Intraoperative Use of Intra-Aortic Balloon Pump to Generate Pulsatile Flow During Heart Transplantation: A Single-Center Experience.

The physiologic impact of pulsatile flow (PF) on end-organ perfusion during cardiopulmonary bypass (CPB) is controversial. Using an intra-aortic balloon pump (IABP) to maintain PF during CPB for patients undergoing heart transplantation (HT) may impact end-organ perfusion, with implications for postoperative outcomes. A single-center retrospective study of 76 patients bridged to HT with IABP was conducted between January 2018 and December 2022. Beginning in May 2022, patients received IABP-generated PF during CPB at an internal rate of 80 beats/minute. Fifty-eight patients underwent HT with the IABP turned off (IABP-Off), whereas 18 patients underwent HT with IABP-generated PF (IABP-On). The unmatched IABP-On group experienced shorter organ ischemia times (180 vs. 203 minutes, p = 0.015) and CPB times (104 vs. 116 minutes, p = 0.022). The cohort was propensity matched according to age, organ ischemia time, and CPB time. Elevations in postoperative lactates in the immediate (2.8 vs. 1.5, p = 0.062) and 24 hour (4.7 vs. 2.4, p = 0.084) postoperative periods trended toward significance in the matched IABP-Off group. There was no difference in postoperative vasoactive inotropic score (VIS), postoperative creatinine, or length of stay. This limited preliminary data suggest that maintaining counterpulsation to generate PF during CPB may improve end-organ perfusion in this patient population as suggested by lower postoperative lactate levels.

Let's make size not matter: tumor control and toxicity outcomes of hypofractionated Gamma Knife radiosurgery for large brain metastases.

PURPOSE: Management of patients with large brain metastases poses a clinical challenge, with poor local control and high risk of adverse radiation events when treated with single-fraction stereotactic radiosurgery (SF-SRS). Hypofractionated SRS (HF-SRS) may be considered, but clinical data remains limited, particularly with Gamma Knife (GK) radiosurgery. We report our experience with GK to deliver mask-based HF-SRS to brain metastases greater than 10 cc in volume and present our control and toxicity outcomes. METHODS: Patients who received hypofractionated GK radiosurgery (HF-GKRS) for the treatment of brain metastases greater than 10 cc between January 2017 and June 2022 were retrospectively identified. Local failure (LF) and adverse radiation events of CTCAE grade 2 or higher (ARE) were identified. Clinical, treatment, and radiological information was collected to identify parameters associated with clinical outcomes. RESULTS: Ninety lesions (in 78 patients) greater than 10 cc were identified. The median gross tumor volume was 16.0 cc (range 10.1-56.0 cc). Prior surgical resection was performed on 49 lesions (54.4%). Six- and 12-month LF rates were 7.3% and 17.6%; comparable ARE rates were 1.9% and 6.5%. In multivariate analysis, tumor volume larger than 33.5 cc (p = 0.029) and radioresistant histology (p = 0.047) were associated with increased risk of LF (p = 0.018). Target volume was not associated with increased risk of ARE (p = 0.511). CONCLUSIONS: We present our institutional experience treating large brain metastases using mask-based HF-GKRS, representing one of the largest studies implementing this platform and technique. Our LF and ARE compare favorably with the literature, suggesting that target volumes less than 33.5 cc demonstrate excellent control rates with low ARE. Further investigation is needed to optimize treatment technique for larger tumors.

The Project Baseline Health Study: a step towards a broader mission to map human health.

The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

Quantifying neurologic disease using biosensor measurements in-clinic and in free-living settings in multiple sclerosis.

Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p = 0.0070), several aspects of turning including turn angle (0.437; p = 0.0372), and maximum angular velocity (0.653; p = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting.

Finding useful biomarkers for Parkinson's disease.

The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.

An optimized microfabricated platform for the optical generation and detection of hyperpolarized 129Xe.

Low thermal-equilibrium nuclear spin polarizations and the need for sophisticated instrumentation render conventional nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) incompatible with small-scale microfluidic devices. Hyperpolarized 129Xe gas has found use in the study of many materials but has required very large and expensive instrumentation. Recently a microfabricated device with modest instrumentation demonstrated all-optical hyperpolarization and detection of 129Xe gas. This device was limited by 129Xe polarizations less than 1%, 129Xe NMR signals smaller than 20 nT, and transport of hyperpolarized 129Xe over millimeter lengths. Higher polarizations, versatile detection schemes, and flow of 129Xe over larger distances are desirable for wider applications. Here we demonstrate an ultra-sensitive microfabricated platform that achieves 129Xe polarizations reaching 7%, NMR signals exceeding 1 µT, lifetimes up to 6 s, and simultaneous two-mode detection, consisting of a high-sensitivity in situ channel with signal-to-noise of 105 and a lower-sensitivity ex situ detection channel which may be useful in a wider variety of conditions. 129Xe is hyperpolarized and detected in locations more than 1 cm apart. Our versatile device is an optimal platform for microfluidic magnetic resonance in particular, but equally attractive for wider nuclear spin applications benefitting from ultra-sensitive detection, long coherences, and simple instrumentation.

Gradient-free microfluidic flow labeling using thin magnetic films and remotely detected MRI.

Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) may be employed as noninvasive measurements yielding detailed information about the chemical and physical parameters that define microscale flows. Despite these advantages, magnetic resonance has been difficult to combine with microfluidics, largely due to its low sensitivity when detecting small sample volumes and the difficulty of efficiently addressing individual flow pathways for parallel measurements without utilizing large electric currents to create pulsed magnetic field gradients. Here, we demonstrate that remotely-detected MRI (RD-MRI) employing static magnetic field gradients produced by thin magnetic films can be used to encode flow and overcome some of these limitations. We show how flow path and history can be selected through the use of these thin film labels and through the application of synchronized, frequency-selective pulses. This obviates the need for large electric currents to produce pulsed magnetic field gradients and may allow for further application of NMR and MRI experiments on microscale devices.

Ultra-low-field NMR relaxation and diffusion measurements using an optical magnetometer.

Nuclear magnetic resonance (NMR) relaxometry and diffusometry are important tools for the characterization of heterogeneous materials and porous media, with applications including medical imaging, food characterization and oil-well logging. These methods can be extremely effective in applications where high-resolution NMR is either unnecessary, impractical, or both, as is the case in the emerging field of portable chemical characterization. Here, we present a proof-of-concept experiment demonstrating the use of high-sensitivity optical magnetometers as detectors for ultra-low-field NMR relaxation and diffusion measurements.

Optically detected cross-relaxation spectroscopy of electron spins in diamond.

The application of magnetic resonance spectroscopy at progressively smaller length scales may eventually permit 'chemical imaging' of spins at the surfaces of materials and biological complexes. In particular, the negatively charged nitrogen-vacancy (NV(-)) centre in diamond has been exploited as an optical transducer for nanoscale nuclear magnetic resonance. However, the spectra of detected spins are generally broadened by their interaction with proximate paramagnetic NV(-) centres through coherent and incoherent mechanisms. Here we demonstrate a detection technique that can resolve the spectra of electron spins coupled to NV(-) centres, in this case, substitutional nitrogen and neutral nitrogen-vacancy centres in diamond, through optically detected cross-relaxation. The hyperfine spectra of these spins are a unique chemical identifier, suggesting the possibility, in combination with recent results in diamonds harbouring shallow NV(-) implants, that the spectra of spins external to the diamond can be similarly detected.

Genetically encoded reporters for hyperpolarized xenon magnetic resonance imaging.

Magnetic resonance imaging (MRI) enables high-resolution non-invasive observation of the anatomy and function of intact organisms. However, previous MRI reporters of key biological processes tied to gene expression have been limited by the inherently low molecular sensitivity of conventional (1)H MRI. This limitation could be overcome through the use of hyperpolarized nuclei, such as in the noble gas xenon, but previous reporters acting on such nuclei have been synthetic. Here, we introduce the first genetically encoded reporters for hyperpolarized (129)Xe MRI. These expressible reporters are based on gas vesicles (GVs), gas-binding protein nanostructures expressed by certain buoyant microorganisms. We show that GVs are capable of chemical exchange saturation transfer interactions with xenon, which enables chemically amplified GV detection at picomolar concentrations (a 100- to 10,000-fold improvement over comparable constructs for (1)H MRI). We demonstrate the use of GVs as heterologously expressed indicators of gene expression and chemically targeted exogenous labels in MRI experiments performed on living cells.

Optical hyperpolarization and NMR detection of 129Xe on a microfluidic chip.

Optically hyperpolarized (129)Xe gas has become a powerful contrast agent in nuclear magnetic resonance (NMR) spectroscopy and imaging, with applications ranging from studies of the human lung to the targeted detection of biomolecules. Equally attractive is its potential use to enhance the sensitivity of microfluidic NMR experiments, in which small sample volumes yield poor sensitivity. Unfortunately, most (129)Xe polarization systems are large and non-portable. Here we present a microfabricated chip that optically polarizes (129)Xe gas. We have achieved (129)Xe polarizations >0.5% at flow rates of several microlitres per second, compatible with typical microfluidic applications. We employ in situ optical magnetometry to sensitively detect and characterize the (129)Xe polarization at magnetic fields of 1 µT. We construct the device using standard microfabrication techniques, which will facilitate its integration with existing microfluidic platforms. This device may enable the implementation of highly sensitive (129)Xe NMR in compact, low-cost, portable devices.

Hyperpolarized xenon-based molecular sensors for label-free detection of analytes.

Nuclear magnetic resonance (NMR) can reveal the chemical constituents of a complex mixture without resorting to chemical modification, separation, or other perturbation. Recently, we and others have developed magnetic resonance agents that report on the presence of dilute analytes by proportionately altering the response of a more abundant or easily detected species, a form of amplification. One example of such a sensing medium is xenon gas, which is chemically inert and can be optically hyperpolarized, a process that enhances its NMR signal by up to 5 orders of magnitude. Here, we use a combinatorial synthetic approach to produce xenon magnetic resonance sensors that respond to small molecule analytes. The sensor responds to the ligand by producing a small chemical shift change in the Xe NMR spectrum. We demonstrate this technique for the dye, Rhodamine 6G, for which we have an independent optical assay to verify binding. We thus demonstrate that specific binding of a small molecule can produce a xenon chemical shift change, suggesting a general approach to the production of xenon sensors targeted to small molecule analytes for in vitro assays or molecular imaging in vivo.

Higher order amyloid fibril structure by MAS NMR and DNP spectroscopy.

Protein magic angle spinning (MAS) NMR spectroscopy has generated structural models of several amyloid fibril systems, thus providing valuable information regarding the forces and interactions that confer the extraordinary stability of the amyloid architecture. Despite these advances, however, obtaining atomic resolution information describing the higher levels of structural organization within the fibrils remains a significant challenge. Here, we detail MAS NMR experiments and sample labeling schemes designed specifically to probe such higher order amyloid structure, and we have applied them to the fibrils formed by an eleven-residue segment of the amyloidogenic protein transthyretin (TTR(105-115)). These experiments have allowed us to define unambiguously not only the arrangement of the peptide ß-strands into ß-sheets but also the ß-sheet interfaces within each protofilament, and in addition to identify the nature of the protofilament-to-protofilament contacts that lead to the formation of the complete fibril. Our efforts have resulted in 111 quantitative distance and torsion angle restraints (10 per residue) that describe the various levels of structure organization. The experiments benefited extensively from the use of dynamic nuclear polarization (DNP), which in some cases allowed us to shorten the data acquisition time from days to hours and to improve significantly the signal-to-noise ratios of the spectra. The ß-sheet interface and protofilament interactions identified here revealed local variations in the structure that result in multiple peaks for the exposed N- and C-termini of the peptide and in inhomogeneous line-broadening for the residues buried within the interior of the fibrils.

Sensitive magnetic control of ensemble nuclear spin hyperpolarization in diamond.

Dynamic nuclear polarization, which transfers the spin polarization of electrons to nuclei, is routinely applied to enhance the sensitivity of nuclear magnetic resonance. This method is particularly useful when spin hyperpolarization can be produced and controlled optically or electrically. Here we show complete polarization of nuclei located near optically polarized nitrogen-vacancy centres in diamond. Close to the ground-state level anti-crossing condition of the nitrogen-vacancy electron spins, (13)C nuclei in the first shell are polarized in a pattern that depends sensitively upon the magnetic field. Based on the anisotropy of the hyperfine coupling and of the optical polarization mechanism, we predict and observe a reversal of the nuclear spin polarization with only a few millitesla change in the magnetic field. This method of magnetic control of high nuclear polarization at room temperature can be applied in sensitivity enhanced nuclear magnetic resonance of bulk nuclei, nuclear-based spintronics, and quantum computation in diamond.

Atomic structure and hierarchical assembly of a cross-ß amyloid fibril.

The cross-ß amyloid form of peptides and proteins represents an archetypal and widely accessible structure consisting of ordered arrays of ß-sheet filaments. These complex aggregates have remarkable chemical and physical properties, and the conversion of normally soluble functional forms of proteins into amyloid structures is linked to many debilitating human diseases, including several common forms of age-related dementia. Despite their importance, however, cross-ß amyloid fibrils have proved to be recalcitrant to detailed structural analysis. By combining structural constraints from a series of experimental techniques spanning five orders of magnitude in length scale--including magic angle spinning nuclear magnetic resonance spectroscopy, X-ray fiber diffraction, cryoelectron microscopy, scanning transmission electron microscopy, and atomic force microscopy--we report the atomic-resolution (0.5 Å) structures of three amyloid polymorphs formed by an 11-residue peptide. These structures reveal the details of the packing interactions by which the constituent ß-strands are assembled hierarchically into protofilaments, filaments, and mature fibrils.

Compressive sampling with prior information in remotely detected MRI of microfluidic devices.

The design and operation of microfluidic analytical devices depends critically on tools to probe microscale chemistry and flow dynamics. Magnetic resonance imaging (MRI) seems ideally suited to this task, but its sensitivity is compromised because the fluid-containing channels in "lab on a chip" devices occupy only a small fraction of the enclosing detector's volume; as a result, the few microfluidic applications of NMR have required custom-designed chips harboring many detectors at specific points of interest. To overcome this limitation, we have developed remotely detected microfluidic MRI, in which an MR image is stored in the phase and intensity of each analyte's NMR signal and sensitively detected by a single, volume-matched detector at the device outflow, and combined it with compressed sensing for rapid image acquisition. Here, we build upon our previous work and introduce a method that incorporates our prior knowledge of the microfluidic device geometry to further decrease acquisition times. We demonstrate its use in multidimensional velocimetric imaging of a microfluidic mixer, acquiring microscopically detailed images 128 times faster than is possible with conventional sampling. This prior information also informs our choice of sampling schedule, resulting in a scheme that is optimized for a specific flow geometry. Finally, we test our approach in synthetic data and explore potential reconstruction errors as a function of optimization and reconstruction parameters.

Measurement of Arterial Input Function in Hyperpolarized 13C Studies.

Recently, hyperpolarized substrates generated through dynamic nuclear polarization have been introduced to study in vivo metabolism. Injection of hyperpolarized [1-13C]pyruvate, the most widely used substrate, allows detection of time courses of [1-13C]pyruvate and its metabolic products, such as [1-13C]lactate and 13C-bicarbonate, in various organs. However, quantitative metabolic modeling of in vivo data to measure specific metabolic rates remains challenging without measuring the input function. In this study, we demonstrate that the input function of [1-13C]pyruvate can be measured in vivo in the rat carotid artery using an implantable coil.

Band-selective chemical exchange saturation transfer imaging with hyperpolarized xenon-based molecular sensors.

Molecular imaging based on saturation transfer in exchanging systems is a tool for amplified and chemically specific magnetic resonance imaging. Xenon-based molecular sensors are a promising category of molecular imaging agents in which chemical exchange of dissolved xenon between its bulk and agent-bound phases has been use to achieve sub-picomolar detection sensitivity. Control over the saturation transfer dynamics, particularly when multiple exchanging resonances are present in the spectra, requires saturation fields of limited bandwidth and is generally accomplished by continuous wave irradiation. We demonstrate instead how band-selective saturation sequences based on multiple pulse inversion elements can yield saturation bandwidth tuneable over a wide range, while depositing less RF power in the sample. We show how these sequences can be used in imaging experiments that require spatial-spectral and multispectral saturation. The results should be applicable to all CEST experiments and, in particular, will provide the spectroscopic control required for applications of arrays of xenon chemical sensors in microfluidic chemical analysis devices.

Remotely detected NMR for the characterization of flow and fast chromatographic separations using organic polymer monoliths.

An application of remotely detected magnetic resonance imaging is demonstrated for the characterization of flow and the detection of fast, small molecule separations within hypercrosslinked polymer monoliths. The hyper-cross-linked monoliths exhibited excellent ruggedness, with a transit time relative standard deviation of less than 2.1%, even after more than 300 column volumes were pumped through at high pressure and flow. Magnetic resonance imaging enabled high-resolution intensity and velocity-encoded images of mobile phase flow through the monolith. The images confirm that the presence of a polymer monolith within the capillary disrupts the parabolic laminar flow profile that is characteristic of mobile phase flow within an open tube. As a result, the mobile phase and analytes are equally distributed in the radial direction throughout the monolith. Also, in-line monitoring of chromatographic separations of small molecules at high flow rates is shown. The coupling of monolithic chromatography columns and NMR provides both real-time peak detection and chemical shift information for small aromatic molecules. These experiments demonstrate the unique power of magnetic resonance, both direct and remote, in studying chromatographic processes.