Comparison of pulse-dose and high-dose corticosteroids with no corticosteroid treatment for COVID-19 pneumonia in the intensive care unit.

Corticosteroid dosing in the range of 0.5-2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID-19 pneumonia based on positive results of randomized trials and a meta-analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID-19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID-19 pneumonia, we compared patients treated with 0.5-2 mg/kg/day in methylprednisolone equivalents (high-dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse-dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU-free days at Day 28, and complications potentially attributable to corticosteroids. Pulse-dose corticosteroid therapy was associated with a significant increase in ICU-free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05-2.02; p = 0.03) and compared with high-dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high-dose corticosteroids-but not of pulse-dose corticosteroids-significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12-0.77; p = 0.01). High-dose corticosteroids reduced mortality compared to pulse-dose corticosteroids (p = 0.04). Pulse-dose corticosteroids-but not high-dose corticosteroids-significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27-9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse-dose group when compared to the high-dose group (p = 0.05 for the comparison). In this single-center study, pulse-dose corticosteroid therapy for COVID-19 pneumonia in the ICU was associated with an increase in ICU-free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high-dose corticosteroids on mortality was favorable.

Implications of Frailty in COVID-19.

As the global coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory distress syndrome coronavirus 2 continues to cause higher mortality and hospitalization rates among older adults, strategies such as frailty screening have been suggested for resource allocation and clinical management. Frailty is a physiologic condition characterized by a decreased reserve to stressors and is associated with disability, hospitalization, and death. Measuring frailty can be a useful tool to determine the risk and prognosis of COVID-19 patients in the acute setting, and to provide higher quality of care for vulnerable individuals in the outpatient setting. A literature review was conducted to examine current research regarding frailty and COVID-19. Frailty can inform holistic care of COVID-19 patients, and further investigation is needed to elucidate how measuring frailty should guide treatment and prevention of COVID-19.

Stimulation and Recording of the Hippocampus Using the Same Pt-Ir Coated Microelectrodes.

Same-electrode stimulation and recording with high spatial resolution, signal quality, and power efficiency is highly desirable in neuroscience and neural engineering. High spatial resolution and signal-to-noise ratio is necessary for obtaining unitary activities and delivering focal stimulations. Power efficiency is critical for battery-operated implantable neural interfaces. This study demonstrates the capability of recording single units as well as evoked potentials in response to a wide range of electrochemically safe stimulation pulses through high-resolution microelectrodes coated with co-deposition of Pt-Ir. It also compares signal-to-noise ratio, single unit activity, and power efficiencies between Pt-Ir coated and uncoated microelectrodes. To enable stimulation and recording with the same microelectrodes, microelectrode arrays were treated with electrodeposited platinum-iridium coating (EPIC) and tested in the CA1 cell body layer of rat hippocampi. The electrodes' ability to (1) inject a large range of electrochemically reversable stimulation pulses to the tissue, and (2) record evoked potentials and single unit activities were quantitively assessed over an acute time period. Compared to uncoated electrodes, EPIC electrodes recorded signals with higher signal-to-noise ratios (coated: 9.77 ± 1.95 dB; uncoated: 1.95 ± 0.40 dB) and generated lower voltages (coated: 100 mV; uncoated: 650 mV) for a given stimulus (5 µA). The improved performance corresponded to lower energy consumptions and electrochemically safe stimulation above 5 µA (>0.38 mC/cm2), which enabled elicitation of field excitatory post synaptic potentials and population spikes. Spontaneous single unit activities were also modulated by varying stimulation intensities and monitored through the same electrodes. This work represents an example of stimulation and recording single unit activities from the same microelectrode, which provides a powerful tool for monitoring and manipulating neural circuits at the single neuron level.

63-year-old man with right biceps and right pectoralis major abscesses: an unusual case of pyomyositis.

Pyomyositis is considered a great mimicker and masquerader. This case is of a 63-year-old man with diabetes who initially presented to the outpatient clinic afebrile with right shoulder pain. His work-up was negative, and he was discharged home. He subsequently presented to the emergency room (ER) two times for worsening right shoulder pain. During his first visit to the ER, his work-up was unremarkable, and he was discharged home. On his return to the ER, he was now febrile with inflammation involving his right upper extremity and right chest wall. Imaging studies of his right upper extremity and his right chest wall were consistent with multiple abscesses. Methicillin resistant Staphylococcus aureus was cultured from the abscess, and from blood and urine cultures. The diagnosis of pyomyositis was confirmed. This case illustrates the difficulty of diagnosing pyomyositis and the importance of including it in the differential diagnosis, especially in an immunocompromised patient.

Electrochemical and biological characterization of thin-film platinum-iridium alloy electrode coatings: a chronic in vivo study.

OBJECTIVE: To evaluate the electrochemical properties, biological response, and surface characterization of an electrodeposited Platinum-Iridium (Pt-Ir) electrode coating on cochlear implants subjected to chronic stimulation in vivo. APPROACH: Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL), and voltage transient (VT) impedance were measured bench-top before and after implant and in vivo. Coated Pt-Ir and uncoated Pt electrode arrays were implanted into cochlea of normal hearing rats and stimulated for ∼4 h d, 5 d week-1 for 5 weeks at levels within the normal clinical range. Neural function was monitored using electrically-evoked auditory brainstem responses. After explant, the electrode surfaces were assessed, and cochleae examined histologically. MAIN RESULTS: When measured on bench-top before and after stimulation, Pt-Ir coated electrodes had significantly lower VT impedance (p < 0.001) and significantly higher CSC (p < 0.001) and CIL (p < 0.001) compared to uncoated Pt electrodes. In vivo, the CSC and CIL of Pt-Ir were significantly higher than Pt throughout the implantation period (p= 0.047 and p< 0.001, respectively); however, the VT impedance (p= 0.3) was not. There was no difference in foreign body response between material cohorts, although cochleae implanted with coated electrodes contained small deposits of Pt-Ir. There was no evidence of increased neural loss or loss of neural function in either group. Surface examination revealed no Pt corrosion on any electrodes. SIGNIFICANCE: Electrodeposited Pt-Ir electrodes demonstrated significant improvements in electrochemical performance on the bench-top and in vivo compared to uncoated Pt. Neural function and tissue response to Pt-Ir electrodes were not different from uncoated Pt, despite small deposits of Pt-Ir in the tissue capsule. Electrodeposited Pt-Ir coatings offer promise as an improved electrode coating for active neural prostheses.

Electrodeposited platinum-iridium coating improves in vivo recording performance of chronically implanted microelectrode arrays.

Reliable single unit neuron recordings from chronically implanted microelectrode arrays (MEAs) are essential tools in the field of neural engineering. However, following implantation, MEAs undergo a foreign body response that functionally isolates them from the brain and reduces the useful longevity of the array. We tested a novel electrodeposited platinum-iridium coating (EPIC) on penetrating recording MEAs to determine if it improved recording performance. We chronically implanted the arrays in rats and used electrophysiological and histological measurements to compare quantitatively the single unit recording performance of coated vs. uncoated electrodes over a 12-week period. The coated electrodes had substantially lower impedance at 1 kHz and reduced noise, increased signal-to-noise ratio, and increased number of discernible units per electrode as compared to uncoated electrodes. Post-mortem immunohistochemistry showed no significant differences in the immune response between coated and uncoated electrodes. Overall, the EPIC arrays provided superior recording performance than uncoated arrays, likely due to lower electrode impedance and reduced noise.

Electrochemical and mechanical performance of reduced graphene oxide, conductive hydrogel, and electrodeposited Pt-Ir coated electrodes: an active in vitro study.

OBJECTIVE: To systematically compare the in vitro electrochemical and mechanical properties of several electrode coatings that have been reported to increase the efficacy of medical bionics devices by increasing the amount of charge that can be delivered safely to the target neural tissue. APPROACH: Smooth platinum (Pt) ring and disc electrodes were coated with reduced graphene oxide, conductive hydrogel, or electrodeposited Pt-Ir. Electrodes with coatings were compared with uncoated smooth Pt electrodes before and after an in vitro accelerated aging protocol. The various coatings were compared mechanically using the adhesion-by-tape test. Electrodes were stimulated in saline for 24 hours/day 7 days/week for 21 d at 85 °C (1.6-year equivalence) at a constant charge density of 200 µC/cm2/phase. Electrodes were graded on surface corrosion and trace analysis of Pt in the electrolyte after aging. Electrochemical measurements performed before, during, and after aging included electrochemical impedance spectroscopy, cyclic voltammetry, and charge injection limit and impedance from voltage transient recordings. MAIN RESULTS: All three coatings adhered well to smooth Pt and exhibited electrochemical advantage over smooth Pt electrodes prior to aging. After aging, graphene coated electrodes displayed a stimulation-induced increase in impedance and reduction in the charge injection limit (p  < 0.001), alongside extensive corrosion and release of Pt into the electrolyte. In contrast, both conductive hydrogel and Pt-Ir coated electrodes had smaller impedances and larger charge injection limits than smooth Pt electrodes (p  < 0.001) following aging regardless of the stimulus level and with little evidence of corrosion or Pt dissolution. SIGNIFICANCE: This study rigorously tested the mechanical and electrochemical performance of electrode coatings in vitro and provided suitable candidates for future in vivo testing.

MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia.

Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the development of leukemia. We performed a gain-of-function screen to identify proteins that enhanced signaling by leukemia-associated Notch1 mutants. The transcription factors MAFB and ETS2 emerged as candidates that individually enhanced Notch1 signaling, and when coexpressed, they synergistically increased signaling to an extent similar to that induced by core components of the Notch transcriptional complex. In mouse models of T-ALL, MAFB enhanced leukemogenesis by the naturally occurring Notch1 mutants, decreased disease latency, and increased disease penetrance. Decreasing MAFB abundance in mouse and human T-ALL cells reduced the expression of Notch1 target genes, including MYC and HES1, and sustained MAFB knockdown impaired T-ALL growth in a competitive setting. MAFB bound to ETS2 and interacted with the acetyltransferases PCAF and P300, highlighting its importance in recruiting coactivators that enhance Notch1 signaling. Together, these data identify a mechanism for enhancing the oncogenic potential of weak Notch1 mutants in leukemia models, and they reveal the MAFB-ETS2 transcriptional axis as a potential therapeutic target in T-ALL.

Long-term stability of intracortical recordings using perforated and arrayed Parylene sheath electrodes.

OBJECTIVE: Acquisition of reliable and robust neural recordings with intracortical neural probes is a persistent challenge in the field of neuroprosthetics. We developed a multielectrode array technology to address chronic intracortical recording reliability and present in vivo recording results. APPROACH: The 2 × 2 Parylene sheath electrode array (PSEA) was microfabricated and constructed from only Parylene C and platinum. The probe includes a novel three-dimensional sheath structure, perforations, and bioactive coatings that improve tissue integration and manage immune response. Coatings were applied using a sequential dip-coating method that provided coverage over the entire probe surface and interior of the sheath structure. A sharp probe tip taper facilitated insertion with minimal trauma. Fabricated probes were subject to examination by optical and electron microscopy and electrochemical testing prior to implantation. MAIN RESULTS: 1 × 2 arrays were successfully fabricated on wafer and then packaged together to produce 2 × 2 arrays. Then, probes having electrode sites with adequate electrochemical properties were selected. A subset of arrays was treated with bioactive coatings to encourage neuronal growth and suppress inflammation and another subset of arrays was implanted in conjunction with a virally mediated expression of Caveolin-1. Arrays were attached to a custom-made insertion shuttle to facilitate precise insertion into the rat motor cortex. Stable electrophysiological recordings were obtained during the period of implantation up to 12 months. Immunohistochemical evaluation of cortical tissue around individual probes indicated a strong correlation between the electrophysiological performance of the probes and histologically observable proximity of neurons and dendritic sprouting. SIGNIFICANCE: The PSEA demonstrates the scalability of sheath electrode technology and provides higher electrode count and density to access a greater volume for recording. This study provided support for the importance of creating a supportive biological environment around the probes to promote the long-term electrophysiological performance of flexible probes in the cerebral cortex. In particular, we demonstrated beneficial effects of the Matrigel coating and the long-term expression of Caveolin-1. Furthermore, we provided support to an idea of using an artificial acellular tissue compartment as a way to counteract the walling-off effect of the astrocytic scar formation around the probes as a means of establishing a more intimate and stable neural interface.

Matrigel coatings for Parylene sheath neural probes.

The biologically derived hydrogel Matrigel (MG) was used to coat a Parylene-based sheath intracortical electrode to act as a mechanical and biological buffer as well as a matrix for delivering bioactive molecules to modulate the cellular response and improve recording quality. MG was loaded with dexamethasone to reduce the immune response together with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) to maintain neuronal density and encourage neuronal ingrowth toward electrodes within the sheath. Coating the Parylene sheath electrode with the loaded MG significantly improved the signal-to-noise ratio for neural events recorded from the motor cortex in rat for more than 3 months. Electron microscopy showed even coverage of both the Parylene substrate and the platinum recording electrodes. Electrochemical impedance spectroscopy (EIS) of coated electrodes in 1× phosphate-buffered saline demonstrated low impedance required for recording neural signals. This result was confirmed by in vivo EIS data, showing significantly decreased impedance during the first week of recording. Dexamethasone, NGF, and BDNF loaded into MG were released within 1 day in 1× phosphate-buffered saline. Although previous studies showed that MG loaded with either the immunosuppressant or the neurotrophic factor cocktail provided modest improvement in recording quality in a 1-month in vivo study, the combination of these bioactive molecules did not improve the signal quality over coating probes with only MG in a 3-month in vivo study. The MG coating may further improve recording quality by optimizing the in vivo release profile for the bioactive molecules.