Extracellular vesicles (EVs) have emerged as important regulators of inter‐cellular and inter‐organ communication, in part via the transfer of their cargo to recipient cells. Although circulating EVs ...have been previously studied as biomarkers of aging, how circulating EVs change with age and the underlying mechanisms that contribute to these changes are poorly understood. Here, we demonstrate that aging has a profound effect on the circulating EV pool, as evidenced by changes in concentration, size, and cargo. Aging also alters particle function; treatment of cells with EV fractions isolated from old plasma reduces macrophage responses to lipopolysaccharide, increases phagocytosis, and reduces endothelial cell responses to vascular endothelial growth factor compared to cells treated with young EV fractions. Depletion studies indicate that CD63+ particles mediate these effects. Treatment of macrophages with EV‐like particles revealed that old particles increased the expression of EV miRNAs in recipient cells. Transfection of cells with microRNA mimics recapitulated some of the effects seen with old EV‐like particles. Investigation into the underlying mechanisms using bone marrow transplant studies revealed circulating cell age does not substantially affect the expression of aging‐associated circulating EV miRNAs in old mice. Instead, we show that cellular senescence contributes to changes in particle cargo and function. Notably, senolytic treatment of old mice shifted plasma particle cargo and function toward that of a younger phenotype. Collectively, these results demonstrate that senescent cells contribute to changes in plasma EVs with age and suggest a new mechanism by which senescent cells can affect cellular functions throughout the body.
Senescent cells accumulate in the body with aging and alter circulating extracellular vesicle microRNA content. This can be replicated in young mice by inducing senescence using sub‐lethal irradiation. Conversely, removal of senescent cells in aged mice by senolytic treatment restores circulating extracellular vesicle microRNA expression to that of a younger phenotype.
Cell therapy has received significant attention as a novel therapeutic approach to restore cardiac function after injury. CD34-positive (CD34+) stem cells have been investigated for their ability to ...promote angiogenesis and contribute to the prevention of remodelling after infarct. However, there are significant differences between murine and human CD34+ cells; understanding these differences might benefit the therapeutic use of these cells. Herein we discuss the function of the CD34 cell and highlight the similarities and differences between murine and human CD34 cell function, which might explain some of the differences between the animal and human evolutions. We also summarize the studies that report the application of murine and human CD34+ cells in preclinical studies and clinical trials and current limitations with the application of cell therapy for cardiac repair. Finally, to overcome these limitations we discuss the application of novel humanized rodent models that can bridge the gap between preclinical and clinical studies as well as rejuvenation strategies for improving the quality of old CD34+ cells for future clinical trials of autologous cell transplantation.
Le traitement par des cellules souches attire beaucoup d’attention comme démarche thérapeutique novatrice dans le rétablissement de la fonction cardiaque à la suite d’une lésion. Les cellules souches CD34 (CD34+) ont été étudiées en vue d’évaluer leur capacité à promouvoir l’angiogenèse et à contribuer à la prévention du remodelage cardiaque après un infarctus. Toutefois, les différences sont marquées entre les cellules CD34+ murines et humaines; comprendre ces différences pourrait être utile dans l’usage thérapeutique de ces cellules. Dans cet article, nous traitons de la fonction des cellules CD34 et mettons en évidence les similarités et les différences entre les fonctions des cellules CD34 murines et humaines, lesquelles pourraient expliquer certaines des variations entre les évolutions humaines et animales. Nous offrons aussi un résumé des études qui traitent de l’usage des cellules CD34+ humaines et murines pendant des études précliniques et des essais cliniques ainsi que de leurs limites actuelles dans la réparation des lésions cardiaques. Finalement, pour surmonter ces limites, nous discutons de l’application de nouveaux modèles humanisés de rongeurs qui pourraient combler l’écart entre les études précliniques et cliniques. Nous discutons également des stratégies de renouvellement permettant d’améliorer la qualité des cellules CD34+ vieillissantes en vue d’études ultérieures sur la transplantation de cellules souches autologues.
A message from Elina Cook (President): Demystifying and promoting the MD-PhD/MSc world—our progress
Clinician Investigator Trainee Association of Canada (CITAC) seeks to promote, support and advocate ...for trainees whose goal is to become physician/ clinician/surgeon investigators. These include trainees of MD-PhD/MSc programs and Clinician Investigator Programs (CIP), who are preparing themselves to succeed in the overlapping world of medicine and research. Thanks to the wealth of talent, skill and motivation of the CITAC leadership this year, we are delivering new opportunities to these trainees in a number of ways: 1) developing international partnerships and initiatives; 2) revitalizing the Annual General Meeting (AGM); 3) advocating for clinician/physician/surgeon-scientist trainee support among influencers and policy makers; and 4) collecting data on the academic “health” of our training programs and trainees across Canada.
Abstract
The clinical laboratory plays a critical role in healthcare delivery by providing objective data on specific biomarkers that directly aid in the diagnosis and monitoring of a wide range of ...clinical disorders. Reliable and accurate reference intervals for laboratory analyses are integral for correct interpretation of clinical laboratory test results and, therefore, for appropriate clinical decision-making. Ideally, reference intervals should be established based on a healthy population and stratified for key covariates including age, gender and ethnicity. However, establishing reference intervals can be challenging as it requires the collection of large numbers of samples from healthy individuals. This challenge is further augmented in pediatrics, where dynamic changes due to child growth and development markedly affect circulating levels of disease biomarkers. As a result, even larger reference populations are required to reliably calculate reference intervals. In this review, we outline the challenges specific to establishing pediatric reference intervals and highlight recent initiatives aimed at closing existing gaps in current knowledge. We also outline recommended approaches to the development of reference intervals and detail several alternative approaches. Finally, reference intervals for emerging and novel biomarkers of pediatric disease are discussed along with a number of potential alternative sample types.
Atherosclerotic intraplaque hemorrhage (IPH) is a source of free hemoglobin that binds the haptoglobin protein and forms a complex cleared by CD163 macrophages. Compared to the other common ...haptoglobin genotypes, hemoglobin-haptoglobin2-2 complex has the lowest affinity for tissue macrophages resulting in lower rate of hemoglobin uptake and increased oxidative burden. We hypothesized that haptoglobin2-2 patients' failure to clear hemoglobin results in a greater prevalence and progression of IPH.
Prevalence and volume of IPH were measured in eighty patients with advanced vascular disease using MRI. Haptoglobin was genotyped using PCR. Mixed Models Repeated Measures Analyses were performed to detect any differences in prevalence and volume of IPH between the haptoglobin genotypes.
Haptoglobin2-2 patients had a statistically significant higher prevalence of baseline IPH (OR=4.34, p-value: 0.01, 95% CI: 1.31–14.35). Longitudinal analysis of 48 IPH positive carotids indicated a statistically significant progression of IPH volume over time in haptoglobin2-2 patients (Type 3 test for fixed effect p-value=0.0106; baseline vs. year 3: β=0.11, SE=0.05, p-value=0.03; year 2 vs. year 3: β=0.05, SE=0.02, p-value=0.03).
Patients with the Hp2-2 genotype had a significantly higher prevalence of carotid baseline IPH, which progressed over a two year follow up period. Detection of pre-symptomatic vascular disease using haptoglobin genotyping may allow for better risk stratification of populations at risk of stroke and in need of more targeted imaging investigations.
As an integral aspect of health care, digital technology has enabled modelling of complex relationships to detect, screen, diagnose, and predict patient outcomes. With massive data sets, artificial ...intelligence (AI) can have marked effects on 3 levels: for patients, clinicians, and health systems. In this review, we discuss contemporary AI-enabled wearable devices undergoing research in the field of cardiovascular medicine. These include devices such as smart watches, electrocardiogram patches, and smart textiles such as smart socks and chest sensors for diagnosis, management, and prognostication of conditions such as atrial fibrillation, heart failure, and hypertension as well as monitoring for cardiac rehabilitation. We review the evolution of machine learning algorithms used in wearable devices from random forest models to the use of convolutional neural networks and transformers. We further discuss frameworks for wearable technologies such as the V3-stage process of verification, analytical validation, and clinical validation as well as challenges of AI integration in medicine such as data veracity, validity, and security and provide a reference framework to maintain fairness and equity. Last, clinician and patient perspectives are discussed to highlight the importance of considering end-user feedback in development and regulatory processes.
Partie intégrale des soins de santé, la technologie numérique permet de modéliser des relations complexes pour détecter, dépister et diagnostiquer les maladies et prédire les issues pour les patients. En utilisant d’imposants ensembles de données, l’intelligence artificielle (IA) peut avoir des effets marqués tant pour les patients que pour les cliniciens et le système de santé. Dans cette revue, nous nous penchons sur les appareils portables contemporains utilisant l’intelligence artificielle qui font l’objet de recherches dans le domaine de la médecine cardiovasculaire. Cela comprend des dispositifs comme les montres intelligentes, les timbres d’électrocardiogramme et les textiles intelligents comme des chaussettes intelligentes et des capteurs thoraciques utilisés pour le diagnostic, la prise en charge et le pronostic de maladies comme la fibrillation auriculaire, l’insuffisance cardiaque et l’hypertension, ou qui sont utilisés pour le suivi de la réadaptation cardiaque. Nous avons passé en revue l’évolution des algorithmes d’apprentissage automatique utilisés dans les dispositifs portables depuis les modèles de forêt aléatoire jusqu’à l’utilisation de réseaux de neurones à convolution et de réseaux autoattentifs. Nous étudions aussi les systèmes utilisés pour les technologies portables comme le processus de vérification V3, de validation analytique et de validation clinique, de même que des défis d’intégration de l’IA en médecine comme la véracité, la validité et la sécurité des données. Enfin, nous proposons un cadre de référence pour maintenir l’équité et l’impartialité. Pour terminer, les perspectives des cliniciens et des patients sont abordées pour souligner l’importance de tenir compte des rétroactions des utilisateurs finaux dans les processus de développement et de réglementation.
The CALIPER program recently established a comprehensive database of age- and sex-stratified pediatric reference intervals for 40 biochemical markers. However, this database was only directly ...applicable for Abbott ARCHITECT assays. We therefore sought to expand the scope of this database to biochemical assays from other major manufacturers, allowing for a much wider application of the CALIPER database.
Based on CLSI C28-A3 and EP9-A2 guidelines, CALIPER reference intervals were transferred (using specific statistical criteria) to assays performed on four other commonly used clinical chemistry platforms including Beckman Coulter DxC800, Ortho Vitros 5600, Roche Cobas 6000, and Siemens Vista 1500. The resulting reference intervals were subjected to a thorough validation using 100 reference specimens (healthy community children and adolescents) from the CALIPER bio-bank, and all testing centers participated in an external quality assessment (EQA) evaluation.
In general, the transferred pediatric reference intervals were similar to those established in our previous study. However, assay-specific differences in reference limits were observed for many analytes, and in some instances were considerable. The results of the EQA evaluation generally mimicked the similarities and differences in reference limits among the five manufacturers' assays. In addition, the majority of transferred reference intervals were validated through the analysis of CALIPER reference samples.
This study greatly extends the utility of the CALIPER reference interval database which is now directly applicable for assays performed on five major analytical platforms in clinical use, and should permit the worldwide application of CALIPER pediatric reference intervals.
•CALIPER reference intervals were transferred to four clinical chemistry platforms•Transferred reference intervals were validated by analyzing CALIPER specimens•This database should permit global application of CALIPER reference intervals
On October 27–28, 2012, the SickKids Labatt Family Heart Centre and the Heart Centre Biobank Registry hosted the second international GenomeHeart symposium in Toronto, Ontario. The symposium featured ...experts in cardiology, developmental biology, pharmacology, genomics, bioinformatics, stem cell biology, biobanking, and ethics. The theme of this year's symposium was the application of emerging technologies in genomics, proteomics, transcriptomics, and bioinformatics to diagnostics and therapeutics of the child with heart disease. Social, ethical, and economic issues were also discussed in the context of clinical translation. We highlight some of the themes that emerged from this exciting 2‐day event.
Translational research (TR) is a multidirectional and multidisciplinary integration of basic research, patient-oriented research and population-based research, with the long-term goal of improving ...human health. Unfortunately, the current scientific training system does not adequately align with the goals of TR. To address this issue, an organization called Apollo Toronto was established at the University of Toronto in Toronto, Ontario. Apollo Toronto is a medical student-run international collaborative project between the Eureka Institute for Translational Medicine and the University of Toronto (one of Eureka Institute’s partner universities), and provides a general overview of TR to interested medical and graduate students. Through local and international initiatives, the various Apollo chapters (including Apollo Toronto) aim to establish a network of trainees equipped to address systemic issues that impede the translation of an ever-growing body of scientific literature into health solutions.
The 2018 Annual General Meeting (AGM) and Young Investigators’ Forum (YIF) of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of ...Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Toronto, Ontario on November 19–20, 2018, in conjunction with the University of
Toronto Clinician Investigator Program Research Day. The theme for the meeting was “Prepare for Success—Things to Master Now for Clinician Scientists in Training”; with lectures and workshops that were designed to provide knowledge and hands-on skills to navigate life as a clinician investigator. The opening remarks were by Jason Berman (President of CSCI), Josh Abraham (President of CITAC/ACCFC) and Nicola Jones (University of Toronto Clinician Investigator Symposium Chair). The keynote speakers were Dr. Ruth Ann Marrie (University of Manitoba), who received the Distinguished Scientist Award, Dr. Davinder Jassal (University of Manitoba), who received the CSCI-RCPSC Henry Friesen Award, and Dr. Aleixo Muise (University of Toronto), who received the Joe Doupe Young Investigator Award. Dr. Minna Woo (University of Toronto), Canada Research Chair in Diabetes Signal Transduction, delivered the keynote lecture “From Onion Cells to Single Cell Seq—A Constant Change in Lenses: A perspective of an evolving clinician scientist”.
The workshops, focusing on career development for clinician-scientists, were hosted by Drs. Robert Chen, Stephen Juvet, Lorraine Kalia, Phyllis Billia, Neil Goldenberg, Nicola Jones, Srdjanaa Filipovic, Jason Berman, Josh Abraham, Melanie Szweras, Joseph Ferenbok and Uri Tabori. The AGM also included presentations from clinician investigator trainees from across the country, and these abstracts are summarized in this review. Over 80 abstracts were showcased at this year’s meeting during the poster session, with six outstanding abstracts selected for oral presentations during the President’s Forum.
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