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The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell-cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: BUDA-cEPI has been shown to achieve high-quality, high-resolution diffusion magnetic resonance imaging (dMRI) with fast acquisition time, particularly when used in conjunction with S-LORAKS reconstruction. However, this comes at a cost of more complex reconstruction that is computationally prohibitive. In this work we develop rapid reconstruction pipeline for BUDA-cEPI to pave the way for its deployment in routine clinical and neuroscientific applications. The proposed reconstruction includes the development of ML-based unrolled reconstruction as well as rapid ML-based B0 and eddy current estimations that are needed. The architecture of the unroll network was designed so that it can mimic S-LORAKS regularization well, with the addition of virtual coil channels., Methods: BUDA-cEPI RUN-UP - a model-based framework that incorporates off-resonance and eddy current effects was unrolled through an artificial neural network with only six gradient updates. The unrolled network alternates between data consistency (i.e., forward BUDA-cEPI and its adjoint) and regularization steps where U-Net plays a role as the regularizer. To handle the partial Fourier effect, the virtual coil concept was also introduced into the reconstruction to effectively take advantage of the smooth phase prior and trained to predict the ground-truth images obtained by BUDA-cEPI with S-LORAKS., Results: The introduction of the Virtual Coil concept into the unrolled network was shown to be key to achieving high-quality reconstruction for BUDA-cEPI. With the inclusion of an additional non-diffusion image (b-value = 0 s/mm 2 ), a slight improvement was observed, with the normalized root mean square error further reduced by approximately 5 %. The reconstruction times for S-LORAKS and the proposed unrolled networks were approximately 225 and 3 s per slice, respectively., Conclusion: BUDA-cEPI RUN-UP was shown to reduce the reconstruction time by ~88× when compared to the state-of-the-art technique, while preserving imaging details as demonstrated through DTI application., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this publication., (Copyright © 2024. Published by Elsevier Inc.)

The study of neurodegenerative diseases, particularly tauopathies like Pick's disease (PiD) and Alzheimer's disease (AD), offers insights into the underlying regulatory mechanisms. By investigating epigenomic variations in these conditions, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched non-coding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine-mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database (http://swaruplab.bio.uci.edu/scROAD) to visualize predicted single-cell TF occupancy and regulatory networks., Competing Interests: COMPETING FINANCIAL INTERESTS The authors declare no competing interests.

Background: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients., Methods: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK)., Findings: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing., Conclusions: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients., Funding: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center., Competing Interests: Declaration of interests L.B.D., A.L., R.L., and G.T. have a provisional patent regarding this work. C.M.C. is an employee at Agilent Technologies. B.M.W. has received institutional research support from Celgene, Eli Lilly, Novartis, and Revolution Medicines; B.M.W. also consults for Celgene, GRAIL, and Mirati Therapeutics outside the described work. D.A.R. is an advisor for Axial Therapeutics (2022–present). He has consulted for Augmenix (2017–2019), Boston Scientific (2020–2021), Instylla (2022–present), Taiho (2023), and SirTex (2023). Complete details for R.L. can be found at the following link: https://www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0. Complete details of all relationships for profit and not for profit for G.T. can be found at the following link. https://www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

The agonist-antagonist myoneural interface (AMI) is an amputation surgery that preserves sensorimotor signaling mechanisms of the central-peripheral nervous systems. Our first neuroimaging study investigating AMI subjects conducted by Srinivasan et al. (2020) focused on task-based neural signatures, and showed evidence of proprioceptive feedback to the central nervous system. The study of resting state neural activity helps non-invasively characterize the neural patterns that prime task response. In this study on resting state functional magnetic resonance imaging in AMI subjects, we compared functional connectivity in patients with transtibial AMI (n = 12) and traditional (n = 7) amputations (TA). To test our hypothesis that we would find significant neurophysiological differences between AMI and TA subjects, we performed a whole-brain exploratory analysis to identify a seed region; namely, we conducted ANOVA, followed by t-test statistics to locate a seed in the salience network. Then, we implemented a seed-based connectivity analysis to gather cluster-level inferences contrasting our subject groups. We show evidence supporting our hypothesis that the AMI surgery induces functional network reorganization resulting in a neural configuration that significantly differs from the neural configuration after TA surgery. AMI subjects show significantly less coupling with regions functionally dedicated to selecting where to focus attention when it comes to salient stimuli. Our findings provide researchers and clinicians with a critical mechanistic understanding of the effect of AMI amputation on brain networks at rest, which has promising implications for improved neurorehabilitation and prosthetic control., (© 2024. The Author(s).)

Purpose: This study aims to develop a high-resolution whole-brain multi-parametric quantitative MRI approach for simultaneous mapping of myelin-water fraction (MWF), T 1 , T 2 , and proton-density (PD), all within a clinically feasible scan time., Methods: We developed 3D visualization of short transverse relaxation time component (ViSTa)-MRF, which combined ViSTa technique with MR fingerprinting (MRF), to achieve high-fidelity whole-brain MWF and T 1 /T 2 /PD mapping on a clinical 3T scanner. To achieve fast acquisition and memory-efficient reconstruction, the ViSTa-MRF sequence leverages an optimized 3D tiny-golden-angle-shuffling spiral-projection acquisition and joint spatial-temporal subspace reconstruction with optimized preconditioning algorithm. With the proposed ViSTa-MRF approach, high-fidelity direct MWF mapping was achieved without a need for multicompartment fitting that could introduce bias and/or noise from additional assumptions or priors., Results: The in vivo results demonstrate the effectiveness of the proposed acquisition and reconstruction framework to provide fast multi-parametric mapping with high SNR and good quality. The in vivo results of 1 mm- and 0.66 mm-isotropic resolution datasets indicate that the MWF values measured by the proposed method are consistent with standard ViSTa results that are 30× slower with lower SNR. Furthermore, we applied the proposed method to enable 5-min whole-brain 1 mm-iso assessment of MWF and T 1 /T 2 /PD mappings for infant brain development and for post-mortem brain samples., Conclusions: In this work, we have developed a 3D ViSTa-MRF technique that enables the acquisition of whole-brain MWF, quantitative T 1 , T 2 , and PD maps at 1 and 0.66 mm isotropic resolution in 5 and 15 min, respectively. This advancement allows for quantitative investigations of myelination changes in the brain., (© 2023 International Society for Magnetic Resonance in Medicine.)

Despite numerous studies in the field of dementia and Alzheimer's disease (AD), a comprehensive understanding of this devastating disease remains elusive. Bulk transcriptomics have provided insights into the underlying genetic factors at a high level. Subsequent technological advancements have focused on single-cell omics, encompassing techniques such as single-cell RNA sequencing and epigenomics, enabling the capture of RNA transcripts and chromatin states at a single cell or nucleus resolution. Furthermore, the emergence of spatial omics has allowed the study of gene responses in the vicinity of amyloid beta plaques or across various brain regions. With the vast amount of data generated, utilizing gene regulatory networks to comprehensively study this disease has become essential. This review delves into some techniques employed in the field of AD, explores the discoveries made using these techniques, and provides insights into the future of the field., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: This study aims to develop a high-efficiency and high-resolution 3D imaging approach for simultaneous mapping of multiple key tissue parameters for routine brain imaging, including T 1 , T 2 , proton density (PD), ADC, and fractional anisotropy (FA). The proposed method is intended for pushing routine clinical brain imaging from weighted imaging to quantitative imaging and can also be particularly useful for diffusion-relaxometry studies, which typically suffer from lengthy acquisition time., Methods: To address challenges associated with diffusion weighting, such as shot-to-shot phase variation and low SNR, we integrated several innovative data acquisition and reconstruction techniques. Specifically, we used M1-compensated diffusion gradients, cardiac gating, and navigators to mitigate phase variations caused by cardiac motion. We also introduced a data-driven pre-pulse gradient to cancel out eddy currents induced by diffusion gradients. Additionally, to enhance image quality within a limited acquisition time, we proposed a data-sharing joint reconstruction approach coupled with a corresponding sequence design., Results: The phantom and in vivo studies indicated that the T 1 and T 2 values measured by the proposed method are consistent with a conventional MR fingerprinting sequence and the diffusion results (including diffusivity, ADC, and FA) are consistent with the spin-echo EPI DWI sequence., Conclusion: The proposed method can achieve whole-brain T 1 , T 2 , diffusivity, ADC, and FA maps at 1-mm isotropic resolution within 10 min, providing a powerful tool for investigating the microstructural properties of brain tissue, with potential applications in clinical and research settings., (© 2023 International Society for Magnetic Resonance in Medicine.)

Postoperative ileus (POI) is the leading cause of prolonged hospital stay after abdominal surgery and is characterized by a functional paralysis of the digestive tract, leading to symptoms such as constipation, vomiting, and functional obstruction. Current treatments are mainly supportive and inefficacious and yield acute side effects. Although electrical stimulation studies have demonstrated encouraging pacing and entraining of the intestinal slow waves, no devices exist today to enable targeted intestinal reanimation. Here, we developed an ingestible self-propelling device for intestinal reanimation (INSPIRE) capable of restoring peristalsis through luminal electrical stimulation. Optimizing mechanical, material, and electrical design parameters, we validated optimal deployment, intestinal electrical luminal contact, self-propelling capability, safety, and degradation of the device in ex vivo and in vivo swine models. We compared the INSPIRE's effect on motility in models of normal and depressed motility and chemically induced ileus. Intestinal contraction improved by 44% in anesthetized animals and up to 140% in chemically induced ileus cases. In addition, passage time decreased from, on average, 8.6 days in controls to 2.5 days with the INSPIRE device, demonstrating significant improvement in motility. Luminal electrical stimulation of the intestine via the INSPIRE efficaciously restored peristaltic activity. This noninvasive option offers a promising solution for the treatment of ileus and other motility disorders.

Millions of people worldwide suffer from low back pain and disability associated with intervertebral disc (IVD) degeneration. IVD degeneration is highly correlated with aging, as the nucleus pulposus (NP) dehydrates and the annulus fibrosus (AF) fissures form, which often results in intervertebral disc herniation or disc space collapse and related clinical symptoms. Currently available options for treating intervertebral disc degeneration are symptoms control with therapy modalities, and/or medication, and/or surgical resection of the IVD with or without spinal fusion. As such, there is an urgent clinical demand for more effective disease-modifying treatments for this ubiquitous disorder, rather than the current paradigms focused only on symptom control. Hydrogels are unique biomaterials that have a variety of distinctive qualities, including (but not limited to) biocompatibility, highly adjustable mechanical characteristics, and most importantly, the capacity to absorb and retain water in a manner like that of native human nucleus pulposus tissue. In recent years, various hydrogels have been investigated in vitro and in vivo for the repair of intervertebral discs, some of which are ready for clinical testing. In this review, we summarize the latest findings and developments in the application of hydrogel technology for the repair and regeneration of intervertebral discs.

3D printed/bioprinted tissue constructs are utilized for the regeneration of damaged tissues and as in vitro models. Most of the fabricated 3D constructs fail to undergo functional maturation in conventional in vitro settings. There is a challenge to provide a suitable niche for the fabricated tissue constructs to undergo functional maturation. Bioreactors have emerged as a promising tool to enhance tissue maturation of the engineered constructs by providing physical/biological cues along with a controlled nutrient supply under dynamic in vitro conditions. Bioreactors provide an ambient microenvironment most appropriate for the development of functionally matured tissue constructs by promoting cell proliferation, differentiation, and maturation for transplantation and drug screening applications. Due to the huge cost and limited availability of commercial bioreactors, there is a need to develop strategies to make customized bioreactors. Additive manufacturing (AM) may be a viable tool to fabricate custom designed bioreactors with better efficiency and at low cost. In this review, we have extensively discussed the importance of bioreactors in functionalizing tissue engineered/3D bioprinted scaffolds for bone, cartilage, skeletal muscle, nerve, and vascular tissue. In addition, the importance and fabrication of customized 3D printed bioreactors for the maturation of tissue engineered constructs are discussed in detail. Finally, the current challenges and future perspectives in translating commercial and custom 3D printed bioreactors for clinical applications are outlined.

Effective therapies for obesity require invasive surgical and endoscopic interventions or high patient adherence, making it challenging for patients with obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. We designed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill, an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release and yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, P < 0.0001) and minimized the weight gain rate ( P < 0.05) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

Background: While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal., Methods: We describe the design and validation of a platform technology for nerve regeneration and interfacing: adaptive, conductive, and electrotherapeutic scaffolds (ACESs). ACESs are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open surgical and minimally invasive percutaneous approaches., Findings: In a rodent model of sciatic nerve repair, ACESs significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACESs enabled atraumatic, percutaneous removal of leads at forces significantly lower than controls (p < 0.05). In a porcine model, ultrasound-guided percutaneous placement of leads with an injectable ACES near the femoral and cervical vagus nerves facilitated stimulus conduction at significantly greater lengths than saline controls (p < 0.05)., Conclusion: Overall, ACESs facilitated lead placement, stabilization, stimulation, and atraumatic removal, enabling therapeutic PNS as demonstrated in small- and large-animal models., Funding: This work was supported by K. Lisa Yang Center for Bionics at MIT., Competing Interests: Declaration of interests S.S., L.G., P.K., A.S., R.L., and G.T. report a provisional patent application (63/240,061) describing the ACES system. Complete details of all relationships for profit and not for profit for G.T. can be found at the following link: https://dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0. Complete details for R.L. can be found at the following link: https://dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0. A.S. was chief medical officer and on the board of CareSignal Health, a digital health company, unrelated to the current work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To develop a high-fidelity diffusion MRI acquisition and reconstruction framework with reduced echo-train-length for less T 2 * image blurring compared to typical highly accelerated echo-planar imaging (EPI) acquisitions at sub-millimeter isotropic resolution., Methods: We first proposed a circular-EPI trajectory with partial Fourier sampling on both the readout and phase-encoding directions to minimize the echo-train-length and echo time. We then utilized this trajectory in an interleaved two-shot EPI acquisition with reversed phase-encoding polarity, to aid in the correction of off-resonance-induced image distortions and provide complementary k-space coverage in the missing partial Fourier regions. Using model-based reconstruction with structured low-rank constraint and smooth phase prior, we corrected the shot-to-shot phase variations across the two shots and recover the missing k-space data. Finally, we combined the proposed acquisition/reconstruction framework with an SNR-efficient RF-encoded simultaneous multi-slab technique, termed gSlider, to achieve high-fidelity 720 µm and 500 µm isotropic resolution in-vivo diffusion MRI., Results: Both simulation and in-vivo results demonstrate the effectiveness of the proposed acquisition and reconstruction framework to provide distortion-corrected diffusion imaging at the mesoscale with markedly reduced T 2 *-blurring. The in-vivo results of 720 µm and 500 µm datasets show high-fidelity diffusion images with reduced image blurring and echo time using the proposed approaches., Conclusions: The proposed method provides high-quality distortion-corrected diffusion-weighted images with ∼40% reduction in the echo-train-length and T 2 * blurring at 500µm-isotropic-resolution compared to standard multi-shot EPI., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Localization and tracking of ingestible microdevices in the gastrointestinal (GI) tract is valuable for the diagnosis and treatment of GI disorders. Such systems require a large field-of-view of tracking, high spatiotemporal resolution, wirelessly operated microdevices and a non-obstructive field generator that is safe to use in practical settings. However, the capabilities of current systems remain limited. Here, we report three dimensional (3D) localization and tracking of wireless ingestible microdevices in the GI tract of large animals in real time and with millimetre-scale resolution. This is achieved by generating 3D magnetic field gradients in the GI field-of-view using high-efficiency planar electromagnetic coils that encode each spatial point with a distinct magnetic field magnitude. The field magnitude is measured and transmitted by the miniaturized, low-power and wireless microdevices to decode their location as they travel through the GI tract. This system could be useful for quantitative assessment of the GI transit-time, precision targeting of therapeutic interventions and minimally invasive procedures., Competing Interests: Competing interests S.S., M.G.S. and A.E. have joint US patents (20,210,137,412 and 11,457,835 B2) on the localization and magnetic-field generation concepts. M.G.S. and A.E. are founding members of Tychon Technologies. All the other authors declare no competing interests.

MicroRNAs (miRNAs - ~22 nucleotides) are a type of non-coding RNAs that are involved in post-transcriptional gene silencing. They are known to regulate gene expression in diverse biological processes, such as apoptosis, development, and differentiation. Several studies have demonstrated that cancer initiation and progression are highly regulated by miRNA expression. The nutrients present in the diet may regulate the different stages of carcinogenesis. Interestingly, plant-based foods, like fruits and vegetables, have been shown to play a significant role in cancer prevention. Phytochemicals are bioactive compounds derived from plant sources, and they have been shown to have antiinflammatory, antioxidant, and anticancer properties. Recent findings suggest that dietary phytochemicals, such as genistein, resveratrol, and curcumin, exert significant anticancer effects by regulating various miRNAs. In this review, we focus on the role of dietary phytochemicals in cancer prevention and treatment through the modulation of miRNA expression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The evaluation of the tone and contractile patterns of the gastrointestinal (GI) tract via manometry is essential for the diagnosis of GI motility disorders. However, manometry is expensive and relies on complex and bulky instrumentation. Here we report the development and performance of an inexpensive and easy-to-manufacture catheter-like device for capturing manometric data across the dynamic range observed in the human GI tract. The device, which we designed to resemble the quipu-knotted strings used by Andean civilizations for the capture and transmission of information-consists of knotted piezoresistive pressure sensors made by infusing a liquid metal (eutectic gallium-indium) through thin silicone tubing. By exploring a range of knotting configurations, we identified optimal design schemes that led to sensing performances comparable to those of commercial devices for GI manometry, as we show for the sensing of GI motility in multiple anatomic sites of the GI tract of anaesthetized pigs. Disposable and customizable piezoresistive catheters may broaden the use of GI manometry in low-resource settings., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Oral drug delivery of proteins is limited by the degradative environment of the gastrointestinal tract and poor absorption, requiring parenteral administration of these drugs. Luminal mucus represents the initial steric and dynamic barrier to absorption. To overcome this barrier, we report the development of the RoboCap, an orally ingestible, robotic drug delivery capsule that locally clears the mucus layer, enhances luminal mixing, and topically deposits the drug payload in the small intestine to enhance drug absorption. RoboCap's mucus-clearing and churning movements are facilitated by an internal motor and by surface features that interact with small intestinal plicae circulares, villi, and mucus. Vancomycin (1.4 kilodaltons of glycopeptide) and insulin (5.8 kilodaltons of peptide) delivery mediated by RoboCap resulted in enhanced bioavailability 20- to 40-fold greater in ex vivo and in vivo swine models when compared with standard oral delivery ( P  < 0.05). Further, insulin delivery via the RoboCap resulted in therapeutic hypoglycemia, supporting its potential to facilitate oral delivery of drugs that are normally precluded by absorption limitations.

Background: Elucidating underlying mechanisms in subject-specific motor control and perception after amputation could guide development of advanced surgical and neuroprosthetic technologies. In this study, relationships between preserved agonist-antagonist muscle strain within the residual limb and preserved motor control and perception capacity are investigated., Methods: Fourteen persons with unilateral transtibial amputations spanning a range of ages, etiologies, and surgical procedures underwent evaluations involving free-space mirrored motions of their lower limbs. Research has shown that varied motor control in biologically intact limbs is executed by the activation of muscle synergies. Here, we assess the naturalness of phantom joint motor control postamputation based on extracted muscle synergies and their activation profiles. Muscle synergy extraction, degree of agonist-antagonist muscle strain, and perception capacity are estimated from electromyography, ultrasonography, and goniometry, respectively., Results: Here, we show significant positive correlations ( P  < 0.005-0.05) between sensorimotor responses and residual limb agonist-antagonist muscle strain. Identified trends indicate that preserving even 20-26% of agonist-antagonist muscle strain within the residuum compared to a biologically intact limb is effective in preserving natural motor control postamputation, though preserving limb perception capacity requires more (61%) agonist-antagonist muscle strain preservation., Conclusions: The results suggest that agonist-antagonist muscle strain is a characteristic, readily ascertainable residual limb structural feature that can help explain variability in amputation outcome, and agonist-antagonist muscle strain preserving surgical amputation strategies are one way to enable more effective and biomimetic sensorimotor control postamputation., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Purpose: To improve image quality and accelerate the acquisition of 3D MR fingerprinting (MRF)., Methods: Building on the multi-axis spiral-projection MRF technique, a subspace reconstruction with locally low-rank constraint and a modified spiral-projection spatiotemporal encoding scheme called tiny golden-angle shuffling were implemented for rapid whole-brain high-resolution quantitative mapping. Reconstruction parameters such as the locally low-rank regularization parameter and the subspace rank were tuned using retrospective in vivo data and simulated examinations. B 0 inhomogeneity correction using multifrequency interpolation was incorporated into the subspace reconstruction to further improve the image quality by mitigating blurring caused by off-resonance effect., Results: The proposed MRF acquisition and reconstruction framework yields high-quality 1-mm isotropic whole-brain quantitative maps in 2 min at better quality compared with 6-min acquisitions of prior approaches. The proposed method was validated to not induce bias in T 1 and T 2 mapping. High-quality whole-brain MRF data were also obtained at 0.66-mm isotropic resolution in 4 min using the proposed technique, where the increased resolution was shown to improve visualization of subtle brain structures., Conclusions: The proposed tiny golden-angle shuffling, MRF with optimized spiral-projection trajectory and subspace reconstruction enables high-resolution quantitative mapping in ultrafast acquisition time., (© 2022 International Society for Magnetic Resonance in Medicine.)

Recent advances in single-cell transposase-accessible chromatin using a sequencing assay (scATAC-seq) allow cellular heterogeneity dissection and regulatory landscape reconstruction with an unprecedented resolution. However, compared to bulk-sequencing, its ultra-high missingness remarkably reduces usable reads in each cell type, resulting in broader, fuzzier peak boundary definitions and limiting our ability to pinpoint functional regions and interpret variant impacts precisely. We propose a weakly supervised learning method, scEpiLock, to directly identify core functional regions from coarse peak labels and quantify variant impacts in a cell-type-specific manner. First, scEpiLock uses a multi-label classifier to predict chromatin accessibility via a deep convolutional neural network. Then, its weakly supervised object detection module further refines the peak boundary definition using gradient-weighted class activation mapping (Grad-CAM). Finally, scEpiLock provides cell-type-specific variant impacts within a given peak region. We applied scEpiLock to various scATAC-seq datasets and found that it achieves an area under receiver operating characteristic curve (AUC) of ~0.9 and an area under precision recall (AUPR) above 0.7. Besides, scEpiLock's object detection condenses coarse peaks to only ⅓ of their original size while still reporting higher conservation scores. In addition, we applied scEpiLock on brain scATAC-seq data and reported several genome-wide association studies (GWAS) variants disrupting regulatory elements around known risk genes for Alzheimer's disease, demonstrating its potential to provide cell-type-specific biological insights in disease studies.

Mapping chromatin insulator loops is crucial to investigating genome evolution, elucidating critical biological functions, and ultimately quantifying variant impact in diseases. However, chromatin conformation profiling assays are usually expensive, time-consuming, and may report fuzzy insulator annotations with low resolution. Therefore, we propose a weakly supervised deep learning method, InsuLock, to address these challenges. Specifically, InsuLock first utilizes a Siamese neural network to predict the existence of insulators within a given region (up to 2000 bp). Then, it uses an object detection module for precise insulator boundary localization via gradient-weighted class activation mapping (~40 bp resolution). Finally, it quantifies variant impacts by comparing the insulator score differences between the wild-type and mutant alleles. We applied InsuLock on various bulk and single-cell datasets for performance testing and benchmarking. We showed that it outperformed existing methods with an AUROC of ~0.96 and condensed insulator annotations to ~2.5% of their original size while still demonstrating higher conservation scores and better motif enrichments. Finally, we utilized InsuLock to make cell-type-specific variant impacts from brain scATAC-seq data and identified a schizophrenia GWAS variant disrupting an insulator loop proximal to a known risk gene, indicating a possible new mechanism of action for the disease.

Implantable and ingestible biomedical electronic devices can be useful tools for detecting physiological and pathophysiological signals, and providing treatments that cannot be done externally. However, one major challenge in the development of these devices is the limited lifetime of their power sources. The state-of-the-art of powering technologies for implantable and ingestible electronics is reviewed here. The structure and power requirements of implantable and ingestible biomedical electronics are described to guide the development of powering technologies. These powering technologies include novel batteries that can be used as both power sources and for energy storage, devices that can harvest energy from the human body, and devices that can receive and operate with energy transferred from exogenous sources. Furthermore, potential sources of mechanical, chemical, and electromagnetic energy present around common target locations of implantable and ingestible electronics are thoroughly analyzed; energy harvesting and transfer methods befitting each energy source are also discussed. Developing power sources that are safe, compact, and have high volumetric energy densities is essential for realizing long-term in-body biomedical electronics and for enabling a new era of personalized healthcare., Competing Interests: Conflict of Interest G. T. is a co-inventor on multiple patent applications involving energy harvesting systems as well as systems involving electronics for therapeutic applications. G.T. reports receiving consulting fees from Novo Nordisk, Verily, Merck. G.T. has a financial interest in Lyndra Therapeutics, Suono Bio and Celero Systems which are all biotechnology companies developing therapeutics via the gastrointestinal tract which can include electronics in some embodiments. Complete details of all relationships for profit and not for profit for G.T. can found at the following link: https://www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0.

We live in an era of wearable sensing, where our movement through the world can be continuously monitored by devices. Yet, we lack a portable sensor that can continuously monitor muscle, tendon, and bone motion, allowing us to monitor performance, deliver targeted rehabilitation, and provide intuitive, reflexive control over prostheses and exoskeletons. Here, we introduce a sensing modality, magnetomicrometry, that uses the relative positions of implanted magnetic beads to enable wireless tracking of tissue length changes. We demonstrate real-time muscle length tracking in an in vivo turkey model via chronically implanted magnetic beads while investigating accuracy, biocompatibility, and long-term implant stability. We anticipate that this tool will lay the groundwork for volitional control over wearable robots via real-time tracking of muscle lengths and speeds. Further, to inform future biomimetic control strategies, magnetomicrometry may also be used in the in vivo tracking of biological tissues to elucidate biomechanical principles of animal and human movement., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: We combine SNR-efficient acquisition and model-based reconstruction strategies with newly available hardware instrumentation to achieve distortion-free in vivo diffusion MRI of the brain at submillimeter-isotropic resolution with high fidelity and sensitivity on a clinical 3T scanner., Methods: We propose blip-up/down acquisition (BUDA) for multishot EPI using interleaved blip-up/blip-down phase encoding and incorporate B 0 forward-modeling into structured low-rank reconstruction to enable distortion-free and navigator-free diffusion MRI. We further combine BUDA-EPI with an SNR-efficient simultaneous multislab acquisition (generalized slice-dithered enhanced resolution ["gSlider"]), to achieve high-isotropic-resolution diffusion MRI. To validate gSlider BUDA-EPI, whole-brain diffusion data at 860-μm and 780-μm data sets were acquired. Finally, to improve the conditioning and minimize noise penalty in BUDA reconstruction at very high resolutions where B 0 inhomogeneity can have a detrimental effect, the level of B 0 inhomogeneity was reduced by incorporating slab-by-slab dynamic shimming with a 32-channel AC/DC coil into the acquisition. Whole-brain 600-μm diffusion data were then acquired with this combined approach of gSlider BUDA-EPI with dynamic shimming., Results: The results of 860-μm and 780-μm datasets show high geometry fidelity with gSlider BUDA-EPI. With dynamic shimming, the BUDA reconstruction's noise penalty was further alleviated. This enables whole-brain 600-μm isotropic resolution diffusion imaging with high image quality., Conclusions: The gSlider BUDA-EPI method enables high-quality, distortion-free diffusion imaging across the whole brain at submillimeter resolution, where the use of multicoil dynamic B 0 shimming further improves reconstruction performance, which can be particularly useful at very high resolutions., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background: Masseter vestibular evoked myogenic potential (mVEMP) is a recent tool for the assessment of vestibular and trigeminal pathways. Though a few studies have recorded mVEMP using click stimuli, there are no reports of these potentials using the more conventional VEMP eliciting stimuli, the tone bursts., Purpose: The aim of the study is to establish normative values and determine the test-retest reliability of tone burst evoked mVEMP., Research Design: The research design type is normative study design., Study Sample: Forty-four healthy participants without hearing and vestibular deficits in the age range of 18 to 50 years participated in the study., Data Collection and Analysis: All participants underwent mVEMP testing using 500 Hz tone-burst stimuli at 125 dB peSPL. Ten participants underwent second mVEMP testing within 1 month of the initial testing to estimate the test-retest reliability., Results: Tone burst mVEMP showed robust responses in all participants. There were no significant ear and sex differences on any mVEMP parameter ( p  > 0.05); however, males had significantly higher EMG normalized peak-to-peak amplitude than females. Intraclass correlation coefficient (ICC) values of tone burst mVEMP showed excellent test-retest reliability (ICC >0.75) for ipsilateral and contralateral p11 latency, ipsilateral EMG normalized p11-n21 peak to peak amplitude, and amplitude asymmetry ratio. Fair and good test-retest reliability (0.4 < ICC > 0.75) was observed for ipsilateral and contralateral n21 latency, contralateral EMG normalized peak-to-peak amplitude, and amplitude asymmetry ratio., Conclusion: Tone burst mVEMP is a robust and reliable test for evaluating the functional integrity of the vestibulomasseteric reflex pathway., Competing Interests: None declared., (American Academy of Audiology. This article is published by Thieme.)

Healthcare innovation is impeded by high costs, the need for diverse skillsets, and complex regulatory processes. The COVID-19 pandemic exposed critical gaps in the current framework, especially those lying at the boundary between cutting-edge academic research and industry-scale manufacturing and production. While many resource-rich geographies were equipped with the required expertise to solve challenges posed by the pandemic, mechanisms to unite the appropriate institutions and scale up, fund, and mobilize solutions at a time-scale relevant to the emergency were lacking. We characterize the orthogonal spatial and temporal axes that dictate innovation. Improving on their limitations, we propose a "pre-emptive innovation infrastructure" incorporating in-house hospital innovation teams, consortia-based assembly of expertise, and novel funding mechanisms to combat future emergencies. By leveraging the strengths of academic, medical, government, and industrial institutions, this framework could improve ongoing innovation and supercharge the infrastructure for healthcare emergencies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramadi and Srinivasan.)

Despite advancements in prosthetic technologies, patients with amputation today suffer great diminution in mobility and quality of life. We have developed a modified below-knee amputation (BKA) procedure that incorporates agonist-antagonist myoneural interfaces (AMIs), which surgically preserve and couple agonist-antagonist muscle pairs for the subtalar and ankle joints. AMIs are designed to restore physiological neuromuscular dynamics, enable bidirectional neural signaling, and offer greater neuroprosthetic controllability compared to traditional amputation techniques. In this prospective, nonrandomized, unmasked study design, 15 subjects with AMI below-knee amputation (AB) were matched with 7 subjects who underwent a traditional below-knee amputation (TB). AB subjects demonstrated significantly greater control of their residual limb musculature, production of more differentiable efferent control signals, and greater precision of movement compared to TB subjects ( P < 0.008). This may be due to the presence of greater proprioceptive inputs facilitated by the significantly higher fascicle strains resulting from coordinated muscle excursion in AB subjects ( P < 0.05). AB subjects reported significantly greater phantom range of motion postamputation (AB: 12.47 ± 2.41, TB: 10.14 ± 1.45 degrees) when compared to TB subjects ( P < 0.05). Furthermore, AB subjects also reported less pain (12.25 ± 5.37) than TB subjects (17.29 ± 10.22) and a significant reduction when compared to their preoperative baseline ( P < 0.05). Compared with traditional amputation, the construction of AMIs during amputation confers the benefits of enhanced physiological neuromuscular dynamics, proprioception, and phantom limb perception. Subjects' activation of the AMIs produces more differentiable electromyography (EMG) for myoelectric prosthesis control and demonstrates more positive clinical outcomes., Competing Interests: Competing interest statement: H.M.H., M.J.C., and S.S.S. hold a patent related to AMI surgical amputation procedures., (Copyright © 2021 the Author(s). Published by PNAS.)

Competing Interests: Conflicts of interest: Dr. Herr has a consulting relationship with Ottobock. Drs. Herr and Carty are inventors on an issued patent describing the AMI concept. Drs. Herr, Carty, Clites, and Srinivasan are inventors on a pending patent describing the Ewing procedure. MIT holds both patents. None of the other authors has a financial interest in any of the products, devices, or drugs mentioned in this article.

The brain undergoes marked changes in function and functional connectivity after limb amputation. The agonist-antagonist myoneural interface (AMI) amputation is a procedure that restores physiological agonist-antagonist muscle relationships responsible for proprioceptive sensory feedback to enable greater motor control. We compared results from the functional neuroimaging of individuals ( n = 29) with AMI amputation, traditional amputation, and no amputation. Individuals with traditional amputation demonstrated a significant decrease in proprioceptive activity, measured by activation of Brodmann area 3a, whereas functional activation in individuals with AMIs was not significantly different from controls with no amputation ( P < 0.05). The degree of proprioceptive activity in the brain strongly correlated with fascicle activity in the peripheral muscles and performance on motor tasks ( P < 0.05), supporting the mechanistic basis of the AMI procedure. These results suggest that surgical techniques designed to restore proprioceptive peripheral neuromuscular constructs result in desirable central sensorimotor plasticity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

High-quality Quantitative Susceptibility Mapping (QSM) with Nonlinear Dipole Inversion (NDI) is developed with pre-determined regularization while matching the image quality of state-of-the-art reconstruction techniques and avoiding over-smoothing that these techniques often suffer from. NDI is flexible enough to allow for reconstruction from an arbitrary number of head orientations and outperforms COSMOS even when using as few as 1-direction data. This is made possible by a nonlinear forward-model that uses the magnitude as an effective prior, for which we derived a simple gradient descent update rule. We synergistically combine this physics-model with a Variational Network (VN) to leverage the power of deep learning in the VaNDI algorithm. This technique adopts the simple gradient descent rule from NDI and learns the network parameters during training, hence requires no additional parameter tuning. Further, we evaluate NDI at 7 T using highly accelerated Wave-CAIPI acquisitions at 0.5 mm isotropic resolution and demonstrate high-quality QSM from as few as 2-direction data., (© 2020 John Wiley & Sons, Ltd.)

The field of electroceuticals has attracted considerable attention over the past few decades as a novel therapeutic modality. The gastrointestinal (GI) tract (GIT) holds significant potential as a target for electroceuticals as the intersection of neural, endocrine, and immune systems. We review recent developments in electrical stimulation of various portions of the GIT (including esophagus, stomach, and small and large intestine) and nerves projecting to the GIT and supportive organs. This has been tested with varying degrees of success for several dysmotility, inflammatory, hormonal, and neurologic disorders. We outline a vision for the future of GI electroceuticals, building on advances in mechanistic understanding of GI physiology coupled with novel ingestible technologies. The next wave of electroceutical therapies will be minimally invasive and more targeted than current approaches, making them an indispensable tool in the clinical armamentarium., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Strategies to split ventilators to support multiple patients requiring ventilatory support have been proposed and used in emergency cases in which shortages of ventilators cannot otherwise be remedied by production or procurement strategies. However, the current approaches to ventilator sharing lack the ability to individualize ventilation to each patient, measure pulmonary mechanics, and accommodate rebalancing of the airflow when one patient improves or deteriorates, posing safety concerns to patients. Potential cross-contamination, lack of alarms, insufficient monitoring, and inability to adapt to sudden changes in patient status have prevented widespread acceptance of ventilator sharing. We have developed an individualized system for augmenting ventilator efficacy (iSAVE) as a rapidly deployable platform that uses a single ventilator to simultaneously and more safely support two individuals. The iSAVE enables individual-specific volume and pressure control and the rebalancing of ventilation in response to improvement or deterioration in an individual's respiratory status. The iSAVE incorporates mechanisms to measure pulmonary mechanics, mitigate cross-contamination and backflow, and accommodate sudden flow changes due to individual interdependencies within the respiratory circuit. We demonstrate these capacities through validation using closed- and open-circuit ventilators on linear test lungs. We show that the iSAVE can temporarily ventilate two pigs on one ventilator as efficaciously as each pig on its own ventilator. By leveraging off-the-shelf medical components, the iSAVE could rapidly expand the ventilation capacity of health care facilities during emergency situations such as pandemics., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To assess how staff attitudes before, during, and after implementation of a real-time location system (RTLS) that uses radio-frequency identification tags on staff and patient identification badges and on equipment affected staff's intention to use and actual use of an RTLS., Participants and Methods: A series of 3 online surveys were sent to staff at an emergency department with plans to implement an RTLS between June 1, 2015, and November 29, 2016. Each survey corresponded with a different phase of implementation: preimplementation, midimplementation, and postimplementation. Multiple logistic regression with backward elimination was used to assess the relationship between demographic variables, attitudes about RTLSs, and intention to use or actual use of an RTLS., Results: Demographic variables were not associated with intention to use or actual use of the RTLS. Before implementation, poor perceptions about the technology's usefulness and lack of trust in how employers would use tracking data were associated with weaker intentions to use the RTLS. During and after implementation, attitudes about the technology's use, not issues related to autonomy and privacy, were associated with less use of the technology., Conclusion: Real-time location systems have the potential to assess patterns of health care delivery that could be modified to reduce costs and improve the quality of care. Successful implementation, however, may hinge on how staff weighs attitudes and concerns about their autonomy and personal privacy with organizational goals. With the large investments required for new technology, serious consideration should be given to address staff attitudes about privacy and technology in order to assure successful implementation., (© 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Background: Traditional approaches to amputation are not capable of reproducing the dynamic muscle relationships that are essential for proprioceptive sensation and joint control. In this study, the authors present two caprine models of the agonist-antagonist myoneural interface (AMI), a surgical approach designed to improve bidirectional neural control of a bionic limb. The key advancement of the AMI is the surgical coaptation of natively innervated agonist-antagonist muscle pairs within the residual limb., Methods: One AMI was surgically created in the hindlimb of each of two African Pygmy goats at the time of primary transtibial amputation. Each animal was also implanted with muscle electrodes and sonomicrometer crystals to enable measurement of muscle activation and muscle state, respectively. Coupled agonist-antagonist excursion in the agonist-antagonist myoneural interface muscles was measured longitudinally for each animal. Fibrosis in the residual limb was evaluated grossly in each animal as part of a planned terminal procedure., Results: Electromyographic and muscle state measurements showed coupled agonist-antagonist motion within the AMI in the presence of both neural activation and artificial muscle stimulation. Gross observation of the residual limb during a planned terminal procedure revealed a thin fibrotic encapsulation of the AMI constructs, which was not sufficient to preclude coupled muscle excursion., Conclusions: These findings highlight the AMI's potential to provide coupled motion of distal agonist-antagonist muscle pairs preserved during below- or above-knee amputation at nearly human scale. Guided by these findings, it is the authors' expectation that further development of the AMI architecture will improve neural control of advanced limb prostheses through incorporation of physiologically relevant muscle-tendon proprioception.

Introduction: Gliomas are the most common brain tumors in adults originating from the glial cells. Glioblastoma multiforme is the most malignant and frequent among all gliomas. In recent years, the antibody Mindbomb Homolog-1 (MIB-1) has evolved as a measure of the proliferative nature of the glial tumors. This study aims to investigate the MIB-1 index value as an independent prognostic factor in high-grade gliomas and its correlation with outcome and survival., Materials and Methods: Mean MIB-1 index was determined in 51 high-grade glioma tissue samples in formalin. Its correlation with outcome by assessing the clinicoradiological parameters and median survival of patients in months were assessed. Survival analysis was studied by using the Kaplan-Meier bivariate analysis and Cox proportional ratio., Results: Preoperative Karnofsky Performance Score, WHO-PS, Neurological Performance Scale, and Mini-Mental Status Examination (MMSE) were statistically significant with respect to outcome and survival, whereas tumor factors such as size and perilesional edema were not. In particular, midline-crossing tumors and deep-seated tumors were significantly associated with high MIB-1 index and by correlation with outcome. There were significantly higher number ( P < 0.0001) of patients with Grade IV tumors, with an MIB-1 index value above an arbitrary cutoff of 10% compared to Grade III tumors. In addition, median survival period of patients with low MIB-1 index was longer irrespective of tumor grade., Conclusion: Significant correlation between high-grade glioma and MIB-1 index suggests MIB-1 index to be a good prognostic tool, with MIB-1 index and midline-crossing variables being independent prognostic parameters., Competing Interests: There are no conflicts of interest.

While amputation has traditionally been viewed as a failure of therapy, recent developments in amputation surgery and neural interfacing demonstrate improved functionality and bidirectional communication with prosthetic devices. The agonist antagonist myoneural interface (AMI) is one such bi-directional neural communication model comprised of two muscles, an agonist and an antagonist, surgically connected in series within the amputated residuum such that contraction of one muscle stretches the other. By preserving agonist-antagonist muscle dynamics, the AMI allows proprioceptive signals from mechanoreceptors within both muscles to be communicated to the central nervous system. Preliminary human evidence suggests that AMIs have the capacity to provide high fidelity control of a prosthetic device, force feedback, and natural proprioception. However, AMIs have been implemented only in planned amputations and require healthy distal tissues, whereas the majority of amputations occur in patients who do not have healthy distal tissues. Through the use of a dual-stage surgical procedure which leverages existent tissues, this study proposes a revision model for implementation of the AMI in patients who are undergoing traumatic amputation or have already undergone a standard amputation. This paper validates the resulting AMI's physiology, revealing robust viability and mechanical and electrophysiological function. We demonstrate the presence of H-waves in regenerative grafts, indicating the incorporation of the AMI into physiological reflexive loops.

Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies., Competing Interests: The authors declare no conflict of interest.

Background: The field of infodemiology uses health care trends found in public networks, such as social media, to track and quantify the spread of disease. Type 2 diabetes is on the rise worldwide, and social media may be useful in identifying prediabetes through behavior exhibited through social media platforms such as Facebook and thus in designing and administering early interventions and containing further progression of the disease., Objective: This pilot study is designed to investigate the social media behavior of individuals with prediabetes, before and after diagnosis. Pre- and postdiagnosis Facebook content (posts) of such individuals will be used to create a taxonomy of prediabetes indicators and to identify themes and factors associated with an actual diagnosis of prediabetes., Methods: This is a single-center exploratory retrospective study that examines 20 adults with prediabetes. The investigators will code Facebook posts 3 months before through 3 months after prediabetes diagnosis. Data will be analyzed using both qualitative content analysis methodology as well as quantitative methodology to characterize participants and compare their posts pre- and postdiagnosis., Results: The project was funded for 2015-2018, and enrollment will be completed by the end of 2018. Data coding is currently under way and the first results are expected to be submitted for publication in 2019. Results will include both quantitative and qualitative data about participants and the similarities and differences between coded social media posts., Conclusions: This pilot study is the first step in creating a taxonomy of social media indicators for prediabetes. Such a taxonomy would provide a tool for researchers and health care professionals to use social media postings for identifying those at greater risk of having prediabetes., International Registered Report Identifier (irrid): DERR1-10.2196/10720., (©Xiaomeng Xu, Michelle L Litchman, Perry M Gee, Webb Whatcott, Loni Chacon, John Holmes, Sankara Subramanian Srinivasan. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 14.12.2018.)