Improvement in inpatient discharge planning for patients with alcohol use disorder with the implementation of a team-based multidisciplinary workflow.

BACKGROUND: Alcohol use disorder (AUD) is a major economic and healthcare burden in the United States. While there is evidence-based medication-assisted treatment (MAT) for AUD, few physicians implement these therapies on a regular basis. OBJECTIVE: To determine the impact of a pharmacy-guided AUD discharge planning workflow on the rate of MAT prescriptions and inpatient readmissions. METHODS: This was a single-centered pre-and-post intervention study over a 6-month period, with a 90-day pre-intervention period and a 90-day post-intervention period. The study included all patients over the age of 18 years admitted to a medicine or surgery floor bed who presented with alcohol withdrawal at any point during their hospital course. The intervention involved a pharmacy workflow, in which a list of patients admitted with alcohol withdrawal was automatically generated and referred to pharmacists, who then provided recommendations to the primary physician regarding prescriptions for naltrexone, acamprosate, and/or gabapentin. The patients were then contacted within 30 days after discharge for post-hospitalization follow-up. Our outcome measures were change in prescription rate of MATs, change in total and alcohol-related 90-day readmission rates, and change in total and alcohol-related 90-day emergency department (ED) visit rates. RESULTS: The pre-intervention period consisted of 49 patients and the post-intervention period consisted of 41 patients. Our workflow demonstrated a 195% increase in the prescription rate of MATs at discharge (p < 0.001), 61% reduction in 90-day total readmission rate (p < 0.05), 40% reduction in 90-day total ED visit rate (p = 0.09), 92% reduction in 90-day alcohol-related readmission rate (p < 0.05), and 88% reduction in 90-day alcohol-related ED visit rate (p < 0.05). CONCLUSIONS: Our intervention demonstrated that a pharmacy-based AUD discharge planning workflow has the potential to reduce inpatient readmissions and ED visits for patients with AUD, thus demonstrating improved patient outcomes with the potential to reduce healthcare costs.

Machine learning-directed electrical impedance tomography to predict metabolically vulnerable plaques.

The characterization of atherosclerotic plaques to predict their vulnerability to rupture remains a diagnostic challenge. Despite existing imaging modalities, none have proven their abilities to identify metabolically active oxidized low-density lipoprotein (oxLDL), a marker of plaque vulnerability. To this end, we developed a machine learning-directed electrochemical impedance spectroscopy (EIS) platform to analyze oxLDL-rich plaques, with immunohistology serving as the ground truth. We fabricated the EIS sensor by affixing a six-point microelectrode configuration onto a silicone balloon catheter and electroplating the surface with platinum black (PtB) to improve the charge transfer efficiency at the electrochemical interface. To demonstrate clinical translation, we deployed the EIS sensor to the coronary arteries of an explanted human heart from a patient undergoing heart transplant and interrogated the atherosclerotic lesions to reconstruct the 3D EIS profiles of oxLDL-rich atherosclerotic plaques in both right coronary and left descending coronary arteries. To establish effective generalization of our methods, we repeated the reconstruction and training process on the common carotid arteries of an unembalmed human cadaver specimen. Our findings indicated that our DenseNet model achieves the most reliable predictions for metabolically vulnerable plaque, yielding an accuracy of 92.59% after 100 epochs of training.

A self-assembled implantable microtubular pacemaker for wireless cardiac electrotherapy.

The current cardiac pacemakers are battery dependent, and the pacing leads are prone to introduce valve damage and infection, plus a complete pacemaker retrieval is needed for battery replacement. Despite the reported wireless bioelectronics to pace the epicardium, open-chest surgery (thoracotomy) is required to implant the device, and the procedure is invasive, requiring prolonged wound healing and health care burden. We hereby demonstrate a fully biocompatible wireless microelectronics with a self-assembled design that can be rolled into a lightweight microtubular pacemaker for intravascular implantation and pacing. The radio frequency was used to transfer energy to the microtubular pacemaker for electrical stimulation. We show that this pacemaker provides effective pacing to restore cardiac contraction from a nonbeating heart and have the capacity to perform overdrive pacing to augment blood circulation in an anesthetized pig model. Thus, this microtubular pacemaker paves the way for the minimally invasive implantation of leadless and battery-free microelectronics.

A Case of Non-cirrhotic Hyperammonemic Encephalopathy in a Patient With Metastatic Gastrointestinal Stromal Tumor.

Acute toxic encephalopathy (ATE) is a widely recognized medical emergency with an expansive differential. One particular known etiology for ATE is elevated ammonia, a powerful neurotoxin that often presents with clinical findings of confusion, disorientation, tremors, and in severe cases, coma and death. Hyperammonemia is most commonly associated with liver disease and presents as hepatic encephalopathy in the setting of decompensated cirrhosis; however, in rare cases, a patient may suffer from non-cirrhotic hyperammonemic encephalopathy. We describe the case of a 61-year-old male with metastatic gastrointestinal stromal tumor who was diagnosed with non-cirrhotic hyperammonemic encephalopathy, and briefly explore the literature describing its mechanisms.

Miniaturized wireless gastric pacing via inductive power transfer with non-invasive monitoring using cutaneous Electrogastrography.

BACKGROUND: Gastroparesis is a debilitating disease that is often refractory to pharmacotherapy. While gastric electrical stimulation has been studied as a potential treatment, current devices are limited by surgical complications and an incomplete understanding of the mechanism by which electrical stimulation affects physiology. METHODS: A leadless inductively-powered pacemaker was implanted on the gastric serosa in an anesthetized pig. Wireless pacing was performed at transmitter-to-receiver distances up to 20 mm, frequency of 0.05 Hz, and pulse width of 400 ms. Electrogastrogram (EGG) recordings using cutaneous and serosal electrode arrays were analyzed to compute spectral and spatial statistical parameters associated with the slow wave. RESULTS: Our data demonstrated evident change in EGG signal patterns upon initiation of pacing. A buffer period was noted before a pattern of entrainment appeared with consistent and low variability in slow wave direction. A spectral power increase in the EGG frequency band during entrainment also suggested that pacing increased strength of the slow wave. CONCLUSION: Our preliminary in vivo study using wireless pacing and concurrent EGG recording established the foundations for a minimally invasive approach to understand and optimize the effect of pacing on gastric motor activity as a means to treat conditions of gastric dysmotility.

Recent advances in the treatment of juvenile idiopathic arthritis-associated uveitis.

Juvenile idiopathic arthritis-associated uveitis has an estimated prevalence of 10-20% in patients with juvenile idiopathic arthritis, making it the most common cause of chronic anterior uveitis in children. Prompt treatment is important to prevent development of ocular complications and permanent vision loss. In this review, we will discuss the use of immunosuppression in treatment of juvenile idiopathic arthritis-associated uveitis. This will include the use of conventional immunosuppressants, such as methotrexate, biologic anti-tumor necrosis factor agents, such as adalimumab, as well as other anti-tumor necrosis factor agents, including infliximab and golimumab. In addition, we will discuss medications currently in clinical trials or under consideration for juvenile idiopathic arthritis-associated uveitis, including interleukin-6 inhibitors (tocilizumab) and Janus kinase inhibitors (tofacitinib, baricitinib).

In Vivo Intravascular Pacing Using a Wireless Microscale Stimulator.

Millions of patients worldwide are implanted with permanent pacemakers for the treatment of cardiac arrhythmias and conduction disorders. The increased use of these devices has established a growing clinical need to mitigate associated complications. Pacemaker leads, in particular, present the primary risks in most implants. While wireless power transfer holds great promise in eliminating implantable device leads, anatomical constraints limit efficient wireless transmission over the necessary operational range. We thereby developed a transmitter-centered control system for wireless power transfer with sufficient power for continuous cardiac pacing. Device safety was validated using a computational model of the system within an MRI-based anatomical model. The pacer was then fabricated to meet the acute constraints of the anterior cardiac vein (ACV) to enable intravascular deployment while maintaining power efficiency. Our computational model revealed the wireless system to operate at > 50 times below the tissue energy absorption safety criteria. We further demonstrated the capacity for ex vivo pacing of pig hearts at 60 beats per minute (BPM) and in vivo pacing at 120 BPM following pacer deployment in the ACV. This work thus established the capacity for wireless intravascular pacing with the potential to eliminate complications associated with current lead-based deep tissue implants.

Three-dimensional Imaging Coupled with Topological Quantification Uncovers Retinal Vascular Plexuses Undergoing Obliteration.

Introduction: Murine models provide microvascular insights into the 3-D network disarray seen in retinopathy and cardiovascular diseases. Light-sheet fluorescence microscopy (LSFM) has emerged to capture retinal vasculature in 3-D, allowing for assessment of the progression of retinopathy and the potential to screen new therapeutic targets in mice. We hereby coupled LSFM, also known as selective plane illumination microscopy, with topological quantification, to characterize the retinal vascular plexuses undergoing preferential obliteration. Method and Result: In postnatal mice, we revealed the 3-D retinal microvascular network in which the vertical sprouts bridge the primary (inner) and secondary (outer) plexuses, whereas, in an oxygen-induced retinopathy (OIR) mouse model, we demonstrated preferential obliteration of the secondary plexus and bridging vessels with a relatively unscathed primary plexus. Using clustering coefficients and Euler numbers, we computed the local versus global vascular connectivity. While local connectivity was preserved (p > 0.05, n = 5 vs. normoxia), the global vascular connectivity in hyperoxia-exposed retinas was significantly reduced (p < 0.05, n = 5 vs. normoxia). Applying principal component analysis (PCA) for auto-segmentation of the vertical sprouts, we corroborated the obliteration of the vertical sprouts bridging the secondary plexuses, as evidenced by impaired vascular branching and connectivity, and reduction in vessel volumes and lengths (p < 0.05, n = 5 vs. normoxia). Conclusion: Coupling 3-D LSFM with topological quantification uncovered the retinal vasculature undergoing hyperoxia-induced obliteration from the secondary (outer) plexus to the vertical sprouts. The use of clustering coefficients, Euler's number, and PCA provided new network insights into OIR-associated vascular obliteration, with translational significance for investigating therapeutic interventions to prevent visual impairment.

Endoscopic Anterior Skull Base Reconstruction: A Meta-Analysis and Systematic Review of Graft Type.

OBJECTIVE: The influence of graft type (nonautologous vs. autologous) on surgical outcomes in endoscopic anterior skull base (EASB) reconstruction is not well understood. This review systematically evaluated rates of postoperative complications of EASB repairs that utilized autologous or nonautologous grafts. METHODS: Original studies reporting EASB reconstruction outcomes were extracted from PubMed, Ovid, and the Cochrane Library from database inception to 2019. Risk ratios, risk differences, χ2 tests, and multivariate logistic regression were used to evaluate outcome measures: postoperative cerebrospinal fluid (CSF) leaks, meningitis, and other major complications (OMCs). RESULTS: A total of 2275 patients from 29 studies were analyzed. Rates of postoperative CSF leaks, meningitis, and OMCs were 4.0%, 1.6%, and 2.3%, respectively, using autologous grafts, and 5.0%, 0.3%, and 1.0%, respectively, using nonautologous grafts. Multivariate analysis of 118 patients demonstrated no significant differences in age, CSF flow rate, single or multilayer reconstruction, and presence of intraoperative CSF leak or lumbar drain. Meta-analyses of 6 studies yielded a risk ratio of 0.64 (95% confidence interval [CI], 0.19-2.14; P = 0.47) for postoperative CSF leakage, and risk differences of -0.01 (95% CI, -0.06 to 0.05; P = 0.80) and -0.02 (95% CI, -0.09 to 0.05; P = 0.51) for postoperative meningitis and OMCs, respectively. There were no significant differences in postoperative CSF leakage (P = 0.95) and OMCs (P = 0.41) between graft types among cases with intraoperative CSF leaks. However, meningitis rates were lower (P = 0.04) in the nonautologous group. CONCLUSIONS: EASB reconstructions utilizing autologous and nonautologous grafts are associated with similar rates of postoperative CSF leakage and OMCs. In cases with intraoperative CSF leakage, nonautologous grafts were associated with reduced postoperative meningitis.

A Multi-Dimensional Analysis of a Novel Approach for Wireless Stimulation.

The elimination of integrated batteries in biomedical implants holds great promise for improving health outcomes in patients with implantable devices. However, despite extensive research in wireless power transfer, achieving efficient power transfer and effective operational range have remained a hindering challenge within anatomical constraints. OBJECTIVE: We hereby demonstrate an intravascular wireless and batteryless microscale stimulator, designed for (1) low power dissipation via intermittent transmission and (2) reduced fixation mechanical burden via deployment to the anterior cardiac vein (ACV, ∼3.8 mm in diameter). METHODS: We introduced a unique coil design circumferentially confined to a 3 mm diameter hollow-cylinder that was driven by a novel transmitter-based control architecture with improved power efficiency. RESULTS: We examined wireless capacity using heterogenous bovine tissue, demonstrating >5 V stimulation threshold with up to 20 mm transmitter-receiver displacement and 20° of misalignment. Feasibility for human use was validated using Finite Element Method (FEM) simulation of the cardiac cycle, guided by pacer phantom-integrated Magnetic Resonance Images (MRI). CONCLUSION: This system design thus enabled sufficient wireless power transfer in the face of extensive stimulator miniaturization. SIGNIFICANCE: Our successful feasibility studies demonstrated the capacity for minimally invasive deployment and low-risk fixation.

Wireless Pacing Using an Asynchronous Three-Tiered Inductive Power Transfer System.

Despite numerous advancements in pacemaker technology for the treatment of cardiac arrhythmias and conduction disorders, lead-related complications associated with these devices continue to compromise patient safety and survival. In this work, we present a system architecture that has the capacity to deliver power to a wireless, batteryless intravascular pacer. This was made possible through a three-tiered, dual-sub-system, four-coil design, which operates on two different frequencies through intermittent remote-controlled inductive power transfer. System efficiency was enhanced using coil design optimization, and validated using numerical simulations and experimental analysis. Our pacemaker design was concepted to achieve inductive power transfer over a 55 mm range to a microscale pacer with a 3 mm diameter. Thus, the proposed system design enabled long-range wireless power transfer to a small implanted pacer with the capacity for intravascular deployment to the anterior cardiac vein. This proposed stent-like fixation mechanism can bypass the multitude of complications associated with pacemaker wires while wireless power can eliminate the need for repeated procedures for battery replacement.

Simulating Developmental Cardiac Morphology in Virtual Reality Using a Deformable Image Registration Approach.

While virtual reality (VR) has potential in enhancing cardiovascular diagnosis and treatment, prerequisite labor-intensive image segmentation remains an obstacle for seamlessly simulating 4-dimensional (4-D, 3-D + time) imaging data in an immersive, physiological VR environment. We applied deformable image registration (DIR) in conjunction with 3-D reconstruction and VR implementation to recapitulate developmental cardiac contractile function from light-sheet fluorescence microscopy (LSFM). This method addressed inconsistencies that would arise from independent segmentations of time-dependent data, thereby enabling the creation of a VR environment that fluently simulates cardiac morphological changes. By analyzing myocardial deformation at high spatiotemporal resolution, we interfaced quantitative computations with 4-D VR. We demonstrated that our LSFM-captured images, followed by DIR, yielded average dice similarity coefficients of 0.92 ± 0.05 (n = 510) and 0.93 ± 0.06 (n = 240) when compared to ground truth images obtained from Otsu thresholding and manual segmentation, respectively. The resulting VR environment simulates a wide-angle zoomed-in view of motion in live embryonic zebrafish hearts, in which the cardiac chambers are undergoing structural deformation throughout the cardiac cycle. Thus, this technique allows for an interactive micro-scale VR visualization of developmental cardiac morphology to enable high resolution simulation for both basic and clinical science.

Non-Invasive Electrical Impedance Tomography for Multi-Scale Detection of Liver Fat Content.

Introduction: Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). While Magnetic Resonance Imaging (MRI) is a non-invasive gold standard to detect fatty liver, we demonstrate a low-cost and portable electrical impedance tomography (EIT) approach with circumferential abdominal electrodes for liver conductivity measurements. Methods and Results: A finite element model (FEM) was established to simulate decremental liver conductivity in response to incremental liver lipid content. To validate the FEM simulation, we performed EIT imaging on an ex vivo porcine liver in a non-conductive tank with 32 circumferentially-embedded electrodes, demonstrating a high-resolution output given a priori information on location and geometry. To further examine EIT capacity in fatty liver detection, we performed EIT measurements in age- and gender-matched New Zealand White rabbits (3 on normal, 3 on high-fat diets). Liver conductivity values were significantly distinct following the high-fat diet (p = 0.003 vs. normal diet, n=3), accompanied by histopathological evidence of hepatic fat accumulation. We further assessed EIT imaging in human subjects with MRI quantification for fat volume fraction based on Dixon procedures, demonstrating average liver conductivity of 0.331 S/m for subjects with low Body-Mass Index (BMI < 25 kg/m²) and 0.286 S/m for high BMI (> 25 kg/m²). Conclusion: We provide both the theoretical and experimental framework for a multi-scale EIT strategy to detect liver lipid content. Our preliminary studies pave the way to enhance the spatial resolution of EIT as a marker for fatty liver disease and metabolic syndrome.

Integrating light-sheet imaging with virtual reality to recapitulate developmental cardiac mechanics.

Currently, there is a limited ability to interactively study developmental cardiac mechanics and physiology. We therefore combined light-sheet fluorescence microscopy (LSFM) with virtual reality (VR) to provide a hybrid platform for 3D architecture and time-dependent cardiac contractile function characterization. By taking advantage of the rapid acquisition, high axial resolution, low phototoxicity, and high fidelity in 3D and 4D (3D spatial + 1D time or spectra), this VR-LSFM hybrid methodology enables interactive visualization and quantification otherwise not available by conventional methods, such as routine optical microscopes. We hereby demonstrate multiscale applicability of VR-LSFM to (a) interrogate skin fibroblasts interacting with a hyaluronic acid-based hydrogel, (b) navigate through the endocardial trabecular network during zebrafish development, and (c) localize gene therapy-mediated potassium channel expression in adult murine hearts. We further combined our batch intensity normalized segmentation algorithm with deformable image registration to interface a VR environment with imaging computation for the analysis of cardiac contraction. Thus, the VR-LSFM hybrid platform demonstrates an efficient and robust framework for creating a user-directed microenvironment in which we uncovered developmental cardiac mechanics and physiology with high spatiotemporal resolution.

3-D Electrochemical Impedance Spectroscopy Mapping of Arteries to Detect Metabolically Active but Angiographically Invisible Atherosclerotic Lesions.

We designed a novel 6-point electrochemical impedance spectroscopy (EIS) sensor with 15 combinations of permutations for the 3-D mapping and detection of metabolically active atherosclerotic lesions. Two rows of 3 stretchable electrodes circumferentially separated by 120° were mounted on an inflatable balloon for intravascular deployment and endoluminal interrogation. The configuration and 15 permutations of 2-point EIS electrodes allowed for deep arterial penetration via alternating current (AC) to detect varying degrees of lipid burden with distinct impedance profiles (Ω). By virtue of the distinctive impedimetric signature of metabolically active atherosclerotic lesions, a detailed impedance map was acquired, with the 15 EIS permutations uncovering early stages of disease characterized by fatty streak lipid accumulation in the New Zealand White rabbit model of atherosclerosis. Both the equivalent circuit and statistical analyses corroborated the 3-D EIS permutations to detect small, angiographically invisible, lipid-rich lesions, with translational implications for early atherosclerotic disease detection and prevention of acute coronary syndromes or strokes.

Inductively powered wireless pacing via a miniature pacemaker and remote stimulation control system.

Pacemakers have existed for decades as a means to restore cardiac electrical rhythms. However, lead-related complications have remained a clinical challenge. While market-released leadless devices have addressed some of the issues, their pacer-integrated batteries cause new health risks and functional limitations. Inductive power transfer enables wireless powering of bioelectronic devices; however, Specific Absorption Rate and size limitations reduce power efficiency for biomedical applications. We designed a remote-controlled system in which power requirements were significantly reduced via intermittent power transfer to control stimulation intervals. In parallel, the cardiac component was miniaturized to facilitate intravascular deployment into the anterior cardiac vein. Given size constraints, efficiency was optimal via a circular receiver coil wrapped into a half-cylinder with a meandering tail. The pacemaker was epicardially tested in a euthanized pig at 60 beats per minute, 2 V amplitude, and 1 ms pulse width, restoring mean arterial pressure from 0 to 37 mmHg. Power consumption was 1 mW at a range of > 3 cm with no misalignment and at 2 cm with 45° displacement misalignment, 45° x-axis angular misalignment, or 45° y-axis angular misalignment. Thus, we demonstrated a remote-controlled miniaturized pacing system with low power consumption, thereby providing a basis for the next generation of wireless implantable devices.

Light-sheet fluorescence imaging to localize cardiac lineage and protein distribution.

Light-sheet fluorescence microscopy (LSFM) serves to advance developmental research and regenerative medicine. Coupled with the paralleled advances in fluorescence-friendly tissue clearing technique, our cardiac LSFM enables dual-sided illumination to rapidly uncover the architecture of murine hearts over 10 by 10 by 10 mm3 in volume; thereby allowing for localizing progenitor differentiation to the cardiomyocyte lineage and AAV9-mediated expression of exogenous transmembrane potassium channels with high contrast and resolution. Without the steps of stitching image columns, pivoting the light-sheet and sectioning the heart mechanically, we establish a holistic strategy for 3-dimentional reconstruction of the "digital murine heart" to assess aberrant cardiac structures as well as the spatial distribution of the cardiac lineages in neonates and ion-channels in adults.

Ultrasonic Transducer-Guided Electrochemical Impedance Spectroscopy to Assess Lipid-Laden Plaques.

Plaque rupture causes acute coronary syndromes and stroke. Intraplaque oxidized low density lipoprotein (oxLDL) is metabolically unstable and prone to induce rupture. We designed an intravascular ultrasound (IVUS)-guided electrochemical impedance spectroscopy (EIS) sensor to enhance the detection reproducibility of oxLDL-laden plaques. The flexible 2-point micro-electrode array for EIS was affixed to an inflatable balloon anchored onto a co-axial double layer catheter (outer diameter = 2 mm). The mechanically scanning-driven IVUS transducer (45 MHz) was deployed through the inner catheter (diameter = 1.3 mm) to the acoustic impedance matched-imaging window. Water filled the inner catheter to match acoustic impedance and air was pumped between the inner and outer catheters to inflate the balloon. The integrated EIS and IVUS sensor was deployed into the ex vivo aortas dissected from the fat-fed New Zealand White (NZW) rabbits (n=3 for fat-fed, n= 5 normal diet). IVUS imaging was able to guide the 2-point electrode to align with the plaque for EIS measurement upon balloon inflation. IVUS-guided EIS signal demonstrated reduced variability and increased reproducibility (p < 0.0001 for magnitude, p < 0.05 for phase at < 15 kHz) as compared to EIS sensor alone (p < 0.07 for impedance, p < 0.4 for phase at < 15 kHz). Thus, we enhanced topographic and EIS detection of oxLDL-laden plaques via a catheter-based integrated sensor design to enhance clinical assessment for unstable plaque.

Full range physiological mass transport control in 3D tissue cultures.

We report the first demonstration of a microfluidic platform that captures the full physiological range of mass transport in 3-D tissue culture. The basis of our method used long microfluidic channels connected to both sides of a central microtissue chamber at different downstream positions to control the mass transport distribution within the chamber. Precise control of the Péclet number (Pe), defined as the ratio of convective to diffusive transport, over nearly five orders of magnitude (0.0056 to 160) was achieved. The platform was used to systematically investigate the role of physiological mass transport on vasculogenesis. We demonstrate, for the first time, that vasculogenesis can be independently stimulated by interstitial flow (Pe > 10) or hypoxic conditions (Pe < 0.1), and not by the intermediate state (normal living tissue). This simple platform can be applied to physiological and biological studies of 3D living tissue followed by pathological disease studies, such as cancer research and drug screening.