Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Herein, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to identify ligand-mediated interactions between distinct cellular compartments. To test this approach, we selected a model of amyotrophic lateral sclerosis (ALS), in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) kill wild-type motor neurons (MNs) by an unknown mechanism. Our integrative analysis that combines proteomics and regulatory network analysis infers the interaction between astrocyte-released amyloid precursor protein (APP) and death receptor-6 (DR6) on MNs as the top predicted ligand-receptor pair. The inferred deleterious role of APP and DR6 is confirmed in vitro in models of ALS. Moreover, the DR6 knockdown in MNs of transgenic mutSOD1 mice attenuates the ALS-like phenotype. Our results support the usefulness of integrative, systems biology approach to gain insights into complex neurobiological disease processes as in ALS and posit that the proposed methodology is not restricted to this biological context and could be used in a variety of other non-cell-autonomous communication mechanisms.

BACKGROUND: Intracerebral hemorrhage (ICH) carries significant morbidity and mortality. Previous single-center retrospective analysis suggests that end-stage renal disease (ESRD) is a risk factor for severe ICH and worse outcomes. This investigation aims to examine the impact of ESRD on ICH severity, complications, and outcomes using a multicenter national database. METHODS: The International Classification of Disease, Ninth and Tenth Revision Clinical Modification codes were used to query the National Inpatient Sample for patients with ICH and ESRD between 2010 and 2019. Primary endpoints were the functional outcome, length of stay (LOS), and in-hospital mortality. Multivariate variable regression models and a propensity-score matched analysis were established to analyze patient outcomes associated with baseline patient characteristics. RESULTS: We identified 211,266 patients with ICH, and among them, 7,864 (3.77%) patients had a concurrent diagnosis of ESRD. Patients with ESRD were younger (60.85 vs. 67.64, P < 0.01) and demonstrated increased ICH severity (0.78 vs. 0.77, P < 0.01). ESRD patients experienced higher rates of sepsis (15.9% vs. 6.15%, P < 0.01), acute myocardial infarction (8.05% vs. 3.65%, P < 0.01), and cardiac arrest (5.94% vs. 2.4%, P < 0.01). In addition, ESRD predicted poor discharge disposition (odds ratio [OR]: 2.385, 95% confidence interval [CI]: 2.227–2.555, P < 0.01), longer hospital LOS (OR: 1.629, 95% CI: 1.553–1.709, P < 0.01), and in-hospital mortality (OR: 2.786, 95% CI: 2.647–2.932, P < 0.01). CONCLUSIONS: This study utilizes a multicenter database to analyze the effect of ESRD on ICH outcomes. ESRD is a significant predictor of poor functional outcomes, in-hospital mortality, and prolonged stay in the ICH population.

To assess the impact of vagus nerve stimulation (VNS) on quality of life contributors such as rescue medications. Using the seizure diary application SeizureTracker™ database, we examined trends in rescue administration frequency before and after the first recorded VNS magnet swipe in patients with drug-resistant epilepsy who had 1) At least one VNS magnet swipe recorded in the diary, and 2) Recorded usage of a benzodiazepine rescue medication (RM) within 90 days prior to the first swipe. A paired Wilcoxon rank-sum test was used to assess changes in RM usage frequency between 30-, 60-, 90-, 180- and 360-day intervals beginning 30 days after first magnet swipe. Longitudinal changes in RM usage frequency were assessed with a generalized estimating equation model. We analyzed data of 95 patients who met the inclusion criteria. Median baseline seizure frequency was 8.3 seizures per month, with median baseline rescue medication usage frequency of 2.1 administrations per month (SD 3.3). Significant reductions in rescue medication usage were observed in the 91 to 180 day interval after first VNS magnet swipe, and at 181 to 360 days and at 361 to 720 days, with the magnitude of reduction increasing over time. Decreases in rescue medication usage were sustained when controlling for patients who did not record rescue medication use after the first VNS magnet swipe (N=91). Significant predictors of reductions in rescue medication included baseline frequency of rescue medication usage and time after first VNS magnet swipe. This retrospective analysis suggests that usage of rescue medications is reduced following the start of VNS treatment in patients with epilepsy, and that the magnitude of reduction may progressively increase over time.

Objectives: Chronic inflammation of the gastrointestinal tract is a hallmark of inflammatory bowel disease (IBD). This increased inflammation is thought to induce a hypercoagulable state that increases the risk for stroke. However, few studies have examined the association between IBD and acute ischemic stroke (AIS). Thus, this study aims to investigate the incidence, treatments, complications, and outcomes of AIS in patients with IBD. Materials & Methods: ICD-9-CM and ICD-10-CM codes were used to query the National Inpatient Sample for AIS and IBD diagnosis. Baseline demographics, clinical characteristics, complications, treatments, and outcomes were assessed through descriptive statistics, multivariate regression, and propensity score matching (PSM) analysis. Acute stroke severity was assessed using the National Institute of Heath's Stroke Severity Score (SSS) as a template. Results: 1,609,817 patients were diagnosed with AIS between 2010 through 2019. 7468 (0.46%) had concomitant diagnoses of IBD. AIS patients with IBS were younger, more likely to be white and female, but less likely to be obese. Although IBD patients had comparable stroke severities (p = 0.64) to their non-IBS counterparts, they received stroke intervention at statistically different rates than their non-IBD counterparts. Additionally, IBD patients had higher rates of in-hospital complications (p < 0.01) and longer lengths of stay (LOS) (p < 0.01). Conclusions: IBD patients develop AIS at a younger age with similar rates of stroke severity to their non-IBD counterparts, but receive higher rates of tissue plasminogen activator administration and decreased rates of mechanical thrombectomy. Our research shows that patients with IBD are at risk for AIS at an earlier age and are more likely to have complications. This underlies a connection between IBD and a hypercoagulable state that could predispose patients to AIS.

Background: Limited literature exists on the morbidity and mortality of AVM associated intracerebral hemorrhage (ICH) compared with non-AVM ICH. Objective: We examine morbidity and mortality in cAVM in a large nationwide inpatient sample to create a prognostic inpatient ruptured AVM mortality score. Methods: This retrospective cohort study from 2008 to 2014 compares outcomes in cAVM related hemorrhages and ICH utilizing the National Inpatient Sample database. Diagnostic codes for ICH and AVM underlying ICH were identified. We compared case fatality according to medical complications. Multivariate analysis was used to derive hazard ratios and 95% confidence intervals to assess odds of mortality. Results: We identified 6496 patients with ruptured AVMs comparing them to 627,185 admitted with ICH. Mortality was lower for ruptured AVMs (11%) compared to ICH (22%) [ p < 0.01]. Mortality associated factors were liver disease (OR 2.64, CI 1.81–3.85, p < .001), diabetes mellitus (OR 2.42, CI 1.38–4.22, p = 0.002), alcohol abuse (OR 1.81, CI 1.31–2.49, p = 0.001), hydrocephalus (OR 3.35 CI 2.81–4.00, p < 0.001), cerebral edema (OR 1.5, 1.25–1.85, p < 0.001), cardiac arrest (OR 15, CI 7.9–30, p < 0.001), and pneumonia (OR 1.93, CI 1.51–2.47, p < 0.001). A 0–5 ruptured AVM mortality score was developed: Cardiac arrest (=3), age >60 (=1), Black race (=1), chronic liver failure (=1) diabetes mellitus (=1), pneumonia (=1), alcohol abuse (=1) and cerebral edema (=1). Mortality increased with score. No patient with 5 or more points survived. Conclusion: The Ruptured AVM Mortality Score allows for risk stratification on patients with ICH due to ruptured AVM. This scale could prove useful in prognostication and patient education.