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A dynamic STIRPAT model used in the current study is based on panel data from the eight most populous countries from 1975 to 2020, revealing the nonlinear effects of urbanization routes (percentage of total urbanization, percentage of small cities and percentage of large cities) on carbon dioxide (CO2) emissions. Using "Dynamic Display Unrelated Regression (DSUR)" and "Fully Modified Ordinary Least Squares (FMOLS)" regressions, the outcomes reflect that percentage of total urbanization and percentage of small cities have an incremental influence on carbon dioxide emissions. However, square percentage of small cities and square percentage of total urbanization have significant adverse effects on carbon dioxide (CO2) emissions. The positive relationship between the percentage of small cities, percentage of total urbanization and CO2 emissions and the negative relationship between the square percentage of small cities, square percentage of total urbanization and CO2 emissions legitimize the inverted U-shaped EKC hypothesis. The impact of the percentage of large cities on carbon dioxide emissions is significantly negative, while the impact of the square percentage of large cities on carbon dioxide emissions is significantly positive, validating a U-shaped EKC hypothesis. The incremental effect of percentage of small cities and percentage of total urbanization on long-term environmental degradation can provide support for ecological modernization theory. Energy intensity, Gross Domestic Product (GDP), industrial growth and transport infrastructure stimulate long-term CO2 emissions. Country-level findings from the AMG estimator support a U-shaped link between the percentage of small cities and CO2 emissions for each country in the entire panel except the United States. In addition, the Dumitrescu and Hulin causality tests yield a two-way causality between emission of carbon dioxide and squared percentage of total urbanization, between the percentage of the large cities and emission of carbon dioxide, and between energy intensity and emission of carbon dioxide. This study proposes renewable energy options and green city-friendly technologies to improve the environmental quality of urban areas. [ABSTRACT FROM AUTHOR]

Aims Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias. Methods and results Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (ICD) shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/cardiac resynchronization therapy-defibrillator (CRT-D) use, and the effect of sacubitril/valsartan was analysed. Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 0.65-0.97; p = 0.025). The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71-1.21) versus 0.53 (95% CI 0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020). Conclusions Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology. [ABSTRACT FROM AUTHOR]

On May 5, 2009, the U.S. Food and Drug Administration granted accelerated approval to bevacizumab injection (Avastin®; Genentech, Inc., South San Francisco, CA) as a single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroid use). Two trials evaluating bevacizumab, 10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brain hemorrhage were excluded. One trial enrolled 78 independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%-36.1%) of the patients. The median response duration was 4.2 months (95% CI, 3.0-5.7 months). The second trial enrolled 56GBMpatients. Partial responses were observed in 19.6% (95% CI, 10.9%-31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4-17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design. The Oncologist 2009;14:1131-1138 [ABSTRACT FROM AUTHOR]

Objective: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications. Background: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives. Methods: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes. Results: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications. Conclusions: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications. Trial registration: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015. [ABSTRACT FROM AUTHOR]

Background: Systems of care have been developed across the United States to standardize care processes and improve outcomes in patients with ST-segment-elevation myocardial infarction (STEMI). The effect of contemporary STEMI systems of care on racial and ethnic disparities in achievement of time-to-treatment goals and mortality in STEMI is uncertain., Methods: We analyzed 178 062 patients with STEMI (52 293 women and 125 769 men) enrolled in the American Heart Association Get With The Guidelines-Coronary Artery Disease registry between January 1, 2015, and December 31, 2021. Patients were stratified into and outcomes compared among 3 racial and ethnic groups: non-Hispanic White, Hispanic White, and Black. The primary outcomes were the proportions of patients achieving the following STEMI process metrics: prehospital ECG obtained by emergency medical services; hospital arrival to ECG obtained within 10 minutes for patients not transported by emergency medical services; arrival-to-percutaneous coronary intervention time within 90 minutes; and first medical contact-to-device time within 90 minutes. A secondary outcome was in-hospital mortality. Analyses were performed separately in women and men, and all outcomes were adjusted for age, comorbidities, acuity of presentation, insurance status, and socioeconomic status measured by social vulnerability index based on patients' county of residence., Results: Compared with non-Hispanic White patients with STEMI, Hispanic White patients and Black patients had lower odds of receiving a prehospital ECG and achieving targets for door-to-ECG, door-to-device, and first medical contact-to-device times. These racial disparities in treatment goals were observed in both women and men, and persisted in most cases after multivariable adjustment. Compared with non-Hispanic White women, Hispanic White women had higher adjusted in-hospital mortality (odds ratio, 1.39 [95% CI, 1.12-1.72]), whereas Black women did not (odds ratio, 0.88 [95% CI, 0.74-1.03]). Compared with non-Hispanic White men, adjusted in-hospital mortality was similar in Hispanic White men (odds ratio, 0.99 [95% CI, 0.82-1.18]) and Black men (odds ratio, 0.96 [95% CI, 0.85-1.09])., Conclusions: Race- or ethnicity-based disparities persist in STEMI process metrics in both women and men, and mortality differences are observed in Hispanic White compared with non-Hispanic White women. Further research is essential to evolve systems of care to mitigate racial differences in STEMI outcomes., Competing Interests: Disclosures None.

BACKGROUND: Three novel acute treatments for migraine-lasmiditan, ubrogepant, and rimegepant-were approved by the FDA in 2019 and 2020 for adults with migraine with and without aura. American Headache Society guidance recommends that these novel acute treatments be considered for patients who are contraindicated to or fail to respond or tolerate oral triptans, the current standard of acute care. OBJECTIVE: To estimate, from a US commercial plan perspective, the budget impact of adding lasmiditan as an option to a formulary that already includes ubrogepant and rimegepant. METHODS: Epidemiologic data were drawn from US Census data, the American Migraine Prevalence and Preventive study, and the first wave of the OVERCOME US survey, a web-based survey that included 21,000 patients with migraine. A model with a 3-year time horizon was built assuming that demand for the novel acute treatments would not vary based on whether lasmiditan is included in the formulary. The model examined a variety of populations, in particular beneficiaries with previous use of 1 or more oral triptans or contraindicated to triptans and beneficiaries with previous use of 2 or more oral triptans or contraindicated to triptans. Primary outcomes were the incremental differences in total cost and average cost per member per month (PMPM) between scenarios with and without lasmiditan. One-way sensitivity analyses with model parameters that were varied by plus or minus 15% were conducted to assess the effect of key parameters on the incremental total cost over 3 years. RESULTS: The addition of lasmiditan to a formulary that already includes ubrogepant and rimegepant resulted in a total savings of -$927,657 (-1.5% compared with the scenario without lasmiditan) over a 3-year time horizon in the population with previous history of using 1 or more oral triptans or contraindicated to a triptan. In the population with previous history of using 2 or more oral triptans or contraindicated, the addition of lasmiditan resulted in a total budget impact of -$466,518 (-1.3%) over a 3-year time horizon. Most of the cost savings was attributable to reductions in drug acquisition cost. Savings in total costs resulted in average incremental cost per PMPM of -0.03 and -$0.01, respectively. CONCLUSIONS: The addition of lasmiditan to the formulary as a novel acute treatment option for migraine alongside ubrogepant and rimegepant resulted in lower budget impact on a 3-year time horizon from a US commercial payer's perspective. This result is important to US commercial payers as they seek to incorporate the emerging novel acute treatments for migraine into their benefit designs. DISCLOSURES : This work was funded by Eli Lilly and Company. Milev and Sun are employed by Evidera, which received funding from Eli Lilly and Company for work on this project. Pohl, Mason, Njuguna, and Loo are employees and stockholders of Eli Lilly and Company.