969-100 Changing Profile of the Cardiac Donor

AbstractAs the demand for organs for cardiac transplantation has increased, donor criteria have evolved. We reviewed the characteristics of 190 cardiac donors from 1983 to 1993 to identify trends in donor profile and to determine if recipient outcome were affected. Donors were divided into early(1983–1987; n=86) and late (1988-1993; n=104) groups according to operative era, While mean donor age has not changed significantly (24 ± 0.9 to 26 ± 1.3 years), the proportion of donors older than 40 years has increased from 1% (1/86) to 15% (16/104) (p<0.001). Trauma was the cause of death in 93% (80/86) of the early group and 65% of the late group (68/104) (p<0.001); in the total series, donors older than 40 years were less likely to have died from trauma 131%; 5/16) than younger donors (83%; 143/173) (p=0.001). The proportion of out-of-state donors has fallen from 71% (61/86) to 27% (28/104) (p<0.001), while the proportion of ethnic minorities increased from 10% (9/86) to 25% (26/1041 (p<0.001). There have been no significant changes in gender profile; males constituted 78% (67/86) of the early group and 72% (75/104) of the late group. Five year survival after transplant was not predicted by donor age, mode of donor death, recipient age, or recipient UNOS status. In summary, donors in the current era are more likely (1) to be older, (2) to be within the state, (3) to come from an ethnic minority, and (4) to have died from causes other than trauma when compared to donors from the earlier era

Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

Background: The use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP) monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s) can theoretically promote the emergence and transmission of drug resistant parasites. Methods: We developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant) and both poor quality and good quality (artemether-lumefantrine) antimalarial use. Findings: The model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy. Interpretation: Our findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria

Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach

Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains. Genetic mapping coupled with transcriptomic analysis in the liver was used to identify several candidate susceptibility genes including epoxide hydrolase 2, interferon regulatory factor 3, and mitochondrial fission factor. Gene pathway analysis revealed that oxidative stress and immune response pathways were activated in response to tolvaptan treatment across all strains, but genes involved in regulation of bile acid homeostasis were most associated with tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase inhibitor (Slpi) mRNA was also induced in the susceptible strains and was associated with increased plasma levels of Slpi protein, suggesting a potential serum marker for DILI susceptibility. In summary, tolvaptan induced signs of oxidative stress, mitochondrial dysfunction, and innate immune response in all strains, but variation in bile acid homeostasis was most associated with susceptibility to the liver response. This CC study has indicated potential mechanisms underlying tolvaptan DILI and biomarkers of susceptibility that may be useful in managing the risk of DILI in ADPKD patients

A further cost for the sicker sex? Evidence for male-biased parasite-induced vulnerability to predation

Males are typically the sicker sex. Data from multiple taxa indicate that they are more likely to be infected with parasites, and are less ‘tolerant’, or less able to mitigate the fitness costs of a given infection, than females. One cost of infection for many animals is an increased probability of being captured by a predator. A clear, hitherto untested, prediction is therefore that this parasite-induced vulnerability to predation is more pronounced among males than females. We tested this prediction in the sexually size dimorphic guppy, Poecilia reticulata, in which females are typically larger than males. We either sham or experimentally infected guppies with Gyrodactylus turnbulli, elicited their escape response using an established protocol and measured the distance they covered during 60 ms. To discriminate between the effects of body size and those of other inherent sex differences, we size-matched fish across treatment groups. Infection with G. turnbulli reduced the distance covered during the escape response of small adults by 20.1%, whereas that of large fish was unaffected. This result implies that parasite-induced vulnerability to predation is male-biased in the wild: although there was no difference in escape response between our experimentally size-matched groups of males and females, males are significantly smaller across natural guppy populations. These results are consistent with Bateman’s principle for immunity: natural selection for larger body sizes and longevity in females seems to have resulted in the evolution of increased infection tolerance. We discuss the potential implications of male-biased parasite-induced vulnerability for the evolutionary ecology of this host-parasite interaction in natural communities

Label-free classification of cultured cells through diffraction imaging

Automated classification of biological cells according to their 3D morphology is highly desired in a flow cytometer setting. We have investigated this possibility experimentally and numerically using a diffraction imaging approach. A fast image analysis software based on the gray level co-occurrence matrix (GLCM) algorithm has been developed to extract feature parameters from measured diffraction images. The results of GLCM analysis and subsequent classification demonstrate the potential for rapid classification among six types of cultured cells. Combined with numerical results we show that the method of diffraction imaging flow cytometry has the capacity as a platform for high-throughput and label-free classification of biological cells

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

Project ACHIEVE – Using Implementation Research to Guide the Evaluation of Transitional Care Effectiveness

Background: Poorly managed hospital discharges and care transitions between health care facilities can cause poor outcomes for both patients and their caregivers. Unfortunately, the usual approach to health care delivery does not support continuity and coordination across the settings of hospital, doctors’ offices, home or nursing homes. Though complex efforts with multiple components can improve patient outcomes and reduce 30-day readmissions, research has not identified which components are necessary. Also we do not know how delivery of core components may need to be adjusted based on patient, caregiver, setting or characteristics of the community, or how system redesign can be accelerated. Methods/design: Project ACHIEVE focuses on diverse Medicare populations such as individuals with multiple chronic diseases, patients with low health literacy/numeracy and limited English proficiency, racial and ethnic minority groups, low-income groups, residents of rural areas, and individuals with disabilities. During the first phase, we will use focus groups to identify the transitional care outcomes and components that matter most to patients and caregivers to inform development and validation of assessment instruments. During the second phase, we will evaluate the comparative effectiveness of multi-component care transitions programs occurring across the U.S. Using a mixed-methods approach for this evaluation, we will study historical (retrospective) and current and future (prospective) groups of patients, caregivers and providers using site visits, surveys, and clinical and claims data. In this natural experiment observational study, we use a fractional factorial study design to specify comparators and estimate the individual and combined effects of key transitional care components. Discussion: Our study will determine which evidence-based transitional care components and/or clusters most effectively produce patient and caregiver desired outcomes overall and among diverse patient and caregiver populations in different healthcare settings. Using the results, we will develop concrete, actionable recommendations regarding how best to implement these strategies. Finally, this work will provide tools for hospitals, community-based organizations, patients, caregivers, clinicians and other stakeholders to help them make informed decisions about which strategies are most effective and how best to implement them in their communities. Trial registration: Registered as NCT02354482 on clinicaltrials.gov on 1/29/201

Search for Radiative Decays of Upsilon(1S) into eta and eta'

We report on a search for the radiative decay of Upsilon(1S) to the pseudoscalar mesons eta and etaprime in 21.2 +/- 0.2 times 10^6 Upsilon(1S) decays collected with the CLEO III detector at the Cornell Electron Storage Ring (CESR). The eta meson was reconstructed in the three modes eta to gamma-gamma, eta to pi+pi-pi0 and eta to 3pi0. The etaprime meson was reconstructed in the mode etaprime to pi+ pi- eta with eta decaying through any of the above three modes, and also etaprime to gamma rho, where rho decays to pi^+ pi^-. Five out of the seven sub-modes are found to be virtually background-free. In four of them we find no signal candidates and in one Upsilon(1S) to gamma-etaprime, etaprime to pi+ pi- eta, eta to pi+pi-pi0 there are two good signal candidates, which is insufficient evidence to claim a signal. The other two sub-modes eta to gamma-gamma and etaprime to gamma rho are background limited, and show no excess of events in their signal regions. We combine the results from different channels and obtain upper limits at the 90% C.L. which are B(Upsilon(1S) to gamma eta) < 1.0 times 10^-6 and B(Upsilon(1S) to gamma etaprime) < 1.9 times 10^-6. Our limits are an order of magnitude tighter than the previous ones and below the predictions made by some theoretical models.Comment: 14 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2007/, Submitted to PR

Search for psi(2S)--> eta_c pi^+ pi^- pi^0

Using 5.63 pb^-1 of data accumulated at the psi(2S) resonance with the CLEO III and CLEO-c detectors corresponding to 3.08 million psi(2S) decays, a search is performed for the decay psi(2S) -> eta_c pi^+pi^-pi^0 to test a theoretical prediction based upon the assumption that the c \bar c pair in the psi(2S) does not annihilate directly into three gluons but rather survives before annihilating. No signal is observed, and a combined upper limit from six eta_c decay modes is determined to be B(psi(2S) -> eta_c pi^+pi^-pi^0) < 1.0 x 10^-3 at 90% C.L. This upper limit is about an order of magnitude below the theoretical expectation.Comment: 8 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2006

Measurement of Interference between Electromagnetic and Strong Amplitudes in psi(2S) Decays to Two Pseudoscalar Mesons

Using a sample of 3.08 million psi(2S) decays collected at sqrt{s} = 3.686 GeV with the CLEO detector at the Cornell Electron Storage Ring, we have measured the branching fractions for psi(2S) decays to pseudoscalar pairs pi+pi-, K+K-, and KsKl. We obtain B(psi(2S) -> pi+pi-) < 2.1 x 10^{-5} (90% C.L.), B(psi(2S) -> K+K-) = (6.3 +- 0.6(stat) +- 0.3(syst)) x 10^{-5}, and B(psi(2S) -> KsKl) = (5.8 +- 0.8(stat) +- 0.4(syst)) x 10^{-5}. The branching fractions allow extraction of the relative phase Delta = (95 +- 15) degrees and strength ratio R = (2.5 +- 0.4) of the three-gluon and one-photon amplitudes for these modes.Comment: 8 pages postscript,also available through this http://www.lns.cornell.edu/public/CLNS/2005/, Submitted to PR