Publications by authors named "Nicholas Kerr"

7 Publications

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Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation.

Br J Pharmacol 2021 Nov 26. Epub 2021 Nov 26.

Victor Chang Cardiac Research Institute, Sydney, Australia.

Background And Purpose: Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat COVID-19. While concern already existed around their proarrhythmic potential there is little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles.

Experimental Approach: Potency of hERG block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals.

Key Results: Chloroquine and hydroxychloroquine blocked hERG with IC of 1.47±0.07 μM and 3.78±0.17 μM respectively, indicating proarrhythmic risk at concentrations effective against SARS-CoV-2 in vitro. Hypokalaemia and hypermagnesemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure, and identified specific genetic backgrounds associated with emergence of arrhythmia.

Conclusion And Implications: Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.
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http://dx.doi.org/10.1111/bph.15757DOI Listing
November 2021

Ex Vivo Assessment of Different Oral Anticoagulant Regimens on Pump Thrombosis in a HeartWare Ventricular Assist Device.

Circ Heart Fail 2021 07 2;14(7):e007231. Epub 2021 Jul 2.

Heart and Lung Transplant Unit, St. Vincent's Hospital, Darlinghurst, NSW, Australia (N.P.K., K.M., P.J., D.R., P.J., C.S.H.).

Background: In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents.

Methods: A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity.

Results: Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, =0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points.

Conclusions: In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007231DOI Listing
July 2021

Esophageal T-tube: A novel approach to atrioesophageal fistula repair.

HeartRhythm Case Rep 2017 Oct 1;3(10):483-486. Epub 2017 Aug 1.

Cardiology Department, St Vincent's Hospital, Sydney, Australia.

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http://dx.doi.org/10.1016/j.hrcr.2017.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643856PMC
October 2017

Mindfulness Self-Care Strategies for Clinicians #316.

Authors:
Nicholas Kerr

J Palliat Med 2016 11 25;19(11):1226-1227. Epub 2016 May 25.

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http://dx.doi.org/10.1089/jpm.2016.0207DOI Listing
November 2016

Radial versus femoral access for cardiac catheterisation.

Lancet 2015 Dec;386(10011):2392

St Vincent's Hospital, Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(15)01195-2DOI Listing
December 2015

Determinants of intrinsic aminoglycoside resistance in Pseudomonas aeruginosa.

Antimicrob Agents Chemother 2012 Nov 20;56(11):5591-602. Epub 2012 Aug 20.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.

Screening of a transposon insertion mutant library of Pseudomonas aeruginosa for increased susceptibility to paromomycin identified a number of genes whose disruption enhanced susceptibility of this organism to multiple aminoglycosides, including tobramycin, amikacin, and gentamicin. These included genes associated with lipid biosynthesis or metabolism (lptA, faoA), phosphate uptake (pstB), and two-component regulators (amgRS, PA2797-PA2798) and a gene of unknown function (PA0392). Deletion mutants lacking these showed enhanced panaminoglycoside susceptibility that was reversed by the cloned genes, confirming their contribution to intrinsic panaminoglycoside resistance. None of these mutants showed increased aminoglycoside permeation of the cell envelope, indicating that increased susceptibility was not related to enhanced aminoglycoside uptake owing to a reduced envelope barrier function. Several mutants (pstB, faoA, PA0392, amgR) did, however, show increased cytoplasmic membrane depolarization relative to wild type following gentamicin exposure, consistent with the membranes of these mutants being more prone to perturbation, likely by gentamicin-generated mistranslated polypeptides. Mutants lacking any two of these resistance genes in various combinations invariably showed increased aminoglycoside susceptibility relative to single-deletion mutants, confirming their independent contribution to resistance and highlighting the complexity of the intrinsic aminoglycoside resistome in P. aeruginosa. Deletion of these genes also compromised the high-level panaminoglycoside resistance of clinical isolates, emphasizing their important contribution to acquired resistance.
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http://dx.doi.org/10.1128/AAC.01446-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486610PMC
November 2012

Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes.

Am J Med Genet B Neuropsychiatr Genet 2005 Apr;134B(1):56-9

Garvan Institute of Medical Research, Sydney, Australia.

Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected individuals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder.
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http://dx.doi.org/10.1002/ajmg.b.30131DOI Listing
April 2005
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