Cross-Axis projection error in optically pumped magnetometers and its implication for magnetoencephalography systems.

Optically pumped magnetometers (OPMs) developed for magnetoencephalography (MEG) typically operate in the spin-exchange-relaxation-free (SERF) regime and measure a magnetic field component perpendicular to the propagation axis of the optical-pumping photons. The most common type of OPM for MEG employs alkali atoms, e.g. 87Rb, as the sensing element and one or more lasers for preparation and interrogation of the magnetically sensitive states of the alkali atoms ensemble. The sensitivity of the OPM can be greatly enhanced by operating it in the SERF regime, where the alkali atoms' spin exchange rate is much faster than the Larmor precession frequency. The SERF regime accommodates remnant static magnetic fields up to ±5 nT. However, in the presented work, through simulation and experiment, we demonstrate that multi-axis magnetic signals in the presence of small remnant static magnetic fields, not violating the SERF criteria, can introduce significant error terms in OPM's output signal. We call these deterministic errors cross-axis projection errors (CAPE), where magnetic field components of the MEG signal perpendicular to the nominal sensing axis contribute to the OPM signal giving rise to substantial amplitude and phase errors. Furthermore, through simulation, we have discovered that CAPE can degrade localization and calibration accuracy of OPM-based magnetoencephalography (OPM-MEG) systems.

Calibration and Localization of Optically Pumped Magnetometers Using Electromagnetic Coils.

In this paper, we propose a method to estimate the position, orientation, and gain of a magnetic field sensor using a set of (large) electromagnetic coils. We apply the method for calibrating an array of optically pumped magnetometers (OPMs) for magnetoencephalography (MEG). We first measure the magnetic fields of the coils at multiple known positions using a well-calibrated triaxial magnetometer, and model these discreetly sampled fields using vector spherical harmonics (VSH) functions. We then localize and calibrate an OPM by minimizing the sum of squared errors between the model signals and the OPM responses to the coil fields. We show that by using homogeneous and first-order gradient fields, the OPM sensor parameters (gain, position, and orientation) can be obtained from a set of linear equations with pseudo-inverses of two matrices. The currents that should be applied to the coils for approximating these low-order field components can be determined based on the VSH models. Computationally simple initial estimates of the OPM sensor parameters follow. As a first test of the method, we placed a fluxgate magnetometer at multiple positions and estimated the RMS position, orientation, and gain errors of the method to be 1.0 mm, 0.2°, and 0.8%, respectively. Lastly, we calibrated a 48-channel OPM array. The accuracy of the OPM calibration was tested by using the OPM array to localize magnetic dipoles in a phantom, which resulted in an average dipole position error of 3.3 mm. The results demonstrate the feasibility of using electromagnetic coils to calibrate and localize OPMs for MEG.

A Comparison of the Safety and Efficacy of HX575 (Epoetin Alfa Proposed Biosimilar) with Epoetin Alfa in Patients with End-Stage Renal Disease.

BACKGROUND: HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia. METHODS: This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28). RESULTS: Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was -0.093 g/dL, with 90% CI (-0.23 to 0.04) entirely within the pre-specified equivalence limits (-0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies. CONCLUSIONS: SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety.

Characterization of chicken Mda5 activity: regulation of IFN-ß in the absence of RIG-I functionality.

In mammals, Mda5 and RIG-I are members of the evolutionary conserved RIG-like helicase family that play critical roles in the outcome of RNA virus infections. Resolving influenza infection in mammals has been shown to require RIG-I; however, the apparent absence of a RIG-I homolog in chickens raises intriguing questions regarding how this species deals with influenza virus infection. Although chickens are able to resolve certain strains of influenza, they are highly susceptible to others, such as highly pathogenic avian influenza H5N1. Understanding RIG-like helicases in the chicken is of critical importance, especially for developing new therapeutics that may use these systems. With this in mind, we investigated the RIG-like helicase Mda5 in the chicken. We have identified a chicken Mda5 homolog (ChMda5) and assessed its functional activities that relate to antiviral responses. Like mammalian Mda5, ChMda5 expression is upregulated in response to dsRNA stimulation and following IFN activation of cells. Furthermore, RNA interference-mediated knockdown of ChMda5 showed that ChMda5 plays an important role in the IFN response of chicken cells to dsRNA. Intriguingly, although ChMda5 levels are highly upregulated during influenza infection, knockdown of ChMda5 expression does not appear to impact influenza proliferation. Collectively, although Mda5 is functionally active in the chicken, the absence of an apparent RIG-I-like function may contribute to the chicken's susceptibility to highly pathogenic influenza.

The effect of spatial sampling on the resolution of the magnetostatic inverse problem.

In magnetoencephalography, linear minimum norm inverse methods are commonly employed when a solution with minimal a priori assumptions is desirable. These methods typically produce spatially extended inverse solutions, even when the generating source is focal. Various reasons have been proposed for this effect, including intrisic properties of the minimum norm solution, effects of regularization, noise, and limitations of the sensor array. In this work, we express the lead field in terms of the magnetostatic multipole expansion and develop the minimum-norm inverse in the multipole domain. We demonstrate the close relationship between numerical regularization and explicit suppression of spatial frequencies of the magnetic field. We show that the spatial sampling capabilities of the sensor array and regularization together determine the resolution of the inverse solution. For the purposes of stabilizing the inverse estimate, we propose the multipole transformation of the lead field as an alternative or complementary means to purely numerical regularization.

Effects of head modeling errors on the spatial frequency representation of MEG.

Objectives.We aim to investigate the effects of head model inaccuracies on signal and source reconstruction accuracies for various sensor array distances to the head. This allows for the assessment of the importance of head modeling for next-generation magnetoencephalography (MEG) sensors, optically-pumped magnetometers (OPM).Approach.A 1-shell boundary element method (BEM) spherical head model with 642 vertices of radius 9 cm and conductivity of 0.33 S m-1was defined. The vertices were then randomly perturbed radially up to 2%, 4%, 6%, 8% and 10% of the radius. For each head perturbation case, the forward signal was calculated for dipolar sources located at 2 cm, 4 cm, 6 cm and 8 cm from the origin (center of the sphere), and for a 324 sensor array located at 10 cm to 15 cm from the origin. Equivalent current dipole (ECD) source localization was performed for each of these forward signals. The signal for each perturbed spherical head case was then analyzed in the spatial frequency domain, and the signal and ECD errors were quantified relative to the unperturbed case.Main results.In the noiseless and high signal-to-noise ratio (SNR) case of approximately ≥6 dB, inaccuracies in our spherical BEM head conductor models lead to increased signal and ECD inaccuracies when sensor arrays are placed closer to the head. This is true especially in the case of deep and superficial sources. In the noisy case however, the higher SNR for closer sensor arrays allows for an improved ECD fit and outweighs the effects of head geometry inaccuracies.Significance.OPMs may be placed directly on the head, as opposed to the more commonly used superconducting quantum interference device sensors which must be placed a few centimeters away from the head. OPMs thus allow for signals of higher spatial resolution to be captured, resulting in potentially more accurate source localizations. Our results suggest that an increased emphasis on accurate head modeling for OPMs may be necessary to fully realize its improved source localization potential.

Single-trial classification of evoked responses to auditory tones using OPM- and SQUID-MEG.

Objective.Optically pumped magnetometers (OPMs) are emerging as a near-room-temperature alternative to superconducting quantum interference devices (SQUIDs) for magnetoencephalography (MEG). In contrast to SQUIDs, OPMs can be placed in a close proximity to subject's scalp potentially increasing the signal-to-noise ratio and spatial resolution of MEG. However, experimental demonstrations of these suggested benefits are still scarce. Here, to compare a 24-channel OPM-MEG system to a commercial whole-head SQUID system in a data-driven way, we quantified their performance in classifying single-trial evoked responses.Approach.We measured evoked responses to three auditory tones in six participants using both OPM- and SQUID-MEG systems. We performed pairwise temporal classification of the single-trial responses with linear discriminant analysis as well as multiclass classification with both EEGNet convolutional neural network and xDAWN decoding.Main results.OPMs provided higher classification accuracies than SQUIDs having a similar coverage of the left hemisphere of the participant. However, the SQUID sensors covering the whole helmet had classification scores larger than those of OPMs for two of the tone pairs, demonstrating the benefits of a whole-head measurement.Significance.The results demonstrate that the current OPM-MEG system provides high-quality data about the brain with room for improvement for high bandwidth non-invasive brain-computer interfacing.

The KIDNEYCODE Program: Diagnostic Yield and Clinical Features of Individuals with CKD.

Background: Despite increasing recognition that CKD may have underlyi ng genetic causes, genetic testing remains limited. This study evaluated the diagnostic yield and phenotypic spectrum of CKD in individuals tested through the KIDNEYCODE sponsored genetic testing program. Methods: Unrelated individuals who received panel testing (17 genes) through the KIDNEYCODE sponsored genetic testing program were included. Individuals had to meet at least one of the following eligibility criteria: eGFR ≤90 ml/min per 1.73m2 and hematuria or a family history of kidney disease; or suspected/biopsy-confirmed Alport syndrome or FSGS in tested individuals or relatives. Results: Among 859 individuals, 234 (27%) had molecular diagnoses in genes associated with Alport syndrome (n=209), FSGS (n=12), polycystic kidney disease (n=6), and other disorders (n=8). Among those with positive findings in a COL4A gene, the majority were in COL4A5 (n=157, 72 hemizygous male and 85 heterozygous female individuals). A positive family history of CKD, regardless of whether clinical features were reported, was more predictive of a positive finding than was the presence of clinical features alone. For the 248 individuals who had kidney biopsies, a molecular diagnosis was returned for 49 individuals (20%). Most (n=41) individuals had a molecular diagnosis in a COL4A gene, 25 of whom had a previous Alport syndrome clinical diagnosis, and the remaining 16 had previous clinical diagnoses including FSGS (n=2), thin basement membrane disease (n=9), and hematuria (n=1). In total, 491 individuals had a previous clinical diagnosis, 148 (30%) of whom received a molecular diagnosis, the majority (89%, n=131) of which were concordant. Conclusions: Although skewed to identify individuals with Alport syndrome, these findings support the need to improve access to genetic testing for patients with CKD-particularly in the context of family history of kidney disease, hematuria, and hearing loss.

Hedgehog signaling plays a conserved role in inhibiting fat formation.

Hedgehog (Hh) signals regulate invertebrate and vertebrate development, yet the role of the cascade in adipose development was undefined. To analyze a potential function, we turned to Drosophila and mammalian models. Fat-body-specific transgenic activation of Hh signaling inhibits fly fat formation. Conversely, fat-body-specific Hh blockade stimulated fly fat formation. In mammalian models, sufficiency and necessity tests showed that Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARgamma, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2. These data support the notion that Hh signaling plays a conserved role, from invertebrates to vertebrates, in inhibiting fat formation and highlighting the potential of the Hh pathway as a therapeutic target for osteoporosis, lipodystrophy, diabetes, and obesity.

Non-Invasive Functional-Brain-Imaging with an OPM-based Magnetoencephalography System.

A non-invasive functional-brain-imaging system based on optically-pumped-magnetometers (OPM) is presented. The OPM-based magnetoencephalography (MEG) system features 20 OPM channels conforming to the subject's scalp. We have conducted two MEG experiments on three subjects: assessment of somatosensory evoked magnetic field (SEF) and auditory evoked magnetic field (AEF) using our OPM-based MEG system and a commercial MEG system based on superconducting quantum interference devices (SQUIDs). We cross validated the robustness of our system by calculating the distance between the location of the equivalent current dipole (ECD) yielded by our OPM-based MEG system and the ECD location calculated by the commercial SQUID-based MEG system. We achieved sub-centimeter accuracy for both SEF and AEF responses in all three subjects. Due to the proximity (12 mm) of the OPM channels to the scalp, it is anticipated that future OPM-based MEG systems will offer enhanced spatial resolution as they will capture finer spatial features compared to traditional MEG systems employing SQUIDs.

A 20-channel magnetoencephalography system based on optically pumped magnetometers.

We describe a multichannel magnetoencephalography (MEG) system that uses optically pumped magnetometers (OPMs) to sense the magnetic fields of the human brain. The system consists of an array of 20 OPM channels conforming to the human subject's head, a person-sized magnetic shield containing the array and the human subject, a laser system to drive the OPM array, and various control and data acquisition systems. We conducted two MEG experiments: auditory evoked magnetic field and somatosensory evoked magnetic field, on three healthy male subjects, using both our OPM array and a 306-channel Elekta-Neuromag superconducting quantum interference device (SQUID) MEG system. The described OPM array measures the tangential components of the magnetic field as opposed to the radial component measured by most SQUID-based MEG systems. Herein, we compare the results of the OPM- and SQUID-based MEG systems on the auditory and somatosensory data recorded in the same individuals on both systems.

The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors.

Mutations in ric-3 (resistant to inhibitors of cholinesterase) suppress the neuronal degenerations caused by a gain of function mutation in the Caenorhabditis elegans DEG-3 acetylcholine receptor. RIC-3 is a novel protein with two transmembrane domains and extensive coiled-coil domains. It is expressed in both muscles and neurons, and the protein is concentrated within the cell bodies. We demonstrate that RIC-3 is required for the function of at least four nicotinic acetylcholine receptors. However, GABA and glutamate receptors expressed in the same cells are unaffected. In ric-3 mutants, the DEG-3 receptor accumulates in the cell body instead of in the cell processes. Moreover, co-expression of ric-3 in Xenopus laevis oocytes enhances the activity of the C.elegans DEG-3/DES-2 and of the rat alpha-7 acetylcholine receptors. Together, these data suggest that RIC-3 is specifically required for the maturation of acetylcholine receptors.