The stress radionuclide assessment of diastolic function

Background Many patients are referred from primary care with suspected heart failure and are found to have preserved systolic function. These patients may be labelled as having normal ejection fraction or diastolic heart failure, the diagnosis of which is both controversial and difficult. Previous work has identified a large proportion of these patients to have an alternative, pre- existing diagnosis. This thesis prospectively assesses the prevalence of undiagnosed ischaemic heart disease and respiratory disease in this patient group and assess diastolic function using multiple methods. The central hypothesis being tested was that first third fractional filling, a radionuclide ventriculogram (RNVG) parameter previously used to assess diastolic function at rest, would identify diastolic dysfunction more accurately under stress conditions. Methods Patients were recruited from an open access echocardiography service. Echocardiography, including tissue Doppler assessment, was carried out independently by 2 experienced observers. Confounding diagnoses including coronary artery disease and respiratory disease were actively sought by myocardial perfusion imaging and spirometry. N-terminal proBNP was measured. List mode radionuclide ventriculography was performed at rest supine and during upright bicycle exercise with simultaneous measurement of VO2 max. Validation of the reliability and reproducibility of first third fractional filling, peak filling rate, time to peak filling and other radionuclide parameters of systolic and diastolic function was undertaken. This demonstrated that it was possible to measure both first third fractional filling and peak filling rate with the short acquisition times necessary for assessment during stress. Time to peak filling was poorly reproducible under these conditions. A normal range for first third fractional filling at rest and during exercise was established. Due to a strong inverse relationship between heart rate and first third fractional filling, a continuous reference range was constructed using an exponential model. This unique approach enables the calculation of the lower limit of normal at any heart rate. A more conventional mean ± 2 standard deviations was used for the other RNVG parameters. Results Eighty three patients were recruited and completed an extensive multi-modality assessment of systolic and diastolic function. As with previous work in this field, the patients were predominantly female (82%) and elderly (mean age 66.7). Mild left ventricular systolic dysfunction as determined by RNVG was missed by echocardiography in one third of patients. Systolic dysfunction more significant than this was not observed. N-terminal proBNP was elevated in 21 of 82 patients where it was available with no significant difference in left ventricular ejection fraction between those with normal and elevated levels. Myocardial perfusion scanning was normal in 46 of 83 patients and showed significant ischaemia in 20 of 83. Spirometry was normal in 58 of 82 patients, with mild airflow obstruction in 20 patients and moderate obstruction in 4. In only one patient were no alternative diagnoses present. There was poor correlation between indices of diastolic function at rest including first third fractional filling, echocardiographic parameters and NT-proBNP. The assessment of diastolic function using stress radionuclide ventriculography did not improve the correlation between measured indices. On stress, however, low first third fractional filling predicted exercise intolerance as an inability to reach anaerobic threshold. Conclusions Alternative diagnoses to diastolic dysfunction are present almost universally in patients with suspected normal ejection fraction heart failure. This is true even where these diagnoses are not previously established. This thesis underlines the need to fully assess this patient group to allow appropriate targeting of therapy. It is also clear that echocardiography alone is potentially misleading and it is suggested that it is better placed within a tiered assessment process. The assessment of diastolic function using stress radionuclide ventriculography, although an appealing concept, does not improve diagnostic accuracy within this patient group. The marked heterogeneity of this patient group is likely to have played a role in this and it may be of interest to reassess stress radionuclide ventriculography in a more acute heart failure population

Imaginary-time matrix product state impurity solver for dynamical mean-field theory

We present a new impurity solver for dynamical mean-field theory based on imaginary-time evolution of matrix product states. This converges the self-consistency loop on the imaginary-frequency axis and obtains real-frequency information in a final real-time evolution. Relative to computations on the real-frequency axis, required bath sizes are much smaller and less entanglement is generated, so much larger systems can be studied. The power of the method is demonstrated by solutions of a three band model in the single and two-site dynamical mean-field approximation. Technical issues are discussed, including details of the method, efficiency as compared to other matrix product state based impurity solvers, bath construction and its relation to real-frequency computations and the analytic continuation problem of quantum Monte Carlo, the choice of basis in dynamical cluster approximation, and perspectives for off-diagonal hybridization functions.Comment: 8 pages + 4 pages appendix, 9 figure

An efficient perturbation theory of density matrix renormalization group

Density matrix renormalization group (DMRG) is one of the most powerful numerical methods available for many-body systems. In this work, we develop a perturbation theory of DMRG (PT-DMRG) to largely increase its accuracy in an extremely simple and efficient way. By using the canonical matrix product state (MPS) representation for the ground state of the considered system, a set of orthogonal basis functions $\left\lbrace | \psi_i \rangle \right\rbrace$ is introduced to describe the perturbations to the ground state obtained by the conventional DMRG. The Schmidt numbers of the MPS that are beyond the bond dimension cut-off are used to define such perturbation terms. The perturbed Hamiltonian is then defined as $\tilde{H}_{ij}= \langle \psi_i | \hat{H} | \psi_j \rangle$; its ground state permits to calculate physical observables with a considerably improved accuracy as compared to the original DMRG results. We benchmark the second-order perturbation theory with the help of one-dimensional Ising chain in a transverse field and the Heisenberg chain, where the precision of DMRG is shown to be improved $\rm O(10)$ times. Furthermore, for moderate length $L$ the errors of DMRG and PT-DMRG both scale linearly with $L^{-1}$. The linear relation between the dimension cut-off of DMRG and that of PT-DMRG with the same precision shows a considerable improvement of efficiency, especially for large dimension cut-off's. In thermodynamic limit we show that the errors of PT-DMRG scale with $\sqrt{L^{-1}}$. Our work suggests an effective way to define the tangent space of the ground state MPS, which may shed lights on the properties beyond the ground state. Such second-order PT-DMRG can be readily generalized to higher orders, as well as applied to the models in higher dimensions

Biological control networks suggest the use of biomimetic sets for combinatorial therapies

Cells are regulated by networks of controllers having many targets, and targets affected by many controllers, but these "many-to-many" combinatorial control systems are poorly understood. Here we analyze distinct cellular networks (transcription factors, microRNAs, and protein kinases) and a drug-target network. Certain network properties seem universal across systems and species, suggesting the existence of common control strategies in biology. The number of controllers is ~8% of targets and the density of links is 2.5% \pm 1.2%. Links per node are predominantly exponentially distributed, implying conservation of the average, which we explain using a mathematical model of robustness in control networks. These findings suggest that optimal pharmacological strategies may benefit from a similar, many-to-many combinatorial structure, and molecular tools are available to test this approach.Comment: 33 page

Tubular secretion of creatinine and kidney function: an observational study.

BackgroundPrior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts.MethodsTo fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time.ResultsObserved CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories.ConclusionsThese data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR

Single-Shot Electron Diffraction using a Cold Atom Electron Source

Cold atom electron sources are a promising alternative to traditional photocathode sources for use in ultrafast electron diffraction due to greatly reduced electron temperature at creation, and the potential for a corresponding increase in brightness. Here we demonstrate single-shot, nanosecond electron diffraction from monocrystalline gold using cold electron bunches generated in a cold atom electron source. The diffraction patterns have sufficient signal to allow registration of multiple single-shot images, generating an averaged image with significantly higher signal-to-noise ratio than obtained with unregistered averaging. Reflection high-energy electron diffraction (RHEED) was also demonstrated, showing that cold atom electron sources may be useful in resolving nanosecond dynamics of nanometre scale near-surface structures.Comment: This is an author-created, un-copyedited version of an article published in Journal of Physics B: Atomic, Molecular and Optical Physics. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at http://dx.doi.org/10.1088/0953-4075/48/21/21400

Ship rat density in urban Dunedin and the development of a non-invasive estimation method

In New Zealand ship rats (Rattus rattus) are one of the major threats to endemic fauna and flora. Rural ship rat populations have been implicated in the ongoing decline and extinction of many species of endemic wildlife. The role ship rats have in structuring urban ecosystems, directly through predation, and indirectly through food and habitat competition is poorly understood in New Zealand. Understanding the role of ship rats in the urban environment is impeded by a lack of information on their distribution and robust estimates of their density. Rat presence and distribution across different urban habitats was determined by the identification of genus-specific bite marks on wax blocks. The results from the wax block survey suggest that rats are either absent from, or at very low densities within the housed residential sites sampled in this study. In urban bush fragments rats were detected infrequently using wax blocks. High rates of non-target species interference may obscure the rate of rat detection in urban areas. Density is a fundamental biological parameter, however unbiased density estimation can be extremely difficult for certain species. Ship rats are nocturnal and highly dispersed, which makes them particularly difficult to sample using conventional techniques. Currently the most accurate and reliable estimates of absolute ship rat density are obtained through cage-trapping and spatially explicit capture-recapture analysis. This sampling method is both laborious and intrusive. Invasive sampling methods are also not always suitable for use in urban areas. This study describes the application of a non-invasive genetic technique for the estimation of urban ship rat density. Individual genotyping of ship rats was facilitated by analysing nine microsatellite loci amplified from the tissue of ship rat hair follicles. Hair samples were collected using hair-snag tubes (220 mm lengths of 65 mm PVC down pipe). Hair samples were retained on adhesive coated rubber bands that partly occluded the opening at both ends of the hair tubes. Hair tubes were baited with peanut butter and set in a known array. Ship rat density was estimated using spatially explicit capture-recapture analysis (DENSITY 4.1). Maximum likelihood was used to fit a range of candidate models to the spatial dimensions of hair tube re-visitation data. The efficacy of the hair tube methodology was initially verified in the Orongorongo Valley on a well studied population of ship rats. In the Orongorongo Valley the density estimate of 1.17 ± 0.42 (SE) rats/ha was in accordance with recent cage-trapping estimates from the same sampling grid. Very low densities (0.26 ± 0.10 (SE) ha) of ship rats were found in Dunedin urban bush fragments. The overall effect of ship rats as predators on urban birdlife is inferred to be much less than in rural areas, where higher ship rat densities exist. If rats exist in high densities within urban Dunedin it seems likely they do so within small pockets of favourable habitat i.e. areas that are not frequently controlled, where food is abundant or where domestic cat densities are low. Systematic sampling and genetic profiling of ship rat hair for spatially explicit density estimation requires fewer human resources than cage-trapping and provides robust estimates of absolute density, but involves increased costs in laboratory analysis