Neuromodulation in Intractable Epilepsy Through Responsive Vagal Nerve Stimulation: A Three-Year Retrospective Study at the University of Texas Medical Branch, Galveston.

BACKGROUND: Vagus nerve stimulation (VNS) functions through neuromodulatory mechanisms to provide quality of life improvements to those with drug-resistant epilepsy. Responsive VNS (rVNS) generators are designed to further reduce seizure burden by detecting ictal tachycardia and aborting seizures soon after their onset.  Methods: Electronic medical records were accessed from January 2015 to December 2018 to identify patients with epilepsy managed with rVNS generators. Data were collected on seizure burden before and after rVNS implantation. Seizure burden was compared using t-tests, and monthly seizure reductions were gauged with the McHugh scale. Twenty-seven individuals met inclusion criteria; 10 were eliminated due to prior VNS implantation or undocumented seizure frequencies. RESULTS: The average seizure burden prior to rVNS implantation was 24.78 seizures/month. Following generator placement, the mean seizure frequencies at three months, six months, 12 months, and 18 months were 6.81, 16.57, 5.65, and 5.78 seizures/month, respectively. However, despite documented reductions in the average monthly seizure frequency, we found no statistically significant differences in seizure frequency relative to baseline. CONCLUSION: While many participants showed individual reductions in seizure burden, this study was unable to definitively conclude that rVNS therapy leads to statistically significant reduction in seizure burden.

Impact of Acute Confusional State in Patients With COVID-19 and a Predictive Score.

BACKGROUND: Acute confusional state (ACS) in COVID-19 is shown to be associated with poor clinical outcomes. METHODS: We assessed the impact of ACS - defined as a documented deterioration of mental status from baseline on the alertness and orientation to time, place, and person - on inpatient mortality and the need for intensive care unit (ICU) transfer in inpatient admissions with active COVID-19 infection in a single-center retrospective cohort of inpatient admissions from a designated COVID-19 tertiary care center using an electronic health record system. Furthermore, we developed and validated a neurological history and symptom-based predictive score of developing ACS. RESULTS: Thirty seven out of 245 (15%) patients demonstrated ACS. Nineteen (51%) patients had multifactorial ACS, followed by 11 (30%) patients because of hypoxemia. ACS patients were significantly older (80 [70-85] years vs 50.5 [38-69] years, p < 0.001) and demonstrated more frequent history of dementia (43% vs 9%, p < 0.001) and epilepsy (16% vs 2%, p = 0.001). ACS patients observed significantly higher in-hospital mortality (45.9% vs 1.9%, aOR [adjusted odds ratio]: 15.7, 95% CI = 3.6-68.0, p < 0.001) and need for ICU transfer (64.9% vs 35.1%, aOR: 2.7, 95% CI = 1.2-6.1, p = 0.015). In patients who survived hospitalization, ACS was associated with longer hospital stay (6 [3.5-10.5] days vs 3 [2-7] day, p = 0.012) and numerically longer ICU stay (6 [4-10] days vs 3 [2-6] days, p = 0.078). A score to predict ACS demonstrated 75.68% sensitivity and 81.73% specificity at a cutoff of ≥3. CONCLUSION: A high prevalence of ACS was found in patients with COVID-19 in our study cohort. Patients with ACS demonstrated increased mortality and need for ICU care. An internally validated score to predict ACS demonstrated high sensitivity and specificity in our cohort.

Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is unclear whether HDACs modulate chronic inflammation or autoantibody production associated with MG pathogenesis. We examined expression profiles and serum levels of key inflammatory cytokines (IL-6 and IL-21) and acetylcholine receptor (AChR)-specific autoantibodies following pharmacological inhibition of key HDAC isoforms in a mouse model of MG. We found that HDAC inhibition significantly reduced the production of IL-6, but not IL-21, in AChR-stimulated PBMCs and splenocytes (n = 5 per group). Trichostatin (pan-HDAC inhibitor) treatment of MG-PBMCs (n = 2) also exhibited reduced production of induced IL-6. Although HDAC1 inhibition lowered IL-6 levels the most, HDAC2 inhibition depleted intracellular IL-6 and markedly reduced serum anti-AChR IgG2b in EAMG mice. The transcriptomic profiling and pathway mapping also revealed that autoimmunity-linked, major cell signaling pathways were differentially altered by HDAC1/2 inhibition. HDAC inhibition-mediated reduction in IL-6 and autoantibody levels also correlated with milder disease and preservation of muscle AChR in the treated mice. Overall, our findings revealed isoform-specific functional variance of HDACs in reducing inflammation and identified HDAC-regulated many genes underlying specific inflammatory and autoantibody pathways in EAMG. Thus, the study provides a rationale for further research to evaluate the HDACs or their gene targets as a potential adjunct treatment for MG.

Tales of diversity: Genomic and morphological characteristics of forty-six Arthrobacter phages.

The vast bacteriophage population harbors an immense reservoir of genetic information. Almost 2000 phage genomes have been sequenced from phages infecting hosts in the phylum Actinobacteria, and analysis of these genomes reveals substantial diversity, pervasive mosaicism, and novel mechanisms for phage replication and lysogeny. Here, we describe the isolation and genomic characterization of 46 phages from environmental samples at various geographic locations in the U.S. infecting a single Arthrobacter sp. strain. These phages include representatives of all three virion morphologies, and Jasmine is the first sequenced podovirus of an actinobacterial host. The phages also span considerable sequence diversity, and can be grouped into 10 clusters according to their nucleotide diversity, and two singletons each with no close relatives. However, the clusters/singletons appear to be genomically well separated from each other, and relatively few genes are shared between clusters. Genome size varies from among the smallest of siphoviral phages (15,319 bp) to over 70 kbp, and G+C contents range from 45-68%, compared to 63.4% for the host genome. Although temperate phages are common among other actinobacterial hosts, these Arthrobacter phages are primarily lytic, and only the singleton Galaxy is likely temperate.