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

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

Development of a coupled simulation toolkit for computational radiation biology based on Geant4 and CompuCell3D

RL acknowledges support from Consortium for Risk Evaluation and Stakeholder Participation (http://cresp.org). JAG acknowledges support from National Science Foundation grant NSF 1720625 and National Institutes of Health, National Institute of General Medical Sciences grants U01 GM111243 and R01 GM076692, JAG and MS acknowledge support from National Institutes of Health, National Institute of General Medical Sciences grant R01 GM122424.Understanding and designing clinical radiation therapy is one of the most important areas of state-of-the-art oncological treatment regimens. Decades of research have gone into developing sophisticated treatment devices and optimization protocols for schedules and dosages. In this paper, we presented a comprehensive computational platform that facilitates building of the sophisticated multi-cell-based model of how radiation affects the biology of living tissue. We designed and implemented a coupled simulation method, including a radiation transport model, and a cell biology model, to simulate the tumor response after irradiation. The radiation transport simulation was implemented through Geant4 which is an open-source Monte Carlo simulation platform that provides many flexibilities for users, as well as low energy DNA damage simulation physics, Geant4-DNA. The cell biology simulation was implemented using CompuCell3D (CC3D) which is a cell biology simulation platform. In order to couple Geant4 solver with CC3D, we developed a "bridging" module, RADCELL, that extracts tumor cellular geometry of the CC3D simulation (including specification of the individual cells) and ported it to the Geant4 for radiation transport simulation. The cell dose and cell DNA damage distribution in multicellular system were obtained using Geant4. The tumor response was simulated using cell-based tissue models based on CC3D, and the cell dose and cell DNA damage information were fed back through RADCELL to CC3D for updating the cell properties. By merging two powerful and widely used modeling platforms, CC3D and Geant4, we delivered a novel tool that can give us the ability to simulate the dynamics of biological tissue in the presence of ionizing radiation, which provides a framework for quantifying the biological consequences of radiation therapy. In this introductory methods paper, we described our modeling platform in detail and showed how it can be applied to study the application of radiotherapy to a vascularized tumor.PostprintPeer reviewe

The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking

Two intraflagellar transport (IFT) complexes, IFT-A and IFT-B, build and maintain primary cilia and are required for activity of the Sonic hedgehog (Shh) pathway. A weak allele of the IFT-A gene, Ift144, caused subtle defects in cilia structure and ectopic activation of the Shh pathway. In contrast, strong loss of IFT-A, caused by either absence of Ift144 or mutations in two IFT-A genes, blocked normal ciliogenesis and decreased Shh signaling. In strong IFT-A mutants, the Shh pathway proteins Gli2, Sufu, and Kif7 localized correctly to cilia tips, suggesting that these pathway components were trafficked by IFT-B. In contrast, the membrane proteins Arl13b, ACIII, and Smo failed to localize to primary cilia in the absence of IFT-A. We propose that the increased Shh activity seen in partial loss-of-function IFT-A mutants may be a result of decreased ciliary ACIII and that the loss of Shh activity in the absence of IFT-A is a result of severe disruptions of cilia structure and membrane protein trafficking

Experimental and computational study of the injection of antiprotons into a positron plasma for antihydrogen production

One of the goals of synthesizing and trapping antihydrogen is to study the validity of charge-parity-time symmetry through precision spectroscopy on the anti-atoms, but the trapping yield achieved in recent experiments must be significantly improved before this can be realized. Antihydrogen atoms are commonly produced by mixing antiprotons and positrons stored in a nested Penning-Malmberg trap, which was achieved in ALPHA by an autoresonant excitation of the antiprotons, injecting them into the positron plasma. In this work, a hybrid numerical model is developed to simulate antiproton and positron dynamics during the mixing process. The simulation is benchmarked against other numerical and analytic models, as well as experimental measurements. The autoresonant injection scheme and an alternative scheme are compared numerically over a range of plasma parameters which can be reached in current and upcoming antihydrogen experiments, and the latter scheme is seen to offer significant improvement in trapping yield as the number of available antiprotons increases