Publications by authors named "Joseph Tucci"

50 Publications

Novel Drexlerviridae bacteriophage KMI8 with specific lytic activity against Klebsiella michiganensis and its biofilms.

PLoS One 2021 7;16(9):e0257102. Epub 2021 Sep 7.

Department of Pharmacy and Biomedical Science, La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia.

The bacterial genus Klebsiella includes the closely related species K. michiganensis, K. oxytoca and K. pneumoniae, which are capable of causing severe disease in humans. In this report we describe the isolation, genomic and functional characterisation of the lytic bacteriophage KMI8 specific for K. michiganensis. KMI8 belongs to the family Drexlerviridae, and has a novel genome which shares very little homology (71.89% identity over a query cover of only 8%) with that of its closest related bacteriophages (Klebsiella bacteriophage LF20 (MW417503.1); Klebsiella bacteriophage 066039 (MW042802.1). KMI8, which possess a putative endosialidase (depolymerase) enzyme, was shown to be capable of degrading mono-biofilms of a strain of K. michiganensis that carried the polysaccharide capsule KL70 locus. This is the first report of a lytic bacteriophage for K. michiganensis, which is capable of breaking down a biofilm of this species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423285PMC
September 2021

Large variability in plasma efavirenz concentration in Papua New Guinea HIV/AIDS patients associated with high frequency of CYP2B6 516T allele.

Clin Transl Sci 2021 Aug 20. Epub 2021 Aug 20.

Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.

Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.516G>T and patient demographics on plasma efavirenz (EFV) and 8-hydroxyefavirenz (8OH-EFV) concentrations, metabolic ratio (8OH-EFV/EFV) (MR), and their association with adverse effects, in PNG patients with HIV/AIDS. For 156 PNG patients with HIV/AIDS taking EFV 600 mg/day (for 3-156 months), plasma EFV and 8OH-EFV concentrations were quantified, CYP2B6 c.516G>T genotyped, and demographic and self-reported adverse effects data recorded. Genotype differences in EFV and 8OH-EFV concentrations, MR, and percent within therapeutic range (1000-4000 ng/ml) were examined, in addition to EFV and 8OH-EFV concentration differences between patients experiencing adverse effects. CYP2B6 c.516T allele frequency was 53%. Plasma EFV (p < 0.0001), 8OH-EFV (p < 0.01), and MR (p < 0.0001) differed significantly between genotypes, with genotype explaining 38%, 10%, and 50% of variability, respectively. Plasma EFV concentrations were significantly higher in T/T (median = 5168 ng/ml) than G/G (1036 ng/ml, post hoc p < 0.0001) and G/T (1502 ng/ml, p < 0.0001) genotypes, with all patients above therapeutic range (n = 23) being T/T genotype (p < 0.0001). EFV and 8OH-EFV concentrations were not significantly higher in patients experiencing adverse effects. In PNG HIV/AIDS population where the 516T frequency is very high, it explains a substantial portion of variability (38%) in EFV disposition; however, at least for the patients receiving EFV long term, this does not translate into significant side effects.
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http://dx.doi.org/10.1111/cts.13120DOI Listing
August 2021

Isolation and Functional Characterization of Fusobacterium nucleatum Bacteriophage.

Methods Mol Biol 2021 ;2327:51-68

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia.

Bacteriophages are viruses that specifically lyse bacteria. They have demonstrated potential in applications as antibacterial agents in medicine, agriculture, and environmental remediation. Due to the complex and dynamic nature of the oral microbiome, antibiotic treatment of chronic, polymicrobial oral diseases may lead to dysbiosis. In these diseases, bacteriophages may provide targeted activity against oral bacteria without such disruption to the broader microbial community. In this chapter, we describe the methods for screening samples that may contain bacteriophages against oral pathogenic bacteria, and using the example of FNU1, the bacteriophage we isolated against Fusobacterium nucleatum, describe the process of bacteriophage purification and characterization.
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http://dx.doi.org/10.1007/978-1-0716-1518-8_4DOI Listing
January 2021

Instability of Efavirenz Metabolites Identified During Method Development and Validation.

J Pharm Sci 2021 Oct 24;110(10):3362-3366. Epub 2021 Jun 24.

Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.

Accurate quantification of efavirenz metabolites in patient samples is required to investigate their potential contribution to efavirenz adverse events. This study aimed to validate a LC-MS/MS method to quantify and investigate the stability of efavirenz and metabolites in human plasma. Compounds were extracted from plasma by supported liquid extraction and resolved on a C18 column. Validation was performed following FDA bioanalytical method validation guidelines. Stability under common conditions of sample pre-treatment and storage were assessed. Efavirenz and 8-hydroxyefavirenz were stable for all conditions tested. 7-Hydroxyefavirenz and 8,14-dihydroxyefavirenz were not stable in plasma at room temperature for 24 h (46%-69% loss), -20°C for 90 days (17%-50% loss), or 60°C for 1 h (90%-95% loss). Efavirenz and 8-hydroxyefavirenz concentrations in HIV/AIDS patient (n=5) plasma prepared from pre-treated (60°C for 1 h) whole blood varied from 517-8564 ng/mL and 131-813 ng/mL, respectively. 7-Hydroxyefavirenz and 8,14-dihydroxyefavirenz concentrations were below validated lower limits of quantification (0.25 and 0.5 ng/mL, respectively), most likely due to sample pre-treatment. This is the first report of 7-hydroxyefavirenz and 8,14-dihydroxyefavirenz instability under conditions commonly used in preparation of samples from HIV/AIDS patients. Alternative biosafety measures to heat pre-treatment must therefore be used for accurate quantification of plasma 7-hydroxyefavirenz and 8,14-dihydroxyefavirenz.
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http://dx.doi.org/10.1016/j.xphs.2021.06.028DOI Listing
October 2021

Lytic Bacteriophage EFA1 Modulates HCT116 Colon Cancer Cell Growth and Upregulates ROS Production in an Co-culture System.

Front Microbiol 2021 31;12:650849. Epub 2021 Mar 31.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia.

is an opportunistic pathogen in the gut microbiota that's associated with a range of difficult to treat nosocomial infections. It is also known to be associated with some colorectal cancers. Its resistance to a range of antibiotics and capacity to form biofilms increase its virulence. Unlike antibiotics, bacteriophages are capable of disrupting biofilms which are key in the pathogenesis of diseases such as UTIs and some cancers. In this study, bacteriophage EFA1, lytic against , was isolated and its genome fully sequenced and analyzed . Electron microscopy images revealed EFA1 to be a . The bacteriophage was functionally assessed and shown to disrupt biofilms as well as modulate the growth stimulatory effects of in a HCT116 colon cancer cell co-culture system, possibly via the effects of ROS. The potential exists for further testing of bacteriophage EFA1 in these systems as well as models.
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http://dx.doi.org/10.3389/fmicb.2021.650849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044584PMC
March 2021

Bacteriophage manipulation of the microbiome associated with tumour microenvironments-can this improve cancer therapeutic response?

FEMS Microbiol Rev 2021 Sep;45(5)

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Sharon St. Bendigo, Victoria 3550, Australia.

Some cancer treatment failures have been attributed to the tumour microbiota, with implications that microbiota manipulation may improve treatment efficacy. While antibiotics have been used to control bacterial growth, their dysbiotic effects on the microbiome, failure to penetrate biofilms and decreased efficacy due to increasing antimicrobial resistance by bacteria, suggest alternatives are needed. Bacteriophages may provide a precise means for targeting oncobacteria whose relative abundance is increased in tumour tissue microbiomes. Fusobacterium, Streptococcus, Peptostreptococcus, Prevotella, Parvimonas, and Treponema species are prevalent in tumour tissue microbiomes of some cancers. They may promote cancer growth by dampening immunity, stimulating release of proinflammatory cytokines, and directly interacting with cancer cells to stimulate proliferation. Lytic bacteriophages against some of these oncobacteria have been isolated and characterised. The search continues for others. The possibility exists for their testing as adjuncts to complement existing therapies. In this review, we highlight the role of oncobacteria, specifically those whose relative abundance in the intra-tumour microbiome is increased, and discuss the potential for bacteriophages against these micro-organisms to augment existing cancer therapies. The capacity for bacteriophages to modulate immunity and kill specific bacteria makes them suitable candidates to manipulate the tumour microbiome and negate the effects of these oncobacteria.
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http://dx.doi.org/10.1093/femsre/fuab017DOI Listing
September 2021

Potential for bacteriophage therapy for pneumonia with influenza A coinfection.

Future Microbiol 2021 02 4;16(3):135-142. Epub 2021 Feb 4.

Flinders University of South Australia, College of Medicine and Public Health, Bedford Park, SA, 5042, Australia.

The ability of influenza A virus to evolve, coupled with increasing antimicrobial resistance, could trigger an influenza pandemic with great morbidity and mortality. Much of the 1918 influenza pandemic mortality was likely due to bacterial coinfection, including pneumonia. resists many antibiotics. The lack of new antibiotics suggests alternative antimicrobials, such as bacteriophages, are needed. Potential delivery routes for bacteriophage therapy (BT) include inhalation and intravenous injection. BT has recently been used successfully in compassionate access pulmonary infection cases. Phage lysins, enzymes that hydrolyze bacterial cell walls and which are bactericidal, are efficacious in animal pneumonia models. Clinical trials will be needed to determine whether BT can ameliorate disease in influenza and coinfection.
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http://dx.doi.org/10.2217/fmb-2020-0163DOI Listing
February 2021

Genetic variation of Ascosphaera apis and colony attributes do not explain chalkbrood disease outbreaks in Australian honey bees.

J Invertebr Pathol 2021 03 29;180:107540. Epub 2021 Jan 29.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute of Molecular Science, La Trobe University, PO Box 199, Bendigo, Victoria 3552, Australia. Electronic address:

Chalkbrood infection caused by the fungus Ascosphaera apis currently has a significant impact on Australia's apicultural industry. We investigated the genetic variation of A. apis and colony and apiary level conditions to determine if an emerging, more virulent strain or specific conditions were responsible for the prevalence of the disease. We identified six genetically distinct strains of A. apis, four have been reported elsewhere and two are unique to Australia. Colonies and individual larvae were found to be infected with multiple strains of A. apis, neither individual strains, combinations of strains, or obvious colony or apiary characteristics were found to be predictive of hive infection levels. These results suggest that host genotype plays an important role in colony level resistance to chalkbrood infection in Australia.
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http://dx.doi.org/10.1016/j.jip.2021.107540DOI Listing
March 2021

Characterization of Novel Lytic Bacteriophages of Isolated from a Pneumonia Patient.

Viruses 2020 10 8;12(10). Epub 2020 Oct 8.

Department of Pharmacy and Biomedical Science, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria 3552, Australia.

spp. are becoming increasingly associated with lung infections in patients suffering from cystic fibrosis (CF). , which is closely related to , has been isolated from the lungs of CF patients and other human infections. This article describes the isolation, morphology and characterization of two lytic bacteriophages specific for an strain isolated from a pneumonia patient. This host strain was the causal agent of hospital acquired pneumonia-the first clinical report of such an occurrence. Full genome sequencing revealed bacteriophage genomes ranging in size from 45901 to 46,328 bp. Transmission electron microscopy revealed that the two bacteriophages AMA1 and AMA2 belonged to the family. Host range analysis showed that their host range did not extend to . The possibility exists for future testing of such bacteriophages in the control of infections such as those seen in CF and other infections of the lungs. The incidence of antibiotic resistance in this genus highlights the importance of seeking adjuncts and alternatives in CF and other lung infections.
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http://dx.doi.org/10.3390/v12101138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600146PMC
October 2020

Novel Bacteriophages Capable of Disrupting Biofilms From Clinical Strains of .

Front Microbiol 2020 14;11:194. Epub 2020 Feb 14.

Department of Pharmacy and Biomedical Science, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.

The increase in global warming has favored growth of a range of opportunistic environmental bacteria and allowed some of these to become more pathogenic to humans. is one such organism. Surviving in moist conditions in temperate climates, these bacteria have been associated with a range of diseases in humans, and in systemic infections can cause mortality in up to 46% of cases. Their capacity to form biofilms, carry antibiotic resistance mechanisms, and survive disinfection, has meant that they are not easily treated with traditional methods. Bacteriophage offer a possible alternative approach for controlling their growth. This study is the first to report the isolation and characterization of bacteriophages lytic against clinical strains of which carry intrinsic antibiotic resistance genes. Functionally, these novel bacteriophages were shown to be capable of disrupting biofilms caused by clinical isolates of The potential exists for these to be tested in clinical and environmental settings.
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http://dx.doi.org/10.3389/fmicb.2020.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033617PMC
February 2020

Bacteriophages in Natural and Artificial Environments.

Pathogens 2019 Jul 12;8(3). Epub 2019 Jul 12.

Department of Physiology, Anatomy & Microbiology, La Trobe University, Bundoora, VIC 3086, Australia.

Bacteriophages (phages) are biological entities that have attracted a great deal of attention in recent years. They have been reported as the most abundant biological entities on the planet and their ability to impact the composition of bacterial communities is of great interest. In this review, we aim to explore where phages exist in natural and artificial environments and how they impact communities. The natural environment in this review will focus on the human body, soils, and the marine environment. In these naturally occurring environments there is an abundance of phages suggesting a role in the maintenance of bacterial community homeostasis. The artificial environment focuses on wastewater treatment plants, industrial processes, followed by pharmaceutical formulations. As in natural environments, the existence of bacteria in manmade wastewater treatment plants and industrial processes inevitably attracts phages. The presence of phages in these environments can inhibit the bacteria required for efficient water treatment or food production. Alternatively, they can have a positive impact by eliminating recalcitrant organisms. Finally, we conclude by describing how phages can be manipulated or formulated into pharmaceutical products in the laboratory for use in natural or artificial environments.
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http://dx.doi.org/10.3390/pathogens8030100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789717PMC
July 2019

Genomic, morphological and functional characterisation of novel bacteriophage FNU1 capable of disrupting Fusobacterium nucleatum biofilms.

Sci Rep 2019 06 24;9(1):9107. Epub 2019 Jun 24.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia.

Fusobacterium nucleatum is an important oral bacterium that has been linked to the development of chronic diseases such as periodontitis and colorectal cancer. In periodontal disease, F. nucleatum forms the backbone of the polymicrobial biofilm and in colorectal cancer is implicated in aetiology, metastasis and chemotherapy resistance. The control of this bacteria may be important in assisting treatment of these diseases. With increased rates of antibiotic resistance globally, there is need for development of alternatives such as bacteriophages, which may complement existing therapies. Here we describe the morphology, genomics and functional characteristics of FNU1, a novel bacteriophage lytic against F. nucleatum. Transmission electron microscopy revealed FNU1 to be a large Siphoviridae virus with capsid diameter of 88 nm and tail of approximately 310 nm in length. Its genome was 130914 bp, with six tRNAs, and 8% of its ORFs encoding putative defence genes. FNU1 was able to kill cells within and significantly reduce F. nucleatum biofilm mass. The identification and characterisation of this bacteriophage will enable new possibilities for the treatment and prevention of F. nucleatum associated diseases to be explored.
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http://dx.doi.org/10.1038/s41598-019-45549-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591296PMC
June 2019

Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia.

BMC Cancer 2019 Feb 27;19(1):179. Epub 2019 Feb 27.

Department of Pharmacy and Applied Sciences, La Trobe Institute for Molecular Science (LIMS), La Trobe University, P.O. Box 199, Bendigo, Victoria, Australia.

Background: Daunorubicin is commonly used in the treatment of acute lymphoblastic leukaemia (ALL). The aim of this study was to explore the kinetics of double strand break (DSB) formation of three ALL cell lines following exposure to daunorubicin and to investigate the effects of daunorubicin on the cell cycle and the protein kinases involved in specific checkpoints following DNA damage and recovery periods.

Methods: Three ALL cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes were examined following 4 h treatment with daunorubicin chemotherapy and 4, 12 and 24 h recovery periods. Cell viability was measured via MTT (3-(4,5-dimethylthiazol-2-yl)-2-5 diphenyltetrazolium bromide) assay, reactive oxygen species (ROS) production by flow cytometry, double stranded DNA breaks by detecting γH2AX levels while stages of the cell cycle were detected following propidium iodide staining and flow cytometry. Western blotting was used to detect specific proteins while RNA was extracted from all cell lines and converted to cDNA to sequence Ataxia-telangiectasia mutated (ATM).

Results: Daunorubicin induced different degrees of toxicity in all cell lines and consistently generated reactive oxygen species. Daunorubicin was more potent at inducing DSB in MOLT-4 and CCRF-CEM cell lines while SUP-B15 cells showed delays in DSB repair and significantly more resistance to daunorubicin compared to the other cell lines as measured by γH2AX assay. Daunorubicin also causes cell cycle arrest in all three cell lines at different checkpoints at different times. These effects were not due to mutations in ATM as sequencing revealed none in any of the three cell lines. However, p53 was phosphorylated at serine 15 only in CCRF-CEM and MOLT-4 but not in SUP-B15 cells. The lack of active p53 may be correlated to the increase of SOD2 in SUP-B15 cells.

Conclusions: The delay in DSB repair and lower sensitivity to daunorubicin seen in the B lymphocyte derived SUP-B15 cells could be due to loss of function of p53 that may be correlated to increased expression of SOD2 and lower ROS production.
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http://dx.doi.org/10.1186/s12885-019-5377-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391779PMC
February 2019

Implementation of a clinical tool to assess and address pain management requests in the pharmacy.

Res Social Adm Pharm 2019 07 30;15(7):852-857. Epub 2018 Dec 30.

Department of Community and Allied Health, La Trobe Rural Health School, College of Science, Health and Engineering, La Trobe University, Edwards Rd Bendigo, Victoria, 3550, Australia. Electronic address:

Background: Morbidity and mortality associated with inappropriate use of over-the-counter combination analgesics containing codeine (OTC CACC) in Australia resulted in it being upscheduled in 2010 from "Pharmacy Only" (Schedule 2) to "Pharmacist Only" (Schedule 3), and further to "Prescription Only" (Schedule 4) in February 2018. There have been a number of concerns and challenges identified by community pharmacists in the provision of OTC CACC. In practice, sub-optimal management of patients accessing these medications has been demonstrated. To assist the management of patients using OTC CACC, the development of a management and referral pathway would be advantageous.

Objectives: To evaluate the use of an online interactive clinical tool and/or clinical information via an online PDF-based platform for managing OTC CACC requests and codeine dependence.

Method: Two interactive online clinical tools to aid management of patients who presented requesting OTC CACC were developed. Evaluation of these tools was undertaken using responses to multiple choice questions and feedback from pharmacist surveys.

Results: Of the 904 pharmacists who responded to the evaluation survey, 66.7% had not used the tool in the preceding 12 months. The most common reason why pharmacists did not access either the online interactive, or online PDF clinical tools was that they had no knowledge of them. Older age of the pharmacist (50 years or older compared to younger than 30) predicted tool access (adjusted proportional odds ratio = 3.16, 95% CI 1.72-5.80, p < 0.001). The access of the tool was positively associated with it being perceived as useful (adjusted odds ratio = 14.7, 95% CI 6.7-32.5, p < 0.001).

Conclusion: A number of pharmacists participating in the evaluation had never accessed either the online interactive or online PDF clinical tool, as they were not aware of them. Further research needs to be conducted into how to best promote and increase awareness of online clinical tools to pharmacists, especially younger pharmacists, and determine the best way to integrate online clinical tools effectively and efficiently into current practice.
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http://dx.doi.org/10.1016/j.sapharm.2018.12.009DOI Listing
July 2019

Isolation and characterization of bacteriophage NTR1 infectious for Nocardia transvalensis and other Nocardia species.

Virus Genes 2019 Apr 17;55(2):257-265. Epub 2018 Dec 17.

Department of Physiology, Anatomy & Microbiology, La Trobe University, Bundoora, VIC, Australia.

We describe here the isolation and characterization of the bacteriophage, NTR1 from activated sludge. This phage is lytic for Nocardia transvalensis, Nocardia brasiliensis and Nocardia farcinica. NTR1 phage has a genome sequence of 65,275 bp in length, and its closest match is to the Skermania piniformis phage SPI1 sharing over 36% of its genome. The phage belongs to the Siphoviridae family, possessing a long non-contractile tail and icosahedral head. Annotation of the genome reveals 97 putative open reading frames arranged in the characteristic modular organization of Siphoviridae phages and contains a single tRNA-Met gene.
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http://dx.doi.org/10.1007/s11262-018-1625-5DOI Listing
April 2019

The mediating role of sleep in the relationship between Indigenous status and body mass index in Australian school-aged children.

J Paediatr Child Health 2019 Aug 24;55(8):915-920. Epub 2018 Nov 24.

Department of Psychology, University of Copenhagen, Copenhagen, Denmark.

Aim: Associations between sleep duration and obesity and between obesity and chronic illness are established. Current rates of obesity for all Australian people are rising. Recent reports indicate that high body mass index (BMI) is a leading contributor to overall burden of disease for Indigenous Australians. Understanding the factors that contribute to higher rates of obesity in Indigenous people is critical to developing effective interventions for reducing morbidity and premature mortality in this population. To explore the effect of sleep duration on the relationship between Indigenous status and BMI in Australian children.

Methods: 716 non-Indigenous and 186 Indigenous children aged 5-12 years in the Australian Health Survey 2011-2013. Primary carers were interviewed regarding children's sleep times; BMI was derived from measurement.

Results: Analysis of covariance revealed that regardless of a number of demographic and socio-economic status markers, sleep duration and Indigenous status were independent predictors of BMI. However when both predictors were considered together, only sleep duration remained predictive of BMI.

Conclusions: Sleep duration plays an important mediating role in the relationship between Indigenous status and BMI in this Australian sample. Modification of sleep duration for Indigenous children may lead to longer-term positive health outcomes.
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http://dx.doi.org/10.1111/jpc.14308DOI Listing
August 2019

Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety.

Pharmacogenet Genomics 2018 06;28(6):153-164

Discipline of Pharmacology, Adelaide Medical School, University of Adelaide.

Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide. For example, CYP2B6*6 is over 50%, and CYP2C19*2 and *3 are over 40 and 25%, respectively. Conversely, CYP2A6*9, 2B6*2, *3, *4 and *18, and 2C8*3 appear to be much lower than in Whites. CYP2D6 known variants are unclear, and for phase II enzymes, only UGT2B7 and UGT1A9 data are available, with variant frequencies either slightly lower than or similar to Whites. Although almost all PNG people tested are rapid acetylators, but which variant(s) define this phenotype is not known. For HLA-B*13:01, HLA-B*35:05 and HLA-C*04:01, the frequencies show some regioselectivity, but the clinical implications with respect to adverse drug reactions are not known. There are minimal phenotype data for the CYPs and nothing is known about drug transporter or receptor genetics. Determination of genetic variants that are rare in Whites or Asians but common in PNG people is a topic of both scientific and clinical importance, and further research needs to be carried out. Optimizing the safety and efficacy of infectious disease drug therapy through pharmacogenetic studies that have translation potential is a priority.
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http://dx.doi.org/10.1097/FPC.0000000000000335DOI Listing
June 2018

Semi-Solid and Solid Dosage Forms for the Delivery of Phage Therapy to Epithelia.

Pharmaceuticals (Basel) 2018 Feb 26;11(1). Epub 2018 Feb 26.

Department of Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University Bendigo Campus, PO Box 199, Bendigo 3550, Australia.

The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases.
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http://dx.doi.org/10.3390/ph11010026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874722PMC
February 2018

Normocalcemic primary hyperparathyroidism associated with progressive cortical bone loss - A case report.

Authors:
Joseph R Tucci

Bone Rep 2017 Dec 10;7:152-155. Epub 2017 Oct 10.

Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI, USA.

The existence of normocalcemic primary hyperparathyroidism (NPHP) was acknowledged at the Third and Fourth International Proceedings on primary hyperparathyroidism PHPT but data relating to its clinical presentation, natural history, and skeletal status were limited and there was no information nor guidelines as to definitive therapy. Herein are reported biochemical, hormonal, and densitometry data in a postmenopausal woman seen initially for osteoporosis who was found to have increased serum PTH levels and normal serum total and ionized calcium levels without evidence of secondary hyperparathyroidism. Over a seven year period, the patient exhibited continuing preferential cortical bone loss at the one-third site of the radius in the face of relatively stable readings at the lumbar spine and hip that led to a subtotal parathyroidectomy for parathyroid hyperplasia with resultant normalization of serum PTH.
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http://dx.doi.org/10.1016/j.bonr.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736859PMC
December 2017

Eikelboom filamentous morphotypes 0675 and 0041 embrace members of the Chloroflexi: resolving their phylogeny, and design of fluorescence in situ hybridisation probes for their identification.

FEMS Microbiol Ecol 2017 10;93(10)

Microbiology Department, La Trobe University, Bundoora, VIC 3083, Australia.

Although the phylogeny of many of the filamentous bacteria responsible for bulking in activated sludge plants is now known, and fluorescence in situ hybridisation (FISH) probes have been designed for their in situ identification, there are some noticeable exceptions. This study reports the identification of the Eikelboom morphotypes 0041 and 0675. Because these morphotypes differ only in their filament diameters, they are often considered together in surveys based on microscopic identifications. Here we show that they are phylogenetically distinct, and so should be viewed no longer as morphological variants of a single population. Amplicon sequencing data of Australian EBPR plant biomass containing types 0041 and 0675, and phylogenetic analysis have revealed that both, like many other bulking filament morphotypes, are members of the phylum Chloroflexi and probably representatives of two different genera. FISH probes are described here targeting each. Surveys carried out on Australian activated sludge plants suggest that type 0675 occurs more in plants designed to remove phosphorus, while type 0041 shows no such preference, and was seen in biomass samples from a wide range of plant configurations.
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http://dx.doi.org/10.1093/femsec/fix115DOI Listing
October 2017

Characterization and formulation into solid dosage forms of a novel bacteriophage lytic against Klebsiella oxytoca.

PLoS One 2017 17;12(8):e0183510. Epub 2017 Aug 17.

La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.

Aim: To isolate and characterize bacteriophage lytic for the opportunistic pathogen Klebsiella oxytoca and their formulation into a range of solid dosage forms for in-vitro testing.

Methods And Results: We report the isolation, genomic and functional characterization of a novel bacteriophage lytic for Klebsiella oxytoca, which does not infect the closely related Klebsiella pneumoniae. This bacteriophage was formulated into suppositories and troches and shown to be released and lyse underlying Klebsiella oxytoca bacteria in an in-vitro model. These bacteriophage formulations were stable for at least 49 days at 4°C.

Conclusions: The successful in-vitro assay of these formulations here suggests that they could potentially be tested in-vivo to determine whether such a therapeutic approach could modulate the gut microbiome, and control Klebsiella oxytoca overgrowth, during antibiotic therapy regimes.

Significance And Impact Of The Study: This study reports a novel bacteriophage specific for Klebsiella oxytoca which can be formulated into solid dosage forms appropriate for potential delivery in testing as a therapy to modulate gut microbiome during antibiotic therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183510PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560551PMC
October 2017

Association between short sleep duration and body mass index in Australian Indigenous children.

J Paediatr Child Health 2018 01 16;54(1):49-54. Epub 2017 Aug 16.

School of Psychological and Clinical Sciences, Charles Darwin University, Darwin, Northern Territory, Australia.

Aim: Associations between short sleep duration and obesity and the relationship between obesity and chronic illness are well documented. Obese children are likely to become obese adults. To date, there is a paucity of information regarding sleep duration and quality for Indigenous Australian people. It may be that poor-quality, short sleep is contributing to the gap in health outcomes for Indigenous people compared with non-Indigenous adults and children. This study sought to investigate the possibility that poor sleep quality may be contributing to health outcomes for Indigenous children by exploring associations between sleep duration and body mass index (BMI).

Methods: Participants included 1253 children aged 7-12 years in Wave 7 of the national Longitudinal Study of Indigenous Children survey. Interviewers asked primary carers about children's sleep times. BMI was derived from measurements of children made by researchers.

Results: Regardless of age, relative socio-economic disadvantage and level of remoteness, unhealthy weight was associated with less sleep duration than healthy weight for Indigenous children.

Conclusion: The relationship between short sleep duration and BMI in Indigenous children has important implications for their future health outcomes. Both overweight conditions and short sleep are established modifiable risk factors for metabolic dysfunction and other chronic illnesses prominent in the Indigenous population. It is important to consider strategies to optimise both for Indigenous children in an attempt to help 'close the gap' in health outcomes and life expectancy between Indigenous and non-Indigenous people.
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http://dx.doi.org/10.1111/jpc.13658DOI Listing
January 2018

Bacteriophage formulated into a range of semisolid and solid dosage forms maintain lytic capacity against isolated cutaneous and opportunistic oral bacteria.

J Pharm Pharmacol 2017 Mar 29;69(3):244-253. Epub 2016 Dec 29.

La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia.

Background: Resistance of bacteria to antimicrobial agents is of grave concern. Further research into the development of bacteriophage as therapeutic agents against bacterial infections may help alleviate this problem.

Objectives: To formulate bacteriophage into a range of semisolid and solid dosage forms and investigate the capacity of these preparations to kill bacteria under laboratory conditions.

Methods: Bacteriophage suspensions were incorporated into dosage forms such as creams, ointments, pastes, pessaries and troches. These were applied to bacterial lawns in order to ascertain lytic capacity. Stability of these formulations containing phage was tested under various storage conditions.

Key Findings: A range of creams and ointments were able to support phage lytic activity against Propionibacterium acnes. Assessment of the stability of these formulations showed that storage at 4 °C in light-protected containers resulted in optimal phage viability after 90 days. Pessaries/suppositories and troches were able to support phage lytic activity against Rhodococcus equi.

Conclusions: We report here the in-vitro testing of semisolid and solid formulations of bacteriophage lytic against a range of bacteria known to contribute to infections of the epithelia. This study provides a basis for the future formulation of diverse phage against a range of bacteria that infect epithelial tissues.
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http://dx.doi.org/10.1111/jphp.12673DOI Listing
March 2017

Chronic disease, medications and lifestyle: perceptions from a regional Victorian Aboriginal community.

Pharm Pract (Granada) 2016 Jul-Sep;14(3):798. Epub 2016 Sep 15.

Department of Pharmacy & Applied Sciences, La Trobe Institute of Molecular Sciences, La Trobe University . Bendigo, VIC ( Australia ).

Background: Poor medication management may contribute to the increased morbidity and mortality of Aboriginal people in Australia. Yet while there is extensive literature about the perceptions of healthcare providers on this issue, there is limited information on the perceptions of Aboriginal people themselves.

Objectives: To investigate the perceptions of a group of Aboriginal people attending a Victorian regional Aboriginal Health Service (AHS) with diagnosed medical conditions requiring medications, of their lifestyle, disease management and medication usage.

Methods: Data was collected through one to one in depth interviews using a semi-structured 'yarning' process. Twenty patients were invited to participate in the study and were interviewed by Aboriginal Health Workers in a culturally appropriate manner. The interviews were recorded and transcribed verbatim. The data were analysed using descriptive statistics.

Results: Our results show that the majority of participants perceived that changes in lifestyle factors such as diet, exercise, and smoking cessation would help improve their health. Most patients reported having been counselled on their medicines, and while the majority reported adherence and acknowledgement of the efficacy of their medicines, there was a lack of clarity regarding long term maintenance on regimens. Finally, while the majority reported taking over the counter products, some did not see the need to inform their doctor about this, or chose not to.

Conclusion: Chronic illness was perceived as common in families and community. Patients relied mostly on their health care professionals as sources for their drug information. Patients may have benefited from further counselling in the area of complementary and other over the counter medicines, as well as on the necessity of maintenance of regimes for chronic disease management. Finally, lifestyle changes such as dietary improvements and smoking cessation were identified as areas that may assist in improving health outcomes.
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http://dx.doi.org/10.18549/PharmPract.2016.03.798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061524PMC
September 2016

Omega 3 polyunsaturated fatty acids and the treatment of depression.

Crit Rev Food Sci Nutr 2017 Jan;57(1):212-223

b School of Pharmacy, La Trobe University , Victoria , Australia.

Depression is a common, recurrent, and debilitating illness that has become more prevalent over the past 100 years. This report reviews the etiology and pathophysiology of depression, and explores the role of omega 3 polyunsaturated fatty acids (n-3 PUFA) as a possible treatment. In seeking to understand depression, genetic factors and environmental influences have been extensively investigated. Research has led to several hypotheses for the pathophysiological basis of depression but a definitive pathogenic mechanism, or group thereof, has hitherto remained equivocal. To date, treatment has been based on the monoamine hypothesis and hence, selective serotonin reuptake inhibitors have been the most widely used class of medication. In the last decade, there has been considerable interest in n-3 PUFAs and their role in depression. These fatty acids are critical for development and function of the central nervous system. Increasing evidence from epidemiological, laboratory, and randomized placebo-controlled trials suggests deficiency of dietary n-3 PUFAs may contribute to development of mood disorders, and supplementation with n-3 PUFAs may provide a new treatment option. Conclusions based on systematic reviews and meta-analyses of published trials to date vary. Research into the effects of n-3 PUFAs on depressed mood is limited. Furthermore, results from such have led to conflicting conclusions regarding the efficacy of n-3 PUFAs in affecting reduction in symptoms of depression. PUFAs are generally well tolerated by adults and children although mild gastrointestinal effects are reported. There is mounting evidence to suggest that n-3 PUFAs play a role in depression and deserve greater research efforts.
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http://dx.doi.org/10.1080/10408398.2013.876959DOI Listing
January 2017

Dynamic interactions between prophages induce lysis in Propionibacterium acnes.

Res Microbiol 2017 Feb - Mar;168(2):103-112. Epub 2016 Sep 14.

Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia. Electronic address:

Progress in next-generation sequencing technologies has facilitated investigations into microbial dynamics. An important bacterium in the dairy industry is Propionibacterium freudenreichii, which is exploited to manufacture Swiss cheeses. A healthy culture of these bacteria ensures a consistent cheese with formed 'eyes' and pleasant flavour profile, and the investigation of prophages and their interactions with these bacteria could assist in the maintenance of the standard of this food product. Two bacteriophages, termed PFR1 and PFR2, were chemically induced using mitomycin C from two different dairy strains of P. freudenreichii. Both phages have identical genomes; however, PFR2 was found to contain an insertion sequence, IS204. Host range characterisation showed that PFR1 was able to form plaques on a wild type Propionibacterium acnes strain, whereas PFR2 could not. The lytic plaques observed on P. acnes were a result of PFR1 inducing the lytic cycle of a pseudolysogenic phage in P. acnes. Further investigation revealed that both PFR1 and PFR2 could infect P. acnes but not replicate. This study demonstrates the dynamic interactions between phages, which may alter their lytic capacity under certain conditions. To our knowledge, this is the first report of two phages interacting to kill their host.
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http://dx.doi.org/10.1016/j.resmic.2016.09.004DOI Listing
March 2017

Locating and Activating Molecular 'Time Bombs': Induction of Mycolata Prophages.

PLoS One 2016 3;11(8):e0159957. Epub 2016 Aug 3.

Department of Physiology, Anatomy and Microbiology, La Trobe University Bundoora, VIC, Australia.

Little is known about the prevalence, functionality and ecological roles of temperate phages for members of the mycolic acid producing bacteria, the Mycolata. While many lytic phages infective for these organisms have been isolated, and assessed for their suitability for use as biological control agents of activated sludge foaming, no studies have investigated how temperate phages might be induced for this purpose. Bioinformatic analysis using the PHAge Search Tool (PHAST) on Mycolata whole genome sequence data in GenBank for members of the genera Gordonia, Mycobacterium, Nocardia, Rhodococcus, and Tsukamurella revealed 83% contained putative prophage DNA sequences. Subsequent prophage inductions using mitomycin C were conducted on 17 Mycolata strains. This led to the isolation and genome characterization of three novel Caudovirales temperate phages, namely GAL1, GMA1, and TPA4, induced from Gordonia alkanivorans, Gordonia malaquae, and Tsukamurella paurometabola, respectively. All possessed highly distinctive dsDNA genome sequences.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159957PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972346PMC
August 2017

Skeletal Fluorosis Due To Inhalation Abuse of a Difluoroethane-Containing Computer Cleaner.

J Bone Miner Res 2017 01 14;32(1):188-195. Epub 2016 Oct 14.

Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.

Skeletal fluorosis (SF) is endemic in many countries and millions of people are affected worldwide, whereas in the United States SF is rare with occasional descriptions of unique cases. We report a 28-year-old American man who was healthy until 2 years earlier when he gradually experienced difficulty walking and an abnormal gait, left hip pain, loss of mobility in his right wrist and forearm, and progressive deformities including enlargement of the digits of both hands. Dual-energy X-ray absorptiometry (DXA) of his lumbar spine, femoral neck, total hip, and the one-third forearm revealed bone mineral density (BMD) Z-scores of +6.2, +4.8, +3.0, and -0.2, respectively. Serum, urine, and bone fluoride levels were all elevated and ultimately explained by chronic sniffing abuse of a computer cleaner containing 1,1-difluoroethane. Our findings reflect SF due to the unusual cause of inhalation abuse of difluoroethane. Because this practice seems widespread, particularly in the young, there may be many more such cases. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.2923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977397PMC
January 2017

Genome Sequences of Pseudomonas oryzihabitans Phage POR1 and Pseudomonas aeruginosa Phage PAE1.

Genome Announc 2016 Jun 16;4(3). Epub 2016 Jun 16.

Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia

We report the genome sequences of two double-stranded DNA siphoviruses, POR1 infective for Pseudomonas oryzihabitans and PAE1 infective for Pseudomonas aeruginosa The phage POR1 genome showed no nucleotide sequence homology to any other DNA phage sequence in the GenBank database, while phage PAE1 displayed synteny to P. aeruginosa phages M6, MP1412, and YuA.
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http://dx.doi.org/10.1128/genomeA.01515-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911491PMC
June 2016

The Formulation of Bacteriophage in a Semi Solid Preparation for Control of Propionibacterium acnes Growth.

PLoS One 2016 10;11(3):e0151184. Epub 2016 Mar 10.

La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC, Australia.

Aims: To isolate and characterise phage which could lyse P. acnes and to formulate the phage into a delivery form for potential application in topical treatment of acne infection.

Methods And Results: Using standard phage isolation techniques, ten phage capable of lysing P. acnes were isolated from human skin microflora. Their genomes showed high homology to previously reported P. acnes phage. These phage were formulated into cetomacrogol cream aqueous at a concentration of 2.5x108 PFU per gram, and shown to lyse underlying P. acnes cells grown as lawn cultures. These phage formulations remained active for at least 90 days when stored at four degrees Celsius in a light protected container.

Conclusions: P. acnes phage formulated into cetomacrogol cream aqueous will lyse surrounding and underlying P. acnes bacteria, and are effective for at least 90 days if stored appropriately.

Significance And Impact Of The Study: There are few reports of phage formulation into semi solid preparations for application as phage therapy. The formulation method described here could potentially be applied topically to treat human acne infections. The potential exists for this model to be extended to other phage applied to treat other bacterial skin infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786141PMC
November 2016
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