ABSTRACT
Background: Coronavirus disease 2019 (COVID-19), a novel respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can progress to critical illness and the development of acute respiratory distress syndrome (ARDS). Variability in clinical presentation has led to 2 distinct theoretical classifications of COVID-19 ARDS based on different phenotypical presentations. The first of which follows closely to traditional ARDS presenting as severe hypoxemia with markedly reduced lung compliance, whereas the second presents as severe hypoxemia with preserved to high lung compliance. With uncertainty surrounding the specific pathological and mechanistic nature of COVID-19, we designed this study to elucidate the potential benefits of inhaled epoprostenol in COVID-19 ARDS. Methods: This was a retrospective, observational, cohort study conducted at a 425-bed teaching hospital. Chart reviews of patients' electronic medical records were conducted and the following data were documented on a password-protected spreadsheet: patient demographics, administration of intravenous fluids and/or corticosteroids, rate and duration of inhaled epoprostenol (0.01-0.05 mcg/kg/min over 7 mL/hr per dose), and ventilator settings while on inhaled epoprostenol, mortality, and intensive care unit (ICU) length of stay (LOS). The primary objective was to evaluate the effect of inhaled epoprostenol on the number of ventilator-free days in COVID-19 patients. Secondary objectives included assessing the effects on ventilator settings, mortality, and ICU LOS. Results: Over the span of 8 months, the charts of 848 patients diagnosed with COVID-19 were reviewed for inclusion in the study. Of those patients, 40 patients (intervention arm) who received at least 1 dose of inhaled epoprostenol (0.01-0.05 mcg/kg/min over 7 mL/hr per dose) were randomly selected for entry into the study. In the control arm, 40 patients with a diagnosis of COVID-19 who did not receive epoprostenol were randomly selected. There were no statistically significant differences in outcomes between the epoprostenol and control arms, in regard to ventilator-free days, ICU LOS, hospital LOS, and in-hospital mortality. Based on maximum ventilator settings during the first 3 days of inhaled epoprostenol use, there were no statistically significant differences between the 2 groups except for an unexpectedly lower oxygen saturation in the epoprostenol group. Conclusion: The use of inhaled epoprostenol did not have a statistically significant effect on ventilator-free days, ventilator settings, hospital and ICU LOS, and overall in-hospital mortality.
ABSTRACT
Background: Functional recovery of arm movement typically plateaus following a stroke, leaving chronic motor deficits. Brain-computer interfaces (BCI) may be a potential treatment for post-stroke deficits. Methods: In this n-of-1 trial (NCT03913286), a person with chronic subcortical stroke with upper-limb motor impairment used a powered elbow-wrist-hand orthosis that opened and closed the affected hand using cortical activity, recorded from a percutaneous BCI comprised of four microelectrode arrays implanted in the ipsilesional precentral gyrus, based on decoding of spiking patterns and high frequency field potentials generated by imagined hand movements. The system was evaluated in a home setting for 12 weeks. Results: Robust single unit activity, modulating with attempted or imagined movement, was present throughout the precentral gyrus. The participant acquired voluntary control over a hand-orthosis, achieving 10 points on the Action Research Arm Test using the BCI, compared to 0 without any device, and 5 using myoelectric control. Strength, spasticity, the Fugl-Meyer scores improved. Conclusions: We demonstrate in a human being that ensembles of individual neurons in the cortex overlying a chronic supratentorial, subcortical stroke remain active and engaged in motor representation and planning and can be used to electrically bypass the stroke and promote limb function. The participant's ability to rapidly acquire control over otherwise paralyzed hand opening, more than 18 months after a stroke, may justify development of a fully implanted movement restoration system to expand the utility of fully implantable BCI to a clinical population that numbers in the tens of millions worldwide.
ABSTRACT
BACKGROUND: Nuclear receptor 4A2 (NR4A2) is an orphan nuclear receptor and constitutively active transcription factor expressed at elevated levels in inflamed joint tissues from patients with arthritis. Inflammatory mediators rapidly and potently induce NR4A2 expression in resident joint cells and infiltrating immune cells. This receptor promotes synovial hyperplasia by increasing proliferation of synoviocytes and inducing transcription of matrix degrading enzymes and pro-inflammatory mediators. In order to further elucidate the molecular mechanisms of NR4A2, we conducted a gene expression screen to identify novel transcriptional targets of NR4A2 that may contribute to arthritis progression. METHODS: NR4A2 was over-expressed in human synoviocytes by lentiviral transduction and gene expression changes were measured using qPCR arrays specific for inflammation, proliferation, adhesion, and migration pathways. Subsequent analysis focused on the most potently induced gene prolactin (PRL). Messenger RNA levels of PRL and PRL receptor (PRL-R) were measured by RT-qPCR and protein levels were measured by ELISA. PRL promoter studies were conducted in synoviocytes transiently transfected with NR4A2 and PRL reporter constructs. Molecular responses to PRL in synoviocytes were addressed using qPCR arrays specific for JAK/STAT signaling pathways. RESULTS: PRL was the most potently induced gene on the qPCR arrays, exhibiting a 68-fold increase in response to ectopic NR4A2. This gene encodes an immunomodulatory peptide hormone with roles in autoimmune diseases and inflammation. Induction of PRL mRNA and secreted protein by NR4A2 was confirmed in subsequent experiments, with increases of 300-fold and 18-fold respectively. Depletion of endogenous NR4A receptors with shRNA reduced basal and PGE2-induced PRL levels by 95%. At the transcriptional level, NR4A2 requires a functional DNA binding domain to transactivate the distal PRL promoter. Deletional analysis indicates that NR4A2 targets a region of the distal PRL promoter spanning -270 to -32 bp. In synoviocytes, recombinant PRL regulates several genes involved in inflammation, proliferation, and cell survival, suggesting that NR4A2 induced PRL may also impact these pathways and contribute to arthritis progression. CONCLUSIONS: These results provide the first evidence for transcriptional regulation of the immunomodulatory peptide hormone PRL by NR4A2 in synoviocytes, and highlight a novel molecular pathway in inflammatory arthritis.
