404 results on '"O'Brien DP"'
Search Results
2. Precision Medicine in Cats: Novel Niemann‐Pick Type C1 Diagnosed by Whole‐Genome Sequencing
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Mauler, DA, Gandolfi, B, Reinero, CR, O'Brien, DP, Spooner, JL, Lyons, LA, Aberdein, Danielle, Alves, Paulo C, Barsh, Gregory S, Beale, Holly C, Boyko, Adam R, Brockman, Jeffrey A, Castelhano, Marta G, Chan, Patricia P, Matthew Ellinwood, N, Fogle, Jonathan E, Garrick, Dorian J, Helps, Christopher R, Hytönen, Marjo K, Kaukonen, Maria, Kaelin, Christopher B, Leclerc, Emilie, Leeb, Tosso, Lohi, Hannes, Longeri, Maria, Malik, Richard, Montague, Michael J, Munday, John S, Murphy, William J, Pedersen, Niels C, Rothschild, Max F, Stern, Joshua A, Swanson, William F, Terio, Karen A, Todhunter, Rory J, Ueda, Yu, Warren, Wesley C, Wilcox, Elizabeth A, and Wildschutte, Julia H
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Genetics ,HIV/AIDS ,Human Genome ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Generic health relevance ,Good Health and Well Being ,Animals ,Cat Diseases ,Cats ,Female ,Genome ,Niemann-Pick Disease ,Type C ,Precision Medicine ,Sequence Analysis ,DNA ,and 99 Lives Consortium ,Felis silvestris catus ,NPC1 ,WGS ,Feline ,Lysosomal storage ,Veterinary Sciences - Abstract
State-of-the-art health care includes genome sequencing of the patient to identify genetic variants that contribute to either the cause of their malady or variants that can be targeted to improve treatment. The goal was to introduce state-of-the-art health care to cats using genomics and a precision medicine approach. To test the feasibility of a precision medicine approach in domestic cats, a single cat that presented to the University of Missouri, Veterinary Health Center with an undiagnosed neurologic disease was whole-genome sequenced. The DNA variants from the cat were compared to the DNA variant database produced by the 99 Lives Cat Genome Sequencing Consortium. Approximately 25× genomic coverage was produced for the cat. A predicted p.H441P missense mutation was identified in NPC1, the gene causing Niemann-Pick type C1 on cat chromosome D3.47456793 caused by an adenine-to-cytosine transversion, c.1322A>C. The cat was homozygous for the variant. The variant was not identified in any other 73 domestic and 9 wild felids in the sequence database or 190 additionally genotyped cats of various breeds. The successful effort suggested precision medicine is feasible for cats and other undiagnosed cats may benefit from a genomic analysis approach. The 99 Lives DNA variant database was sufficient but would benefit from additional cat sequences. Other cats with the mutation may be identified and could be introduced as a new biomedical model for NPC1. A genetic test could eliminate the disease variant from the population.
- Published
- 2017
3. The missing large impact craters on Ceres.
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Marchi, S, Ermakov, AI, Raymond, CA, Fu, RR, O'Brien, DP, Bland, MT, Ammannito, E, De Sanctis, MC, Bowling, T, Schenk, P, Scully, JEC, Buczkowski, DL, Williams, DA, Hiesinger, H, and Russell, CT
- Abstract
Asteroids provide fundamental clues to the formation and evolution of planetesimals. Collisional models based on the depletion of the primordial main belt of asteroids predict 10-15 craters >400 km should have formed on Ceres, the largest object between Mars and Jupiter, over the last 4.55 Gyr. Likewise, an extrapolation from the asteroid Vesta would require at least 6-7 such basins. However, Ceres' surface appears devoid of impact craters >∼280 km. Here, we show a significant depletion of cerean craters down to 100-150 km in diameter. The overall scarcity of recognizable large craters is incompatible with collisional models, even in the case of a late implantation of Ceres in the main belt, a possibility raised by the presence of ammoniated phyllosilicates. Our results indicate that a significant population of large craters has been obliterated, implying that long-wavelength topography viscously relaxed or that Ceres experienced protracted widespread resurfacing.
- Published
- 2016
4. Gregarious behaviour in crustacean micronekton (Euphausiacea, Mysidacea)
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O'Brien, DP
- Abstract
Certain species of pelagic euphausiids and hyperbenthic mysids (Crustacea) show highly integrated social behaviour comparable in many aspects to schooling in higher marine organisms such as fish, squid and mammals. The ethology, form, maintenance, occurrence and population structure of aggregations of three species of euphausiid and six species of mysid are described. An attempt is made to define the adaptive advantages and selective pressures determining the characteristics of social behaviour of marine crustaceans as a whole, between orders, and between species. The general internal structure and dynamics of aggregations were determined using a three-dimensional stereophotographic technique capable of estimating distances between individuals as small as 5 mm in length. Results show that euphausiid and mysid aggregations are similar in overall structure. Within species, schools and swarms showed similar characteristics apart from their degree of polarization. Physical parameters, e.g., current and light, had little effect on internal structure; variation between species could generally be related to differences in habitat selection, i.e., pelagic or hyperbenthic, substrate or non-substrate associated. The degree of behavioural integration was demonstrated in the array of escape responses exhibited by these crustaceans. A scheme is proposed in which the responses are divided into three categories (primary, secondary and tertiary). Manifestation of a particular level of response was dependant upon the level of integration between individuals, the size of the aggregation, and predator size and distance. With increased threat the group response (predominantly primary and secondary forms) was progressively substituted by an individual response (tertiary form). In mysids substrate attraction also influenced the form of response. External morphology of the aggregations varied according to the behavioural state, movement and/or relative substrate attraction. The direction and polarization of light can influence individual alignment and the overall direction of travel in euphausiids. Aggregations of all species were generally derived from a single size/age class, and had a relatively constant sex ratio of 1 : 1. Mysids aggregated throughout the year, with variation in the gregarious habit within a species being determined by such external influences as antipredator responses and/or strong currents, and variation between species determined in the main by habitat selection. A new scheme describing mysid aggregations based on mechanisms influencing their formation and maintenance is proposed. Evidence for the persistence of social behaviour throughout the year in euphausiids is also presented, with variation within species being related to behavioural influences such as food availability, reproduction, maintenance of contact with conspecifics and possibly maturation in sub-adults. Stranding behaviour in the local species of euphausiid, Nyctiphanes australls, is shown to occur on a regular seasonal basis, and I provide evidence for the hypothesis that the swarm migrations associated with stranding events are probably related to reproductive facilitation. A new form of aggregative behaviour in euphausiids, termed matting, is described which occurs synchronously with stranding behaviour. The high level of integration and absence of strong passive mechanisms in the formation of aggregations, together with the relatively small influence of physical parameters on internal structure suggest that micronektonic crustacean aggregations are formed in response to internal biological mechanisms. Crustaceans demonstrate the ability to adapt their social behaviour in response to variation in both intrinsic and extrinsic factors. The selective pressures determining the form of aggregative behaviour in crustaceans are generally similar for the species studied.
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- 2023
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5. Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides
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O'Brien, DP, Jones, HBL, Guenther, F, Murphy, EJ, England, KS, Anderson, M, Brennan, P, Davis, JB, Pinto-Fernandez, A, Turnbull, AP, and Kessler, BM
- Abstract
Dampening functional levels of the mitochondrial deubiquitylating enzyme USP30 has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson’s Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide containing compound,39. Activity-based protein profiling (ABPP) mass spectrometry confirmed target engagement, the high selectivity, and potency of39for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line.In vitrocharacterization of39enzyme kinetics infers slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen-deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with39, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that39binds to the thumb-palm cleft that guides the ubiquitin C-terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.
- Published
- 2022
6. Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19
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Vere, G, Alam, MR, Farrar, S, Kealy, R, Kessler, BM, O’Brien, DP, and Pinto-Fernández, A
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SARS-CoV-2 ,Ubiquitin ,Ubiquitination ,Animals ,COVID-19 ,Cytokines ,Humans ,Protein Processing, Post-Translational ,Ubiquitins ,Molecular Biology ,Biochemistry ,COVID-19 Drug Treatment - Abstract
Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways by removing ubiquitin and/or ISG15 from proteins using a protease called PLpro, but also by interacting with enzymes involved in ubiquitin/ISG15 machinery. These enable viral replication and avoidance of the host immune system. In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host–pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease.
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- 2022
7. A PCR-RFLP marker for the erythroid aminolevulinate synthase gene (ALAS2) on canine chromosome X
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D Nonneman, Gary S. Johnson, G Boyer, Hisashi Shibuya, O'Brien Dp, and S J Stoy
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Male ,X Chromosome ,Molecular Sequence Data ,Biology ,Polymerase Chain Reaction ,Dogs ,Gene mapping ,Genetics ,Animals ,Gene ,Aminolevulinate synthase ,X chromosome ,Alleles ,DNA Primers ,chemistry.chemical_classification ,Base Sequence ,Chromosome Mapping ,General Medicine ,ALAS2 ,Molecular biology ,Pedigree ,Enzyme ,chemistry ,Genetic marker ,Animal Science and Zoology ,Female ,Restriction fragment length polymorphism ,Polymorphism, Restriction Fragment Length ,5-Aminolevulinate Synthetase - Published
- 1995
8. Localised Mycobacterium ulcerans infection in four dogs
- Author
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O'Brien, CR, primary, McMillan, E, additional, Harris, O, additional, O'Brien, DP, additional, Lavender, CJ, additional, Globan, M, additional, Legione, AR, additional, and Fyfe, JA, additional
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- 2011
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9. Comparison of fine-needle aspiration biopsy, Doppler ultrasound, and radionuclide scintigraphy in the diagnosis of acute allograft dysfunction in renal transplant recipients: sensitivity, specificity, and cost analysis
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Campbell Wg, Delaney, Bourke Je, Ling Bn, O'Brien Dp rd, Taylor At, Fekete Ps, and Whelchel Jd
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Graft Rejection ,medicine.medical_specialty ,Scintigraphy ,Sensitivity and Specificity ,Nephropathy ,Biopsy ,medicine ,Humans ,Radionuclide Imaging ,Acute tubular necrosis ,Ultrasonography ,medicine.diagnostic_test ,business.industry ,Biopsy, Needle ,Kidney Tubular Necrosis, Acute ,Ciclosporin ,medicine.disease ,Kidney Transplantation ,Transplantation ,Fine-needle aspiration ,Evaluation Studies as Topic ,Acute Disease ,Costs and Cost Analysis ,Cyclosporine ,Radiology ,Complication ,business ,medicine.drug - Abstract
150 episodes of allograft dysfunction in 128 renal transplant recipients, 77 due to acute rejection, 32 secondary to acute-on-chronic rejection, 33 due to either prerenal factors, acute tubular necrosis, or ciclosporin A nephrotoxicity, and 8 secondary to multiple causes, were evaluated by fine-needle aspiration biopsy (FNAB), Doppler ultrasound (DUS), and radionuclide scintigraphy (RS), each performed within a 24-hour period and prior to any specific therapeutic intervention. Tests were interpreted by appropriate specialists in a large transplant center without access to clinical information. The final diagnosis was based primarily upon response to therapeutic maneuvers with histological (core biopsy) confirmation in 123 episodes. RS was the most sensitive (70%) test for the diagnosis of acute rejection during the early posttransplant period, exceeding both FNAB (52%) and DUS (43%). The predictive accuracy of either FNAB, DUS, RS, or core biopsy in the detection of a steroid-responsive component to acute rejection when superimposed upon chronic rejection was low at approximately 50%. When the underlying cause of renal dysfunction was either prerenal, acute tubular necrosis, or ciclosporin A nephrotoxicity, FNAB, DUS, and RS each gave an erroneous diagnosis of acute rejection in about 50% of the episodes. Cost analysis revealed that core biopsy was the most expensive test, but only 9% more than RS, with FNAB the least costly. In conclusion, the lack of ideal sensitivity and specificity combined with the expense of present-day FNAB, DUS, RS, and core biopsy in the diagnosis of a therapeutically reversible component to acute-on-chronic rejection and of FNAB, DUS, and RS in the diagnosis of acute rejection during the early posttransplant period should prompt research into ways to improve their diagnostic yield or alternate modalities.
- Published
- 1993
10. Purification and characterization of factor VII 304-Gln: a variant molecule with reduced activity isolated from a clinically unaffected male
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O'Brien, DP, primary, Gale, KM, additional, Anderson, JS, additional, McVey, JH, additional, Miller, GJ, additional, Meade, TW, additional, and Tuddenham, EG, additional
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- 1991
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11. Purification and characterization of factor VIII 372-Cys: a hypofunctional cofactor from a patient with moderately severe hemophilia A
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O'Brien, DP, primary, Pattinson, JK, additional, and Tuddenham, EG, additional
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- 1990
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12. Dengue Fever in travelers returning from southeast Asia.
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Sung V, O'Brien DP, Matchett E, Brown GV, Torresi J, Sung, Valerie, O'Brien, Daniel P, Matchett, Elizabeth, Brown, Graham V, and Torresi, Joseph
- Abstract
Background: Dengue fever is an important illness facing travelers from nonendemic to endemic countries.Methods: We reviewed 696 consecutive returned travelers managed at an Australian tertiary-care hospital for an illness acquired overseas. Patients with dengue fever were compared to those with a dengue-like illness, malaria, typhoid fever and rickettsial infections.Results: In total, 19 cases of dengue fever and 20 cases of dengue-like illness were diagnosed, with 85% of cases acquired in Asia. The most common presenting features of dengue were fever (100%), myalgia (79%), rash (74%), headache (68%), nausea (37%), and diarrhea (37%). Compared to those with malaria, typhoid fever and rickettsial infections, patients with dengue were significantly more likely to have myalgia and a temperature <39 degrees C. Compared to all other illnesses in our returned travelers, dengue fever was 18 times more likely if fever and leukopenia were present, 71 times if fever and rash were present, and 230 times if fever, rash and leukopenia were present. All patients with dengue recovered completely.Conclusions: Dengue fever is an important health problem for travelers not only to Southeast Asia but to all endemic countries. The prevalence appears to be increasing in travelers, and health care professionals need to be familiar with its presentation in travelers. The clinical presenting features provide important guides to establishing the diagnosis. [ABSTRACT FROM AUTHOR]- Published
- 2003
13. Automated purification of DNA from large samples: a study of effectiveness and labor efficiency.
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O'Brien DP, Benedict KA, Morken NW, Heath EM, Bleecker ER, and Howard TD
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Investigations into the underlying genetic contributions to human disease are transitioning from small family-based traditional linkage analyses to large population-based studies designed to identify genetic factors in more complex and common diseases that have the greatest impact on human health. These types of studies have driven the need for larger numbers of samples for analysis and more efficient and effective methods for DNA purification, especially for large samples that provide sufficient quantities of DNA for extensive analysis. The AUTOPURE LST Nucleic Acid Purification Instrument, by Gentra Systems, Inc., a platform capable of high-throughput sample purification from large samples, was developed to meet the demands of these large studies. This article presents data demonstrating the equivalency of DNA purified using the AUTOPURE LS automated instrument and the manual method based on the same purification process. In addition, we present data demonstrating the in-lab time savings realized by automating the purification process. [ABSTRACT FROM AUTHOR]
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- 2002
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14. "Paradoxical" immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure.
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O'Brien DP, Robson ME, Callan PP, McDonald AH, O'Brien, Daniel P, Robson, Michael E, Callan, Peter P, and McDonald, Anthony H
- Abstract
We present the first clinical descriptions of immune-mediated paradoxical reactions to effective antibiotic treatment for Mycobacterium ulcerans infection, which result in clinical deterioration after initial improvement. Recognition of this phenomenon could prevent unnecessary changes to antibiotic regimens, and might obviate the need for, or reduce the extent of, further surgery. [ABSTRACT FROM AUTHOR]
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- 2009
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15. Acute rheumatic fever: an unusual cause of fever in a returned traveler.
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Catanchin A, O'Brien DP, Athan E, Catanchin, Andrei, O'Brien, Daniel P, and Athan, Eugene
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Acute rheumatic fever presenting as fever in a returned traveler has not previously been described. We report one such case. [ABSTRACT FROM AUTHOR]
- Published
- 2005
16. Purification and characterization of factor VIII 1,689-Cys: a nonfunctional cofactor occurring in a patient with severe hemophilia A
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O'Brien, DP and Tuddenham, EG
- Abstract
We have purified the factor VIII from a CRM+ Hemophilia A plasma (90 U/dL VIII:Ag but 0 U/dL VIII:C) and analyzed the protein before and after thrombin activation by Western blotting with monoclonal antibodies (MoAbs). Normal or patient citrated plasma was ultracentrifuged, cryo-ethanol-precipitated and chromatographed on Sepharose 6B. The void volume fractions were reduced and subjected to ion exchange chromatography yielding material of specific activity approximately 1,000 U/mg protein (VIII:C or VIII:Ag). Factor VIII purified in this way from normal plasma is fully activatable by thrombin with proteolytic fragmentation as previously described by F. Rotblat et al (Biochemistry 24: 4294, 1985). Factor VIII 1,689-Cys has the normal distribution of factor VIII light and heavy chains prior to thrombin activation. After exposure to thrombin the heavy chain polypeptides were fully proteolysed but the light chain was totally resistant to cleavage. This is consistent with the demonstration in the patient's leucocyte DNA of a C to T transition in codon 1,689 converting Arg to Cys at the light chain thrombin cleavage site as previously described by J. Gitschier et al (Blood 72:1022, 1988). Uncleaved light chain of Factor VIII 1,689-Cys is not released from von Willebrand factor (vWF) by thrombin, but this is not the sole cause of the functional defect since the protein purified free of vWF has no coagulant activity. We conclude that the functional defect in factor VIII 1,689-Cys is a consequence of failure to release the acidic peptide from the light chain upon thrombin activation.
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- 1989
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17. Preparation of factor IX deficient human plasma by immunoaffinity chromatography using a monoclonal antibody
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Goodall, AH, Kemble, G, O'Brien, DP, Rawlings, E, Rotblat, F, Russell, GC, Janossy, G, and Tuddenham, EG
- Abstract
A murine hybridoma clone is described that grows continuously in culture and produces a monoclonal antibody we have called Royal Free Monoclonal Antibody to factor IX No. 1 (RFF-IX/1). This has high affinity for a coagulation site on factor IX. RFF-IX/1 immobilised on sepharose can be used to deplete factor IX from normal human plasma. This immunoaffinity depleted plasma is indistinguishable from severe Christmas disease plasma and can be used as the substrate in a one stage coagulation assay for factor IX. The affinity column has high capacity and can be regenerated so that large scale production from normal plasma of factor IX deficient plasma as a diagnostic reagent is now feasible.
- Published
- 1982
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18. Intramedullary spinal ependymoma in a dog
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Ely Rw, Zachary Jf, and O'Brien Dp
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0301 basic medicine ,Ependymoma ,Male ,medicine.medical_specialty ,030102 biochemistry & molecular biology ,General Veterinary ,business.industry ,medicine.disease ,law.invention ,Intramedullary rod ,03 medical and health sciences ,0302 clinical medicine ,Dogs ,law ,030220 oncology & carcinogenesis ,medicine ,Animals ,Radiology ,Dog Diseases ,Spinal Cord Neoplasms ,business - Published
- 1981
19. Direct observations of clustering (schooling and swarming) behaviour in mysids (Crustacea: Mysidacea)
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O'Brien, DP, primary
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- 1988
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20. Surface schooling behaviour of the coastal krill Nyctiphanes australis (Crustacea: Euphausiacea) off Tasmania, Australia
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O'Brien, DP, primary
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- 1988
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21. Act fast, stop COVID: The successful implementation of the first decentralised Victorian COVID-19 contact tracing and monitoring unit.
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McNamara BJ, McDonald J, Heard K, Friedman ND, Diver F, Athan E, Wade AJ, Brennan F, Warburton M, Bartolo C, Maggs C, Miller N, Smith M, Stenos J, and O'Brien DP
- Abstract
Objectives: To describe the operational model, epidemiology and outcomes of COVID-19 cases managed by the first decentralised Victorian Public Health Unit (PHU) in the Barwon South-West (BSW) region in 2020., Methods: The Barwon Health team used a clinician-led, locally-based interprofessional model of care, combining clinical care and monitoring, contact tracing and public health measures., Results: From 7th March to 5th October 2020, 575 confirmed COVID-19 cases (82 in Wave 1; 493 in Wave 2) were identified in residents of the BSW region. Overall, 4.7% were admitted to local hospitals (0.7% to intensive care units) and 1.7% died. COVID-19 incidence in the region was 129 cases/100,000. Wave 2 in the region featured community transmission in high-risk settings and among culturally and linguistically diverse and mobile populations. Within 3 months of the initial local case in Wave 2, SARS-COV-2 was eliminated from the community., Conclusions: A local interprofessional model of care was key to the containment of community transmission and complex outbreaks with the elimination of COVID-19 in the community., Implications for Public Health: Key successes and learnings from the BSW PHU contributed to the improvement of statewide systems and responses and provided an impetus for the implementation of a decentralised public health model for Victoria., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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22. Prevalence, risk factors, and outcomes of secondary infections among hospitalized patients with COVID-19 or post-COVID-19 conditions in Victoria, 2020-2023.
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Murray HC, Muleme M, Cooper D, McNamara BJ, Hussain MA, Bartolo C, O'Brien DP, and Athan E
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- Humans, Victoria epidemiology, Female, Male, Risk Factors, Aged, Middle Aged, Prevalence, Adult, Young Adult, Adolescent, Length of Stay statistics & numerical data, Aged, 80 and over, Coinfection epidemiology, Child, Preschool, Infant, Child, Intensive Care Units statistics & numerical data, Sepsis epidemiology, Sepsis mortality, Bacterial Infections epidemiology, Bacterial Infections mortality, Mycoses epidemiology, Infant, Newborn, COVID-19 epidemiology, COVID-19 mortality, Hospitalization statistics & numerical data, SARS-CoV-2
- Abstract
Objectives: Estimates of secondary infections are variedly reported, with few studies done in Australia. We investigated the occurrence and impact of secondary infections complicating COVID-19 and post-COVID-19 admissions in Victoria, Australia, 2020-2023., Methods: We used linked population-wide data sets and specific International Classification of Disease, 10th Revision codes to identify and estimate the occurrence of secondary infections. Using hospital/intensive care unit length of stay in negative binomial regression and mortality, we examined the impact of secondary infections., Results: Secondary infections were identified in 6.9% (13,467 of 194,660) of COVID-19 and post-COVID-19 admissions: 6.0% (11,651 of 194,660) bacterial, 0.9% (1691 of 194,660) viral, and 0.2% (385 of 194,660) fungal. Prevalence was highest during the pre-Delta (10.4%) and Omicron-BA2 (8.1%) periods. Sepsis and pneumonia were the most reported syndromes; the occurrence of sepsis declined gradually over time. The odds of secondary infections were higher among the ≥70-year-olds (adjusted odds ratio (aOR) 3.76, 95% confidence interval [CI] 3.43-4.14, vs 20-29-year-olds), individuals with chronic conditions (aOR 3.15, 95% CI 2.88-3.45, vs those without), the unvaccinated (aOR 1.59, 95% CI 1.45-1.75), and the lowest socioeconomic group (aOR 1.12, 95% CI 1.05-1.19). Patients with secondary infections had 2.43 times longer hospital length of stay and 9.60 times longer intensive care unit length of stay than those without secondary infections. The mortality risk was 2.17 times higher in those with secondary infections., Conclusions: Secondary infections occurred in 69 per 1000 COVID-19-associated hospital admissions in Victoria, mostly in high-risk groups, and were associated with severe outcomes., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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23. Editorial: Beyond protein degradation and lysine modification: novel insights into non-canonical ubiquitination.
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Sapmaz A, Gan J, O'Brien DP, and Pinto-Fernández A
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2024
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24. Deubiquitinases in muscle physiology and disorders.
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Olie CS, O'Brien DP, Jones HBL, Liang Z, Damianou A, Sur-Erdem I, Pinto-Fernández A, Raz V, and Kessler BM
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- Humans, Animals, Muscle, Skeletal metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism, Neuromuscular Diseases metabolism, Neuromuscular Diseases genetics, Neuromuscular Diseases physiopathology, Neuromuscular Diseases enzymology, Muscular Diseases metabolism, Muscular Diseases genetics, Mice, Proteostasis, Deubiquitinating Enzymes metabolism
- Abstract
In vivo, muscle and neuronal cells are post-mitotic, and their function is predominantly regulated by proteostasis, a multilayer molecular process that maintains a delicate balance of protein homeostasis. The ubiquitin-proteasome system (UPS) is a key regulator of proteostasis. A dysfunctional UPS is a hallmark of muscle ageing and is often impacted in neuromuscular disorders (NMDs). Malfunction of the UPS often results in aberrant protein accumulation which can lead to protein aggregation and/or mis-localization affecting its function. Deubiquitinating enzymes (DUBs) are key players in the UPS, controlling protein turnover and maintaining the free ubiquitin pool. Several mutations in DUB encoding genes are linked to human NMDs, such as ATXN3, OTUD7A, UCHL1 and USP14, whilst other NMDs are associated with dysregulation of DUB expression. USP5, USP9X and USP14 are implicated in synaptic transmission and remodeling at the neuromuscular junction. Mice lacking USP19 show increased maintenance of lean muscle mass. In this review, we highlight the involvement of DUBs in muscle physiology and NMDs, particularly in processes affecting muscle regeneration, degeneration and inflammation following muscle injury. DUBs have recently garnered much respect as promising drug targets, and their roles in muscle maturation, regeneration and degeneration may provide the framework for novel therapeutics to treat muscular disorders including NMDs, sarcopenia and cachexia., (© 2024 The Author(s).)
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- 2024
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25. Quantitative proteomics reveals CLR interactome in primary human cells.
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Manolis D, Hasan S, Maraveyas A, O'Brien DP, Kessler BM, Kramer H, and Nikitenko LL
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- Humans, Tandem Mass Spectrometry methods, Proteome metabolism, Proteome analysis, Endothelial Cells metabolism, Chromatography, Liquid methods, Proteomics methods, Calcitonin Receptor-Like Protein metabolism, Calcitonin Receptor-Like Protein genetics
- Abstract
The G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) mediates essential functions in several cell types and is implicated in cardiovascular pathologies, skin diseases, migraine, and cancer. To date, the network of proteins interacting with CLR ("CLR interactome") in primary cells, where this GPCR is expressed at endogenous (physiologically relevant) levels, remains unknown. To address this knowledge gap, we established a novel integrative methodological workflow/approach for conducting a comprehensive/proteome-wide analysis of Homo sapiens CLR interactome. We used primary human dermal lymphatic endothelial cells and combined immunoprecipitation utilizing anti-human CLR antibody with label-free quantitative nano LC-MS/MS and quantitative in situ proximity ligation assay. By using this workflow, we identified 37 proteins interacting with endogenously expressed CLR amongst 4902 detected members of the cellular proteome (by quantitative nano LC-MS/MS) and revealed direct interactions of two kinases and two transporters with this GPCR (by in situ proximity ligation assay). All identified interactors have not been previously reported as members of CLR interactome. Our approach and findings uncover the hitherto unrecognized compositional complexity of the interactome of endogenously expressed CLR and contribute to fundamental understanding of the biology of this GPCR. Collectively, our study provides a first-of-its-kind integrative methodological approach and datasets as valuable resources and robust platform/springboard for advancing the discovery and comprehensive characterization of physiologically relevant CLR interactome at a proteome-wide level in a range of cell types and diseases in future studies., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest related to the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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26. Identification of high-performing antibodies for the reliable detection of Tau proteoforms by Western blotting and immunohistochemistry.
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Ellis MJ, Lekka C, Holden KL, Tulmin H, Seedat F, O'Brien DP, Dhayal S, Zeissler ML, Knudsen JG, Kessler BM, Morgan NG, Todd JA, Richardson SJ, and Stefana MI
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- Humans, Phosphorylation, Alzheimer Disease diagnosis, Alzheimer Disease metabolism, Alzheimer Disease immunology, Reproducibility of Results, tau Proteins metabolism, tau Proteins immunology, Immunohistochemistry methods, Antibodies immunology, Blotting, Western, Brain metabolism, Brain pathology
- Abstract
Antibodies are essential research tools whose performance directly impacts research conclusions and reproducibility. Owing to its central role in Alzheimer's disease and other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau and its multiple proteoforms. Despite this breadth of offer, limited understanding of their performance and poor antibody selectivity have hindered research progress. Here, we validate a large panel of Tau antibodies by Western blot (79 reagents) and immunohistochemistry (35 reagents). We address the reagents' ability to detect the target proteoform, selectivity, the impact of protein phosphorylation on antibody binding and performance in human brain samples. While most antibodies detected Tau at high levels, many failed to detect it at lower, endogenous levels. By WB, non-selective binding to other proteins affected over half of the antibodies tested, with several cross-reacting with the related MAP2 protein, whereas the "oligomeric Tau" T22 antibody reacted with monomeric Tau by WB, thus calling into question its specificity to Tau oligomers. Despite the presumption that "total" Tau antibodies are agnostic to post-translational modifications, we found that phosphorylation partially inhibits binding for many such antibodies, including the popular Tau-5 clone. We further combine high-sensitivity reagents, mass-spectrometry proteomics and cDNA sequencing to demonstrate that presumptive Tau "knockout" human cells continue to express residual protein arising through exon skipping, providing evidence of previously unappreciated gene plasticity. Finally, probing of human brain samples with a large panel of antibodies revealed the presence of C-term-truncated versions of all main Tau brain isoforms in both control and tauopathy donors. Ultimately, we identify a validated panel of Tau antibodies that can be employed in Western blotting and/or immunohistochemistry to reliably detect even low levels of Tau expression with high selectivity. This work represents an extensive resource that will enable the re-interpretation of published data, improve reproducibility in Tau research, and overall accelerate scientific progress., (© 2024. The Author(s).)
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- 2024
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27. Mycobacterium ulcerans challenge strain selection for a Buruli ulcer controlled human infection model.
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Muhi S, Buultjens AH, Porter JL, Marshall JL, Doerflinger M, Pidot SJ, O'Brien DP, Johnson PDR, Lavender CJ, Globan M, McCarthy J, Osowicki J, and Stinear TP
- Subjects
- Humans, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacology, Australia, Mycobacterium ulcerans genetics, Buruli Ulcer microbiology, Buruli Ulcer immunology
- Abstract
Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A controlled human infection model has the potential to accelerate our knowledge of the immunological correlates of disease, to test prophylactic interventions and novel therapeutics. Here we present microbiological evidence supporting M. ulcerans JKD8049 as a suitable human challenge strain. This non-genetically modified Australian isolate is susceptible to clinically relevant antibiotics, can be cultured in animal-free and surfactant-free media, can be enumerated for precise dosing, and has stable viability following cryopreservation. Infectious challenge of humans with JKD8049 is anticipated to imitate natural infection, as M. ulcerans JKD8049 is genetically stable following in vitro passage and produces the key virulence factor, mycolactone. Also reported are considerations for the manufacture, storage, and administration of M. ulcerans JKD8049 for controlled human infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Muhi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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28. Integrative multi-omics profiling in human decedents receiving pig heart xenografts.
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Schmauch E, Piening B, Mohebnasab M, Xia B, Zhu C, Stern J, Zhang W, Dowdell AK, Kim JI, Andrijevic D, Khalil K, Jaffe IS, Loza BL, Gragert L, Camellato BR, Oliveira MF, O'Brien DP, Chen HM, Weldon E, Gao H, Gandla D, Chang A, Bhatt R, Gao S, Lin X, Reddy KP, Kagermazova L, Habara AH, Widawsky S, Liang FX, Sall J, Loupy A, Heguy A, Taylor SEB, Zhu Y, Michael B, Jiang L, Jian R, Chong AS, Fairchild RL, Linna-Kuosmanen S, Kaikkonen MU, Tatapudi V, Lorber M, Ayares D, Mangiola M, Narula N, Moazami N, Pass H, Herati RS, Griesemer A, Kellis M, Snyder MP, Montgomery RA, Boeke JD, and Keating BJ
- Subjects
- Humans, Animals, Swine, Male, Female, Graft Rejection immunology, Graft Rejection genetics, Proteomics, Metabolomics, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear immunology, Transcriptome, Gene Expression Profiling, T-Lymphocytes immunology, T-Lymphocytes metabolism, Lipidomics, Reperfusion Injury immunology, Reperfusion Injury genetics, Reperfusion Injury metabolism, Multiomics, Heart Transplantation, Transplantation, Heterologous, Heterografts
- Abstract
In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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29. Use of targeted SMS messaging to encourage COVID-19 oral antiviral uptake in South West Victoria.
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Clarke NE, O'Keeffe J, Yerramilli A, Bartolo C, Mothobi N, Muleme M, McNamara BJ, O'Brien DP, Athan E, and Hussain A
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- Humans, Middle Aged, Aged, Victoria epidemiology, Cross-Sectional Studies, Surveys and Questionnaires, Antiviral Agents therapeutic use, COVID-19
- Abstract
Objectives: During winter 2022, as part of a multifaceted approach to optimise oral antiviral uptake in the Barwon South West region in Victoria, Australia, the Barwon South West Public Health Unit (BSWPHU) implemented an innovative, targeted SMS messaging program that encouraged people with coronavirus disease 2019 (COVID-19) to be assessed for antiviral treatment. In this study, we investigated patterns of antiviral uptake, identified barriers and facilitators to accessing antivirals, and examined the potential impact of targeted SMS messaging on oral antiviral uptake., Methods: We conducted a cross-sectional study of notified COVID-19 cases aged 50 years and older, and Aboriginal and Torres Strait Islander people aged 30-49 years, in the BSWPHU catchment area over a 6-week period commencing 21 July 2022. We analysed survey data using descriptive statistics and generalised linear models., Results: Of the 3829 survey respondents, 36.7% (95% confidence interval (CI) 35.2, 38.2) reported being prescribed oral antivirals, with 75.4% (95% CI 72.8, 77.9) of these aged ≥70. Antiviral prescriptions increased significantly over the 6-week survey period. Most prescriptions (87.5%; 95% CI 85.7, 89.2) were provided by the respondents' usual general practitioners (GPs). Barriers to receiving antivirals included respondents being unable to get a medical appointment in time (3.7%; 95% CI 3.1, 4.2), testing too late in their illness (2.3%; 95% CI 1.8, 2.8) and being unable to access medications in time after receiving a prescription (0.2%; 95% CI 0.1, 0.6). Facilitators to receiving antivirals included respondents first hearing about antivirals from a trusted source such as a family member, friend or usual doctor. Nearly one in eight people who were prescribed antivirals reported first hearing about them from the SMS message sent by BSWPHU., Conclusions: Oral antiviral treatment uptake in south-west Victoria in July-August 2022 was high among survey respondents and increased over time. GPs were the key prescribers in the community. Targeted SMS messaging to COVID-19 cases is a simple, low-cost intervention that potentially increases antiviral uptake., Competing Interests: None declared
- Published
- 2024
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30. Evaluation of severe traumatic brain injury referrals to the National Tertiary Neurosurgical Centre in the Republic of Ireland.
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Kamaludin AI, Amoo M, Henry J, Geoghegan P, Curley GF, O'Brien DP, and Javadpour M
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- Humans, Aged, Ireland epidemiology, Glasgow Coma Scale, Prognosis, Referral and Consultation, Brain Injuries, Traumatic diagnosis, Brain Injuries, Traumatic surgery
- Abstract
Background: Transfer of all severe TBI patients to a neurosurgical unit (NSU) has been advocated irrespective of levels of complexity and prognostic factors. Previous publications have suggested that only 50% of severe TBI patients in Ireland were managed in NSUs., Aims: This study aims to audit severe TBI referrals to the National Neurosurgical Centre, to evaluate reasons for nonacceptance, assess for differences in the transferred and not transferred cohorts and to analyse observed and expected mortality rates., Methods: Data on all patients with TBI referred in 2021 were prospectively collected using an electronic referral system. Patients with severe TBI (GCS ≤ 8 and AIS ≥ 3) were included and dichotomised into transferred and not transferred cohorts., Results: Of 118 patients referred with severe TBI, 45 patients (38.1%) were transferred to the neurosurgical centre. Patients in the transferred cohort were significantly younger (p < 0.001), had a higher GCS score (p < 0.001) and a lower proportion of bilaterally unreactive pupils (p < 0.001) compared to the not transferred cohort. 93% (68/73) of those not transferred were either >65 years old, or had bilaterally unreactive pupils, or both. Based on the IMPACT model, the observed to expected mortality ratios in the transferred and not transferred cohorts were 0.65 (95% CI 0.25-1.05) and 0.88 (95% CI 0.65-1.11) respectively., Conclusion: The observed mortality rate for severe TBI in Ireland was similar to or better than expected mortality rates when adjusted for important prognostic factors. 93% of severe TBI patients not transferred to a neurosurgical centre were either elderly or had bilaterally unreactive pupils or both. These patients have an extremely poor prognosis and recommendation for transfer cannot be made based on current available evidence., Competing Interests: Declaration of competing interest None of the authors have any pertinent conflicts of interest., (Copyright © 2023 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2024
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31. Tau depletion in human neurons mitigates Aβ-driven toxicity.
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Ng B, Vowles J, Bertherat F, Abey A, Kilfeather P, Beccano-Kelly D, Stefana MI, O'Brien DP, Bengoa-Vergniory N, Carling PJ, Todd JA, Caffrey TM, Connor-Robson N, Cowley SA, and Wade-Martins R
- Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt-/- mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types., (© 2024. The Author(s).)
- Published
- 2024
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32. A lesion in two: Buruli ulcer and squamous cell carcinoma coexistence.
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O'Keeffe JC, Yin AH, and O'Brien DP
- Subjects
- Male, Humans, Aged, Health Personnel, Australia, Buruli Ulcer therapy, Carcinoma, Squamous Cell complications, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell pathology, Skin Neoplasms complications, Skin Neoplasms diagnosis
- Abstract
The concurrent diagnoses of Buruli ulcer (BU) and cutaneous squamous cell carcinoma (SCC) is a phenomenon not previously described, despite the fact that both conditions are highly prevalent in Australia. This report presents an intriguing case of concurrent diagnoses, with clues alluding to more than one skin condition being present. The case involves a 73-year-old man with BU diagnosed on the scalp, an atypical location, which led to the consideration of malignancy, ultimately revealing concurrent SCC. This case highlights the importance of considering both conditions in patients with epidemiological risk factors, necessitating multiple lines of investigation for accurate diagnosis. Medical practitioners must remain vigilant and incorporate this possibility into their diagnostic algorithms for suspicious skin lesions to optimize treatment and outcomes. This is the first recorded instance of simultaneous diagnosis, underlining the need for enhanced awareness and attention to these unique cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 O’Keeffe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
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33. Use of Ultrasound-Assisted, Catheter-Directed Thrombolysis in a Patient With High-Risk Pulmonary Embolism.
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Gill KPS, O'Brien DP, and Soverow JE
- Subjects
- Humans, Female, Thrombolytic Therapy, Ultrasonography, Interventional, Treatment Outcome, Catheters, Tissue Plasminogen Activator adverse effects, Retrospective Studies, Fibrinolytic Agents therapeutic use, Pulmonary Embolism diagnosis, Pulmonary Embolism drug therapy, Pulmonary Embolism etiology
- Abstract
High-risk pulmonary embolism (PE) is a complex clinical entity associated with high mortality rates. Ultrasound-assisted, catheter-directed thrombolysis, typically used for intermediate-risk PE, may be a viable treatment approach for high-risk PE, particularly in patients at increased risk for major bleeding. This report describes a case in which ultrasound-assisted, catheter-directed thrombolysis was successfully used to treat high-risk PE in a female patient with extensive peritoneal metastases from gastric adenocarcinoma. Other examples from the literature, in which ultrasound-assisted, catheter-directed thrombolysis was used to treat high-risk PE, are also provided., (© 2024 The Authors. Published by The Texas Heart Institute®.)
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- 2024
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34. USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism.
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Gan J, Pinto-Fernández A, Flierman D, Akkermans JJLL, O'Brien DP, Greenwood H, Scott HC, Fritz G, Knobeloch KP, Neefjes J, van Dam H, Ovaa H, Ploegh HL, Kessler BM, Geurink PP, and Sapmaz A
- Subjects
- Ubiquitins genetics, Ubiquitins metabolism, Endopeptidases genetics, Endopeptidases metabolism, Peptide Hydrolases metabolism, Deubiquitinating Enzymes, Cytokines metabolism, Interferon Type I genetics, Interferon Type I metabolism
- Abstract
Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive proteases, these remain to be identified. Here, we identify deubiquitinase USP16 as an ISG15 cross-reactive protease by means of ISG15 activity-based profiling. Recombinant USP16 cleaved pro-ISG15 and ISG15 isopeptide-linked model substrates in vitro, as well as ISGylated substrates from cell lysates. Moreover, interferon-induced stimulation of ISGylation was increased by depletion of USP16. The USP16-dependent ISG15 interactome indicated that the deISGylating function of USP16 may regulate metabolic pathways. Targeted enzymes include malate dehydrogenase, cytoplasmic superoxide dismutase 1, fructose-bisphosphate aldolase A, and cytoplasmic glutamic-oxaloacetic transaminase 1. USP16 may thus contribute to the regulation of a subset of metabolism-related proteins during type-I interferon responses., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2023
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35. Is BCG vaccination of possums the solution to the Buruli ulcer epidemic in south-eastern Australia?
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O'Brien DP, Blasdell K, Muhi S, Marais BJ, Buddle B, McNamara B, and Athan E
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- Humans, BCG Vaccine, Vaccination, Australia epidemiology, Buruli Ulcer epidemiology, Buruli Ulcer prevention & control, Mycobacterium ulcerans
- Published
- 2023
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36. Effectiveness of community-based oral antiviral treatments against severe COVID-19 outcomes in people 70 years and over in Victoria, Australia, 2022: an observational study.
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Van Heer C, Majumdar SS, Parta I, Martinie M, Dawson R, West D, Hewett L, Lister D, Sutton B, O'Brien DP, and Cowie BC
- Abstract
Background: Oral Antiviral (OAV) COVID-19 treatments are widely used, but evidence for their effectiveness against the Omicron variant in higher risk, vaccinated individuals is limited., Methods: Retrospective study of two vaccinated cohorts of COVID-19 cases aged ≥70 years diagnosed during a BA.4/5 Omicron wave in Victoria, Australia. Cases received either nirmatrelvir-ritonavir or molnupiravir as their only treatment. Data linkage and logistic regression modelling was used to evaluate the association between treatment and death and hospitalisation and compared with no treatment., Findings: Of 38,933 individuals in the mortality study population, 13.5% (n = 5250) received nirmatrelvir-ritonavir, 51.3% (n = 19,962) received molnupiravir and 35.2% (n = 13,721) were untreated. Treatment was associated with a 57% (OR = 0.43, 95% CI 0.36-0.51) reduction in the odds of death, 73% (OR = 0.27, 95% CI 0.17-0.40) for nirmatrelvir-ritonavir and 55% (OR = 0.45, 95% CI 0.38-0.54) for molnupiravir. Treatment was associated with a 31% (OR = 0.69, 95% CI 0.55-0.86) reduction in the odds of hospitalisation, 40% (OR = 0.60, 95% CI 0.43-0.83) for nirmatrelvir-ritonavir and 29% (OR = 0.71, 95% CI 0.58-0.87) for molnupiravir. Cases treated within 1 day of diagnosis had a 61% reduction in the odds of death (OR = 0.39, 95% CI 0.33-0.46) compared with 33% reduction for a delay of 4 or more days (OR = 0.67, 95% CI 0.44-0.97)., Interpretation: Treatment with both nirmatrelvir-ritonavir or molnupiravir was associated with a reduction in death and hospitalisation in vaccinated ≥70 years individuals during the Omicron era. Timely, equitable treatment with OAVs is an important tool in the fight against COVID-19., Funding: There was no funding for this study., Competing Interests: No conflicts of interest or relevant disclosures existed for the authors., (Crown Copyright © 2023 Published by Elsevier Ltd.)
- Published
- 2023
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37. Comprehensive Case-Control Study of Protective and Risk Factors for Buruli Ulcer, Southeastern Australia.
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McNamara BJ, Blasdell KR, Yerramilli A, Smith IL, Clayton SL, Dunn M, Tay EL, Gibney KB, Waidyatillake NT, Hussain MA, Muleme M, O'Brien DP, and Athan E
- Subjects
- Adult, Humans, Case-Control Studies, Risk Factors, Victoria epidemiology, BCG Vaccine, Buruli Ulcer epidemiology, Buruli Ulcer prevention & control
- Abstract
To examine protective and risk factors for Buruli ulcer (BU), we conducted a case-control study of 245 adult BU cases and 481 postcode-matched controls across BU-endemic areas of Victoria, Australia. We calculated age- and sex-adjusted odds ratios for socio-environmental, host, and behavioral factors associated with BU by using conditional logistic regression. Odds of BU were >2-fold for persons with diabetes mellitus and persons working outdoors who had soil contact in BU-endemic areas (compared with indoor work) but were lower among persons who had bacillus Calmette-Guérin vaccinations. BU was associated with increasing numbers of possums and with ponds and bore water use at residences. Using insect repellent, covering arms and legs outdoors, and immediately washing wounds were protective; undertaking multiple protective behaviors was associated with the lowest odds of BU. Skin hygiene/protection behaviors and previous bacillus Calmette-Guérin vaccination might provide protection against BU in BU-endemic areas.
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- 2023
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38. Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides.
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O'Brien DP, Jones HBL, Guenther F, Murphy EJ, England KS, Vendrell I, Anderson M, Brennan PE, Davis JB, Pinto-Fernández A, Turnbull AP, and Kessler BM
- Subjects
- Mitochondrial Proteins metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitination, Sulfonamides pharmacology, Deubiquitinating Enzymes antagonists & inhibitors, Deubiquitinating Enzymes metabolism, Mitophagy physiology
- Abstract
Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson's Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide-containing compound, USP30
inh . Activity-based protein profiling mass spectrometry confirmed target engagement, high selectivity, and potency of USP30inh for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. In vitro characterization of USP30inh enzyme kinetics inferred slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen-deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with USP30inh , identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that USP30inh binds to this thumb-palm cleft, which guides the ubiquitin C terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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39. Deep Proteomics Network and Machine Learning Analysis of Human Cerebrospinal Fluid in Japanese Encephalitis Virus Infection.
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Bharucha T, Gangadharan B, Kumar A, Myall AC, Ayhan N, Pastorino B, Chanthongthip A, Vongsouvath M, Mayxay M, Sengvilaipaseuth O, Phonemixay O, Rattanavong S, O'Brien DP, Vendrell I, Fischer R, Kessler B, Turtle L, de Lamballerie X, Dubot-Pérès A, Newton PN, Zitzmann N, and SEAe Consortium
- Subjects
- Humans, Chromatography, Liquid methods, Proteomics methods, Tandem Mass Spectrometry methods, Proteome analysis, Encephalitis, Japanese diagnosis, Encephalitis Virus, Japanese
- Abstract
Japanese encephalitis virus is a leading cause of neurological infection in the Asia-Pacific region with no means of detection in more remote areas. We aimed to test the hypothesis of a Japanese encephalitis (JE) protein signature in human cerebrospinal fluid (CSF) that could be harnessed in a rapid diagnostic test (RDT), contribute to understanding the host response and predict outcome during infection. Liquid chromatography and tandem mass spectrometry (LC-MS/MS), using extensive offline fractionation and tandem mass tag labeling (TMT), enabled comparison of the deep CSF proteome in JE vs other confirmed neurological infections (non-JE). Verification was performed using data-independent acquisition (DIA) LC-MS/MS. 5,070 proteins were identified, including 4,805 human proteins and 265 pathogen proteins. Feature selection and predictive modeling using TMT analysis of 147 patient samples enabled the development of a nine-protein JE diagnostic signature. This was tested using DIA analysis of an independent group of 16 patient samples, demonstrating 82% accuracy. Ultimately, validation in a larger group of patients and different locations could help refine the list to 2-3 proteins for an RDT. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD034789 and 10.6019/PXD034789.
- Published
- 2023
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40. Bone flap infections after craniotomy: a review of 63 cases and the implications for definitions, classification and surveillance methodologies.
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O'Donnell S, Creedon M, Walsh J, Dinesh B, O'Brien DP, MacNally S, and Humphreys H
- Subjects
- Adult, Humans, Middle Aged, Retrospective Studies, Surgical Wound Infection diagnosis, Surgical Wound Infection epidemiology, Surgical Wound Infection microbiology, Neurosurgical Procedures, Surgical Flaps surgery, Craniotomy adverse effects
- Abstract
Background: Bone flap infections (BFIs) occur following neurosurgical procedures such as craniotomies. However, they are poorly defined and often not clearly differentiated from other surgical site infection in neurosurgery., Aim: To review data from a national adult neurosurgical centre to explore some clinical aspects to better inform definitions, classification and surveillance methodologies., Methods: We retrospectively reviewed data on clinical samples sent for culture from patients with suspected BFI. We also accessed information recorded prospectively from national and local databases for evidence of BFI or related conditions based on terms used in surgical operative notes or discharge summaries and documented monomicrobial and polymicrobial infections related to craniotomy sites., Findings: Between January 2016 and December 2020, we documented 63 patients with a mean age of 45 years (16-80). Craniectomy for infection of the skull was the most common terminology used to describe BFI in the coding used in a national database, 40/63 (63%), but other terms were used. A malignant neoplasm was the most common underlying condition necessitating craniectomy in 28/63 (44%) cases. Specimens submitted for microbiological investigation included 48/63 (76%) bone flaps, 38/63 (60%) fluid/pus, and 29/63 (46%) tissue. Fifty-eight (92%) patients had at least one culture-positive specimen; 32 (55%) were monomicrobial and 26 (45%) were polymicrobial. Gram-positive bacteria predominated and Staphylococcus aureus was the most common., Conclusion: Greater clarity on how to define BFI is required to enable better classification and the carrying out of appropriate surveillance. This will inform preventative strategies and more effective patient management., (Copyright © 2023 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
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41. Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.
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Fowler SL, Behr TS, Turkes E, Cauhy PM, Foiani MS, Schaler A, Crowley G, Bez S, Ficulle E, Tsefou E, O'Brien DP, Fischer R, Geary B, Gaur P, Miller C, D'Acunzo P, Levy E, Duff KE, and Ryskeldi-Falcon B
- Abstract
The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
- Published
- 2023
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42. Mycobacterium ulcerans culture results according to duration of prior antibiotic treatment: A cohort study.
- Author
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Tweedale B, Collier F, Waidyatillake NT, Athan E, and O'Brien DP
- Subjects
- Humans, Male, Middle Aged, Female, Anti-Bacterial Agents therapeutic use, Cohort Studies, Treatment Outcome, Mycobacterium ulcerans, Buruli Ulcer microbiology
- Abstract
Mycobacterium ulcerans disease is a necrotising disease of the skin and subcutaneous tissue and is effectively treated with eight-weeks antibiotic therapy. Significant toxicities, however, are experienced under this prolonged regimen. Here, we investigated the length of antibiotic duration required to achieve negative cultures of M. ulcerans disease lesions and evaluated the influence of patient characteristics on this outcome. M. ulcerans cases from an observational cohort that underwent antibiotic treatment prior to surgery and had post-excision culture assessment at Barwon Health, Victoria, from May 25 1998 to June 30 2019, were included. Antibiotic duration before surgery was grouped as <2 weeks, ≥2-<4 weeks, ≥4-<6 weeks, ≥6-<8 weeks, ≥8-<10 weeks and ≥10-20 weeks. Cox regression analyses were performed to assess the association between variables and culture positive results. Ninety-two patients fitted the inclusion criteria. The median age was 60 years (IQR 28-74.5) and 51 (55.4%) were male. Rifampicin-based regimens were predominantly used in combination with clarithromycin (47.8%) and ciprofloxacin (46.7%), and the median duration of antibiotic treatment before surgery was 23 days (IQR, 8.0-45.5). There were no culture positive results after 19 days of antibiotic treatment and there was a significant association between antibiotic duration before surgery and a culture positive outcome (p<0.001). The World Health Organisation category of the lesion and the antibiotic regimen used had no association with the culture outcome. Antibiotics appear to be effective at achieving negative cultures of M. ulcerans disease lesions in less than the currently recommended eight-week duration., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tweedale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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43. Severity of COVID-19 among Residents in Aged Care Facilities in Victoria, Australia: A Retrospective Cohort Study Comparing the Delta and Omicron Epidemic Periods.
- Author
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Muleme M, McNamara BJ, Ampt FH, Baptista M, Dittmer J, Osborne A, Ahmed H, Hales G, Kabwe M, Main S, Moreira C, Silverstein S, Sotheran E, Athan E, Johnson PDR, O'Brien DP, and Sullivan SG
- Subjects
- Male, Humans, Aged, Victoria epidemiology, Retrospective Studies, Disease Outbreaks, Pandemics, COVID-19 epidemiology
- Abstract
Objectives: During the COVID-19 pandemic, no country with widespread community transmission has avoided outbreaks or deaths in residential aged care facilities (RACFs). As RACF residents are at high risk of morbidity and mortality from COVID-19, understanding disease severity risk factors is imperative., Design: This retrospective cohort study aimed to compare COVID-19 disease severity (hospitalization and deaths) and associated risk factors among RACF residents in Victoria, Australia, across Delta and Omicron epidemic periods., Settings and Participants: Resident case hospitalization risk (HR) and case fatality risk (CFR) were assessed using Victorian RACFs COVID-19 outbreaks data across 2 epidemic periods; Delta, 994 resident cases linked to 86 outbreaks; and Omicron, 1882 resident cases linked to 209 outbreaks., Methods: Adjusting for outbreak-level clustering, age, sex, up-to-date vaccination status, and time since last vaccination, the odds of hospitalization and death were compared using mixed effects logistic regression., Results: The HR and CFR was lower during the Omicron period compared with the Delta period [HR 8.2% vs 24.6%, odds ratio (OR) 0.17, 95% CI 0.11-0.26, and CFR: 11.4% vs 18.7%, OR 0.40, 95% CI 0.28-0.56]. During both periods, males had higher odds of hospitalization and odds of death; being up to date with vaccination reduced odds of hospitalization by 40% (excluding nonemergency patient transfers) and odds of death by 43%; and for each month since last vaccination, odds of hospitalization increased by 9% and odds of death by 16%., Conclusions and Implications: This study provides empirical evidence of lower COVID-19 severity among RACF residents in the Omicron period and highlights the importance of up-to-date and timely vaccination to reduce disease severity in this cohort., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)
- Published
- 2023
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44. Healthcare worker access to molnupiravir: A case series.
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O'Keeffe JC, Constable M, Chiang J, Somerville M, Yerramilli A, Nolan R, Weeks G, and O'Brien DP
- Subjects
- Humans, Female, Adult, Male, SARS-CoV-2, Australia epidemiology, Health Personnel, COVID-19 epidemiology
- Abstract
Molnupiravir, an oral antiviral shown to reduce COVID-19 severity, is available in Australia via the Pharmaceutical Benefits Scheme (PBS) for treatment of mild-moderate COVID-19. For people less than 70 years of age it is only available with risk factors for severe disease, hence the majority of healthcare workers do not qualify. Currently, Australian health services are under considerable strain due to COVID-related staff shortages. Thirty staff members of a tertiary hospital, not eligible under the PBS, were offered molnupiravir within the first five days of COVID-19 illness. Their median age was 43 years, and 73% were female. All completed treatment with rates of adverse events that were low and comparable with clinical trial data. The reported duration of illness ranged from 1-16 days with a median of four days. A negative rapid antigen test on the final day of treatment was reported in 81% of people, and 73% reported being well enough to return to work at the completion of mandatory isolation. Only 22% of people reported transmission in their household after they commenced treatment. The implementation of a policy allowing access to molnupiravir outside of PBS recommendations for healthcare workers with mild-moderate COVID-19 may have important individual benefits to workers health and wellbeing and help alleviate the acute staff shortages experienced currently by the Australian healthcare workforce., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 O’Keeffe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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45. Letter to the editor: A retrospective review of patients who sustained traumatic brain injury in Ireland 2014-2019 ✰ .
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Javadpour M, Amoo M, O'Brien DP, O'Brien DF, Geoghegan P, and Curley G
- Subjects
- Humans, Retrospective Studies, Ireland, Brain Injuries, Traumatic, Brain Injuries
- Abstract
Competing Interests: Declaration of Competing Interest None of the authors have any pertinent conflicts of interest.
- Published
- 2023
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46. Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in Dogs with Dermatosparactic Ehlers-Danlos Syndrome.
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Jaffey JA, Bullock G, Guo J, Mhlanga-Mutangadura T, O'Brien DP, Coates JR, Morrissey R, Hutchison R, Donnelly KS, Cohn LA, Katz ML, and Johnson GS
- Subjects
- Animals, Dogs, Atrophy, Cicatrix, Homozygote, Joint Instability, Phenotype, Sequence Deletion, ADAMTS Proteins genetics, Ehlers-Danlos Syndrome genetics, Ehlers-Danlos Syndrome veterinary
- Abstract
Tissue fragility, skin hyperextensibility and joint hypermobility are defining characteristics of Ehlers-Danlos syndrome (EDS). Human EDS is subclassified into fourteen types including dermatosparactic EDS, characterized by extreme skin fragility and caused by biallelic ADAMTS2 mutations. We report two novel, ADAMTS2 variants in DNA from EDS-affected dogs. Separate whole-genome sequences from a Pit Bull Terrier and an Alapaha Blue Blood Bulldog each contained a rare, homozygous variant (11:2280117delC, CanFam3.1), predicted to produce a frameshift in the transcript from the first coding ADAMTS2 exon (c.10delC) and a severely truncated protein product, p.(Pro4ArgfsTer175). The clinical features of these dogs and 4 others with the same homozygous deletion included multifocal wounds, atrophic scars, joint hypermobility, narrowed palpebral fissures, skin hyperextensibility, and joint-associated swellings. Due to severe skin fragility, the owners of all 6 dogs elected euthanasia before the dogs reached 13 weeks of age. Cross sections of collagen fibrils in post-mortem dermal tissues from 2 of these dogs showed hieroglyphic-like figures similar to those from cases of severe dermatosparaxis in other species. The whole-genome sequence from an adult Catahoula Leopard Dog contained a homozygous ADAMTS2 missense mutation, [11:2491238G>A; p.(Arg966His)]. This dog exhibited multifocal wounds, atrophic scars, and joint hypermobility, but has survived for at least 9 years. This report expands the spectrum of clinical features of the canine dermatosparactic subtype of EDS and illustrates the potential utility of subclassifying canine EDS by the identity of gene harboring the causal variant.
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- 2022
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47. Environmental risk factors associated with the presence of Mycobacterium ulcerans in Victoria, Australia.
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Blasdell KR, McNamara B, O'Brien DP, Tachedjian M, Boyd V, Dunn M, Mee PT, Clayton S, Gaburro J, Smith I, Gibney KB, Tay EL, Hobbs EC, Waidyatillake N, Lynch SE, Stinear TP, and Athan E
- Subjects
- Animals, Humans, Marsupialia microbiology, Risk Factors, Victoria epidemiology, Buruli Ulcer epidemiology, Environmental Microbiology, Mycobacterium ulcerans isolation & purification
- Abstract
In recent years reported cases of Buruli ulcer, caused by Mycobacterium ulcerans, have increased substantially in Victoria, Australia, with the epidemic also expanding geographically. To develop an understanding of how M. ulcerans circulates in the environment and transmits to humans we analyzed environmental samples collected from 115 properties of recent Buruli ulcer cases and from 115 postcode-matched control properties, for the presence of M. ulcerans. Environmental factors associated with increased odds of M. ulcerans presence at a property included certain native plant species and native vegetation in general, more alkaline soil, lower altitude, the presence of common ringtail possums (Pseudocheirus peregrinus) and overhead powerlines. However, only overhead powerlines and the absence of the native plant Melaleuca lanceolata were associated with Buruli ulcer case properties. Samples positive for M. ulcerans were more likely to be found at case properties and were associated with detections of M. ulcerans in ringtail possum feces, supporting the hypothesis that M. ulcerans is zoonotic, with ringtail possums the strongest reservoir host candidate. However, the disparity in environmental risk factors associated with M. ulcerans positive properties versus case properties indicates the involvement of human behavior or the influence of other environmental factors in disease acquisition that requires further study., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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48. Absence of COVID-19 workplace transmission from hairdressers in Victoria, Australia.
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Swaney E, Murnane B, Heard L, Friedman ND, and O'Brien DP
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- Humans, Victoria epidemiology, Workplace, COVID-19 epidemiology, Occupational Exposure adverse effects
- Abstract
Competing Interests: None declared
- Published
- 2022
- Full Text
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49. Possum bites man: case of Buruli ulcer following possum bite.
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Xu RW, Stinear TP, Johnson PD, and O'Brien DP
- Subjects
- Humans, Male, Bites and Stings, Buruli Ulcer diagnosis, Mycobacterium ulcerans
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- 2022
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50. In Reply: Complications of Cranioplasty in Relation to Material: Systematic Review, Network Meta-Analysis and Meta-Regression.
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Henry J, Amoo M, Taylor J, and O'Brien DP
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- Humans, Network Meta-Analysis, Decompressive Craniectomy, Skull surgery
- Published
- 2022
- Full Text
- View/download PDF
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