Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators.

BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.

Using an interprofessional competency framework to enhance collaborative pediatric nursing education and practice.

BACKGROUND: Interprofessional education (IPE) provides healthcare students with the knowledge and skills necessary to provide safe and effective collaborative care in a variety of clinical settings. Inclusion of IPE in nursing curricula is required for program accreditation in Canada; a variety of learning strategies at varied levels are used to meet this requirement. As this formal requirement only occurred over the last decade, development, facilitation, and evaluation of IPE interventions are ongoing. PURPOSE: The purpose of this study was to examine if exposure to an introductory IPE activity influenced third-year undergraduate nursing students' perceived ability to practice competent interprofessional collaboration (IPC). METHODS: The introductory IPE activity included ten-hours of interactive lectures and related case studies, grounded in the National Interprofessional Competency Framework, delivered by various healthcare professionals in a third-year nursing theory and clinical course. Following completion of the courses, quantitative data were collected via the Interprofessional Collaborative Competencies Attainment Survey (ICCAS) which was used to evaluate nursing students' change in competencies for IPC. Frequencies, percentages, and means were used to analyze the demographic data, the Cronbach's alpha coefficient was used to evaluate the internal reliability of the ICCAS, and paired t-tests were conducted to measure the difference from pre- to post-participation for all 20 items and 6 subscales of the ICCAS. RESULTS: Study participants (n = 111) completed the ICCAS at the end of the courses to measure change in six competencies. The survey results indicated improvements in all competencies following the IPE activity. CONCLUSIONS: The significant findings demonstrate that exposure to introductory IPE activities, involving nursing students and other healthcare professionals, hold promise for enhancing IPC in pediatric clinical settings. These findings can be used to inform the development of formal IPE interventions.

The Association of Matrix Metalloproteinases With Acute Kidney Injury Following CPB-Supported Cardiac Surgery.

BACKGROUND: Cardiac surgery-associated acute kidney injury (AKI) is an adverse outcome that increases morbidity and mortality in patients undergoing cardiac surgical procedures. To date, the use of serum creatinine levels as an early indicator of AKI has limitations because of its slow rise and poor predictive accuracy for renal injury. This delay in diagnosis may lead to prolonged initiation in treatment and increased risk for adverse outcomes. OBJECTIVE: This pilot study explores serum and urine matrix metalloproteinases (MMPs)-2 and MMP-9 and their association, and potentially earlier detection of AKI in patients following cardiopulmonary bypass (CPB)-supported cardiac surgery. We hypothesize that increased activity of serum and urine levels MMP-2 and/ or MMP-9 are associated with AKI. Furthermore, MMP-2 and/ or MMP-9 may provide earlier identification of AKI as compared with serum levels of creatinine. METHODS: During the study period, there were 150 CPB-supported surgeries, 21 of which developed AKI according to the Kidney Disease Improving Global Outcomes criteria. We then selected a sample of 21 matched cases from those patients who went through the surgery without developing AKI. Primary outcomes were the measurement via gel zymography of the serum and urine activity of MMP-2 and MMP-9 drawn at the following intervals: pre-CPB; 10-minute post-CPB; and 4-hour post-CPB time points. Secondary variables were the measurement of serum creatinine, intensive care unit (ICU) fluid balance, and length of ICU stay. RESULTS: At the 10-minute and 4-hour post-CPB time points, the serum MMP-2 activity of AKI patients were significantly higher as compared with non-AKI patients (P < .001 and P = .004), respectively. Similarly, at the 10-minute and 4-hour post-CPB time points, the serum MMP-9 activity of AKI patients was significantly higher as compared with non-AKI patients (P = .001 and P = .014), respectively. The activity of urine MMP-2 and MMP-9 of AKI patients was significantly higher as compared with non-AKI patients at all 3 time points (P = .004, P < .001, P < .001), respectively. CONCLUSION: Although the pilot study may have limitations, it has demonstrated that the serum and urine levels of activity of MMP-2 and MMP-9 are associated with the clinical endpoint of AKI and appear to have earlier rising levels as compared with those of serum creatinine. Furthermore, in depth, exploration is underway with a larger sample size to attempt validation of the analytical performance and reproducibility of the assay for MMP-2 and MMP-9 to aid in earlier diagnosis of AKI following CPB-supported cardiac surgery.

CONTEXTE: L'insuffisance rénale aiguë (IRA) associée à la chirurgie cardiaque est un effet indésirable qui augmente la morbidité et la mortalité des patients qui subissent ce type d'intervention. La mesure de la créatinine sérique comme indicateur précoce de l'IRA continue à ce jour de présenter des limites en raison de sa lente augmentation et de l'imprécision de son pouvoir prédictif. Ce délai dans le diagnostic peut retarder l'initiation du traitement et accroître le risque d'effets indésirables. OBJECTIFS: Cette étude pilote explore les métalloprotéinases matricielles (MPM) -2 et -9 sériques et urinaires, leur association avec l'IRA et leur potentiel pour la détection plus précoce de la maladie chez les patients qui subissent une chirurgie cardiaque assistée par circulation extracorporelle. Nous émettons l'hypothèse qu'une hausse de l'activité des MMP-2 et/ou -9 et de leurs taux sériques et urinaires serait associée à l'IRA. Les MMP-2 et/ou -9 pourraient en outre permettre d'identifier la maladie plus précocement que le taux de créatinine sérique. MÉTHODOLOGIE: Au cours de la période de l'étude, 150 chirurgies cardiaques assistées par circulation extracorporelle ont été effectuées et 21 ont été associées à une IRA telle que définie par les critères du KDIGO (Kidney Disease Improving Global Outcomes). Nous avons sélectionné 21 cas appariés parmi les patients ayant subi l'intervention sans développer d'IRA. Le principal critère d'évaluation était une mesure de l'activité des MMP-2 et -9 obtenue par une zymographie sur gel d'échantillons de sérum et d'urine prélevés aux intervalles suivants: pré-circulation extracorporelle, 10 minutes après la circulation extracorporelle et 4 heures après la circulation extracorporelle. Les variables secondaires étaient la mesure de la créatinine sérique, la mesure de la balance liquidienne durant le séjour à l'unité de soins intensifs (USI) et de la durée du séjour à l'USI. RÉSULTATS: L'activité des MMP-2 sériques des patients atteints d'IRA était significativement plus élevée que celle des patients non atteints d'IRA 10 minutes et 4 heures post-circulation extracorporelle (p < 0,001 et p = 0,004 respectivement). Aux mêmes repères temporels, l'activité des MMP-9 sériques était elle aussi significativement plus élevée chez les patients atteints d'IRA (p = 0,001 [IRA]; p = 0,014 (non IRA). L'activité des MMP-2 et -9 urinaires, elle était elle aussi significativement plus élevée pour les patients atteints d'IRA, et ce, pour les trois points temporels (p = 0,004 [IRA); p < 0,001 [non IRA]). CONCLUSION: Bien que cette étude pilote comporte des limites, elle a tout de même démontré que l'activité des MMP-2 et -9 sériques et urinaires est associée aux paramètres cliniques de l'IRA, et que leurs taux augmentent plus rapidement que les taux de créatinine sérique. Des recherches plus approfondies sur un plus grand échantillon de patients sont en cours afin de valider la performance analytique et la reproductibilité du dosage des MMP-2 et -9 pour diagnostiquer plus rapidement l'IRA après une chirurgie cardiaque assistée par circulation extracorporelle.

A performance comparison of the most commonly used minimally invasive monitors of cardiac output.

BACKGROUND: Shock is common in critically ill and injured patients. Survival during shock is highly dependent on rapid restoration of tissue oxygenation with therapeutic goals based on cardiac output (CO) optimization. Despite the clinical availability of numerous minimally invasive monitors of CO, limited supporting performance data are available. METHODS: Following approval of the University of Saskatchewan Animal Research Ethics Board, we assessed the performance and trending ability of PiCCOplus™, FloTrac™, and CardioQ-ODM™ across a range of CO states in pigs. In addition, we assessed the ability of invasive mean arterial blood pressure (iMAP) to follow changes in CO using a periaortic transit-time flow probe as the reference method. Statistical analysis was performed with function-fail, bias and precision, percent error, and linear regression at all flow, low-flow (> 1 standard deviation [SD] below the mean), and high-flow (> 1 SD above the mean) CO conditions. RESULTS: We made a total of 116,957 paired CO measurements. The non-invasive CO monitors often failed to provide a CO value (CardioQ-ODM: 40.6% failed measurements; 99% confidence interval [CI], 38.5 to 42.6; FloTrac: 9.6% failed measurements; 99% CI, 8.7 to 10.5; PiCCOplus: 4.7% failed measurements; 99% CI, 4.5 to 4.9; all comparisons, P < 0.001). The invasive mean arterial pressure provided zero failures, failing less often than any of the tested CO monitors (all comparisons, P < 0.001). The PiCCOplus was most interchangeable with the flow probe at all flow states: PiCCOplus (20% error; 99% CI, 19 to 22), CardioQ-ODM (25% error; 99% CI, 23 to 27), FloTrac (34% error; 99% CI, 32 to 38) (all comparisons, P < 0.001). At low-flow states, CardioQ-ODM (43% error; 99% CI, 32 to 63) and Flotrac (45% error; 99% CI, 33 to 70) had similar interchangeability (P = 0.07), both superior to PiCCOplus (48% error; 99% CI, 42 to 60) (P < 0.001). Regarding CO trending, the CardioQ-ODM (correlation coefficient, 0.82; 99% CI, 0.81 to 0.83) was statistically superior to other monitors including iMAP, but at low flows iMAP (correlation coefficient, 0.58; 99% CI, 0.58 to 0.60) was superior to all minimally invasive CO monitors (all comparisons P < 0.001). CONCLUSIONS: None of the minimally invasive monitors of CO performed well at all tested flows. Invasive mean arterial blood pressure most closely tracked CO change at critical flow states.

RéSUMé: CONTEXTE: L'état de choc est fréquent chez les patients blessés et en urgence absolue. La survie pendant le choc dépend fortement de la restauration rapide de l'oxygénation tissulaire avec des objectifs thérapeutiques basés sur l'optimisation du débit cardiaque (DC). Malgré la disponibilité clinique de nombreux moniteurs minimalement invasifs du DC, il n'existe que des données limitées sur leur performance pour appuyer leur utilisation. MéTHODE: À la suite de l'approbation du comité d'éthique de la recherche animale de l'Université de la Saskatchewan, nous avons évalué la performance et la capacité de suivi des tendances des appareils PiCCOplus™, FloTrac™ et CardioQ-ODM™ sur une vaste gamme d'état de DC chez des cochons. Nous avons également évalué la capacité de la tension artérielle moyenne invasive (iMAP) à suivre les changements de DC en utilisant une sonde périaortique de débit basée sur le temps de transit comme méthode de référence. L'analyse statistique a été réalisée avec fonction-échec, biais et précision, pourcentage d'erreur et régression linéaire à des conditions de DC de tous les débits, de faible débit (> 1 écart-type [ET] au-dessous de la moyenne) et de débit élevé (> 1 ET au-dessus de la moyenne). RéSULTATS: Nous avons effectué un total de 116 957 mesures de DC appariées. Les moniteurs non invasifs de la DC n'ont souvent pas réussi à fournir une valeur de DC (CardioQ-ODM : 40,6% de mesures échouées; intervalle de confiance [IC] de 99 %, 38,5 à 42,6; FloTrac : 9,6 % de mesures échouées; IC 99 %, 8,7 à 10,5; PiCCOplus : 4,7 % de mesures échouées; IC 99 %, 4,5 à 4,9; toutes les comparaisons, P < 0,001). La tension artérielle moyenne invasive n'a fourni aucun échec plus souvent que n'importe lequel des moniteurs de DC testés (toutes les comparaisons, P < 0,001). Le PiCCOplus était le plus interchangeable avec la sonde de débit à tous les états de débit : PiCCOplus (erreur de 20 %; IC 99 %, 19 à 22), CardioQ-ODM (erreur de 25 %; IC 99 %, 23 à 27), FloTrac (erreur de 34 %; IC 99 %, 32 à 38) (toutes les comparaisons, P < 0,001). Aux états de débit faible, les moniteurs CardioQ-ODM (erreur de 43 %; IC 99 %, 32 à 63) et FloTrac (erreur de 45 %; IC 99 %, 33 à 70) présentaient une interchangeabilité similaire (P = 0,07), tous deux supérieurs au PiCCOplus (erreur de 48 %; IC 99 %, 42 à 60) (P < 0,001). En ce qui concerne le suivi des tendances de DC, le CardioQ-ODM (coefficient de corrélation, 0,82; IC 99 %, 0,81 à 0,83) était statistiquement supérieur aux autres moniteurs, y compris au iMAP, mais à faibles débits, l'iMAP (coefficient de corrélation, 0,58; IC 99 %, 0,58 à 0,60) était supérieure à tous les moniteurs de DC minimalement invasifs (toutes les comparaisons, P < 0,001). CONCLUSION: Aucun des moniteurs de DC minimalement invasif n'a donné de bons résultats à tous les débits testés. La tension artérielle moyenne invasive était le moniteur qui a suivi de plus près les changements de DC dans des états critiques de débit.

Pre-arrest doxycycline protects donation after circulatory death kidneys.

Kidney injury during donation after circulatory determination of death (DCDD) includes warm ischemic (WI) injury from around the time of asystole, and cold ischemic (CI) injury during cold preservation. We have previously shown that Matrix Metalloproteinases (MMPs) are involved in CI injury and that Doxycycline (Doxy), an antibiotic and known MMP inhibitor, protects the transplant kidney during CI. The purpose of our study was to determine if Doxy given before asystole can also prevent injury during WI. A rat model of DCDD was used, including Control, Preemptive Doxy (45 mg/kg iv), and Preemptive and Perfusion (100 microM) Doxy groups. Thirty minutes after asystole, both kidneys were removed. The left kidney was perfused at 4 °C for 22 h, whereas the right was used to establish the degree of warm ischemic injury prior to cold preservation. MMP-2 in the perfusate was significantly reduced in both treatment groups [Control 43.7 ± 7.2 arbitrary units, versus Preemptive Doxy group 23.2 ± 5.5 (p = 0.03), and 'Preemptive and Perfusion' group 18.0 ± 5.6 (p = 0.02)]. Reductions in NGAL, LDH, and MMP-9 were also seen. Electron microscopy showed a marked reduction in mitochondrial injury scores in the treatment groups. Pre-arrest Doxy was associated with a reduction in injury markers and morphologic changes. Doxy may be a simple and safe means of protecting transplant kidneys from both WI and CI.

Transfusion Use and Hemoglobin Levels by Blood Conservation Method After Cardiopulmonary Bypass.

BACKGROUND: Guidelines recommend modified ultrafiltration (MUF) and cell washing for blood conservation after cardiopulmonary bypass (CPB), although information on outcomes is lacking. This research compared online MUF (ultrafiltration of the patient's entire circulating volume) with off-line MUF (ultrafiltration of the residual CPB volume) and centrifugation (cell washing of the residual CPB volume). METHODS: This prospective cohort study enrolled 99 consecutive patients, grouped by method (group I, online MUF, n = 35; group II, off-line MUF, n = 30; group III, centrifugation, n = 34). Primary outcome was transfusion by 18 hours. Secondary outcomes were 18-hour hemoglobin levels, fluid balance (weight change), and biomarker levels indicating coagulation and organ function. RESULTS: By 18 hours, 22.9%, 6.7%, and 14.7% of group I, II, and III patients, respectively, had undergone transfusion (P = .19). Percentage weight gain differed by group (group I, 5.7%; group II, 1.3%; group III, 4.5%; P < .0001). Baseline to 18-hour hemoglobin change also differed by group, with the group I increase significantly exceeding that of group II (P = .002) but not differing from group III (P = .36). After adjustment for European System for Cardiac Operative Risk Evaluation II (EuroSCORE), weight gain, and transfusion, only the group II to III difference remained significant (P = .002). CONCLUSIONS: Online MUF does not appear to offer a reduction in blood transfusion over other methods. Although patients undergoing online MUF had greater improvement in baseline to 18-hour hemoglobin compared with patients undergoing off-line MUF, this benefit appeared attributable to fluid shifting. Off-line MUF was associated with the least frequent transfusions. Although online MUF does not appear to reduce blood transfusion, larger prospective randomized controlled studies are required for confirmation.

The prevalence of undiagnosed Prediabetes/type 2 diabetes, prehypertension/hypertension and obesity among ethnic groups of adolescents in Western Canada.

BACKGROUND: An increased incidence of type 2 diabetes in youth is occurring worldwide. While diverse ethnic groups are disproportionately affected by type 2 diabetes, studies that explore ethnic differences and undiagnosed prediabetes/type 2 diabetes in adolescents are scarce. This paper compares the prevalence of undiagnosed prediabetes and type 2 diabetes and the associated risk factors among various ethnic groups of adolescents living in Western Canada. METHODS: The data for this study were derived from two previous studies in which 396 adolescents, aged 14 to 19 years and living in a western Canadian province, were screened for undiagnosed prediabetes, diabetes, and any associated risk factors. Risk was determined by demographics, family history, anthropometric measurements (body mass index, BMI), blood pressure (BP), and HbA1c. Descriptive and inferential statistics (SPSS) were used to establish both risk and prevalence for prediabetes and type 2 diabetes. Chi-square analyses were done to determine if the risk factors occurred at higher frequencies in certain ethnicities. RESULTS: Based on BP, BMI, and HbA1c measurements, several statistically significant differences were identified in relation to ethnicity. Many of the adolescents had increased HbA1c levels, with 27.3% considered high risk and 2.3% in the prediabetes range; these high risk and prediabetes groups were heavily represented by Filipino (46%), Indigenous (22%), and European (10%) adolescents. Notable prevalence of prehypertension (17.7%) and hypertension (21.7%) were reported in European (59%) followed by Filipino (50%) and Indigenous (26%) adolescents. Higher numbers of adolescents in the European and Filipino ancestry groups had two or more risk factors (BP, BMI, & HbA1c) for developing type 2 diabetes in relation to the adolescents from the Indigenous group. CONCLUSIONS: Ethnic adolescent groups demonstrate a notable prevalence of undiagnosed prediabetes and type 2 diabetes. Specifically, a significant number of Filipino adolescents had both increased HbA1c and blood pressure that has gone undetected. Earlier onset of type 2 diabetes is congruent with an increased risk of developing diabetes-associated complications and, ultimately, diabetes-related morbidity and mortality at a younger age. Future studies should explore how genetic and/or environmental factors among ethnic groups may contribute to early onset hypertension and prediabetes/type 2 diabetes.

Prediabetes: An emerging public health concern in adolescents.

OBJECTIVES: To identify the presence of risk factors for type 2 diabetes (ethnicity, body mass index, blood glucose tolerance and blood pressure) and to determine the prevalence of prediabetes and type 2 diabetes in Canadian adolescents attending two multicultural urban high schools. METHODS: A total of 266 multicultural urban high school students who live in a mid-sized Western Canadian city, aged 14-21, were screened for risk factors of prediabetes and type 2 diabetes in March-April 2018. Data with respect to demographics, family history of diabetes, anthropometrics, blood pressure and haemoglobin A1c (HbA1c) were collected. Data analysis was done using descriptive and inferential statistics in addition to chi-square analyses. RESULTS: Based on body mass index, 38% of the adolescents were classified as either overweight or obese. Overweight rates for females (69.8%) were double than males (30.2%); however, males (52.2%) were more likely to obese than the females (47.8%). Based on HbA1c levels, 29.3% were at high risk to develop either diabetes or prediabetes and 2.6% were classified in the prediabetes range. Prehypertension/hypertension rates of 47% in the sample increased to 51% in those adolescents with elevated HbA1c; the majority of these prehypertensive/hypertensive participants were male. CONCLUSION: High rates of overweight/obesity and prehypertension/hypertension were found in the adolescents studied and indicated the presence of prediabetes and an increased risk to develop type 2 diabetes and associated complications. Obesity and hypertension are major risk factors for developing type 2 diabetes, resulting in earlier exposure to metabolic consequences and, ultimately, long-term complications. Thus, timely research is needed to identify age-appropriate strategies that address risks and to develop recommendations for routine screening of adolescents for prediabetes.

Advanced Glycation End Products:Receptors for Advanced Glycation End Products Axis in Coronary Stent Restenosis: A Prospective Study.

This study was aimed to correlate the pre- and 6-month postpercutaneous coronary intervention (PCI) serum concentrations of advanced glycation end products (AGE), soluble receptors for advanced glycation end products (sRAGE), AGE/sRAGE ratio, and serum malondialdehyde (MDA) levels with in-stent restenosis (ISR) among patients receiving either a drug-eluting stent (DES) or a bare-metal stent (BMS).In-stent restenosis remains as an adverse outcome following PCI. Sixty consecutive nondiabetic, Caucasian male patients, diagnosed with a non-ST-elevation myocardial infarction who received either a DES or BMS via PCI, were enrolled. Baseline levels of serum AGE, sRAGE, AGE/sRAGE ratios, MDA, and angiographic parameters were determined at stenting and at 6 months. Patients with and without ISR at 6 months were compared on both baseline and 6-month biomarker levels and within stent types.The pre-PCI serum AGE levels and AGE/sRAGE ratios were higher in ISR patients compared with non-ISR patients, while the pre-PCI and post-PCI serum sRAGE levels were lower in ISR patients compared with non-ISR patients. The pre and post-PCI levels of MDA were also higher in ISR patients. Comparing stent types, relative levels of MDA between those with and without ISR at the respective time points were similar, although changes between time points appeared type specific.Post-PCI ISR correlates with low serum values of sRAGE and high serum values of AGE, MDA, and AGE/sRAGE ratio which are present at stenting. The associations of baseline AGE, sRAGE, AGE/sRAGE, and MDA levels with ISR appear consistent between stent types.

Recombinant Factor VIII Measurement in a Hemophilia A Patient Undergoing Cardiopulmonary Bypass-Supported Cardiac Surgery.

Patients with hemophilia A (Hem A) requiring cardiopulmonary bypass-supported cardiac surgery pose unique challenges for perioperative hemostatic management. This report describes a staged perioperative approach to clinical hematologic management as applied to an 80-year-old male of O-positive blood type with mild Hem A, who underwent successful, uncomplicated coronary artery bypass graft surgery. Hematologic management primarily consisted of normalization of plasma factor VIII levels followed by standard care. Conventional laboratory methods and point-of-care-testing methods such as thromboelastography and heparin management assays were combined to guide patient care. Minimal blood loss and minimal hemodilution techniques were also used to achieve favorable outcomes. The thorough preparation and execution of care by our multidisciplinary team from perfusion, pathology and laboratory medicine, cardiovascular surgery, transfusion services, nursing, and anesthesia, facilitated a safe, smooth, clinical course and an optimal outcome.

Erratum to: Advanced Glycation End Products: Receptors for Advanced Glycation End Products Axis in Coronary Stent Restenosis: A Prospective Study.

[This corrects the article DOI: 10.1055/s-0038-1673660.].

Atherosclerosis and the Hypercholesterolemic AGE-RAGE Axis.

Background Interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of atherosclerosis. Soluble receptors for advanced glycation end products (sRAGE) act as a decoy for AGE by competing with RAGE and suppressing developing atherosclerosis. Hypercholesterolemia and the oxidative stress are known factors involved in atherosclerosis. High-density lipoprotein cholesterol (HDL-C) is known to exert a protective effect against the development of atherosclerosis. We hypothesize that hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis. Objectives Two objectives to be determined are: (1) if hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and malondialdehyde (MDA: a marker for oxidative stress) and (2) if the protective effect of HDL-C is positively associated with serum sRAGE and negatively correlated with the levels of AGE and AGE/sRAGE. Methods Measurement of serum lipid levels from 100 patients allowed the separation into two groups (hypercholesterolemic and normocholesterolemic). Measurements of serum levels of AGE, sRAGE, and MDA were performed. Results Serum levels of sRAGE were lower, while the levels of AGE and AGE/sRAGE were higher in hypercholesterolemic subjects as compared with normocholesterolemic subjects. sRAGE levels are positively correlated with HDL, while they are negatively correlated with low-density lipoprotein, triglycerides, total cholesterol, and MDA in hypercholesterolemic subjects. Conclusions Hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and MDA. The effect of HDL-C may be due to increases in sRAGE and decreases in the levels of AGE and AGE/sRAGE. Hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis; however, more research must be conducted.

Performance Evaluation of the Plateletworks® in the Measurement of Blood Cell Counts as compared to the Beckman Coulter Unicel DXH 800.

Prior to undergoing cardiac surgery many patients may have impaired platelet function due to platelet inhibition. Point of care testing (POCT) that produces quick results of platelet counts and function allow earlier clinician interpretation, diagnosis and treatment. Before being adopted for routine clinical use, a POCT device's performance must be evaluated by standard laboratory techniques to ensure high quality results. The purpose of this study is to determine the performance of the Plateletworks?V BC 3200 automated hematology analyzer by correlating its precision, accuracy and linearity for the measurement of blood counts to our hospital central laboratory analyzer (Beckman Coulter Unicel DXH 800). The study utilizes well described methods for Within-Run and Day-to-Day precision, comparison of methods (bias), and linearity. Control samples from the manufacturer were used for the precision studies, blood samples from 115 cardiac surgical subjects were used for comparison of methods and accuracy, and pre-diluted control samples from the manufacturer were used for the linearity studies. The precision of the Plateletworks® analyzer was acceptable. The overall coefficient of variation (CV) for the measured parameters at all levels of control for Within-Run precision was acceptable ranging from 0.65-6.4%. Likewise, the CV for the measured parameters at all levels of control for Day-to-Day precision was acceptable ranging from 1.45% to 6.7%. The correlation and accuracy between the two analyzers for the evaluated parameters (platelets, red blood cells, white blood cells, and hemoglobin) was acceptable. The linearity for the measured parameters was also acceptable with a range between 98-100%. The performance of the Plateletworks® analyzer was acceptable for providing blood cell counts as compared to our central hospital laboratory analyzer.

Vitamin E does not regress hypercholesterolemia-induced oxidative stress in heart.

Vitamin E suppresses the hypercholesterolemia-induced cardiac oxidative stress. The objectives were to investigate: if vitamin E regresses the hypercholesterolemia-induced oxidative stress in hearts and if regression is associated with decreases in the antioxidant reserve. The rabbits were assigned to 4 groups: I, regular diet (2-months); II, 0.25% cholesterol diet (2-months); III, 0.25% cholesterol diet (2-months) followed by regular diet (2-months); and IV, 0.25% cholesterol diet (2-months) followed by regular diet with vitamin E (2-months). Blood samples were collected before and at the end of protocol for the measurement of total cholesterol (TC). Hearts were removed at the end of the protocol under anesthesia for the assessment of oxidative stress parameters, malondialdehyde (MDA), and tissue chemiluminescent (CL) activity. High cholesterol diet increased the serum levels of TC, and regular diet with or without vitamin E reduced the TC levels to a similar extent. The MDA content of the heart in groups I, II, III, and IV were 0.074 ± 0.015, 0.234 ± 0.016, 0.183 ± 0.028 and 0.169 ± 0.016 nmol/mg protein, respectively. Regular diet following high cholesterol diet reduced the MDA levels (0.234 ± 0.016 vs. 0.183 ± 0.028 nmol/mg protein but vitamin E did not reduce the MDA levels. The cardiac-CL activities were similar in groups' I, II, and III (30.11 ± 0.7 × 10(6), 32.9 ± 1.43, and 37.92 ± 8.35 × 10(6) RLU/mg protein). The activity decreased in group IV, suggesting that vitamin E increased the antioxidant reserve while lowering serum cholesterol did not increase antioxidant reserve. In conclusion, hypercholesterolemia increases cardiac oxidative stress and regular diet regresses hypercholesterolemia-induced oxidative stress but vitamin E does not further regress hypercholesterolemia-induced cardiac oxidative stress. Vitamin E reduces oxidative stress in the heart tissue in spite of a decrease in CL activity (increase in antioxidant reserve).

Outcomes and biochemical parameters following cardiac surgery: effects of transfusion of residual blood using centrifugation and multiple-pass hemoconcentration.

OBJECTIVES: To determine whether or not there was a significant difference between the methods of centrifugation (CF) and multiple-pass hemoconcentration (MPH) of the residual cardiopulmonary-bypass volume in relation to biochemical measurements and patient outcomes. DESIGN: Prospective, randomized, and controlled. SETTING: Conducted at a western Canadian tertiary care hospital. PARTICIPANTS: Consisted of 61 consecutive male and female patients from ages 40 to 80 who were scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Either the centrifugation or multiple-pass hemoconcentration method was used to process the residual blood from the cardiopulmonary bypass circuit. RESULTS: The 12-hour postoperative levels of serum hemoglobin were not significantly different in the centrifugation group as compared to the multiple-pass hemoconcentration group. However, the serum levels of total protein and albumin were significantly higher in the multiple-pass hemoconcentration group as compared to the centrifugation group. Additionally, after 12-hours postoperatively, the serum fibrinogen and platelet counts were significantly higher in the multiple-pass hemoconcentration group as compared to those of the centrifugation group. The allogeneic product transfusion index and the chest-tube blood drainage indices were lower in the multiple-pass hemoconcentration group as compared to the centrifugation group. CONCLUSION: Although the CF method provided a product in a shorter turnaround time, with consistent clearance of heparin, the MPH method trended towards enhanced biochemical and clinical patient outcomes over the 12-hour postoperative period.

Vitamin E slows the progression of hypercholesterolemia-induced oxidative stress in heart, liver and kidney.

Vitamin E suppresses the hypercholesterolemia-induced oxidative stress in the heart. The objectives were to investigate if: (a) hypercholesterolemia-induced oxidative stress is similar in heart, liver, and kidney, and is dependent upon duration of hypercholesterolemia; and (b) vitamin E slows the progression of oxidative stress in these organs. The rabbits were assigned to 4 groups: I, regular diet (2 months); II, 0.25 % cholesterol diet (2 months); III, 0.25 % cholesterol diet (4 months); and IV, 0.25 % cholesterol diet (2 months) followed by 0.25 % cholesterol diet plus vitamin E (2 months). Blood samples were collected before and at the end of protocol for the measurement of total cholesterol (TC). Hearts, livers, and kidneys were removed at the end of the protocol under anesthesia for the measurement of oxidative parameters, malondialdehyde (MDA), and chemiluminescence (CL). The basal MDA levels in the heart, liver, and kidney of rabbits in Group I were similar, but increased to 14.65-, 3.18-, and 10.35-fold, respectively, with hypercholesterolemia. The increases in MDA levels were dependent upon the duration of hypercholesterolemia. Vitamin E did not alter the TC levels, but reduced the MDA levels in all organs. Hypercholesterolemia and vitamin E had variable effects on CL activity. In conclusion, (i) hypercholesterolemia induces oxidative stress in heart, liver, and kidney, the heart being the most and the liver the least susceptible to oxidative stress; (ii) oxidative stress is positively associated with duration of hypercholesterolemia; and (iii) vitamin E slows the progression of oxidative stress in these organs.

Inverse Association between Cardiac Troponin-I and Soluble Receptor for Advanced Glycation End Products in Patients with Non-ST-Segment Elevation Myocardial Infarction.

Interaction of advanced glycation end products (AGEs) with the receptor for advanced AGEs (RAGE) results in activation of nuclear factor kappa-B, release of cytokines, expression of adhesion molecules, and induction of oxidative stress. Oxygen radicals are involved in plaque rupture contributing to thromboembolism, resulting in acute coronary syndrome (ACS). Thromboembolism and the direct effect of oxygen radicals on myocardial cells cause cardiac damage that results in the release of cardiac troponin-I (cTnI) and other biochemical markers. The soluble RAGE (sRAGE) compete with RAGE for binding with AGE, thus functioning as a decoy and exerting a cytoprotective effect. Low levels of serum sRAGE would allow unopposed serum AGE availability for binding with RAGE, resulting in the generation of oxygen radicals and proinflammatory molecules that have deleterious consequences and promote myocardial damage. sRAGE may stabilize atherosclerotic plaques. It is hypothesized that low levels of sRAGE are associated with high levels of serum cTnI in patients with ACS. The main objective of the study was to determine whether low levels of serum sRAGE are associated with high levels of serum cTnI in ACS patients. The serum levels of sRAGE and cTnI were measured in 36 patients with non-ST-segment elevation myocardial infarction (NSTEMI) and 30 control subjects. Serum levels of sRAGE were lower in NSTEMI patients (802.56 ± 39.32 pg/mL) as compared with control subjects (1311.43 ± 66.92 pg/mL). The levels of cTnI were higher in NSTEMI patients (2.18 ± 0.33 µg/mL) as compared with control subjects (0.012 ± 0.001 µg/mL). Serum sRAGE levels were negatively correlated with the levels of cTnI. In conclusion, the data suggest that low levels of serum sRAGE are associated with high serum levels of cTnI and that there is a negative correlation between sRAGE and cTnI.

Soluble receptors for advanced glycation end products (sRAGE) as a predictor of restenosis following percutaneous coronary intervention.

BACKGROUND: Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) increases expression of inflammatory mediators (tumor necrosis factor alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]) and induces oxygen radicals that are implicated in atherosclerosis. Balloon-injury-induced atherosclerosis is associated with increased expression of AGEs and RAGE. The soluble receptor for AGE (sRAGE), which acts as a decoy for RAGE ligands (AGEs), prevents atherosclerosis in this model. HYPOTHESIS: We evaluated: 1) whether post-percutaneous coronary intervention (PCI) restenosis is associated with low pre-PCI serum sRAGE, high serum AGEs, TNF-α, and sVCAM-1, and high AGE/sRAGE ratio; 2) whether pre-PCI and post-PCI levels of these markers are similar in patients with or without restenosis; and 3) whether sRAGE and AGE/sRAGE ratio have predictive value for post-PCI restenosis. METHODS: Angiography was performed in 46 patients with non-ST-segment elevation myocardial infarction for assessment of restenosis. Serum sRAGE, AGEs, TNF-α, and sVCAM-1 were measured in these patients and 20 control subjects. RESULTS: : Nineteen of the 46 patients developed post-PCI restenosis, which was associated with lower sRAGE and higher TNF-α and sVCAM-1 levels, and higher AGE/sRAGE ratio compared with patients without restenosis. Pre-PCI and post-PCI levels of these biomarkers were similar in both groups, except in patients with restenosis, in whom the post-PCI level of sRAGE was lower and TNF-α was higher than the pre-PCI levels. The sensitivity and negative predictive value of sRAGE were 100%, and were higher than those of AGE/sRAGE ratio in identifying post-PCI restenosis. CONCLUSIONS: Both low serum sRAGE levels and high AGE/sRAGE ratio have predictive value for post-PCI restenosis.

Modulation of high sensitivity C-reactive protein by soluble receptor for advanced glycation end products.

High sensitivity C-reactive protein (hs-CRP) is synthesized mainly by hepatocytes in response to tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6). The interaction of advanced glycation end products (AGEs) with the receptor for advanced glycation end products (RAGE) increases the expression of the cytokines TNF-alpha, IL-1, and IL-6. Soluble receptor for advanced glycation end products (sRAGE) competes with RAGE for binding with AGEs. Hence, low sRAGE levels may increase interaction of AGEs with RAGE resulting in the increased production of cytokines. It is hypothesized that serum levels of sRAGE modulate serum levels of hs-CRP. The objectives are to determine if (i) serum levels of sRAGE are lower and those of TNF-alpha and hs-CRP are higher in non-ST-segment elevation myocardial infarction (NSTEMI) patients compared to control subjects; (ii) serum levels of TNF-alpha and hs-CRP are positively correlated; and (iii) sRAGE is negatively correlated with hs-CRP and TNF-alpha. The study consisted of 36 patients with NSTEMI and 30 age-matched healthy male subjects. Serum levels of sRAGE and TNF-alpha were determined by enzyme-linked immunoassay and hs-CRP was measured using near infrared immunoassay. Serum levels of sRAGE were lower, while those of TNF-alpha and hs-CRP were higher in patients with NSTEMI compared to controls. The levels of sRAGE were negatively correlated with those of TNF-alpha and hs-CRP, while TNF-alpha was positively correlated with hs-CRP in both the control subjects and NSTEMI patients. The data suggest that sRAGE modulates the synthesis of hs-CRP through TNF-alpha.

Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients.

BACKGROUND: Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress - all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis. OBJECTIVES: To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI. METHODS: Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients. RESULTS: sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients. CONCLUSIONS: Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.