Reduction in Thrombolytic Usage in Hemodialysis Patients Following a Quality Assurance Review: A Research Letter.

Background: Catheter malfunction in hemodialysis (HD) is increasingly managed with recombinant tissue plasminogen activator (rt-PA, alteplase), though evidence of improved catheter function is lacking. Objective: To evaluate the effect of a standardized rt-PA administration protocol on rt-PA usage, catheter function, and adverse events. Design: Observational quality improvement study. Setting: Single, urban, community HD unit in Calgary, Alberta. Patients: Patients treated with maintenance in-center HD through central venous catheter. Outcomes: Incidence of rt-PA usage, catheter interventions, hospitalizations, and measures of dialysis efficacy. Methods: The rt-PA protocol was designed following a consultative and iterative design period with dialysis shareholders, which included focusing on standard objective criteria before use and targeting use to the problematic lumen. Protocol implementation occurred over a 6-month period in 2021. Patient and dialysis data were collected through our regional dialysis electronic health record. Results: Implementation of the rt-PA protocol resulted in decreased rt-PA use (standardized per 100 dialysis sessions) compared to the preprotocol period (incidence rate ratio [IRR] of 0.57, 95% confidence interval [CI]: [0.34, 0.94]). Line procedures were also less frequent (IRR = 0.42, 95% CI: [0.18, 0.89]). Hospitalization rates and measures of dialysis efficacy were similar in both periods. Limitations: Small sample size with single dialysis center and short duration of follow-up. Conclusions: Implementation of a multidisciplinary designed rt-PA administration protocol decreased incident rt-PA usage.

Contexte: L'activateur tissulaire du plasminogène recombinant (rt-PA, alteplase) est de plus en plus utilisé pour la prise en charge du dysfonctionnement du cathéter en hémodialyse, bien qu'on manque de preuves sur l'amélioration de la fonction du cathéter. Objectif: Évaluer l'effet d'un protocole normalisé d'administration de rt-PA sur l'utilization de rt-PA, la fonction du cathéter et les événements indésirables. Type d'étude: Étude observationnelle d'amélioration de la qualité. Cadre: L'unité d'hémodialyse communautaire d'un center urbain de Calgary (Alberta). Sujets: Patients traités en center par hémodialyse d'entretien avec cathéter veineux central. Résultats: Mesure de l'efficacité de la dialyze et incidence de l'utilization du rt-PA, des interventions par cathéter et des hospitalisations. Méthodologie: Le protocole rt-PA a été élaboré après une période de consultation et d'itération auprès des intervenants en dialyze qui consistait à mettre l'accent sur les critères objectifs normalisés avant son utilization et à cibler son utilization dans la lumière problématique du cathéter. La mise en œuvre du protocole s'est déroulée sur une période de 6 mois en 2021. Les données sur les patients et les séances de dialyze ont été recueillies par le biais du dossier médical électronique régional pour la dialyze. Résultats: La mise en œuvre du protocole rt-PA a entraîné une diminution de l'utilization de rt-PA (normalisée pour 100 séances de dialyze) par rapport à la période pré-protocole (rapport du taux d'incidence [RTI] de 0,57; intervalle de confiance à 95% [IC 95 %] de 0.34 à 0.94). Les interventions au niveau des cathéters ont également été moins fréquentes (RTI: 0.42; IC 95 %: 0.18-0.89). Les taux d'hospitalization et les mesures de l'efficacité de la dialyze étaient semblables pour les deux périodes. Limites: Étude menée dans un seul center de dialyze, sur un échantillon de petite taille, avec un suivi de courte durée. Conclusion: La mise en œuvre d'un protocole d'administration de rt-PA conçu de façon multidisciplinaire a diminué l'incidence de l'utilization de rt-PA.

Acute Kidney Allograft Rejection Following Coronavirus mRNA Vaccination: A Case Report.

Supplemental Digital Content is available in the text.

Career and research outcomes of the physician-scientist training program at the University of Calgary: a retrospective cohort study.

BACKGROUND: Physician-scientists are integral to medical research, with medical programs throughout Canada invested in training hybrid physician-scientists. Few data exist as to whether these programs are generating the diversity, gender equity and numbers of trainees essential for the future of medical research and teaching. We aimed to identify factors that contribute to research productivity, diversity and retention of individuals as physician-scientists. METHODS: We completed a retrospective cohort study, for the period 1973 to 2015, of the University of Calgary Leaders in Medicine Program in Calgary, Alberta. Participants were coregistered in graduate (master's or PhD) and medical degree programs. Primary outcomes included number of publications and the eventual career paths of graduates, with individuals characterized as physicians or physician-scientists on the basis of these metrics. RESULTS: Of the 307 individuals who were coregistered in or had completed a joint graduate and medical degree, 125 (40.7%) were PhD students/graduates, and 182 (59.3%) were master's trainees/graduates. While in the joint program, male PhD students consistently published more frequently than female PhD students. There was no significant difference in publication records between male and female master's students. Of the 172 individuals who were 5 years or more beyond graduation, 47 (27.3%) were classified as physician-scientists; these individuals consisted of 28 (40.6%) of the 69 PhD graduates and 19 (18.4%) of the 103 master's graduates. INTERPRETATION: Overall, our study shows that graduates receiving both clinical and research training, through master's or PhD programs, continue to be involved in research in their subsequent careers.

A prescription that addresses the decline of basic science education in medical school.

Over 30 years ago a cry rang out through the proverbial halls of academia; "The clinician scientist is an endangered species." These prophetic words have been reverberated in the ears of every specialty and every general medical organization in deafening tones. Why is the role of the clinician scientist or clinician investigator so important that this phrase has been repeated subsequently in medical and educational journals? Simply put, the clinician scientist bridges the ravine between the ever-growing mountain of scientific knowledge and the demanding patient centered clinical care. Here, we describe the current educational model established by the University of Calgary, Leaders in Medicine Program. Our program seeks to train future physicians and clinician scientists by incorporating training in basic science, translational and clinical research with clinical and medical education in a longitudinal program to students of traditional MD/PhD, MD/MSc or MD/MBA stream as well as interested Doctor of Medicine students.

Structural determinants of the catalytic inhibition of human topoisomerase IIα by salicylate analogs and salicylate-based drugs.

We previously identified salicylate as a novel catalytic inhibitor of human DNA topoisomerase II (topo II; EC 5.99.1.3) that preferentially targets the alpha isoform by interfering with topo II-mediated DNA cleavage. Many pharmaceuticals and compounds found in foods are salicylate-based. We have now investigated whether these are also catalytic inhibitors of topo II and the structural determinants modulating these effects. We have determined that a number of hydroxylated benzoic acids attenuate doxorubicin-induced DNA damage signaling mediated by the ATM protein kinase and inhibit topo II decatenation activity in vitro with varying potencies. Based on the chemical structures of these and other derivatives, we identified unique properties influencing topo II inhibition, including the importance of substitutions at the 2'- and 5'-positions. We extended our findings to a number of salicylate-based pharmaceuticals including sulfasalazine and diflunisal and found that both were effective at attenuating doxorubicin-induced DNA damage signaling, topo II DNA decatenation and they blocked stabilization of doxorubicin-induced topo II cleavable complexes in cells. In a manner similar to salicylate, we determined that these agents inhibit topo II-mediated DNA cleavage. This was accompanied by a concomitant decrease in topo II-mediated ATP-hydrolysis. Taken together, these findings reveal a novel function for the broader class of salicylate-related compounds and highlight the need for additional studies into whether they may impact the efficacy of chemotherapy regimens that include topo II poisons.

Salicylate, a catalytic inhibitor of topoisomerase II, inhibits DNA cleavage and is selective for the α isoform.

Topoisomerase II (topo II) is a ubiquitous enzyme that is essential for cell survival through its role in regulating DNA topology and chromatid separation. Topo II can be poisoned by common chemotherapeutics (such as doxorubicin and etoposide), leading to the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. In contrast, nonbreak-inducing topo II catalytic inhibitors have also been described and have more limited use in clinical chemotherapy. These agents, however, may alter the efficacy of regimens incorporating topo II poisons. We previously identified salicylate, the primary metabolite of aspirin, as a novel catalytic inhibitor of topo II. We have now determined the mechanism by which salicylate inhibits topo II. As catalytic inhibitors can act at a number of steps in the topo II catalytic cycle, we used multiple independent, biochemical approaches to interrogate the catalytic cycle. Furthermore, as mammalian cells express two isoforms of topo II (α and ß), we examined whether salicylate was isoform selective. Our results demonstrate that salicylate is unable to intercalate DNA, and does not prevent enzyme-DNA interaction, nor does it promote stabilization of topo IIα in closed clamps on DNA. Although salicylate decreased topo IIα ATPase activity in a dose-dependent noncompetitive manner, this was secondary to salicylate-mediated inhibition of DNA cleavage. Surprisingly, comparison of salicylate's effects using purified human topo IIα and topo IIß revealed that salicylate selectively inhibits the α isoform. These findings provide a definitive mechanism for salicylate-mediated inhibition of topo IIα and provide support for further studies determining the basis for its isoform selectivity.

Sodium salicylate is a novel catalytic inhibitor of human DNA topoisomerase II alpha.

We have previously reported that pretreatment of human lymphoblastoid cells with the hydroxyl radical scavenger, N-acetyl cysteine, attenuates doxorubicin-induced DNA damage signalling through the ATM protein kinase. We sought to extend these studies to examine the effects of other hydroxyl radical scavengers in human breast cancer cells. Using MCF-7 cells, we observed that doxorubicin treatment triggered autophosphorylation of ATM on serine 1981 and the ATM-dependent activation of its downstream effectors p53, Chk2, and SMC1. Furthermore, we demonstrate that this effect was attenuated by pretreatment of cells with the hydroxyl radical scavengers sodium benzoate, sodium salicylate and, to a lesser extent, N-acetyl cysteine, but not Trolox™. Intriguingly, these effects were independent of doxorubicin's ability to redox cycle, were observed with multiple classes of topoisomerase II poisons, but did not represent a general damage-attenuating response. In addition, the observed effects were independent of the ability of sodium salicylate to inhibit cyclooxygenase-2 or NFκB. We demonstrate that sodium salicylate prevented doxorubicin-induced DNA double-strand break generation, which was attributable to inhibition of doxorubicin-stabilized topoisomerase IIα-DNA cleavable complex formation in vivo. Using topoisomerase IIα-DNA cleavage and decatenation assays, we determined that sodium salicylate is a catalytic inhibitor of topoisomerase IIα. Consistent with the observed inhibition of double-strand break formation, pretreatment of cells with sodium salicylate attenuated doxorubicin and etoposide cytotoxicity. These results demonstrate a novel mechanism of action for sodium salicylate and suggest that further study on the mechanism of topoisomerase II inhibition and the effects of related therapeutics on doxorubicin and etoposide cytotoxicity are warranted.