Ten-Year Trend in Age, Sex, and Racial Disparity in tPA (Alteplase) and Thrombectomy Use Following Stroke in the United States.

Background and Purpose: IV tPA (intravenous thrombolysis with alteplase) and mechanical thrombectomy (MT) utilization increased in acute ischemic stroke hospitalizations in the United States over the last decade. It is uncertain whether this increase occurred equally across all age, sex, and racial groups. Methods: Adult acute ischemic stroke hospitalizations (weighted n=4 442 657) contained in the 2008 to 2017 National Inpatient Sample were identified using International Classification of Diseases codes. Proportions of hospitalizations with IV tPA and MT were computed according to age, sex, and race. Joinpoint and multivariable-adjusted logistic regression models were used to evaluate trends over time. Results: Across this period, 32.4% of all hospitalizations were in patients ≥80 years, and 64.7% of these were women. IV tPA and MT use differed by age with highest proportion of utilization of both treatments in patients aged 18 to 39 years (IV tPA, 12.3%) and lowest percentage in patients aged ≥90 years (IV tPA, 7.9%). Utilization of both procedures increased over time in all age groups, but the pace of increase was faster in patients ≥90 years compared with patients aged 18 to 39 years (MT: odds ratio, 1.25 [95% CI, 1.20­1.35] per unit increase in year, P interaction <0.001). Frequency of utilization of IV tPA and MT was lower in Black patients compared with White patients in most age groups. Usage of both procedures increased over time in all races and after 2015, IV tPA utilization was >10% in all demographic subgroups except in Black patients 60 to 79 years and Black patients ≥80 years. Analysis of race-by-time interaction revealed the Black-vs-White treatment gaps for IV tPA (odds ratio, 1.02 [95% CI, 1.01­1.03]) and MT (odds ratio, 1.08 [95% CI,1.05­1.12]) declined over time (both P interaction <0.01). Sex-related differences in IV tPA use were noted, but this gap also declined over time. Conclusions: Age- and sex-related treatment gaps in IV tPA and MT reduced over the last decade. Racial disparity in IV tPA and MT utilization persists with particularly lower frequency of usage of both acute stroke treatments in Black patients compared with White patients, but race-associated treatment gaps also declined over time.

Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.

To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a ß-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated ß-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.

Alcohol withdrawal is associated with poorer outcome in acute ischemic stroke.

OBJECTIVE: To determine the association between alcohol abuse (AA) and alcohol withdrawal (AW) with acute ischemic stroke (AIS) outcomes. METHODS: All adult AIS admissions in the United States from 2004 to 2014 were identified from the National Inpatient Sample (weighted n = 4,438,968). Multivariable-adjusted models were used to evaluate the association of AW with in-hospital medical complications, mortality, cost, and length of stay in patients with AIS. RESULTS: Of the AA admissions, 10.6% of patients, representing 0.4% of all AIS, developed AW. The prevalence of AA and AW in AIS increased by 45.2% and 40.0%, respectively, over time (p for trend <0.001). Patients with AA were predominantly men (80.2%), white (65.9%), and in the 40- to 59-year (44.6%) and 60- to 79-year (45.6%) age groups. After multivariable adjustment, AIS admissions with AW had >50% increased odds of urinary tract infection, pneumonia, sepsis, gastrointestinal bleeding, deep venous thrombosis, and acute renal failure compared to those without AW. Patients with AW were also 32% more likely to die during their AIS hospitalization compared to those without AW (odds ratio 1.32, 95% confidence interval 1.11-1.58). AW was associated with ≈15-day increase in length of stay and ≈$5,000 increase in hospitalization cost (p < 0.001). CONCLUSION: AW is associated with increased cost, longer hospitalizations, and higher odds of medical complications and in-hospital mortality after AIS. Proactive surveillance and management of AW may be important in improving outcomes in these patients.