Browsing by Author "Joffe, Ari R."

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    Cytokines and Chemokines in Pediatric Appendicitis: A Multiplex Analysis of Inflammatory Protein Mediators
    (2019-02-21) Naqvi, S. Ali; Thompson, Graham C.; Joffe, Ari R.; Blackwood, Jaime; Martin, Dori-Ann; Brindle, Mary; Barkema, Herman W.; Jenne, Craig N.
    Objectives. We aimed to demonstrate the potential of precision medicine to describe the inflammatory landscape present in children with suspected appendicitis. Our primary objective was to determine levels of seven inflammatory protein mediators previously associated with intra-abdominal inflammation (C-reactive protein—CRP, procalcitonin—PCT, interleukin-6 (IL), IL-8, IL-10, monocyte chemoattractant protein-1—MCP-1, and serum amyloid A—SAA) in a cohort of children with suspected appendicitis. Subsequently, using a multiplex proteomics approach, we examined an expansive array of novel candidate cytokine and chemokines within this population. Methods. We performed a secondary analysis of targeted proteomics data from Alberta Sepsis Network studies. Plasma mediator levels, analyzed by Luminex multiplex assays, were evaluated in children aged 5-17 years with nonappendicitis abdominal pain (NAAP), acute appendicitis (AA), and nonappendicitis sepsis (NAS). We used multivariate regression analysis to evaluate the seven target proteins, followed by decision tree and heat mapping analyses for all proteins evaluated. Results. 185 children were included: 83 with NAAP, 79 AA, and 23 NAS. Plasma levels of IL-6, CRP, MCP-1, PCT, and SAA were significantly different in children with AA compared to those with NAAP (). Expansive proteomic analysis demonstrated 6 patterns in inflammatory mediator profiles based on severity of illness. A decision tree incorporating the proteins CRP, ferritin, SAA, regulated on activation normal T-cell expressed and secreted (RANTES), monokine induced by gamma interferon (MIG), and PCT demonstrated excellent specificity (0.920) and negative predictive value (0.882) for children with appendicitis. Conclusions. Multiplex proteomic analyses described the inflammatory landscape of children presenting to the ED with suspected appendicitis. We have demonstrated the feasibility of this approach to identify potential novel candidate cytokines/chemokine patterns associated with a specific illness (appendicitis) amongst those with a broad ED presentation (abdominal pain). This approach can be modelled for future research initiatives in pediatric emergency medicine.
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    Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial
    (2024-09-19) O’Hearn, Katie; Menon, Kusum; Albrecht, Lisa; Amrein, Karin; Britz-McKibbin, Philip; Cayouette, Florence; Choong, Karen; Foster, Jennifer R.; Fergusson, Dean A.; Floh, Alejandro; Fontela, Patricia; Geier, Pavel; Gilfoyle, Elaine; Guerra, Gonzalo G.; Gunz, Anna; Helmeczi, Erick; Khamessan, Ali; Joffe, Ari R.; Lee, Laurie; McIntyre, Lauralyn; Murthy, Srinivas; Parsons, Simon J.; Ramsay, Tim; Ryerson, Lindsay; Tucci, Marisa; McNally, Dayre
    Abstract Background The rate of vitamin D deficiency (VDD) in critically ill children worldwide has been estimated at 50%. These children are at risk of multiple organ dysfunction, chronic morbidity, and decreased health related quality of life (HRQL). Pediatric and adult ICU clinical trials suggest that VDD is associated with worse clinical outcomes, although data from supplementation trials are limited and inconclusive. Our group’s phase II multicenter dose evaluation pilot study established the efficacy and safety of an enteral weight-based cholecalciferol loading dose to rapidly restore vitamin D levels in critically ill children. Methods Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained. Discussion The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026. Trial registration Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505
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    The intractable problems with brain death and possible solutions
    (2021-10-09) Joffe, Ari R.; Khaira, Gurpreet; de Caen, Allan R.
    Abstract Brain death has been accepted worldwide medically and legally as the biological state of death of the organism. Nevertheless, the literature has described persistent problems with this acceptance ever since brain death was described. Many of these problems are not widely known or properly understood by much of the medical community. Here we aim to clarify these issues, based on the two intractable problems in the brain death debates. First, the metaphysical problem: there is no reason that withstands critical scrutiny to believe that BD is the state of biological death of the human organism. Second, the epistemic problem: there is no way currently to diagnose the state of BD, the irreversible loss of all brain functions, using clinical tests and ancillary tests, given potential confounders to testing. We discuss these problems and their main objections and conclude that these problems are intractable in that there has been no acceptable solution offered other than bare assertions of an ‘operational definition’ of death. We present possible ways to move forward that accept both the metaphysical problem - that BD is not biological death of the human organism - and the epistemic problem - that as currently diagnosed, BD is a devastating neurological state where recovery of sentience is very unlikely, but not a confirmed state of irreversible loss of all [critical] brain functions. We argue that the best solution is to abandon the dead donor rule, thus allowing vital organ donation from patients currently diagnosed as BD, assuming appropriate changes are made to the consent process and to laws about killing.
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    The Registry and Follow-Up of Complex Pediatric Therapies Program of Western Canada: A Mechanism for Service, Audit, and Research after Life-Saving Therapies for Young Children
    (2011-05-08) Robertson, Charlene M. T.; Sauve, Reg S.; Joffe, Ari R.; Alton, Gwen Y.; Moddemann, Diane M.; Blakley, Patricia M.; Synnes, Anne R.; Dinu, Irina A.; Harder, Joyce R.; Soni, Reeni; Bodani, Jaya P.; Kakadekar, Ashok P.; Dyck, John D.; Human, Derek G.; Ross, David B.; Rebeyka, Ivan M.
    Newly emerging health technologies are being developed to care for children with complex cardiac defects. Neurodevelopmental and childhood school-related outcomes are of great interest to parents of children receiving this care, care providers, and healthcare administrators. Since the 1970s, neonatal follow-up clinics have provided service, audit, and research for preterm infants as care for these at-risk children evolved. We have chosen to present for this issue the mechanism for longitudinal follow-up of survivors that we have developed for western Canada patterned after neonatal follow-up. Our program provides registration for young children receiving complex cardiac surgery, heart transplantation, ventricular assist device support, and extracorporeal life support among others. The program includes multidisciplinary assessments with appropriate neurodevelopmental intervention, active quality improvement evaluations, and outcomes research. Through this mechanism, consistently high (96%) follow-up over two years is maintained.