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Early damage control resuscitation and massive transfusion (MT) protocol activations improve outcomes in trauma patients with hemorrhagic shock, where scores to guide MT prediction are used including: the Assessment of Blood Consumption (ABC), Shock Index (SI), and Revised Assessment of Bleeding and Transfusion (RABT) scores. Our aim was to validate the RABT score in patients from two level I trauma centers in Canada.A retrospective review of adult patients meeting trauma team activation criteria receiving1 unit of red blood cells (RBCs) within 24 h of admission, from 2015 to 2020, was conducted. A RABT score ≥ 2, ABC score ≥ 2, and Shock Index (SI) ≥ 1 was used to predict MT using both research (≥10 RBCs in 24 h) and clinical (≥3 RBCs in 3 h) definitions. Scores were assessed and compared using sensitivity, specificity, and the area under the receiver operating characteristic (AUROC).We analyzed 514 patients with a mean age of 44.4 (19.2) years and a median injury severity score of 29 [18-38]. For both MT definitions, the RABT score trended towards higher sensitivity and lower specificity compared to ABC score and SI. For both research and clinical definitions of MT, the AUROC for the RABT score was not significantly higher (Research - RABT: 0.673 [0.610-0.735], ABC: 0.642 [0.551-0.734], SI 0.691 [0.625-0.757]; Clinical - RABT: 0.653 [0.608-0.698], ABC: 0.646 [0.600-0.691], SI 0.610 [0.559-0.660]).The RABT score is a valid tool for predicting the need for MTPs, performing similarly with a trend towards higher sensitivity when compared to the ABC score and SI.

Background and Objectives The coronavirus disease 2019 (COVID‐19) pandemic raised concerns about the vulnerability of platelet supply and the uncertain impact of the resumption of elective surgery on utilization. We report the impact of COVID‐19 on platelet supply and utilization across a large, integrated healthcare system in the Canadian province of British Columbia (BC). Materials and Methods Historical platelet use in BC by indication was compiled for fiscal year 2010/2011–2019/2020. Platelet collections, initial daily inventory and disposition data were assessed pre‐COVID‐19 (1 April 2018–15 March 2020) and for two COVID‐19 time periods in BC: a shutdown phase with elective surgeries halted (16 March–17 May, 2020) and a renewal phase when elective surgeries resumed (18 May–27 September 2020); comparisons were made provincially and for individual health authorities. Results Historically, elective surgeries accounted for 10% of platelets transfused in BC. Initial daily supplier inventory increased from baseline during both COVID‐19 periods (93/90 units vs. 75 units pre‐COVID‐19). During the shutdown phase, platelet utilization decreased 10.4% (41 units/week; p

Background In March 2020, a state of emergency was declared to facilitate organized responses to the coronavirus disease 2019 (COVID‐19) pandemic in British Columbia, Canada. Emergency blood management committees (EBMCs) were formed regionally and provincially to coordinate transfusion service activities and responses to possible national blood shortages. Study Design and Methods We describe the responses of transfusion services to COVID‐19 in regional health authorities in British Columbia through a collaborative survey, contingency planning meeting minutes, and policy documents, including early trends observed in blood product usage. Results Early strategic response policies were developed locally in collaboration with members of the provincial EBMC and focused on three key areas: utilization management strategies, stakeholder engagement (collaboration with frequent users of the transfusion service, advance notification of potential inventory shortage plans, and development of blood triage guidance documents), and laboratory staffing and infection control procedures. Reductions in transfusion volumes were observed beginning in mid‐March 2020 for red blood cells and platelets relative to the prepandemic baseline (27% and 26% from the preceding year, respectively). There was a slow gradual return toward baseline beginning one month later; no product shortage issues were experienced. Conclusion Provincial collaborative efforts facilitated the development of initiatives focused on minimizing potential COVID‐19–related disruptions in transfusion services in British Columbia. While there have been no supply issues to date, the framework developed early in the pandemic should facilitate timely responses to possible disruptions in future waves of infection.

Background INR is traditionally used as a marker of clinical coagulopathy, but is suboptimal in liver disease patients due to rebalanced hemostasis and its ineffectiveness to predict bleeding. Rotational thromboelastometry (ROTEM) testing evaluates whole blood hemostasis, which may provide more accurate assessments with the EXTEM CT parameter than INR. Thus, in end-stage liver disease (ESLD) patients, we hypothesized that elevated INRs are associated with normal EXTEM CT values. Methods A retrospective study assessing adult (>18) patients with ESLD and elevated INRs undergoing liver transplantation, was performed to assess correlations between INR and EXTEM CT. This included patients post-ROTEM implementation where all had pre-operative ROTEM testing; and patients up to one year pre-ROTEM implementation to compare transfusion utilization. Data abstracted also included patient demographics, coagulation testing results, liver disease etiology, and MELD score. Results The study included 138 patients in the post-ROTEM group and 59 patients in the pre-ROTEM group. Normal EXTEM CT was observed in 95.3 % and 93 % of patients with INR of 1.3–1.8 and up to 3 respectively. There was no correlation between INR of 1.3–1.8 and EXTEM CT (⍴ = 0.239), and only moderate correlation was observed with higher INRs (⍴ = 0.617 with INRs >1.8). ROTEM-guided transfusion in liver transplant surgeries was associated with reduced plasma transfusion (OR 0.27, 95 % CI 0.12−0.58, p = 0.001) after adjusting for red cell utilization and coagulation testing. Conclusion Our study suggests ROTEM may be advantageous for evaluating coagulopathy in patients with liver disease and ROTEM-guided transfusion reduces plasma transfusion.

Objective Preoperative anemia management reduces red blood cell (RBC) transfusion and adverse outcomes, but how best to optimize the patient's hemoglobin (Hgb) before cardiac surgery remains unclear. The authors sought to determine the optimal treatment of anemia using iron and epoetin alfa before cardiac surgery. Design Retrospective cohort study. Setting Sunnybrook Health Sciences Centre, University of Toronto. Participants The study comprised 532 consecutive patients referred to the outpatient Blood Conservation Clinic and who underwent cardiac surgery between 2008 and 2018. Interventions Of the 532 patients, 207 received oral iron, 84 received intravenous (IV) iron, 71 received epoetin alfa, 92 received combination therapy, and 78 received no treatment. Measurements and Main Results Multivariate linear, logistic, and Poisson regressions modelled preoperative Hgb, the change from referral to preoperative Hgb (∆Hgb), the odds of transfusion, and the number of RBC units transfused, while accounting for baseline covariates. Higher ∆Hgb was associated with IV iron >600 mg (9.80 g/L [6.17-13.42]), epoetin alfa >80,000 U (5.80 g/L [2.20-9.40]), and higher referral Hgb (1.91 g/L [1.09-2.74] per 10 g/L). Higher preoperative Hgb (odds ratio 0.76 [0.64-0.90]; count ratio 0.84 [0.77-0.93] per 10 g/L) corresponded to a lower likelihood of being transfused and transfusion of fewer RBC units. Conclusions Preoperative IV iron >600 mg and epoetin alfa >80,000 U each was associated with significant increases in Hgb. Higher preoperative Hgb was associated with a lower likelihood of transfusion and transfusion of fewer RBC units. The authors recommend that cumulative preoperative doses of IV iron >600 mg and epoetin alfa >80,000 U be used for treatment of anemia before cardiac surgery.

Background Current practices prioritize transfusion readiness over preoperative hemoglobin (Hgb) optimization in elective arthroplasty patients. We characterized the relationship between preoperative Hgb and perioperative transfusion among patients undergoing primary hip and knee replacement in order to identify a threshold Hgb at which the probability of transfusion is negligibly low. We then evaluated an alternative preoperative patient management algorithm using an evidence-guided threshold for pre-transfusion testing. Methods We performed a retrospective cohort study of adults undergoing elective primary hip or knee arthroplasty at two academic hospitals between 2010 and 2017. A subset of patients received either no treatment, iron supplementation, or erythropoietin preoperatively. Logistic regressions modelled the likelihood of transfusion, adjusted for baseline covariates. Receiver operating characteristic plots were generated to determine which Hgb threshold best predicted transfusion. Our results informed a quality-improvement initiative involving revised preoperative clinical pathway. Results We included 13,113 patients. A 10 g/L lower Hgb corresponded to 2.81 (95%CI: 2.43–3.25; p Conclusions Our results demonstrate that, at our center, a preoperative Hgb ≤115 g/L distinguishes between joint arthroplasty patients who require transfusion from those who do not. Patient-guided pretransfusion testing may streamline joint arthroplasty program efficiency.

BACKGROUND The optimal method of providing transfusion medicine (TM) education has not been determined. Transfusion Camp was established in 2012 at the University of Toronto as a centrally delivered TM education program for postgraduate trainees. The impact of Transfusion Camp on knowledge, attitudes, and self-reported behavior was evaluated. METHODS Didactic lectures (delivered locally, by webinar, or recorded) and locally facilitated team-based learning seminars were delivered over 5 days during the academic year to 8 sites: 7 in Canada and 1 in the United Kingdom. Knowledge assessment using a validated 20-question multiple-choice exam was conducted before and after Transfusion Camp. Attitudes and self-reported behavior were collected through a survey. RESULTS Over 2 academic years (July 2016 to June 2018), 390 trainees from 16 different specialties (predominantly anesthesia, 41%; hematology, 14%; and critical care, 7%) attended at least 1 day of Transfusion Camp. The mean pretest score was 10.3 of 20 (±2.9; n = 286) compared with posttest score of 13.0 (±2.8; n = 194; p < 0.0001). Lower pretest score and greater attendance (4-5 days compared with 1-3 days) were associated with larger improvement in posttest score; delivery format, specialty, and postgraduate year were not. Trainees reported an improvement in self-rated abilities to manage TM scenarios; 95% rated TM knowledge as very or extremely important in providing patient care; and 81% indicated that they had applied learning from Transfusion Camp into clinical practice. CONCLUSIONS Transfusion Camp increased TM knowledge, fostered a positive attitude toward TM, and enabled a self-reported positive impact on transfusion practice in postgraduate trainees. It is a novel and scalable approach to delivering TM education.

Intraoperative cell salvage (ICS) is used as an alternative to allogeneic blood transfusion in an attempt to avoid or minimize the risks associated with allogeneic blood. Intraoperative cell salvage is generally avoided in surgeries where malignancy is confirmed or suspected due to concern for potential metastasis or cancer recurrence. The application of post-processing methods for ICS is hypothesized to eliminate this potential risk. The purpose of this narrative review is to examine the in vitro experimental evidence as it pertains to the removal of tumour cells from ICS blood and to review the clinical studies where ICS blood has been used in patients with malignancy.A search of the English literature for relevant articles published from 1973 to 2012 was undertaken using MEDLINE and Cochrane databases. Bibliographies were cross-referenced to locate further studies.Leukoreduction filters are an effective method for removal of malignant cells from ICS blood. Small non-randomized clinical studies to date do not show evidence of an increased rate of metastasis or cancer recurrence. Although a theoretical risk of disease recurrence persists, the decision to use autologous ICS blood must be weighed against the known risks of allogeneic blood transfusion.Transfusion of autologous blood harvested via ICS should be considered a viable option for reduction or avoidance of allogeneic product during many oncologic surgeries and may be a lifesaving option for those patients who refuse allogeneic blood products.

Autoimmune (type 1) diabetes results from a loss of β cells that is mediated by self-reactive T cells. Previous studies have shown that a single injection of CFA prevents diabetes in nonobese diabetic (NOD) mice, but the mechanism(s) of protection remain unknown. We show here that NOD mice immunized with CFA have a markedly reduced incidence of diabetes and that this reduced incidence is associated with a decrease in the number of β cell-specific, autoreactive CTL. In addition, the adoptive transfer of diabetes into syngeneic NOD/SCID recipients was prevented by CFA immunization, and the protective effects of CFA were lost when cells expressing the NK cell marker, asialo GM1, were removed from both donor cells and recipient mice. Returning a population of CD3−DX5+ cells to the adoptive transfer restored the protective effects of CFA. Therefore, NK cells mediate the protective effects of CFA possibly through the down-regulation of autoreactive CTL and stimulation of NK cells represents a novel approach to the prevention of autoimmune diabetes.

Activated T cells and their naive precursors display different functional avidities for peptide/MHC, but are thought to have identical antigenic repertoires. We show that, following activation with a cognate mimotope (NRP), diabetogenic CD8+ T cells expressing a single TCR (8.3) respond vigorously to numerous peptide analogs of NRP that were unable to elicit any responses from naive 8.3-CD8+ T cells, even at high concentrations. The NRP-reactive, in vivo activated CD8+ cells arising in pancreatic islets of nonobese diabetic mice are similarly promiscuous for peptide/MHC, and paradoxically this promiscuity expands as the aviditiy of the T cell population for NRP/MHC increases with age. Thus, activation and avidity maturation of T lymphocyte populations can lead to dramatic expansions in the range of peptides that elicit functional T cell responses.

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.

Pain is a subjective experience that is affected by physical, emotional, and psychological factors, and reliable assessment of pain can be a challenge in the pediatric population. A quality improvement project was conducted at one Canadian health care facility to examine the effectiveness of the postoperative pain management strategy for children admitted to the postanesthesia care unit (PACU). Effective control of postoperative pain involves several preventive strategies that include preoperative analgesia, appropriate use of intraoperative analgesic techniques, and identification of children at risk for significant postoperative pain. Successful implementation of these techniques requires a multidisciplinary team approach involving the patient, the PACU nurses, the anesthesia care provider, and other surgical team members.

Despite considerable success in treating newly diagnosed childhood acute lymphoblastic leukemia (ALL), relapsed disease remains a significant clinical challenge. Using a NOD/SCID mouse xenograft model, we report that immunostimulatory DNA oligonucleotides containing CpG motifs (CpG ODNs) stimulate significant immune activity against primary human ALL cells in vivo. The administration of CpG ODNs induced a significant reduction in systemic leukemia burden, mediated continued disease control, and significantly improved survival of mice with established human ALL. The death of leukemia cells in vivo was independent of the ability of ALL cells to respond directly to CpG ODNs and correlated with the production of IL-12p70, IFN-α, and IFN-γ by the host. In addition, depletion of natural killer cells by anti–asialo-GM1 treatment significantly reduced the in vivo antileukemic activity of CpG ODN. This antileukemia effect was not limited to the xenograft model because natural killer cell–dependent killing of ALL by human peripheral blood mononuclear cells (PBMCs) was also increased by CpG ODN stimulation. These results suggest that CpG ODNs have potential as therapeutic agents for the treatment of ALL.

Immunostimulatory DNA containing unmethylated cytosine-phosphate-guanosine (CpG) induces the development of T helper 1 (Th1) immune responses. The response of B cells to CpG stimulation involves increased proliferation, cytokine production, and costimulatory molecule expression. Similar effects have been observed following CpG stimulation of a variety of malignant B cells. Pediatric precursor B acute lymphoblastic leukemia (B-ALL) cells express low levels of costimulatory molecules and are generally poor stimulators of T-cell responses. In this study, we evaluated the impact of CpG stimulation on precursor B-ALL cell lines and pediatric patient-derived samples. The ability to respond to CpG oligodeoxynucleotides was determined by the level of Toll-like receptor 9 (TLR9) expression. In contrast to both nonleukemic B-cell precursors and mature B cells, the response of precursor B-ALL cells was characterized by increased CD40 expression but only small changes in CD86 levels and no induction of CD80 expression. CpG stimulation of ALL blasts produced increased levels of interleukin-6 (IL-6), IL-8, and IL-10 but no detectable IL-12p70 and led to a skewing of allogeneic T cells, with enhanced interferon γ (IFN-γ) production and reduced secretion of IL-5. These results demonstrate the functional relevance of CpG stimulation of precursor B-ALL cells and provide a rational basis for study of these agents for use in treatment of this disease.

Autoimmune (type 1) diabetes mellitus results from the destruction of insulin-producing pancreatic beta-cells by T lymphocytes. Beta-cell death that is induced by autoreactive CTL in diabetes involves both Fas/Fas ligand (FasL)- and perforin/granzyme-mediated pathways, although their relative contributions during the progression of the disease remain unknown. We demonstrate here that despite the preferential use of the Fas/FasL pathway for cytolysis of beta-cell targets, transgenic beta-cell-specific CTL were able to kill targets via the perforin pathway when triggered by a higher affinity stimulus. In addition, we show that the killing mechanism used by islet-associated CD8(+) T cells from non-obese diabetic mice changed as the mice aged and correspondingly, with the stage of diabetes. These results provide direct evidence for age-related changes in the cytotoxic pathways used by diabetogenic T cells during the progression of autoimmune diabetes.

The immune system of the skin has recently been exploited for the development of non-invasive vaccine technologies. However, one of the limitations of current vaccine protocols is the inefficient priming of cytotoxic T lymphocytes (CTL). In this study, we report that the application of either an immunodominant class I MHC restricted ovalbumin peptide or whole ovalbumin protein, to tape-stripped skin together with the co-application of the bacterial enterotoxin cholera toxin (CT) induces antigen-specific CTL. Tape-stripping (TS) was found to enhance the magnitude of antibody responses to co-administered protein and to promote the generation of antigen-specific IgG 2a responses. As well, both cholera toxin and tape-stripping enhanced epidermal dendritic cell (DC) immigration into draining lymph nodes. The adjuvant effect of co-administered cholera toxin and tape-stripping in promoting CTL priming was not dependent on IL-12. Epicutaneous immunization has previously been shown to induce robust antibody responses to administered protein antigen. We now demonstrate the induction of robust and persistent CTL responses to epicutaneously administered protein antigen. Epicutaneous immunization is cheap, simple and effective. These findings suggest the potential use of the skin for the generation of protective immune responses to both viral and tumor challenge.

CTLs are important mediators of pancreatic β cell destruction in the nonobese diabetic mouse model of type 1 diabetes. Cross-presentation of Ag is one means of priming CTLs. The death of Ag-bearing cells has been implicated in facilitating this mode of priming. The role of β cell death in facilitating the onset of spontaneous autoimmune diabetes is unknown. Here, we used an adoptive transfer system to determine the time course of islet-derived Ag presentation to naive β cell-specific CD8 T cells in nonobese diabetic mice and to test the hypothesis that β cell death enhances the presentation of β cell autoantigen. We have determined that β cell death enhances autoantigen presentation. Priming of diabetogenic CD8 T cells in the pancreatic lymph nodes was negligible before 4 wk, progressively increased until 8 wk of age, and was not influenced by gender. Administration of multiple low doses of the β cell toxin streptozotocin augmented in situ β cell apoptosis and accelerated the onset and magnitude of autoantigen presentation to naive CD8 T cells. Increasing doses of streptozotocin resulted in both increased pancreatic β cell death and significantly enhanced T cell priming. These results indicate that in situ β cell death facilitates autoantigen-specific CD8 T cell priming and can contribute to both the initiation and the ongoing amplification of an autoimmune response.

Type 1 diabetes (TID) results from T-cell-mediated destruction of pancreatic b cells in genetically predisposed individuals. Autoreactive CD4(+) T helper cells and CD8(+) cytotoxic T lymphocytes (CTLs) recognize b-cell-derived peptides in the context of major histocompatibility complex class II and I molecules, respectively, in a process that terminates in b-cell death. Many peptide epitopes derived from b-cell proteins have been described for both humans and the nonobese diabetic (NOD) mouse, but their relative importance in disease pathogenesis is unclear. The significance of identifying key b-cell epitopes is underscored by a study showing that in the NOD mouse monitoring of a single population of b-cell-specific CTLs in the peripheral blood using a high-avidity analogue of the endogenous peptide may be used to accurately predict diabetes occurrence. Future studies focused on the discovery of immunodominant b-cell epitopes and their high-avidity analogues should have considerable implications for prediction and immunotherapy of TID.