Whole-Mouse Brain Vascular Analysis Framework: Synthetic Model-Based Validation, Informatics Platform, and Queryable Database

The past decade has seen innovative advancements in light microscopy instrumentation that have afforded the acquisition of whole-brain datasets at micrometer resolution. As the hardware and software used to automate the traditional neuroanatomical workflow become more accessible to researchers around the globe, so will the tools needed to analyze whole-brain datasets. Only recently has the focus begun to shift from the development of instrumentation towards platforms for data-driven quantitative analyses. As a consequence of this, the tools required for large-scale quantitative studies across the whole brain are few and far between. In this dissertation, we aim to change this through the development of a standardized, quantitative approach to the study of whole-brain, cerebrovasculature datasets. Our standardized and quantitative approach has four components. The first is the construction of synthetic cerebrovasculature models that can be used in conjunction with the second component, a model-based validation system. Any cerebrovasculature study conducted using imaging data must first extract the filaments embedded within that dataset. The segmentation algorithms that are commonly used to do this are frequently validated on small-scale datasets that represent only a small selection of cerebrovasculature variability. The question is how do these algorithms perform when applied to large-scale datasets. Our model-based validation system uses biologically inspired, large-scale datasets that asses the accuracy of the segmentation algorithm output against ground truth data. Once the data is segmented, we have implemented an informatics platform that calculates descriptive statistics across the entire volume. Attributes describing each vascular filament are also calculated. These include measures of vascular radius, length, surface area, volume, tortuosity, and others. The result is a massive amount of data for the cerebrovasculature segments. The question becomes how can this be analyzed sensibly. Given that both cerebrovasculature topology and geometry can be capture in graph form, we construct the fourth component of our system: a graph database that stores the cerebrovasculature. The graph model of cerebrovasculature that we have developed allows segments to be searched across the whole-brain based on their attributes and/or location. We also implemented a means to reconstruct the segments returned by a specific query for visualizations. This means that a simple text-based query can retrieve cerebrovasculature geometry and topology of the specified vasculature. For example, a query can return all vessels within the frontal cortex, those with specific attribute(s) value range(s), or any combination of attribute and location. Complex graph algorithms can also be applied, such as the shortest path between two bifurcation points or measures of centrality that are important in determining the robust and fragile aspects of blood flow through the cerebrovasculature system. To illustrate the utility of our system, we construct a whole-brain database of vascular connectivity from the Knife-Edge Scanning Microscope India Ink dataset. Using our cerebrovasculature database, we were able to study the cerebrovasculature system by issuing text-based queries to extract the vessel segments that we were interested in. The outcome of our investigation was a wealth of information about the cerebrovasculature system as a whole, and about the different classifications of vessels comprising it. The results returned from these simple queries even generated some interesting and biologically relevant questions. For instance, the profound spikes in radius distribution for some classes of vessels that did not present in other classes. We expect that the methods described in this dissertation will open the door for data-driven, quantitative investigation across the whole-brain. At the time of writing – and to the best of our knowledge that prior to this work – there was not a systemic way to assess segmentation algorithm performance, calculate attributes for each segment of vasculature extracted across the whole brain, and store those results in a queryable database that also stores geometry and topology of the entire cerebrovasculature system. We believe that our method can and will set the standard for largescale cerebrovasculature research. Therefore, in conclusion, we state that our methods contribute a standardized, quantitative approach to the study of cerebrovasculature datasets acquired using modern imaging techniques

Correlated radio--X-ray variability of Galactic Black Holes: A radio--X-ray flare in Cygnus X-1

We report on the first detection of a quasi-simultaneous radio-X-ray flare of Cygnus X-1. The detection was made on 2005 April 16 with pointed observations by the Rossi X-ray Timing Explorer and the Ryle telescope, during a phase where the black hole candidate was close to a transition from the its soft into its hard state. The radio flare lagged the X-rays by approximately 7 minutes, peaking at 3:20 hours barycentric time (TDB 2453476.63864). We discuss this lag in the context of models explaining such flaring events as the ejection of electron bubbles emitting synchrotron radiation.Comment: 4 pages, 4 figure

Prognostic Utility of a Modified HEART Score When Different Troponin Cut-points Are Used

BACKGROUND: Although the recommended cut-point for cardiac troponin (cTn) is the 99th percentile, many institutions use cut-points that are multiples higher than the 99th percentile for diagnosing acute myocardial infarction (AMI). Prior studies have shown that patients with a HEART score (HS) ≤ 3 and normal serial cTn values (modified HS) are at low risk for adverse events. This study aimed to evaluate the prognostic utility of the HS when various cTn cut-points are used. METHODS: This was a sub-study of TRAPID-AMI, a multicenter, international trial evaluating a rapid rule-out AMI study using high sensitivity cTnT (hs-cTnT). 1,282 patients were evaluated for AMI from 12 centers in Europe, United States of America, and Australia from 2011-2013. Blood samples of hs-cTnT were collected at presentation and 2 hours, and each patient had a HS calculated. The US Food and Drug Administration approved 99th percentile for hs-cTnT (19 ng/L) was used. RESULTS: There were 213 (17%) AMIs. Within 30 days, there were an additional 2 AMIs and 8 deaths. The adverse event rates at 30 days (death/AMI) for a HS ≤ 3 and non-elevated hs-cTnT over 2 hours using increasing hs-cTnT cut-points ranged from 0.6% to 5.1%. CONCLUSIONS: Using the recommended 99th percentile cut-point for hs-cTnT, the combination of a HS ≤ 3 with non-elevated hs-cTnT values over 2 hours identifies a low-risk cohort who can be considered for discharge from the emergency department without further testing. The prognostic utility of this strategy is greatly lessened as higher hs-cTnT cut-points are used

An X-Ray View of the Jet-Cycle in the Radio Loud AGN 3C120

We present a study of the central engine in the broad-line radio galaxy 3C120 using a multi-epoch analysis of a deep XMM-Newton observation and two deep Suzaku pointings (in 2012). In order to place our spectral data into the context of the disk-disruption/jet-ejection cycles displayed by this object, we monitor the source in the UV/X-ray bands, and in the radio band. We find three statistically acceptable spectral models, a disk-reflection model, a jet-model and a jet+disk model. Despite being good descriptions of the data, the disk-reflection model violates the radio constraints on the inclination, and the jet-model has a fine-tuning problem, requiring a jet contribution exceeding that expected. Thus, we argue for a composite jet+disk model. Within the context of this model, we verify the basic predictions of the jet-cycle paradigm, finding a truncated/refilling disk during the Suzaku observations and a complete disk extending down to the innermost stable circular orbit (ISCO) during the XMM-Newton observation. The idea of a refilling disk is further supported by the detection of the ejection of a new jet knot approximately one month after the Suzaku pointings. We also discover a step-like event in one of the Suzaku pointings in which the soft band lags the hard band. We suggest that we are witnessing the propagation of a disturbance from the disk into the jet on a timescale set by the magnetic field.Comment: 14 pages, 10 figures, accepted for publication in Ap

Rationale and Design of the ICON-RELOADED Study: International Collaborative of Nterminal pro-B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department

Objectives The objectives were to reassess use of amino-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations for diagnosis and prognosis of acute heart failure (HF) in patients with acute dyspnea. Background NT-proBNP facilitates diagnosis, prognosis, and treatment in patients with suspected or proven acute HF. As demographics of such patients are changing, previous diagnostic NT-proBNP thresholds may need updating. Additionally, value of in-hospital NT-proBNP prognostic monitoring for HF is less understood. Methods In a prospective, multicenter study in the United States and Canada, patients presenting to emergency departments with acute dyspnea were enrolled, with demographic, medication, imaging, and clinical course information collected. NT-proBNP analysis will be performed using the Roche Diagnostics Elecsys proBNPII immunoassay in blood samples obtained at baseline and at discharge (if hospitalized). Primary end points include positive predictive value of previously established age-stratified NT-proBNP thresholds for the adjudicated diagnosis of acute HF and its negative predictive value to exclude acute HF. Secondary end points include sensitivity, specificity, and positive and negative likelihood ratios for acute HF and, among those with HF, the prognostic value of baseline and predischarge NT-proBNP for adjudicated clinical end points (including all-cause death and hospitalization) at 30 and 180 days. Results A total of 1,461 dyspneic subjects have been enrolled and are eligible for analysis. Follow-up for clinical outcome is ongoing. Conclusions The International Collaborative of N-terminal pro–B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study offers a contemporary opportunity to understand best diagnostic cutoff points for NT-proBNP in acute HF and validate in-hospital monitoring of HF using NT-proBNP

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 201

The Influence of Body Mass Index on Clinical Interpretation of Established and Novel Biomarkers in Acute Heart Failure

Background: Body mass index (BMI) is a known confounder for natriuretic peptides, but its influence on other biomarkers is less well described. We investigated whether BMI interacts with biomarkers’ association with prognosis in patients with acute heart failure (AHF).Methods and Results: B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin I (hs-cTnI), galectin-3, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urine NGAL were measured serially in patients with AHF during hospitalization in the AKINESIS (Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic Heart Failure) study. Cox regression analysis was used to determine the association of biomarkers and their interaction with BMI for 30-day, 90-day and 1-year composite outcomes of death or HF readmission. Among 866 patients, 21.2%, 29.7% and 46.8% had normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2) or obese (≥ 30 kg/m2) BMIs on admission, respectively. Admission values of BNP and hs-cTnI were negatively associated with BMI, whereas galectin-3 and sNGAL were positively associated with BMI. Admission BNP and hs-cTnI levels were associated with the composite outcome within 30 days, 90 days and 1 year. Only BNP had a significant interaction with BMI. When BNP was analyzed by BMI category, its association with the composite outcome attenuated at higher BMIs and was no longer significant in obese individuals. Findings were similar when evaluated by the last-measured biomarkers and BMIs.Conclusions: In patients with AHF, only BNP had a significant interaction with BMI for the outcomes, with its association attenuating as BMI increased; hs-cTnI was prognostic, regardless of BMI.</p

The Goodness of Simultaneous Fits in ISIS

In a previous work, we introduced a tool for analyzing multiple datasets simultaneously, which has been implemented into ISIS. This tool was used to fit many spectra of X-ray binaries. However, the large number of degrees of freedom and individual datasets raise an issue about a good measure for a simultaneous fit quality. We present three ways to check the goodness of these fits: we investigate the goodness of each fit in all datasets, we define a combined goodness exploiting the logical structure of a simultaneous fit, and we stack the fit residuals of all datasets to detect weak features. These tools are applied to all RXTE-spectra from GRO 1008−57, revealing calibration features that are not detected significantly in any single spectrum. Stacking the residuals from the best-fit model for the Vela X-1 and XTE J1859+083 data evidences fluorescent emission lines that would have gone undetected otherwise.M. Kühnel was supported by the Bundesministerium für Wirtschaft und Technologie under Deutsches Zentrum für Luft- und Raumfahrt grants 50OR1113 and 50OR1207