Digital subtraction MR angiography roadmapping for magnetic steerable catheter tracking.

PURPOSE: To develop a high temporal resolution MR imaging technique that could be used with magnetically assisted remote control (MARC) endovascular catheters. MATERIALS AND METHODS: A technique is proposed based on selective intra-arterial injections of dilute MR contrast at the beginning of a fluoroscopic MR angiography acquisition. The initial bolus of contrast is used to establish a vascular roadmap upon which MARC catheters can be tracked. The contrast to noise ratio (CNR) of the achieved roadmap was assessed in phantoms and in a swine animal model. The ability of the technique to permit navigation of activated MARC catheters through arterial branch points was evaluated. RESULTS: The roadmapping mode proved effective in phantoms for tracking objects and achieved a CNR of 35.7 between the intra- and extra-vascular space. In vivo, the intra-arterial enhancement strategy produced roadmaps with a CNR of 42.0. The artifact produced by MARC catheter activation provided signal enhancement patterns on the roadmap that experienced interventionalists could track through vascular structures. CONCLUSION: A roadmapping approach with intra-arterial contrast-enhanced MR angiography is introduced for navigating the MARC catheter. The technique mitigates the artifact produced by the MARC catheter, greatly limits the required specific absorption rate, permits regular roadmap updates due to the low contrast agent requirements, and proved effective in the in vivo setting. Inc.

System architecture for a magnetically guided endovascular microcatheter.

Magnetic resonance imaging (MRI) guided minimally invasive interventions are an emerging technology. We developed a microcatheter that utilizes micro-electromagnets manufactured on the distal tip, in combination with the magnetic field of a MRI scanner, to perform microcatheter steering during endovascular surgery. The aim of this study was to evaluate a user control system for operating, steering and monitoring this magnetically guided microcatheter. The magnetically-assisted remote control (MARC) microcatheter was magnetically steered within a phantom in the bore of a 1.5 T MRI scanner. Controls mounted in an interventional MRI suite, along with a graphical user interface at the MRI console, were developed with communication enabled via MRI compatible hardware modules. Microcatheter tip deflection measurements were performed by evaluating MRI steady-state free precession (SSFP) images and compared to models derived from magnetic moment interactions and composite beam mechanics. The magnitude and direction of microcatheter deflections were controlled with user hand, foot, and software controls. Data from two different techniques for measuring the microcatheter tip location within a 1.5 T MRI scanner showed correlation of magnetic deflections to our model (R(2): 0.88) with a region of linear response (R(2): 0.98). Image processing tools were successful in autolocating the in vivo microcatheter tip within MRI SSFP images. Our system showed good correlation to response curves and introduced low amounts of MRI noise artifact. The center of the artifact created by the energized microcatheter solenoid was a reliable marker for determining the degree of microcatheter deflection and auto-locating the in vivo microcatheter tip.

Health-Analytics Data to Evidence Suite (HADES): Open-Source Software for Observational Research.

The Health-Analytics Data to Evidence Suite (HADES) is an open-source software collection developed by Observational Health Data Sciences and Informatics (OHDSI). It executes directly against healthcare data such as electronic health records and administrative claims, that have been converted to the Observational Medical Outcomes Partnership (OMOP) Common Data Model. Using advanced analytics, HADES performs characterization, population-level causal effect estimation, and patient-level prediction, potentially across a federated data network, allowing patient-level data to remain locally while only aggregated statistics are shared. Designed to run across a wide array of technical environments, including different operating systems and database platforms, HADES uses continuous integration with a large set of unit tests to maintain reliability. HADES implements OHDSI best practices, and is used in almost all published OHDSI studies, including some that have directly informed regulatory decisions.

Magnetic catheter manipulation in the interventional MR imaging environment.

PURPOSE: To evaluate deflection capability of a prototype endovascular catheter, which is remotely magnetically steerable, for use in the interventional magnetic resonance (MR) imaging environment. MATERIALS AND METHODS: Copper coils were mounted on the tips of commercially available 2.3-3.0-F microcatheters. The coils were fabricated in a novel manner by plasma vapor deposition of a copper layer followed by laser lithography of the layer into coils. Orthogonal helical (ie, solenoid) and saddle-shaped (ie, Helmholtz) coils were mounted on a single catheter tip. Microcatheters were tested in water bath phantoms in a 1.5-T clinical MR scanner, with variable simultaneous currents applied to the coils. Catheter tip deflection was imaged in the axial plane by using a "real-time" steady-state free precession MR imaging sequence. Degree of deflection and catheter tip orientation were measured for each current application. RESULTS: The catheter tip was clearly visible in the longitudinal and axial planes. Magnetic field artifacts were visible when the orthogonal coils at the catheter tip were energized. Variable amounts of current applied to a single coil demonstrated consistent catheter deflection in all water bath experiments. Changing current polarity reversed the observed direction of deflection, whereas current applied to two different coils resulted in deflection represented by the composite vector of individual coil activations. Microcatheter navigation through the vascular phantom was successful through control of applied current to one or more coils. CONCLUSIONS: Controlled catheter deflection is possible with laser lithographed multiaxis coil-tipped catheters in the MR imaging environment.

Social influences on physical activity for establishing criteria leading to exercise persistence.

Despite well-documented health benefits from exercise, a study on national trends in achieving the recommended minutes of physical activity guidelines has not improved since the guidelines were published in 2008. Peer interactions have been identified as a critical factor for increasing a population's physical activity. The objective of this study is for establishing criteria for social influences on physical activity for establishing criteria that lead to exercise persistence. A system of differential equations was developed that projects exercise trends over time. The system includes both social and non-social influences that impact changes in physical activity habits and establishes quantitative conditions that delineate population-wide persistence habits from domination of sedentary behavior. The model was generally designed with parameter values that can be estimated to data. Complete absence of social or peer influences resulted in long-term dominance of sedentary behavior and a decline of physically active populations. Social interactions between sedentary and moderately active populations were the most important social parameter that influenced low active populations to become and remain physically active. On the other hand, social interactions encouraging moderately active individuals to become sedentary drove exercise persistence to extinction. Communities should focus on increasing social interactions between sedentary and moderately active individuals to draw sedentary populations to become more active. Additionally, reducing opportunities for moderately active individuals to engage with sedentary individuals through sedentary social activities should be addressed.

Portable microcoil NMR detection coupled to capillary electrophoresis.

High-efficiency separation techniques, such as capillary electrophoresis (CE), coupled to a nondestructive nuclear magnetic resonance (NMR) spectrometer offer the ability to separate, chemically identify, and provide structural information on analytes in small sample volumes. Previous CE-NMR coupled systems utilized laboratory-scale NMR magnets and spectrometers, which require very long separation capillaries. New technological developments in electronics have reduced the size of the NMR system, and small 1-2 T permanent magnets provide the possibilities of a truly portable NMR. The microcoils used in portable and laboratory-scale NMR may offer the advantage of improved mass sensitivity because the limit of detection (LOD) is proportional to the coil diameter. In this work, CE is coupled with a portable, briefcase-sized NMR system that incorporates a microcoil probe and a 1.8 T permanent magnet to measure (19)F NMR spectra. Separations of fluorinated molecules are demonstrated with stopped- and continuous-flow NMR detection. The results demonstrate that coupling CE to a portable NMR instrument is feasible and can provide a low-cost method to obtain structural information on microliter samples. An LOD of 31.8 nmol for perfluorotributylamine with a resolution of 4 ppm has been achieved with this system.

Portable, low-cost NMR with laser-lathe lithography produced microcoils.

Nuclear Magnetic Resonance (NMR) is unsurpassed in its ability to non-destructively probe chemical identity. Portable, low-cost NMR sensors would enable on-site identification of potentially hazardous substances, as well as the study of samples in a variety of industrial applications. Recent developments in RF microcoil construction (i.e. coils much smaller than the standard 5mm NMR RF coils), have dramatically increased NMR sensitivity and decreased the limits-of-detection (LOD). We are using advances in laser pantographic microfabrication techniques, unique to LLNL, to produce RF microcoils for field deployable, high sensitivity NMR-based detectors. This same fabrication technique can be used to produce imaging coils for MRI as well as for standard hardware shimming or "ex-situ" shimming of field inhomogeneities typically associated with inexpensive magnets. This paper describes a portable NMR system based on the use of a 2 kg hand-held permanent magnet, laser-fabricated microcoils, and a compact spectrometer. The main limitations for such a system are the low resolution and sensitivity associated with the low field values and quality of small permanent magnets, as well as the lack of large amounts of sample of interest in most cases. The focus of the paper is on the setting up of this system, initial results, sensitivity measurements, discussion of the limitations and future plans. The results, even though preliminary, are promising and provide the foundation for developing a portable, inexpensive NMR system for chemical analysis. Such a system will be ideal for chemical identification of trace substances on site.

A curated and standardized adverse drug event resource to accelerate drug safety research.

Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies.

ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis.

Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells. A variant isoform of human (h) ERbeta (hERbetacx/2), formed by alternative splicing, has been identified in testicular cDNA libraries by two laboratories. The present study examined the expression of wild-type (ERbeta1) and variant (ERbeta2) beta receptors in human testes by 1) RT-PCR with isoform specific primers, and 2) single and double immunohistochemistry using monoclonal antibodies raised against peptides unique to the C termini of hERbeta1 and hERbeta2. PCR products specific for ERbeta1 and ERbeta2 were amplified from cDNA pools prepared from human testes and granulosa cells. On Western blots, the anti-ERbeta1 monoclonal antibody bound to recombinant ERbeta1 and the anti-ERbeta2 monoclonal to recombinant hERbeta2. Neither bound to the other ERbeta isoform nor to recombinant ERalpha. ERbeta1 and ERbeta2 proteins were both detected in human testis. Immunoexpression of ERbeta1 was most intense in pachytene spermatocytes and round spermatids, whereas low levels of expression were detected in Sertoli cells, spermatogonia, preleptotene, leptotene, zygotene, and diplotene spermatocytes. Highest levels of expression of ERbeta2 protein were detected in Sertoli cells and spermatogonia with low/variable expression in preleptotene, pachytene, and diplotene spermatocytes. No immunostaining was detected in elongating spermatids. Most interstitial cells expressed more ERbeta2 than ERbeta1. It is speculated that the cells most susceptible to modulation by estrogenic ligands are round spermatids in which levels of expression of ERbeta1 are high. In contrast, expression of ERbeta2, an isoform that may act as a dominant negative inhibitor of ER action, in Sertoli cells and spermatogonia, could protect these cells from adverse effects of estrogens.

Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle.

Estrogen action is mediated via two subtypes of the estrogen receptor (ER), usually referred to as ERalpha and ERbeta. We have previously compared the spatial and temporal expressions of ERalpha and ERbeta proteins in human endometrium and reported that endothelial cells exclusively express ERbeta. In the present study we have extended our investigations to compare the pattern of expression of wild-type (ERbeta1) and a newly identified ERbeta variant isoform (ERbetacx/beta2) that lacks the ability to bind steroids. mRNAs encoding both ERbeta1 and ERbetacx/beta2 receptors were identified in human endometrial extracts by RT-PCR. Quantitative TaqMan R-TPCR demonstrated that levels of total mRNAs were increased significantly premenstrually as circulating progesterone levels declined. ERbeta1 and ERbetacx/beta2 proteins were identified within multiple cell types within the endometrium using isotype-specific monoclonal antibodies; immunoexpression of ERbetacx/beta2 appeared less intense than that of ERbeta1 in endometrial glandular epithelium and endothelial cells. Immunoexpression of ERbeta1 appeared unchanged throughout the menstrual cycle. In contrast, levels of ERbetacx/beta2-specific immunoreactivity were specifically reduced in gland cells within the functional layer, but not in those of the basal layer, in the midsecretory phase. It is possible that coexpression of ERbetacx/beta2 in cells containing ERbeta1 and/or ERalpha may modulate the effects of estrogens on the endometrium.

Activin A and follistatin in acute liver failure.

BACKGROUND: Liver regeneration may be impaired in acute liver failure due to either inhibition of the proliferative response or ongoing liver cell death. Activin A, a member of the TGFbeta superfamily, inhibits hepatocyte DNA synthesis and induces apoptosis. METHODS: Levels of activin A and its binding protein follistatin in the serum of 23 patients with acute liver failure were determined by enzyme-linked immunosorbent assay. RESULTS: Serum activin A was significantly increased in acute liver failure patients (median 2.15 ng/ml, range 0.28-6.87 ng/ml) compared to normal controls (median 0.25 ng/ml, range 0.19-0.53 ng/ml; = 10; 0.001). However, this was not linked to the final disease outcome. Higher levels of activin A were found in the serum of patients with acute liver failure due to paracetamol overdose (median 2.87 ng/ml, range 0.72-6.87 ng/ml; = 17) than in patients with acute liver failure due to non-A to E hepatitis (median 1.10 ng/ml, range 0.28-2.70 ng/ml; = 6; 0.05). Serum follistatin was also increased in acute liver failure patients (median 2.84 ng/ml, range 0.57-13.24 ng/ml) compared to normal controls (median 0.68 ng/ml, range 0.32-3.70 ng/ml; 0.01). CONCLUSION: Serum activin A is increased in acute liver failure and could be a factor in the inhibition of liver regeneration.

Magnetically-Assisted Remote Controlled Microcatheter Tip Deflection under Magnetic Resonance Imaging.

X-ray fluoroscopy-guided endovascular procedures have several significant limitations, including difficult catheter navigation and use of ionizing radiation, which can potentially be overcome using a magnetically steerable catheter under MR guidance. The main goal of this work is to develop a microcatheter whose tip can be remotely controlled using the magnetic field of the MR scanner. This protocol aims to describe the procedures for applying current to the microcoil-tipped microcatheter to produce consistent and controllable deflections. A microcoil was fabricated using laser lathe lithography onto a polyimide-tipped endovascular catheter. In vitro testing was performed in a waterbath and vessel phantom under the guidance of a 1.5-T MR system using steady-state free precession (SSFP) sequencing. Various amounts of current were applied to the coils of the microcatheter to produce measureable tip deflections and navigate in vascular phantoms. The development of this device provides a platform for future testing and opportunity to revolutionize the endovascular interventional MRI environment.

RF Heating of MRI-Assisted Catheter Steering Coils for Interventional MRI.

RATIONALE AND OBJECTIVES: The aim of this study was too assess magnetic resonance imaging (MRI) radiofrequency (RF)-related heating of conductive wire coils used in magnetically steerable endovascular catheters. MATERIALS AND METHODS: A three-axis microcoil was fabricated onto a 1.8Fr catheter tip. In vitro testing was performed on a 1.5-T MRI system using an agarose gel-filled vessel phantom, a transmit-receive body RF coil, a steady-state free precession pulse sequence, and a fluoroptic thermometry system. Temperature was measured without simulated blood flow at varying distances from the magnet isocenter and at varying flip angles. Additional experiments were performed with laser-lithographed single-axis microcoil-tipped microcatheters in air and in a saline bath with varied grounding of the microcoil wires. Preliminary in vivo evaluation of RF heating was performed in pigs at 1.5 T with coil-tipped catheters in various positions in the common carotid arteries with steady-state free precession pulse sequence on and off and under physiologic-flow and zero-flow conditions. RESULTS: In tissue-mimicking agarose gel, RF heating resulted in a maximal temperature increase of 0.35°C after 15 minutes of imaging, 15 cm from the magnet isocenter. For a single-axis microcoil, maximal temperature increases were 0.73°C to 1.91°C in air and 0.45°C to 0.55°C in saline. In vivo, delayed contrast-enhanced MRI revealed no evidence of vascular injury, and histopathologic sections from the common carotid arteries confirmed the lack of vascular damage. CONCLUSIONS: Microcatheter tip microcoils for endovascular catheter steering in MRI experience minimal RF heating under the conditions tested. These data provide the basis for further in vivo testing of this promising technology for endovascular interventional MRI.

Electronic characterization of lithographically patterned microcoils for high sensitivity NMR detection.

Nuclear magnetic resonance (NMR) offers a non-destructive, powerful, structure-specific analytical method for the identification of chemical and biological systems. The use of radio frequency (RF) microcoils has been shown to increase the sensitivity in mass-limited samples. Recent advances in micro-receiver technology have further demonstrated a substantial increase in mass sensitivity [D.L. Olson, T.L. Peck, A.G. Webb, R.L. Magin, J.V. Sweedler, High-resolution microcoil H-1-NMR for mass-limited, nanoliter-volume samples, Science 270 (5244) (1995) 1967-1970]. Lithographic methods for producing solenoid microcoils possess a level of flexibility and reproducibility that exceeds previous production methods, such as hand winding microcoils. This paper presents electrical characterizations of RF microcoils produced by a unique laser lithography system that can pattern three dimensional surfaces and compares calculated and experimental results to those for wire wound RF microcoils. We show that existing optimization conditions for RF coil design still hold true for RF microcoils produced by lithography. Current lithographic microcoils show somewhat inferior performance to wire wound RF microcoils due to limitations in the existing electroplating technique. In principle, however, when the pitch of the RF microcoil is less than 100mum lithographic coils should show comparable performance to wire wound coils. In the cases of larger pitch, wire cross sections can be significantly larger and resistances lower than microfabricated conductors.