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Context: Postoperative atrial fibrillation or flutter (AF) is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-polyunsaturated fatty acids (PUFAs) reduce postoperative AF, with mixed results.Objective: To determine whether perioperative n-3-PUFA supplementation reduces postoperative AF.Design, Setting, and Patients: The Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial. A total of 1516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment.Intervention: Patients were randomized to receive fish oil (1-g capsules containing ≥840 mg n-3-PUFAs as ethyl esters) or placebo, with preoperative loading of 10 g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first.Main Outcome Measure: Occurrence of postoperative AF lasting longer than 30 seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse cardiovascular events, 30-day mortality, bleeding, and other adverse events.Results: At enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, 0.96 [95% CI, 0.77-1.20]; P = .74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P = .70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; ≥3 episodes: 18 [2.4%] vs 21 [2.8%]) (P = .73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events.Conclusion: In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00970489. [ABSTRACT FROM AUTHOR]

Neuron migration is a key phase of neurogenesis, critical for the assembly and function of neuronal circuits. In songbirds, this process continues throughout life, but how these newborn neurons disperse through the adult brain is unclear. We address this question using in vivo two-photon imaging in transgenic zebra finches that express GFP in young neurons and other cell types. In juvenile and adult birds, migratory cells are present at a high density, travel in all directions, and make frequent course changes. Notably, these dynamic migration patterns are well fit by a superdiffusive model. Simulations reveal that these superdiffusive dynamics are sufficient to disperse new neurons throughout the song nucleus HVC. These results suggest that superdiffusive migration may underlie the formation and maintenance of nuclear brain structures in the postnatal brain and indicate that transgenic songbirds are a useful resource for future studies into the mechanisms of adult neurogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Perinatal depression is the occurrence of depressive symptoms during the antenatal or postnatal period with an annual incidence of 10% to 20%. The consequences of untreated perinatal depression are significant and include negative impacts on maternal health, pregnancy outcomes, and maternal-infant outcomes. The purpose of this article is to provide perinatal pharmacologic and psychological treatment information to help first-line providers more confidently manage depression in the perinatal period. Treatment strategies including medication management using risk versus risk conversations, psychotherapy, and colocated perinatal mental health clinics are discussed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Directed enzyme-prodrug therapies used for targeted drug delivery require prodrugs that are chemically stable and processed efficiently by the activating enzyme. We recently reported the development of AMS-6-Glu ( 2 ), a glutamate-masked version of the cytotoxic natural product 5'- O -sulfamoyladenosine (AMS, 1 ) that can be activated by Pseudomonas carboxypeptidase G2 (CPG2). Herein, we report the development of a second-generation prodrug, AMS-5'-PHOBA-Glu ( 5 ), that undergoes cleavage by CPG2 with >160-fold higher efficiency. Use of a p -hydroxybenzyl alcohol (PHOBA) self-immolative linker overcame unexpected chemical instability observed with a conventional p -aminobenzyl alchohol (PABA) linker.

Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies., (©2023 The Authors; Published by the American Association for Cancer Research.)

This report describes a 3D microelectrode array integrated on a thin-film flexible cable for neural recording in small animals. The fabrication process combines traditional silicon thin-film processing techniques and direct laser writing of 3D structures at micron resolution via two-photon lithography. Direct laser-writing of 3D-printed electrodes has been described before, but this report is the first to provide a method for producing high-aspect-ratio structures. One prototype, a 16-channel array with 300 µm pitch, demonstrates successful electrophysiological signal capture from bird and mouse brains. Additional devices include 90 µm pitch arrays, biomimetic mosquito needles that penetrate through the dura of birds, and porous electrodes with enhanced surface area. The rapid 3D printing and wafer-scale methods described here will enable efficient device fabrication and new studies examining the relationship between electrode geometry and electrode performance. Applications include small animal models, nerve interfaces, retinal implants, and other devices requiring compact, high-density 3D electrodes., (© 2023. The Author(s).)

Chimeric antigen receptor (CAR) T-cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered "Orexi" CAR T cells to locally secrete a high-affinity CD47 blocker, CV1, at the tumor and treated tumors in combination with an orthogonally targeted monoclonal antibody. Traditional CAR T cells plus the antibody had an additive effect in xenograft models, and this effect was potentiated by CAR T-cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed the immunosuppression of myelomonocytoid cells both in vitro and within the tumor microenvironment. Local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and may prevent systemic toxicities. This combination of CAR T-cell therapy, local CD47 blockade, and orthogonal antibody may be a combinatorial strategy to overcome the limitations of each monotherapy., (© 2023 by The American Society of Hematology.)

Human cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes latent asymptomatic infections in healthy individuals but can cause serious infections in immunocompromised people, resulting in increased risk of morbidity and mortality. The current FDA-approved CMV drugs target late stages of the CMV life-cycle. While these drugs are effective in most cases, they have serious drawbacks, including poor oral bioavailability, dose-limiting toxicity, and a low barrier to resistance. Given the clinical relevance of CMV-associated diseases, novel therapies are needed. Thus, a novel class of compounds that inhibits the early stages of the CMV life-cycle was identified and found to block infection of different strains in physiologically relevant cell types. This class of compounds, N-arylpyrimidinamine (NAPA), demonstrated potent anti-CMV activity against ganciclovir-sensitive and -resistant strains in in vitro replication assays, a selectivity index >30, and favorable in vitro ADME properties. Mechanism of action studies demonstrated that NAPA compounds inhibit an early step of virus infection. NAPA compounds are specific inhibitors of cytomegaloviruses and exhibited limited anti-viral activity against other herpesviruses. Collectively, we have identified a novel class of CMV inhibitor that effectively limits viral infection and proliferation., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Arthroscopic rotator cuff repair (RCR) is a popular treatment for rotator cuff tears. Retear after RCR remains a significant concern even with modern techniques. Augmentation of RCR has been described using multiple different grafts, one option including a cannulated dermal allograft implant (DePuy Mitek). The utilization of this implant avoids significantly increased surgical time, allows for augmentation at the weakest area of repair, and does not lead to any wasted allograft material., (© 2022 The Authors.)

Target identification for chimeric antigen receptor (CAR) T-cell therapies remains challenging due to the limited repertoire of tumor-specific surface proteins. Intracellular proteins presented in the context of cell surface HLA provide a wide pool of potential antigens targetable through T-cell receptor mimic antibodies. Mass spectrometry (MS) of HLA ligands from 8 hematologic and nonhematologic cancer cell lines identified a shared, non-immunogenic, HLA-A*02-restricted ligand (ALNEQIARL) derived from the kinetochore-associated NDC80 gene. CAR T cells directed against the ALNEQIARL:HLA-A*02 complex exhibited high sensitivity and specificity for recognition and killing of multiple cancer types, especially those of hematologic origin, and were efficacious in mouse models against a human leukemia and a solid tumor. In contrast, no toxicities toward resting or activated healthy leukocytes as well as hematopoietic stem cells were observed. This shows how MS can inform the design of broadly reactive therapeutic T-cell receptor mimic CAR T-cell therapies that can target multiple cancer types currently not druggable by small molecules, conventional CAR T cells, T cells, or antibodies., (© 2022 by The American Society of Hematology.)

Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Songbirds provide a powerful model system for studying sensory-motor learning. However, many analyses of birdsong require time-consuming, manual annotation of its elements, called syllables. Automated methods for annotation have been proposed, but these methods assume that audio can be cleanly segmented into syllables, or they require carefully tuning multiple statistical models. Here, we present TweetyNet: a single neural network model that learns how to segment spectrograms of birdsong into annotated syllables. We show that TweetyNet mitigates limitations of methods that rely on segmented audio. We also show that TweetyNet performs well across multiple individuals from two species of songbirds, Bengalese finches and canaries. Lastly, we demonstrate that using TweetyNet we can accurately annotate very large datasets containing multiple days of song, and that these predicted annotations replicate key findings from behavioral studies. In addition, we provide open-source software to assist other researchers, and a large dataset of annotated canary song that can serve as a benchmark. We conclude that TweetyNet makes it possible to address a wide range of new questions about birdsong., Competing Interests: YC, DN, AS, EM, VS, TG No competing interests declared, (© 2022, Cohen et al.)

Objective: Patients with profound cardiogenic shock may require venoarterial (VA) extracorporeal membrane oxygenation (ECMO) for circulatory support most commonly via the femoral vessels. The rate of cardiac recovery in this population remains low, possibly because peripheral VA-ECMO increases ventricular afterload. Whether direct ventricular unloading in peripheral VA-ECMO enhances cardiac recovery is unknown, but is being more frequently utilized. A randomized trial is warranted to evaluate the clinical effectiveness of percutaneous left ventricle venting to enhance cardiac recovery in the setting of VA-ECMO., Methods: We describe the rationale, design, and initial testing of a randomized controlled trial of VA-ECMO with and without percutaneous left ventricle venting using a percutaneous micro-axial ventricular assist device., Results: This is an ongoing prospective randomized controlled trial in adult patients with primary cardiac failure presenting in cardiogenic shock requiring peripheral VA-ECMO, designed to test the safety and effectiveness of percutaneous left ventricle venting in improving the rate of cardiac recovery., Conclusions: The results of this nonindustry-sponsored trial will provide critical information on whether left ventricle unloading in peripheral VA-ECMO is safe and effective., (© 2021 The Author(s).)

Purpose: To report the rate of return to sport after surgical treatment for posterior shoulder instability among athletes., Methods: A systematic review of the literature regarding rate of return to sport after surgical treatment for posterior shoulder instability was undertaken. The primary outcome measure was return to sport. The secondary outcome measures included rate of return to sport to preinjury level, time to return to sport, injury type, reoperations after primary surgery, and objective patient-reported outcome data. Data is summarized with ranges and tables., Results: A total of 23 studies met inclusion criteria. The rate of return to sport ranged from 57.9%-100%. The rate of return to sport to the preinjury level ranged from 47.4%-100%. Time to return to sport ranged from 4.3-7.7 months. Furthermore, 66% of subjects had an acute traumatic injury and 34% were of insidious onset. The most commonly reported outcome measures were American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores and visual analog scale (VAS) pain scores. At a minimum of 1-year follow-up, ASES and VAS pain scores improved. Revision rates ranged from 0%-36.8%., Conclusion: The systematic review demonstrated high rates of return to sport and relatively high rates of return to preinjury level of sport among all athletes who underwent surgical treatment for posterior shoulder instability. Objective patient-reported outcome metrics improved postoperatively whereas revision rates remained low., (© 2020 Published by Elsevier Inc. on behalf of American Shoulder and Elbow Surgeons.)

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying peripheral interfacing technologies. Here, we present a microscale implantable device - the nanoclip - for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high signal-to-noise ratio recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation within the confines of the small device can achieve multi-dimensional control of a small nerve. These results highlight the potential of new microscale design and fabrication techniques for realizing viable devices for long-term peripheral interfacing.

The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.

Coordinated skills such as speech or dance involve sequences of actions that follow syntactic rules in which transitions between elements depend on the identities and order of past actions. Canary songs consist of repeated syllables called phrases, and the ordering of these phrases follows long-range rules 1 in which the choice of what to sing depends on the song structure many seconds prior. The neural substrates that support these long-range correlations are unknown. Here, using miniature head-mounted microscopes and cell-type-specific genetic tools, we observed neural activity in the premotor nucleus HVC 2-4 as canaries explored various phrase sequences in their repertoire. We identified neurons that encode past transitions, extending over four phrases and spanning up to four seconds and forty syllables. These neurons preferentially encode past actions rather than future actions, can reflect more than one song history, and are active mostly during the rare phrases that involve history-dependent transitions in song. These findings demonstrate that the dynamics of HVC include 'hidden states' that are not reflected in ongoing behaviour but rather carry information about prior actions. These states provide a possible substrate for the control of syntax transitions governed by long-range rules.

Hypothesis: Patients receiving reverse total shoulder arthroplasty (RTSA) may reach MMI prior to 12 months postoperatively., Background: With the growth of RTSA indications, there is a paucity of information regarding maximum medical improvement (MMI) after these procedures. Systems of evaluating recovery, such as patient-reported outcome measures and minimal clinically important differences (MCIDs) will allow for measurement of when patients reach maximum medical improvement (MMI) after these procedures., Purpose: To evaluate when patients have reached MMI after RTSA., Methods: Patients were prospectively enrolled in the institution's RTSA registry. All patients undergoing RTSA who agreed to be enrolled were included. Patient-specific factors, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, and pain data were collected preoperatively and at 6 and 12 months postoperatively. Subgroup analysis was performed on preoperative diagnosis before analyzing MCID and MMI. MMI was calculated by using the last time point interval that an MCID did not occur., Results: Of 182 patients, 92 had complete 12-month postoperative data, including visual analog scale (VAS) pain and ASES scores. Subgroup analysis showed preoperative diagnosis of rotator cuff arthropathy, revision surgery, glenohumeral arthritis, proximal humerus fracture, and chronic dislocation. All 5 groups had improvement that exceeded MCID thresholds at 6 months and variable improvement from 6-12 months. Analysis of variance compared the different groups, showing that VAS pain scores and ASES scores were different at all time points except for preoperative VAS pain scores., Conclusions: Patients undergoing RTSA may reach MMI at 6 months instead of the previously reported 1-year time point. Data from this study can allow providers to deliver value care and potentially limit visits after 6 months postoperatively., (© 2020 The Author(s).)

The mission of the American Heart Association is to be a relentless force for a world of longer, healthier lives. The American Heart Association has consistently prioritized the needs and perspective of the patient in taking positions on healthcare reform while recognizing the importance of biomedical research, providers, and healthcare delivery systems in advancing the care of patients and the prevention of disease. The American Heart Association's vision for healthcare reform describes the foundational changes needed for the health system to serve the best interests of patients and to achieve health care and coverage that are adequate, accessible, and affordable for everyone living in the United States. The American Heart Association is committed to advancing the dialogue around healthcare reform and has prepared this updated statement of our principles, placed in the context of the advances in coverage and care that have occurred after the passage of the Affordable Care Act, the rapidly changing landscape of healthcare delivery systems, and our evolving recognition that efforts to prevent cardiovascular disease can have synergistic benefit in preventing other diseases and improving overall well-being. These updated principles focus on expanding access to affordable health care and coverage; enhancing the availability of evidence-based preventive services; eliminating disparities that limit the availability and equitable delivery of health care; strengthening the public health infrastructure to respond to social determinants of health; prioritizing and accelerating investments in biomedical research; and growing a diverse, culturally competent health and healthcare workforce prepared to meet the challenges of delivering high-value health care.

3D printing allows rapid fabrication of complex objects from digital designs. One 3D-printing process, direct laser writing, polymerises a light-sensitive material by steering a focused laser beam through the shape of the object to be created. The highest-resolution direct laser writing systems use a femtosecond laser, steered using mechanised stages or galvanometer-controlled mirrors, to effect two-photon polymerisation. Here we report a new high-resolution direct laser writing system that employs a resonant mirror scanner to achieve a significant increase in printing speed over current methods while maintaining resolution on the order of a micron. This printer is based on a software modification to a commercially available resonant-scanning two-photon microscope. We demonstrate the complete process chain from hardware configuration and control software to the printing of objects of approximately 400 × 400 × 350 μm, and validate performance with objective benchmarks. Released under an open-source license, this work makes micron-scale 3D printing available at little or no cost to the large community of two-photon microscope users, and paves the way toward widespread availability of precision-printed devices., Competing Interests: Conflict of interest Timothy J. Gardner is an employee of Neuralink Inc.

The change in residual stress in plasma enhanced chemical vapor deposition amorphous silicon carbide (a-SiC:H) films exposed to air and wet ambient environments is investigated. A close relationship between stress change and deposition condition is identified from mechanical and chemical characterization of a-SiC:H films. Evidence of amorphous silicon carbide films reacting with oxygen and water vapor in the ambient environment are presented. The effect of deposition parameters on oxidation and stress variation in a-SiC:H film is studied. It is found that the films deposited at low temperature or power are susceptible to oxidation and undergo a notable increase in compressive stress over time. Furthermore, the films deposited at sufficiently high temperature (≥325 C) and power density (≥0.2 W cm -2 ) do not exhibit pronounced oxidation or temporal stress variation. These results serve as the basis for developing amorphous silicon carbide based dielectric encapsulation for implantable medical devices. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1654-1661, 2019., (© 2018 Wiley Periodicals, Inc.)

Human cytomegalovirus (CMV) causes a wide array of disease to diverse populations of immune-compromised individuals. Thus, a more comprehensive understanding of how CMV enters numerous host cell types is necessary to further delineate the complex nature of CMV pathogenesis and to develop targeted therapeutics. To that end, we establish a vaccination strategy utilizing membrane vesicles derived from epithelial cells to generate a library of monoclonal antibodies (mAbs) targeting cell surface proteins in their native conformation. A high-throughput inhibition assay is employed to screen these antibodies for their ability to limit infection, and mAbs targeting CD46 are identified. In addition, a significant reduction of viral proliferation in CD46-KO epithelial cells confirms a role for CD46 function in viral dissemination. Further, we demonstrate a CD46-dependent entry pathway of virus infection in trophoblasts, but not in fibroblasts, highlighting the complexity of CMV entry and identifying CD46 as an entry factor in congenital infection.

Objective: Optical techniques for recording and manipulating neural activity have traditionally been constrained to superficial brain regions due to light scattering. New techniques are needed to extend optical access to large 3D volumes in deep brain areas, while retaining local connectivity., Approach: We have developed a method to implant bundles of hundreds or thousands of optical microfibers, each with a diameter of 8 μm. During insertion, each fiber moves independently, following a path of least resistance. The fibers achieve near total internal reflection, enabling optically interfacing with the tissue near each fiber aperture., Main Results: At a depth of 3 mm, histology shows fibers consistently splay over 1 mm in diameter throughout the target region. Immunohistochemical staining after chronic implants reveals neurons in close proximity to the fiber tips. Models of photon fluence indicate that fibers can be used as a stimulation light source to precisely activate distinct patterns of neurons by illuminating a subset of fibers in the bundle. By recording fluorescent beads diffusing in water, we demonstrate the recording capability of the fibers., Significance: Our histology, modeling and fluorescent bead recordings suggest that the optical microfibers may provide a minimally invasive, stable, bidirectional interface for recording or stimulating genetic probes in deep brain regions-a hyper-localized form of fiber photometry.

Previously introduced bundles of hundreds or thousands of microfibers have the potential to extend optical access to deep brain regions, sampling fluorescence activity throughout a three-dimensional volume. Each fiber has a small diameter ( 8    μ m ) and follows a path of least resistance, splaying during insertion. By superimposing the fiber sensitivity profile for each fiber, we model the interface properties for a simulated neural population. Our modeling results suggest that for small ( < 200 ) bundles of fibers, each fiber will collect fluorescence from a small number of nonoverlapping neurons near the fiber apertures. As the number of fibers increases, the bundle delivers more uniform excitation power to the region, moving to a regime where fibers collect fluorescence from more neurons and there is greater overlap between neighboring fibers. Under these conditions, it becomes feasible to apply source separation to extract individual neural contributions. In addition, we demonstrate a source separation technique particularly suited to the interface. Our modeling helps establish performance expectations for this interface and provides a framework for estimating neural contributions under a range of conditions.

Microelectrode arrays that consistently and reliably record and stimulate neural activity under conditions of chronic implantation have so far eluded the neural interface community due to failures attributed to both biotic and abiotic mechanisms. Arrays with transverse dimensions of 10 µm or below are thought to minimize the inflammatory response; however, the reduction of implant thickness also decreases buckling thresholds for materials with low Young's modulus. While these issues have been overcome using stiffer, thicker materials as transport shuttles during implantation, the acute damage from the use of shuttles may generate many other biotic complications. Amorphous silicon carbide (a-SiC) provides excellent electrical insulation and a large Young's modulus, allowing the fabrication of ultrasmall arrays with increased resistance to buckling. Prototype a-SiC intracortical implants were fabricated containing 8 - 16 single shanks which had critical thicknesses of either 4 µm or 6 µm. The 6 µm thick a-SiC shanks could penetrate rat cortex without an insertion aid. Single unit recordings from SIROF-coated arrays implanted without any structural support are presented. This work demonstrates that a-SiC can provide an excellent mechanical platform for devices that penetrate cortical tissue while maintaining a critical thickness less than 10 µm.

Global efforts to eradicate polio began in 1988, and four of the six World Health Organization (WHO) regions currently have achieved poliofree certification. Within the remaining two regions with endemic poliomyelitis (African and Eastern Mediterranean), Afghanistan, Nigeria, and Pakistan have never interrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus transmission is surveillance for acute flaccid paralysis (AFP) among children aged <15 years, combined with collection and testing of stool specimens for detection of WPV and vaccine-derived polioviruses (VDPVs)* in WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN) (1,2). AFP surveillance is supplemented by environmental surveillance for polioviruses in sewage from selected locations. Genomic sequencing of isolated polioviruses enables the mapping of transmission by time and place, assessment of potential gaps in surveillance, and identification of the emergence of VDPVs (3). This report presents poliovirus surveillance data from 2016-2017, with particular focus on six countries in the Eastern Mediterranean Region (EMR) and 20 countries in the African Region (AFR) that reported WPV or circulating VDPVs (cVDPVs) during 2011-2017. Included in the 20 AFR countries are the three most affected by the 2014-2015 Ebola virus disease (Ebola) outbreak (Guinea, Liberia, and Sierra Leone), even though only one (Guinea) reported WPV or cVDPVs during the surveillance period. During 2017, a total of 14 (70%) of the 20 AFR countries and five (83%) of the six EMR countries met both surveillance quality indicators at the national level; however, provincial-level variation was seen. Surveillance strengthening activities are needed in specific countries of these regions to provide evidence supporting ultimate certification of the interruption of poliovirus circulation., Competing Interests: No conflicts of interest were reported.

Objective: Foreign body response to indwelling cortical microelectrodes limits the reliability of neural stimulation and recording, particularly for extended chronic applications in behaving animals. The extent to which this response compromises the chronic stability of neural devices depends on many factors including the materials used in the electrode construction, the size, and geometry of the indwelling structure. Here, we report on the development of microelectrode arrays (MEAs) based on amorphous silicon carbide (a-SiC)., Approach: This technology utilizes a-SiC for its chronic stability and employs semiconductor manufacturing processes to create MEAs with small shank dimensions. The a-SiC films were deposited by plasma enhanced chemical vapor deposition and patterned by thin-film photolithographic techniques. To improve stimulation and recording capabilities with small contact areas, we investigated low impedance coatings on the electrode sites. The assembled devices were characterized in phosphate buffered saline for their electrochemical properties., Main Results: MEAs utilizing a-SiC as both the primary structural element and encapsulation were fabricated successfully. These a-SiC MEAs had 16 penetrating shanks. Each shank has a cross-sectional area less than 60 µm 2 and electrode sites with a geometric surface area varying from 20 to 200 µm 2 . Electrode coatings of TiN and SIROF reduced 1 kHz electrode impedance to less than 100 kΩ from ~2.8 MΩ for 100 µm 2 Au electrode sites and increased the charge injection capacities to values greater than 3 mC cm -2 . Finally, we demonstrated functionality by recording neural activity from basal ganglia nucleus of Zebra Finches and motor cortex of rat., Significance: The a-SiC MEAs provide a significant advancement in the development of microelectrodes that over the years has relied on silicon platforms for device manufacture. These flexible a-SiC MEAs have the potential for decreased tissue damage and reduced foreign body response. The technique is promising and has potential for clinical translation and large scale manufacturing.