Publications by authors named "M John Kennedy"

3,148 Publications

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The use of diverted pharmaceutical opioids is associated with reduced risk of fentanyl exposure among people using unregulated drugs in Vancouver, Canada.

Drug Alcohol Depend 2021 Sep 25;228:109109. Epub 2021 Sep 25.

British Columbia Centre on Substance Use, 400-1045 Howe Street, Vancouver, BC V6Z 2A9, Canada; University of British Columbia Department of Medicine, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada.

Background: Although non-medical use of pharmaceutical opioids (POs) is associated with a number of risks, in the context of the opioid-overdose crisis, it may have the secondary benefit of decreasing the risk of exposure to more potent opioids from unregulated sources. The aim of this study was to assess the effects of using diverted POs on fentanyl exposure.

Methods: Using data from two prospective community-recruited cohorts of people who use drugs (PWUD) in Vancouver, Canada, we estimated the independent relationship between using diverted POs and fentanyl exposure (assessed through urine drug test [UDT]) between 2016 and 2018. We also explored if participant characteristics modified this relationship.

Results: Over the study period, among 1150 participants, 241 (21.0%) reported using diverted POs in 292 (12.8%) occasions. In adjusted analyses, PWUD using diverted POs had decreased odds of fentanyl exposure (Adjusted odds ratio [AOR] = 0.70, 95% CI: 0.52-0.94). The reduced odds of fentanyl exposure persisted among participants with morphine positive UDT (AOR = 0.57, 95% CI: 0.40-0.82), but not among those with negative morphine UDT (AOR = 0.91, 95% CI: 0.54-1.55).

Conclusion: PWUD using diverted POs in our sample were 30% less likely to be exposed to fentanyl. This reduced likelihood was primarily observed among PWUD with morphine positive UDT, which could partially be explained by longer duration of action and lower street cost of slow-release oral morphine relative to other POs and fentanyl. Findings suggest that access to a regulated supply of pharmaceutical-grade opioids may serve to reduce fentanyl-related harms.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.109109DOI Listing
September 2021

Full thickness quadriceps tendon grafts with bone had similar material properties to bone-patellar tendon-bone and a four-strand semitendinosus grafts: a biomechanical study.

Knee Surg Sports Traumatol Arthrosc 2021 Sep 30. Epub 2021 Sep 30.

Twin Cities Orthopedics, Minneapolis, MN, USA.

Purpose: Despite increasing interest in utilizing quadriceps tendon (QT) grafts in anterior cruciate ligament reconstruction (ACLR), data on the optimal quadriceps graft thickness are limited. The purpose of this study was to characterize the mechanical properties for the quadriceps tendon, comparing full-thickness (FT) QT grafts with and without bone to a partial-thickness (PT) QT graft, and comparing the three QT grafts to four-stranded semitendinosus (4-SST) and bone-patellar tendon-bone (BTB) grafts and one experimental graft, the two-stranded rectus femoris (RF).

Methods: Forty-eight (n = 48) young cadaveric grafts (mean age 32 ± 6 years) were utilized for testing with N = 8 specimens in each of the following groups; (1) FT QT with bone, (2) FT QT without bone, (3) PT QT without bone, (4) BTB, (5) RF, and (6) 4-SST. Each specimen was harvested and rigidly fixed in custom clamps to a dynamic tensile testing machine for biomechanical evaluation. Graft ultimate load and stiffness were recorded. Independent groups one-factor ANOVAs and Tukey's pairwise comparisons were performed for statistical analyses.

Results: FT QT with bone and 4-SST grafts demonstrated similar ultimate loads to BTB grafts (both n.s), whereas PT QT demonstrate statistically significantly lower ultimate loads to BTB grafts (n.s) and 4-SST grafts (n.s). Furthermore, no statistically significant differences were observed between the ultimate loads of FT QT vs. PT QT grafts without bone (n.s) or between FT QT with vs. without bone (n.s). FT QT grafts with bone did not demonstrate statistically significantly greater ultimate loads than PT QT grafts without bone (n.s). The RF graft demonstrated statistically significantly lower ultimate loads to BTB grafts (p < 0.005) and 4-SST grafts (p < 0.014).

Conclusions: Full thickness QT grafts with bone had similar material properties to BTB and a 4-SST grafts, while Partial thickness QT graft without bone had significantly lower material properties than BTB and 4-SST, in a biomechanical setting.
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http://dx.doi.org/10.1007/s00167-021-06738-xDOI Listing
September 2021

Structural basis for isoform-specific inhibition of human CTPS1.

Proc Natl Acad Sci U S A 2021 Oct;118(40)

Department of Biochemistry, University of Washington, Seattle, WA 98195;

Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin ], [] [510], [288-292] ([2014]). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E. Martin ], [] [510], [288-292] ([2014]), satisfying increased demand for nucleic acid and lipid synthesis [L. D. Fairbanks, M. Bofill, K. Ruckemann, H. A. Simmonds], [ ] [270], [29682-29689] ([1995]). Demand for CTP in other tissues is met by the CTPS2 isoform and nucleoside salvage pathways [E. Martin ], [] [510], [288-292] ([2014]). Selective inhibition of the proliferative CTPS1 isoform is therefore desirable in the treatment of immune disorders and lymphocyte cancers, but little is known about differences in regulation of the isoforms or mechanisms of known inhibitors. We show that CTP regulates both isoforms by binding in two sites that clash with substrates. CTPS1 is less sensitive to CTP feedback inhibition, consistent with its role in increasing CTP levels in proliferation. We also characterize recently reported small-molecule inhibitors, both CTPS1 selective and nonselective. Cryo-electron microscopy (cryo-EM) structures reveal these inhibitors mimic CTP binding in one inhibitory site, where a single amino acid substitution explains selectivity for CTPS1. The inhibitors bind to CTPS assembled into large-scale filaments, which for CTPS1 normally represents a hyperactive form of the enzyme [E. M. Lynch ], [] [24], [507-514] ([2017]). This highlights the utility of cryo-EM in drug discovery, particularly for cases in which targets form large multimeric assemblies not amenable to structure determination by other techniques. Both inhibitors also inhibit the proliferation of human primary T cells. The mechanisms of selective inhibition of CTPS1 lay the foundation for the design of immunosuppressive therapies.
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http://dx.doi.org/10.1073/pnas.2107968118DOI Listing
October 2021

Practicing Sport in Cold Environments: Practical Recommendations to Improve Sport Performance and Reduce Negative Health Outcomes.

Int J Environ Res Public Health 2021 Sep 15;18(18). Epub 2021 Sep 15.

Athlete Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB T6G 2R3, Canada.

Although not a barrier to perform sport, cold weather environments (low ambient temperature, high wind speeds, and increased precipitation, i.e., rain/water/snow) may influence sport performance. Despite the obvious requirement for practical recommendations and guidelines to better facilitate training and competition in such cold environments, the current scientific evidence-base is lacking. Nonetheless, this review summarizes the current available knowledge specifically related to the physiological impact of cold exposure, in an attempt to provide practitioners and coaches alike with practical recommendations to minimize any potential negative performance effects, mitigate health issues, and best optimize athlete preparation across various sporting disciplines. Herein, the review is split into sections which explore some of the key physiological effects of cold exposure on performance (i.e., endurance exercise capacity and explosive athletic power), potential health issues (short-term and long-term), and what is currently known with regard to best preparation or mitigation strategies considered to negate the potential negative effects of cold on performance. Specific focus is given to "winter" sports that are usually completed in cold environments and practical recommendations for physical preparation.
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http://dx.doi.org/10.3390/ijerph18189700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471173PMC
September 2021

Amplification of neurotoxic HTTex1 assemblies in human neurons.

Neurobiol Dis 2021 Nov 24;159:105517. Epub 2021 Sep 24.

Biology and Bioengineering, Caltech, Pasadena, CA 91125, USA. Electronic address:

Huntington's disease (HD) is a genetically inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) repeat in the exon-1 of huntingtin protein (HTT). The expanded polyQ enhances the amyloidogenic propensity of HTT exon 1 (HTTex1), which forms a heterogeneous mixture of assemblies with a broad neurotoxicity spectrum. While predominantly intracellular, monomeric and aggregated mutant HTT species are also present in the cerebrospinal fluids of HD patients, however, their biological properties are not well understood. To explore the role of extracellular mutant HTT in aggregation and toxicity, we investigated the uptake and amplification of recombinant HTTex1 assemblies in cell culture models. We find that small HTTex1 fibrils preferentially enter human neurons and trigger the amplification of neurotoxic assemblies; astrocytes or epithelial cells are not permissive. The amplification of HTTex1 in neurons depletes endogenous HTT protein with non-pathogenic polyQ repeat, activates apoptotic caspase-3 pathway and induces nuclear fragmentation. Using a panel of novel monoclonal antibodies and genetic mutation, we identified epitopes within the N-terminal 17 amino acids and proline-rich domain of HTTex1 to be critical in neural uptake and amplification. Synaptosome preparations from the brain homogenates of HD mice also contain mutant HTT species, which enter neurons and behave similar to small recombinant HTTex1 fibrils. These studies suggest that amyloidogenic extracellular mutant HTTex1 assemblies may preferentially enter neurons, propagate and promote neurodegeneration.
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http://dx.doi.org/10.1016/j.nbd.2021.105517DOI Listing
November 2021
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