Pediatric Coronary Allograft Vasculopathy—A Review of Pathogenesis and Risk Factors

Coronary allograft vasculopathy is the current leading cause for late graft loss following cardiac transplantation. Its pathogenesis is multifactorial, including immune, constitutional and genetic factors, metabolism, infection, as well as potential injury from routine immunosuppressive therapy. Children represent a patient group with unique differences: their pretransplant history rarely includes ischemic heart disease and risk factors for atherosclerotic heart disease, but many are presensitized from use of allograft material during reconstructive cardiac surgeries. Compared with older children and adults, infants and young children show significantly lower rates of graft vasculopathy that may be related to the relative immaturity of their immune system. This review summarizes the current concepts of coronary allograft vasculopathy derived mainly from animal models and adult clinical observations. It provides an overview of confirmed risk factors and explains their interactions. The characteristics and unique clinical findings among pediatric transplant recipients will be explored within the context of recent, albeit limited, scientific investigations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92455/1/chd601.pd

Dopamine as a potential rescue therapy for refractory proteinâ losing enteropathy in Fontanâ palliated patients

PLE is an important cause of morbidity and mortality in patients who have undergone Fontan palliation. While multiple PLE therapies have been reported, none has proved consistently effective. Patients who do not respond to â standardâ PLE therapies face poor longâ term outcomes. We report here a significant response to dopamine infusion in three patients with chronic, refractory PLE. We hypothesize that this response may be at least partially due to a dopamine effect on lymphatic receptors rather than to an augmentation of cardiac output.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137378/1/petr12925_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137378/2/petr12925.pd

Clinical significance of antiâ HLA antibodies associated with ventricular assist device use in pediatric patients: A United Network for Organ Sharing database analysis

While VAD use in pediatric patients has previously been associated with antiâ HLA antibody production, the clinical significance of these antibodies is unclear. We investigated the clinical impact of antiâ HLA antibodies associated with VAD use in a large cohort of pediatric HTx recipients. From 2004 to 2011, pediatric cardiomyopathy patients postâ HTx (N=1288) with preâ HTx PRA levels were identified from the United Network for Organ Sharing database. PRA levels were compared between VAD patients and those with no history of MCS. Incidence of rejection and overall survival were compared between VAD and nonâ MCS groups after stratification by PRA and age. VAD recipients were more likely to produce antiâ HLA antibodies than nonâ MCS patients (25.5% vs 10.5% had PRA>10%, P10%) had a higher incidence of rejection within 15 months of HTx compared to sensitized nonâ MCS patients (57.1% vs 35.9%, P=.02). There was no intergroup difference in 15â month mortality. Among pediatric cardiomyopathy patients supported with a VAD, the presence of antiâ HLA antibodies prior to HTx is associated with an increased risk of rejection. The mechanism of the association between VADâ associated antibodies and early rejection is unclear and warrants further investigation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137732/1/petr12938_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137732/2/petr12938.pd

The impact of ischemic time on early rejection after pediatric heart transplant

Prolonged graft ischemia may be a risk factor for early rejection postâ HTx, but this has not been well studied in children. Furthermore, factors moderating the association between IT and early rejection have not been investigated. From 2004 to 2012, pediatric HTx recipients (n = 2381) were identified from the UNOS database. A ROC curve determined the optimal IT discriminating patients by the presence of early rejection. Separate univariate analyses identified factors associated with: (i) early (prior to hospital discharge) rejection, and (ii) IT. A multivariable logistic regression assessed independent risk factors for early rejection. We included interaction terms to evaluate whether IT’s independent risk effect on early rejection is moderated via interaction with associated factors found in univariate analysis. Longer IT was associated with an increased risk of early rejection. In multivariable analysis, IT > 3.1 hours was an independent risk factor for early rejection (AOR 1.44, P = .01). No interaction terms between IT and any associated factors were significant. Longer IT is an independent risk for early rejection in pediatric HTx recipients. Better understanding the association between IT and early rejection may identify interventions to mitigate this risk.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139903/1/petr13034.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139903/2/petr13034_am.pd

Shared behavioral mechanisms underlie <i>C. elegans</i> aggregation and swarming

In complex biological systems, simple individual-level behavioral rules can give rise to emergent group-level behavior. While collective behavior has been well studied in cells and larger organisms, the mesoscopic scale is less understood, as it is unclear which sensory inputs and physical processes matter a priori. Here, we investigate collective feeding in the roundworm C. elegans at this intermediate scale, using quantitative phenotyping and agent-based modeling to identify behavioral rules underlying both aggregation and swarming—a dynamic phenotype only observed at longer timescales. Using fluorescence multi-worm tracking, we quantify aggregation in terms of individual dynamics and population-level statistics. Then we use agent-based simulations and approximate Bayesian inference to identify three key behavioral rules for aggregation: cluster-edge reversals, a density-dependent switch between crawling speeds, and taxis towards neighboring worms. Our simulations suggest that swarming is simply driven by local food depletion but otherwise employs the same behavioral mechanisms as the initial aggregation

Differential effect of body mass index on pediatric heart transplant outcomes based on diagnosis

The impact of nutritional status on HT x waitlist mortality in children is unknown, and there are conflicting data regarding the role of nutrition in post‐ HT x survival. This study examined the influence of nutrition on waitlist and post‐ HT x outcomes in children. Children 2–18 yr listed for HT x from 1997 to 2011 were identified from the OPTN database and stratified by BMI percentile. Multivariable logistic regression evaluated the influence of BMI on waitlist mortality. Cox proportional hazard regression assessed the impact of BMI on post‐ HT x mortality. When all 2712 patients were analyzed, BMI did not impact waitlist, one‐, or five‐yr mortality. However, when stratified by diagnosis, BMI  > 95% ( AOR 1.96; 95% CI 1.24, 3.09) and BMI   95% and BMI  < 1% are independent risk factors for waitlist mortality in patients with CM, but not CHD . This suggests differing risk factors based on disease etiology, and an individualized approach to risk assessment based on diagnosis may be warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108679/1/petr12352.pd

Streptokinase thrombolysis in experimental coronary artery thrombosis: pattern of reflow and effect of a stenosis

We studied recanalization of an obstructed left circumflex coronary artery by streptokinase in open-chest anesthetized dogs. Thrombotic occlusion was induced by a 100 [mu]A anodal current selectively delivered to the intimal surface of the vessel. Intracoronary streptokinase (50,000 U) or saline was infused over a 50-min period beginning at either 30 min or 90 min after occlusion. Continous recordings were made of antegrade circumflex flow and regional myocardial function, which was quantitated using sonomicrometer crystals in the regions of the left anterior descending and circumflex coronary arteries. In some experiments a fixed stenosis, having no effect on mean circumflex coronary artery blood flow, was placed at the site of subsequent thrombus formation. The presence of a stenosis decreased the weight of occlusive thrombi obtained from nonreperfused saline controls by 40% and increased the proportion of animals successfully reperfused by streptokinase from 13 to 76%. Streptokinase reduced thrombus mass by 44% in animals recanalized in the presence of the stenosis. On the average, reflow was established after 26 min of streptokinase infusion, was less in magnitude than pre-occlusion flow, and was unstable and intermittent, being marked by frequent reocclusions. Initiating treatment at 30 min or 90 min post-occlusion did not influence characteristics of the reflow. Return of myocardial contractility in the ischemic bed was not detected during the immediate reperfusion period in the majority of these experiments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24656/1/0000069.pd

Rate of increase in serum lactate level risk-stratifies infants after surgery for congenital heart disease

ObjectiveIncreased blood lactate levels reflect tissue oxygen debt and might be indicative of low cardiac output. We hypothesized that the rate of increase in serum lactate would be an ideal marker to discriminate between infants at high and low risk of a poor outcome after surgical repair of congenital heart disease using cardiopulmonary bypass.MethodsIn the present prospective, observational study in a pediatric cardiac intensive care unit, infants (aged <12 months) undergoing cardiac surgery had serial whole blood lactate levels measured with every arterial blood gas drawn for the first 24 postoperative hours. The composite poor outcome included death, the need for extracorporeal support, and dialysis.ResultsThe lactate levels were measured in 231 infants; 19 infants (8.2%) had a poor outcome. A lactate increase rate of 0.6 mmol/L/h had very good discriminatory ability (area under the curve [AUC], 0.89) with a sensitivity of 90%, specificity of 84%, positive predictive value (PPV) of 34%, and negative predictive value (NPV) of 99%. Similar results were obtained for subgroups stratified by 1- or 2-ventricle heart disease and risk adjustment for congenital heart surgery (RACHS-1) score. In neonates (age <30 days) with single-ventricle physiology (n = 43, poor outcome = 8), a lactate increase of 0.6 mmol/L/h had near perfect discriminatory ability (AUC 0.99) with a sensitivity of 100%, specificity of 51%, PPV of 32%, and NPV of 100%. In 2-ventricle neonates (n = 43, poor outcome = 5), a lactate increase of 0.6 mmol/L/h also had near perfect discriminatory ability (AUC, 0.99), with a sensitivity of 100%, specificity of 90%, PPV of 56%, and NPV of 100%.ConclusionsThe postoperative lactate increase rate allows discrimination between infants at high and low risk of morbidity and mortality after congenital heart disease surgery, and the lactate level can be followed serially for the treatment response

The resource theory of quantum reference frames: manipulations and monotones

Every restriction on quantum operations defines a resource theory, determining how quantum states that cannot be prepared under the restriction may be manipulated and used to circumvent the restriction. A superselection rule is a restriction that arises through the lack of a classical reference frame and the states that circumvent it (the resource) are quantum reference frames. We consider the resource theories that arise from three types of superselection rule, associated respectively with lacking: (i) a phase reference, (ii) a frame for chirality, and (iii) a frame for spatial orientation. Focussing on pure unipartite quantum states (and in some cases restricting our attention even further to subsets of these), we explore single-copy and asymptotic manipulations. In particular, we identify the necessary and sufficient conditions for a deterministic transformation between two resource states to be possible and, when these conditions are not met, the maximum probability with which the transformation can be achieved. We also determine when a particular transformation can be achieved reversibly in the limit of arbitrarily many copies and find the maximum rate of conversion. A comparison of the three resource theories demonstrates that the extent to which resources can be interconverted decreases as the strength of the restriction increases. Along the way, we introduce several measures of frameness and prove that these are monotonically nonincreasing under various classes of operations that are permitted by the superselection rule.Comment: 37 pages, 4 figures, Published Versio