungunya, dengue, Zika and Ebola: A review(Wiley, 2018-11-25) Oliver, Genevieve F; Carr, Jill; Smith, Justine RRecently recognized forms of uveitis include intraocular inflammations that occur during or following one of several emerging infectious diseases: chikungunya fever, dengue, Zika virus disease and Ebola virus disease. Anterior, intermediate, posterior and pan‐uveitis have been described in individuals infected with chikungunya virus. Persons who contract dengue or Zika viruses also may develop different types of uveitis in the course of the infection: maculopathy is a common manifestation of dengue eye disease, and Zika eye disease may cause hypertensive anterior uveitis or mimic a white dot syndrome. Up to one‐third of Ebola survivors develop aggressive uveitis, which is frequently associated with vision loss and complicated by cataract. There are no specific anti‐viral drugs for these forms of uveitis, and thus treatment is largely supportive. In this article, we summarize the systemic infectious diseases and virology, and describe the clinical presentations, outcomes and management of emerging viral forms of uveitis.Item Use of Standardization of Uveitis Nomenclature for Reporting Clinical Data at 10 Years(Elsevier, 2017-03-31) Oliver, Genevieve F; Stathis, Roy M; Spurrier, Nicola Jane; Smith, Justine RUveitis is a heterogeneous group of infectious and noninfectious intraocular inflammatory diseases. Management of both subsets of uveitis is frequently challenging. Since 2000, advances in microbial diagnostics and introduction of biologic drugs, combined with the potential for electronic communication to facilitate research on diseases with low incidence, have provided uveitis specialists with unprecedented opportunities for clinical trials to establish evidence-based management algorithms. Hampering this effort, however, was lack of a common system for describing uveitis, including diagnosis, severity, and outcome. The Standardization of Uveitis Nomenclature (SUN) Project is an effort to develop “international consensus for the use of terms to report on uveitis at academic meetings and in the literature.”Item Grandparent-Grandchild Attachment Scale [Measurement Instrument](2019-11-06) Condon, John TerenceItem Effect of NADPH oxidase 1 and 4 blockade in activated human retinal endothelial cells(Clinical and Experimental Ophthalmology, 2018-08) Appukuttan, Binoy; Ma, Yuefang; Stempel, Andrew; Ashander, Liam M; Deliyanti, Devy; Wilkinson-Berka, Jennifer L; Smith, Justine RBackground Over‐production of reactive oxygen species (ROS) and resulting oxidative stress contribute to retinal damage in vascular diseases that include diabetic retinopathy, retinopathy of prematurity and major retinal vessel occlusions. NADPH oxidase (Nox) proteins are professional ROS‐generating enzymes, and therapeutic targeting in these diseases has strong appeal. Pharmacological inhibition of Nox4 reduces the severity of experimental retinal vasculopathy. We investigated the potential application of this drug approach in humans. Methods Differential Nox enzyme expression was studied by real‐time‐quantitative polymerase chain reaction in primary human retinal endothelial cell isolates and a characterized human retinal endothelial cell line. Oxidative stress was triggered chemically in endothelial cells, by treatment with dimethyloxalylglycine (DMOG; 100 μM); Nox4 and vascular endothelial growth factor (VEGFA) transcript were measured; and production of ROS was detected by 2′,7′‐dichlorofluorescein. DMOG‐stimulated endothelial cells were treated with two Nox1/Nox4 inhibitors, GKT136901 and GKT137831; cell growth was monitored by DNA quantification, in addition to VEGFA transcript and ROS production. Results Nox4 (isoform Nox4A) was the predominant Nox enzyme expressed by human retinal endothelial cells. Treatment with DMOG significantly increased endothelial cell expression of Nox4 over 72 h, accompanied by ROS production and increased VEGFA expression. Treatment with GKT136901 or GKT137831 significantly reduced DMOG‐induced ROS production and VEGFA expression by endothelial cells, and the inhibitory effect of DMOG on cell growth. Conclusions Our findings in experiments on activated human retinal endothelial cells provide translational corroboration of studies in experimental models of retinal vasculopathy and support the therapeutic application of Nox4 inhibition by GKT136901 and GKT137831 in patients with retinal vascular diseases.Item Expression of microRNA in human retinal pigment epithelial cells following infection with Zaire ebolavirus(BMC Research Notes, 2019) Oliver, Genevieve F; Orang, Ayla V; Appukuttan, Binoy; Marri, Shashikanth; Michael, Michael Zenon; Marsh, Glenn A; Smith, Justine RObjective: Survivors of Ebola virus disease (EVD) are at risk of developing blinding intraocular inflammation—or uveitis—which is associated with retinal pigment epithelial (RPE) scarring and persistence of live Zaire ebolavirus (EBOV) within the eye. As part of a large research project aimed at defining the human RPE cell response to being infected with EBOV, this work focused on the microRNAs (miRNAs) associated with the infection. Results: Using RNA-sequencing, we detected 13 highly induced and 2 highly repressed human miRNAs in human ARPE-19 RPE cells infected with EBOV, including hsa-miR-1307-5p, hsa-miR-29b-3p and hsa-miR-33a-5p (up-regulated), and hsa-miR-3074-3p and hsa-miR-27b-5p (down-regulated). EBOV-miR-1-5p was also found in infected RPE cells. Through computational identification of putative miRNA targets, we predicted a broad range of regulatory activities, including effects on innate and adaptive immune responses, cellular metabolism, cell cycle progression, apoptosis and autophagy. The most highly-connected molecule in the miR-target network was leucine-rich repeat kinase 2, which is involved in neuroinflammation and lysosomal processing. Our findings should stimulate new studies on the impact of miRNA changes in EBOV-infected RPE cells to further understanding of intraocular viral persistence and the pathogenesis of uveitis in EVD survivors.Item Current ophthalmology practice patterns for syphilitic uveitis(British Journal of Opthalmology, 2019) Oliver, Genevieve F; Stathis, Roy M; Furtado, João M; Arantes, Tiago E; McCluskey, Peter Joseph; Matthews, Janet M; Smith, Justine RBackground Syphilitic uveitis is re-emerging alongside the systemic infection. In July 2017, an international group of uveitis-specialised ophthalmologists formed the International Ocular Syphilis Study Group to define current practice patterns. Methods 103 Study Group members based in 35 countries completed a 25-item questionnaire focused on case load, clinical presentations, use and interpretation of investigations, treatment and clinical indicators of poor prognosis. Results Members managed a mean of 6.1 patients with syphilitic uveitis in clinics that averaged 707 annual cases of uveitis (0.9%); 53.2% reported increasing numbers over the past decade. Patients presented to more members (40.2%) during secondary syphilis. Uveitis was usually posterior (60.8%) or pan (22.5%); complications included optic neuropathy, macular oedema and posterior synechiae. All members diagnosed syphilitic uveitis using serological tests (simultaneous or sequential testing algorithms), and 97.0% routinely checked for HIV co-infection. Cerebrospinal fluid (CSF) analysis was ordered by 90.2% of members, and 92.7% took uveitis plus Venereal Disease Research Laboratory test (VDRL) or fluorescent treponemal antibody absorption test (FTA-ABS) to indicate neurosyphilis. Patients were commonly co-managed with infectious disease physicians, and treated with penicillin for at least 10–14 days, plus corticosteroid. Features predicting poor outcome included optic neuropathy (86.3%) and initial misdiagnosis (63.7%). Reasons for delayed diagnosis were often practitioner-related. 82.5% of members tested every patient they managed with uveitis for syphilis. Conclusion This comprehensive report by an international group of uveitis-specialised ophthalmologists provides a current approach for the management of syphilitic uveitis.Item Outcomes of Older Patients (≥ 70 Years) Treated With Targeted Therapy in Metastatic Chemorefractory Colorectal Cancer: Retrospective Analysis of NCIC CTG CO.17 and CO.20(Elsevier, 2018-11-28) Wells, J Connor; Tu, Dongsheng; Siu, Lillian L; Shapiro, Jeremy D; Jonker, Derek; Karapetis, Christos Stelios; Simes, John; Liu, Geoffrey; Price, Timothy J; Tebbutt, Niall C; O'Callaghan, Chris JBackground The safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated. Patients and Methods Outcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included. Results A total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03). Conclusion OS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients.Item Effect of Flammulina velutipes on the physicochemical and sensory characteristics of Cantonese sausages(Elsevier, 2019-04-03) Wang, Xuping; Xu, Mingying; Cheng, Jingrong; Zhang, Wei; Liu, Xue-Ming; Zhou, PengfeiThe effects of fresh and dried Flammulina velutipes (FFV and DFV) on quality and sensory characteristics of Cantonese sausages were investigated. Sausage samples were prepared by adding 0% (control), 2.5% FFV, 2.5% and 5.0% DFV, respectively, and their nutritional compositions, free amino acid profiles, lipid and protein oxidation, color and texture properties were determined. Addition of F. velutipes significantly decreased fat content while increased free amino acid contents of Cantonese sausages. Total free amino acid contents of 2.5% FFV, 2.5% DFV and 5.0% DFV incorporation were 2.8-, 2.4- and 3.5-fold as compared to control, respectively. Lipid and protein oxidation of Cantonese sausages were effectively inhibited by the addition of F. velutipes. Both FFV and DFV addition decreased hardness and chewiness while showed different effect on yellowness of samples. DFV added at 2.5% exhibited the best overall sensory acceptance. Therefore, appropriate addition of F. velutipes may be an effective way to improve meat product quality and function.Item Pharmaceutical and preclinical evaluation of Advax adjuvant as a dose-sparing strategy for ant venom immunotherapy(Elsevier, 2019-04-09) Wanandy, Troy; Honda-Okubo, Yoshikazu; Davies, Noel W; Rose, Hayley E; Heddle, Robert John; Brown, Simon G A; Woodman, Richard John; Petrovsky, Nikolai; Wiese, Michael DA major challenge in broader clinical application of Jack Jumper ant venom immunotherapy (JJA VIT) is the scarcity of ant venom which needs to be manually harvested from wild ants. Adjuvants are commonly used for antigen sparing in other vaccines, and thereby could potentially have major benefits to extend JJA supplies if they were to similarly enhance JJA VIT immunogenicity. The purpose of this study was to evaluate the physicochemical and microbiological stability and murine immunogenicity of low-dose JJA VIT formulated with a novel polysaccharide adjuvant referred to as delta inulin or Advax™. Jack Jumper ant venom (JJAV) protein stability was assessed by UPLC-UV, SDS-PAGE, SDS-PAGE immunoblot, and ELISA inhibition. Diffraction light scattering was used to assess particle size distribution of Advax; pH and benzyl alcohol quantification by UPLC-UV were used to assess the physicochemical stability of JJAV diluent, and endotoxin content and preservative efficacy test was used to investigate the microbiological properties of the adjuvanted VIT formulation. To assess the effect of adjuvant on JJA venom immunogenicity, mice were immunised four times with JJAV alone or formulated with Advax adjuvant. JJA VIT formulated with Advax was found to be physicochemically and microbiologically stable for at least 2 days when stored at 4 and 25 °C with a trend for an increase in allergenic potency observed beyond 2 days of storage. Low-dose JJAV formulated with Advax adjuvant induced significantly higher JJAV-specific IgG than a 5-fold higher dose of JJAV alone, consistent with a powerful allergen-sparing effect. The pharmaceutical data provides important guidance on the formulation, storage and use of JJA VIT formulated with Advax adjuvant, with the murine immunogenicity studies providing a strong rationale for a planned clinical trial to test the ability of Advax adjuvant to achieve 4-fold JJAV dose sparing in JJA-allergic human patients.Item Use of illicit amphetamines is associated with long-lasting changes in hand circuitry and control(Elsevier, 2019-02-26) Pearson-Dennett, Verity; Faulkner, Patrick L; Collie, Brittany; Wilcox, Robert Arthur; Vogel, Adam P; Thewlis, Dominic; Esterman, Adrian; McDonnell, Michelle N; Gandevia, Simon C; White, Jason M; Todd, GabrielleObjective The study aim was to determine if use of illicit amphetamines or ecstasy is associated with abnormal excitability of the corticomotoneuronal pathway and manipulation of novel objects with the hand. Methods Three groups of adults aged 18–50 years were investigated: individuals with a history of illicit amphetamine use, individuals with a history of ecstasy use but minimal use of other stimulants, and non-drug users. Transcranial magnetic stimulation was delivered to the motor cortex and the electromyographic response (motor evoked potential; MEP) was recorded from a contralateral hand muscle. Participants also gripped and lifted a novel experimental object consisting of two strain gauges and an accelerometer. Results Resting MEP amplitude was larger in the amphetamine group (6M, 6F) than the non-drug and ecstasy groups (p < 0.005) in males but not females. Overestimation of grip force during manipulation of a novel object was observed in the amphetamine group (p = 0.020) but not the ecstasy group. Conclusions History of illicit amphetamine use, in particular methamphetamine, is associated with abnormal motor cortical and/or corticomotoneuronal excitability in males and abnormal manipulation of novel objects in both males and females. Significance Abnormal excitability and hand function is evident months to years after cessation of illicit amphetamine use.Item Micromanaging aerobic respiration and glycolysis in cancer cells(Elsevier, 2019-02-06) Orang, Ayla V; Petersen, Janni; McKinnon, Ross A; Michael, Michael ZenonBackground Cancer cells possess a common metabolic phenotype, rewiring their metabolic pathways from mitochondrial oxidative phosphorylation to aerobic glycolysis and anabolic circuits, to support the energetic and biosynthetic requirements of continuous proliferation and migration. While, over the past decade, molecular and cellular studies have clearly highlighted the association of oncogenes and tumor suppressors with cancer-associated glycolysis, more recent attention has focused on the role of microRNAs (miRNAs) in mediating this metabolic shift. Accumulating studies have connected aberrant expression of miRNAs with direct and indirect regulation of aerobic glycolysis and associated pathways. Scope of review This review discusses the underlying mechanisms of metabolic reprogramming in cancer cells and provides arguments that the earlier paradigm of cancer glycolysis needs to be updated to a broader concept, which involves interconnecting biological pathways that include miRNA-mediated regulation of metabolism. For these reasons and in light of recent knowledge, we illustrate the relationships between metabolic pathways in cancer cells. We further summarize our current understanding of the interplay between miRNAs and these metabolic pathways. This review aims to highlight important metabolism-associated molecular components in the hunt for selective preventive and therapeutic treatments. Major conclusions Metabolism in cancer cells is influenced by driver mutations but is also regulated by posttranscriptional gene silencing. Understanding the nuanced regulation of gene expression in these cells and distinguishing rapid cellular responses from chronic adaptive mechanisms provides a basis for rational drug design and novel therapeutic strategies.Item A Roberts Syndrome Individual With Differential Genotoxin Sensitivity and a DNA Damage Response Defect(Elsevier, 2018-11-30) McKay, Michael; Craig, Jeffery; Kalitsis, Paul; Kozlov, Sergei; Verschoor, Sandra; Chen, Phillip; Lobachevsky, Pavel; Vasireddy, Raja; Yan, Yuqian; Ryan, Jacinta; McGillivray, George; Savarirayan, Ravi; Lavin, Martin F; Ramsay, Robert G; Xu, HuilingPurpose Roberts syndrome (RBS) is a rare, recessively transmitted developmental disorder characterized by growth retardation, craniofacial abnormalities, and truncation of limbs. All affected individuals to date have mutations in the ESCO2 (establishment of cohesion 2) gene, a key regulator of the cohesin complex, which is involved in sister chromatid cohesion and DNA double-strand break (DSB) repair. Here we characterize DNA damage responses (DDRs) for the first time in an RBS-affected family. Methods and Materials Lymphoblastoid cell lines were established from an RBS family, including the proband and parents carrying ESCO2 mutations. Various DDR assays were performed on these cells, including cell survival, chromosome break, and apoptosis assays; checkpoint activation indicators; and measures of DNA breakage and repair. Results Cells derived from the RBS-affected individual showed sensitivity to ionizing radiation (IR) and mitomycin C–induced DNA damage. In this ESCO2 compound heterozygote, other DDRs were also defective, including enhanced IR-induced clastogenicity and apoptosis; increased DNA DSB induction; and a reduced capacity for repairing IR-induced DNA DSBs, as measured by γ-H2AX foci and the comet assay. Conclusions In addition to its developmental features, RBS can be, like ataxia telangiectasia, considered a DDR-defective syndrome, which contributes to its cellular, molecular, and clinical phenotype.Item Phytol: A review of biomedical activities(Elsevier, 2018-04-18) Islam, Muhammad Torequl; Ali, Eunus S; Uddin, Shaikh Jamal; Shaw, Subrata; Islam, Md Amirul; Ahmed, Md. Iqbal; Shill, Manik Chandra; Karmakar, Utpal Kumar; Yarla, Nagendra Sastry; Khan, Ishaq N; Billah, Md Morsaline; Pieczynska, Magdalena D; Zengin, Gokhan; Malainer, Clemens; Nicoletti, Ferdinando; Gulei, Diana; Berindan-Neagoe, Ioana; Apostolov, Apostol; Banach, Maciej; Yeung, Andy W K; El-Demerdash, Amr; Xiao, Jianbo; Dey, Prasanta; Yele, Santosh; Jozwik, Artur; Strzalkowska, Nina; Marchewka, Joanna; Rengasamy, Kannan R R; Horbanczuk, Jaroslaw; Kamal, Mohammad Amjad; Mubarak, Mohammad S; Mishra, Siddhartha Kumar; Shilpi, Jamil A; Atanasov, Atanas GPhytol (PYT) is a diterpene member of the long-chain unsaturated acyclic alcohols. PYT and some of its derivatives, including phytanic acid (PA), exert a wide range of biological effects. PYT is a valuable essential oil (EO) used as a fragrance and a potential candidate for a broad range of applications in the pharmaceutical and biotechnological industry. There is ample evidence that PA may play a crucial role in the development of pathophysiological states. Focusing on PYT and some of its most relevant derivatives, here we present a systematic review of reported biological activities, along with their underlying mechanism of action. Recent investigations with PYT demonstrated anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. PPARs- and NF-κB-mediated activities are also discussed as mechanisms responsible for some of the bioactivities of PYT. The overall goal of this review is to discuss recent findings pertaining to PYT biological activities and its possible applications.Item Case report: Identification of intra-laboratory blood culture contamination with Staphylococcus aureus by whole genome sequencing(Elsevier, 2019-02-23) Ashokan, Anushia; Papanicolas, Lito E; Leong, Lex E X; Theodossi, Maria; Daniel, Santhosh; Wesselingh, Steven L; Rogers, Geraint B; Gordon, David LlewellynStaphylococcus aureus in blood cultures is rarely considered a contaminant. We report a case of intra-laboratory contamination between blood culture bottles which was confirmed by whole genome sequencing, highlighting the importance of molecular analysis in the clinical laboratory setting.Item Bilateral diffuse pulmonary infiltrates secondary to malignant peritoneal mesothelioma – A rare clinical presentation(Elsevier, 2019-03-04) Haygarth, Madeleine; Zaw, Kyi Kyi; Yachmenikova, Victoria; Pokorny, Adrian M J; Kwong, Kin Keung; Heraganahally, SubashDiffuse pulmonary metastasis secondary to primary peritoneal malignant mesothelioma is rarely reported in the literature. In this report we describe a 59-year-old Caucasian women with no known previous asbestos exposure presenting with bilateral diffuse pulmonary opacities in association with primary malignant peritoneal mesothelioma. The diagnosis was confirmed by ultrasound guided abdominal and bronchoscopy, trans-bronchial lung biopsy. The biopsy demonstrated positive staining with AE1/3, CK7, CK5/6, WT1, calretinin and D2 40. The cells were negative for BerEP4, PAX8, CA125, ER, CD34, ERG, P63, P40, Melan A, Gata3 and mammaglobin. The morphology and immunohistochemical profile supported a diagnosis of epithelioid malignant mesothelioma.Item Sustained improvement in vancomycin dosing and monitoring post-implementation of guidelines: Results of a three-year follow-up after a multifaceted intervention in an Australian teaching hospital(Elsevier, 2018-02) Phillips, Cameron J; McKinnon, Ross A; Woodman, Richard John; Gordon, David LlewellynIntroduction Despite vancomycin being in use for over half-a-century, it is still not dosed or monitored appropriately in many centers around the world. The objective of this study was to determine the effectiveness of a multifaceted intervention to implement a vancomycin dosing and monitoring guideline across multiple medical and surgical units over time. Methods This was an observational before-and-after interventional cohort study. The pre-intervention period was August to December 2010–2011 and the post-intervention period was September to November 2012–2014. The implementation strategy comprised: face-to-face education, online continuing medical education, dissemination of pocket guideline and email reminder. Outcome measures included: appropriate prescribing of loading and maintenance doses, therapeutic drug monitoring, time to attain target range and nephrotoxicity. Results Post-implementation prescribing of loading doses increased (10.4%–43.6%, P=<0.001), guideline adherent first maintenance dose (44%–68.4% P = 0.04), correct dose adjustment from (53.1%–72.2%, P = 0.009). Beneficial effects pre and post-implementation were observed for adherent timing of initial concentration (43.2%–51.9%, P = 0.01), concentrations in target range (32.6%–44.1%, P = 0.001), time to target range (median 6–4 days, P=<0.001), potentially nephrotoxic concentrations (30.7%–20.9%, P=<0.001) and nephrotoxicity (10.4%–6.8%, P=<0.001). Conclusions A multifaceted intervention to implement a vancomycin dosing and monitoring guideline significantly improved prescribing, monitoring, pharmacokinetic and safety outcomes for patients treated with vancomycin over an extended period. However, increased guideline adoption by clinicians is required to maximize and prolong the utility of this important agent.Item Adherence to antibiotic guidelines and reported penicillin allergy: pooled cohort data on prescribing and allergy documentation from two English National Health Service (NHS) trusts(BMJ Publishing group, 2019-03-01) Phillips, Cameron J; Gilchrist, Mark; Cooke, Fiona J; Franklin, Bryony D; Enoch, David A; Murphy, Michael E; Santos, Reem; Brannigan, Eimear T; Holmes, AlisonObjective To investigate documentation of antimicrobial allergy and to determine prescribing adherence to local antibiotic guidelines for inpatients with and without reported penicillin allergy treated for infection in a National Health Service (NHS) context. Setting Data were collected at two English hospital NHS trusts over two time-periods: June 2016 and February 2017. Design Cohort study. Trust 1 data were sourced from prospective point prevalence surveys. Trust 2 data were extracted retrospectively from an electronic report. Participants Inpatients treated for urinary tract infection (UTI), community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP) and skin and soft tissue infection (SSTI). Data on allergy were collected, and antibiotic selection assessed for adherence to trust guidelines with differences between groups presented as adjusted ORs. Results A total of 1497 patients were included, with 2645 antibiotics orders. Patients were treated for CAP (n=495; 33.1%), UTI (407; 27.2%), HAP (330; 22%) and SSTI (265; 17.7%). There were 240 (16%) patients with penicillin allergy. Penicillin allergy was recorded as allergy (n=52; 21.7%), side effect (27; 11.3%) and no documentation (161; 67.1%). Overall, 2184 (82.6%) antibiotic orders were guideline-adherent. Adherence was greatest for those labelled penicillin allergy (453 of 517; 87.6%) versus no allergy (1731 of 2128; 81.3%) (OR 0.52 (95% CI 0.37 to 0.73) p<0.001). Guideline-adherence for CAP was higher if penicillin allergy (151 of 163; 92.6%) versus no allergy (582 of 810; 71.9%) (OR 0.20 (95% CI 0.10 to 0.37) p<0.001). There was no difference in adherence between those with and without penicillin allergy for UTI, HAP or SSTI treatment. Conclusions A relatively high proportion of patients had a penicillin allergy and two thirds of these had no description of their allergy, which has important implications for patient safety. Patients with penicillin allergy treated for CAP, received more guideline adherent antibiotics than those without allergy. Future studies investigating the clinical impact of penicillin allergy should include data on adherence to antibiotic guidelines.Item Interventions targeting the prescribing and monitoring of vancomycin for hospitalized patients: a systematic review with meta-analysis(Dove Press, 2018-10-31) Phillips, Cameron J; Wisdom, Alice J; McKinnon, Ross A; Woodman, Richard John; Gordon, David LlewellynPurpose: Vancomycin prescribing requires individualized dosing and monitoring to ensure efficacy, limit toxicity, and minimize resistance. Although there are nationally endorsed guidelines from several countries addressing the complexities of vancomycin dosing and monitoring, there is limited consideration of how to implement these recommendations effectively. Methods: We conducted a systematic search of multiple databases to identify relevant comparative studies describing the impact of interventions of educational meetings, implementation of guidelines, and dissemination of educational material on vancomycin dosing, monitoring, and nephrotoxicity. Effect size was assessed using ORs and pooled data analyzed using forest plots to provide overall effect measures. Results: Six studies were included. All studies included educational meetings. Two studies used implementation of guidance, educational meetings, and dissemination of educational materials, one used guidance and educational meetings, one educational meetings and dissemination of educational materials, and two used educational meetings solely. Effect sizes for individual studies were more likely to be significant for multifaceted interventions. In meta-analysis, the overall effect of interventions on outcome measures of vancomycin dosing was OR 2.50 (95% CI 1.29–4.84); P< 0.01. A higher proportion of sampling at steady-state concentration was seen following intervention (OR 1.95, 95% CI 1.26–3.02; P<0.01). Interventions had no effect on appropriate timing of trough sample (OR 2.02, 95% CI 0.72–5.72; P=0.18), attaining target concentration in patients (OR 1.50, 95% CI 0.49–4.63; P=0.48, or nephrotoxicity (OR 0.75, 95% CI 0.42–1.34; P=0.33). Conclusion: Multifaceted interventions are effective overall in improving the complex task of dosing vancomycin, as well as some vancomycin-monitoring outcome measures. However, the resulting impact of these interventions on efficacy and toxicity requires further investigation. These findings may be helpful to those charged with designing implementation strategies for vancomycin guidelines or complex prescribing processes in hospitals.Item A data-driven, knowledge-based approach to biomarker discovery: application to circulating microRNA markers of colorectal cancer prognosis(Springer Nature Publishing AG, 2018-06-01) Vafaee, Fatemeh; Diakos, Connie; Kirschner, Michaela B; Reid, Glen; Michael, Michael Zenon; Horvath, Lisa G; Alinejad-Rokny, Hamid; Cheng, Zhangkai Jason; Kuncic, Zdenka; Clarke, StevenRecent advances in high-throughput technologies have provided an unprecedented opportunity to identify molecular markers of disease processes. This plethora of complex-omics data has simultaneously complicated the problem of extracting meaningful molecular signatures and opened up new opportunities for more sophisticated integrative and holistic approaches. In this era, effective integration of data-driven and knowledge-based approaches for biomarker identification has been recognised as key to improving the identification of high-performance biomarkers, and necessary for translational applications. Here, we have evaluated the role of circulating microRNA as a means of predicting the prognosis of patients with colorectal cancer, which is the second leading cause of cancer-related death worldwide. We have developed a multi-objective optimisation method that effectively integrates a data-driven approach with the knowledge obtained from the microRNA-mediated regulatory network to identify robust plasma microRNA signatures which are reliable in terms of predictive power as well as functional relevance. The proposed multi-objective framework has the capacity to adjust for conflicting biomarker objectives and to incorporate heterogeneous information facilitating systems approaches to biomarker discovery. We have found a prognostic signature of colorectal cancer comprising 11 circulating microRNAs. The identified signature predicts the patients’ survival outcome and targets pathways underlying colorectal cancer progression. The altered expression of the identified microRNAs was confirmed in an independent public data set of plasma samples of patients in early stage vs advanced colorectal cancer. Furthermore, the generality of the proposed method was demonstrated across three publicly available miRNA data sets associated with biomarker studies in other diseases.Item Burkholderia lata Infections from Intrinsically Contaminated Chlorhexidine Mouthwash, Australia, 2016(Centers for Disease Control and Prevention, 2018-11) Leong, Lex E X; Lagana, Diana; Carter, Glen P; Wang, Qinning; Smith, Kija; Stinear, Tim P; Shaw, David; Sintchenko, Vitali; Wesselingh, Steven L; Bastian, Ivan; Rogers, Geraint BBurkholderia lata was isolated from 8 intensive care patients at 2 tertiary hospitals in Australia. Whole-genome sequencing demonstrated that clinical and environmental isolates originated from a batch of contaminated commercial chlorhexidine mouthwash. Genomic analysis identified efflux pump–encoding genes as potential facilitators of bacterial persistence within this biocide.