Workflow Times and Outcomes in Patients Triaged for a Suspected Severe Stroke.

INTRODUCTION: Current recommendations for regional stroke destination suggest that patients with severe acute stroke in non-urban areas should be triaged based on the estimated transport time to a referral thrombectomy-capable center. METHODS: We performed a post hoc analysis to evaluate the association of pre-hospital workflow times with neurological outcomes in patients included in the RACECAT trial. Workflow times evaluated were known or could be estimated before transport allocation. Primary outcome was the shift analysis on the modified Rankin score at 90 days. RESULTS: Among the 1,369 patients included, the median time from onset to emergency medical service (EMS) evaluation, the estimated transport time to a thrombectomy-capable center and local stroke center, and the estimated transfer time between centers were 65 minutes (interquartile ratio [IQR] = 43-138), 61 minutes (IQR = 36-80), 17 minutes (IQR = 9-27), and 62 minutes (IQR = 36-73), respectively. Longer time intervals from stroke onset to EMS evaluation were associated with higher odds of disability at 90 days in the local stroke center group (adjusted common odds ratio (acOR) for each 30-minute increment = 1.03, 95% confidence interval [CI] = 1.01-1.06), with no association in the thrombectomy-capable center group (acOR for each 30-minute increment = 1.01, 95% CI = 0.98-1.01, pinteraction  = 0.021). No significant interaction was found for other pre-hospital workflow times. In patients evaluated by EMS later than 120 minutes after stroke onset, direct transport to a thrombectomy-capable center was associated with better disability outcomes (acOR = 1.49, 95% CI = 1.03-2.17). CONCLUSION: We found a significant heterogeneity in the association between initial transport destination and neurological outcomes according to the elapse of time between the stroke onset and the EMS evaluation (ClinicalTrials.gov: NCT02795962). ANN NEUROL 2022;92:931-942.

Workflows and Outcomes in Patients With Suspected Large Vessel Occlusion Stroke Triaged in Urban and Nonurban Areas.

BACKGROUND: We aim to compare the outcome of patients from urban areas, where the referral center is able to perform thrombectomy, with patients from nonurban areas enrolled in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion). METHODS: Patients with suspected large vessel occlusion stroke, as evaluated by a Rapid Arterial Occlusion Evaluation score of ≥5, from urban catchment areas of thrombectomy-capable centers during RACECAT trial enrollment period were included in the Stroke Code Registry of Catalonia. Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with an ischemic stroke. Secondary outcomes included mortality at 90 days, rate of thrombolysis and thrombectomy, time from onset to thrombolysis, and thrombectomy initiation. Propensity score matching was used to assemble a cohort of patients with similar characteristics. RESULTS: The analysis included 1369 patients from nonurban areas and 2502 patients from urban areas. We matched 920 patients with an ischemic stroke from urban areas and nonurban areas based on their propensity scores. Patients with ischemic stroke from nonurban areas had higher degrees of disability at 90 days (median [interquartle range] modified Rankin Scale score, 3 [2-5] versus 3 [1-5], common odds ratio, 1.25 [95% CI, 1.06-1.48]); the observed average effect was only significant in patients with large vessel stroke (common odds ratio, 1.36 [95% CI, 1.08-1.65]). Mortality rate was similar between groups(odds ratio, 1.02 [95% CI, 0.81-1.28]). Patients from nonurban areas had higher odds of receiving thrombolysis (odds ratio, 1.36 [95% CI, 1.16-1.67]), lower odds of receiving thrombectomy(odds ratio, 0.61 [95% CI, 0.51-0.75]), and longer time from stroke onset to thrombolysis (mean difference 38 minutes [95% CI, 25-52]) and thrombectomy(mean difference 66 minutes [95% CI, 37-95]). CONCLUSIONS: In Catalonia, Spain, patients with large vessel occlusion stroke triaged in nonurban areas had worse neurological outcomes than patients from urban areas, where the referral center was able to perform thrombectomy. Interventions aimed at improving organizational practices and the development of thrombectomy capabilities in centers located in remote areas should be pursued. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795962.

Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT Randomized Clinical Trial.

Importance: In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown. Objective: To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center. Design, Setting, and Participants: Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020. Interventions: Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713). Main Outcomes and Measures: The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 [no symptoms] to 6 [death]) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients. Results: Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 [IQR, 65-83] years; median National Institutes of Health Stroke Scale score, 17 [IQR, 11-21]); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio [OR], 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 [47.5%] vs 282/467 [60.4%]; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 [48.8%] vs 184/467 [39.4%]; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 [27.3%] vs 194/713 [27.2%]; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18). Conclusions and Relevance: In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02795962.

Moving forward through the in silico modeling of tuberculosis: a further step with UISS-TB.

BACKGROUND: In 2018, about 10 million people were found infected by tuberculosis, with approximately 1.2 million deaths worldwide. Despite these numbers have been relatively stable in recent years, tuberculosis is still considered one of the top 10 deadliest diseases worldwide. Over the years, Mycobacterium tuberculosis has developed a form of resistance to first-line tuberculosis treatments, specifically to isoniazid, leading to multi-drug-resistant tuberculosis. In this context, the EU and Indian DBT funded project STriTuVaD-In Silico Trial for Tuberculosis Vaccine Development-is supporting the identification of new interventional strategies against tuberculosis thanks to the use of Universal Immune System Simulator (UISS), a computational framework capable of predicting the immunity induced by specific drugs such as therapeutic vaccines and antibiotics. RESULTS: Here, we present how UISS accurately simulates tuberculosis dynamics and its interaction within the immune system, and how it predicts the efficacy of the combined action of isoniazid and RUTI vaccine in a specific digital population cohort. Specifically, we simulated two groups of 100 digital patients. The first group was treated with isoniazid only, while the second one was treated with the combination of RUTI vaccine and isoniazid, according to the dosage strategy described in the clinical trial design. UISS-TB shows to be in good agreement with clinical trial results suggesting that RUTI vaccine may favor a partial recover of infected lung tissue. CONCLUSIONS: In silico trials innovations represent a powerful pipeline for the prediction of the effects of specific therapeutic strategies and related clinical outcomes. Here, we present a further step in UISS framework implementation. Specifically, we found that the simulated mechanism of action of RUTI and INH are in good alignment with the results coming from past clinical phase IIa trials.

Granulocytes-Rich Thrombi in Cerebral Large Vessel Occlusion Are Associated with Increased Stiffness and Poorer Revascularization Outcomes.

We aim to identify a profile of intracranial thrombus resistant to recanalization by mechanical thrombectomy (MT) in acute stroke treatment. The first extracted clot of each MT was analyzed by flow cytometry obtaining the composition of the main leukocyte populations: granulocytes, monocytes, and lymphocytes. Demographics, reperfusion treatment, and grade of recanalization were registered. MT failure (MTF) was defined as final thrombolysis in cerebral infarction score IIa or lower and/or need of permanent intracranial stenting as a rescue therapy. To explore the relationship between stiffness of intracranial clots and cellular composition, unconfined compression tests were performed in other cohorts of cases. Thrombi obtained in 225 patients were analyzed. MTF were observed in 30 cases (13%). MTF was associated with atherosclerosis etiology (33.3% vs. 15.9%; p = 0.021) and higher number of passes (3 vs. 2; p < 0.001). Clot analysis of MTF showed higher percentage of granulocytes [82.46 vs. 68.90% p < 0.001] and lower percentage of monocytes [9.18% vs.17.34%, p < 0.001] in comparison to successful MT cases. The proportion of clot granulocytes (aOR 1.07; 95% CI 1.01-1.14) remained an independent marker of MTF. Among thirty-eight clots mechanically tested, there was a positive correlation between granulocyte proportion and thrombi stiffness (Pearson's r = 0.35, p = 0.032), with a median clot stiffness of 30.2 (IQR, 18.9-42.7) kPa. Granulocytes-rich thrombi are harder to capture by mechanical thrombectomy due to increased stiffness, so a proportion of intracranial granulocytes might be useful to guide personalized endovascular procedures in acute stroke treatment.

Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients.

The antifibrinolytic enzyme carboxypeptidase U (CPU, TAFIa, CPB2) is an appealing target for the treatment of acute ischemic stroke (AIS). Increased insights in CPU activation and inactivation during thrombolysis (rtPA) with or without endovascular thrombectomy (EVT) are required to develop CPU inhibitors as profibrinolytic agents with optimal benefits/risks. Therefore, CPU kinetics during ischemic stroke treatment were evaluated. AIS patients with documented cerebral artery occlusion receiving rtPA (N = 20) or rtPA + EVT (N = 16) were included. CPU activation during thrombolysis was measured by an ultrasensitive HPLC-based CPU activity method and by an ELISA measuring both CPU and inactivated CPU (CPU + CPUi). Intravenous blood samples were collected at admission and throughout the first 24 h. Additional in situ blood samples were collected in the rtPA + EVT cohort proximal from the thrombus. The NIHSS score was determined at baseline and 24 h. CPU activity and CPU + CPUi levels increased upon rtPA administration and reached peak values at the end of thrombolysis (1 h). High inter-individual variability was observed in both groups. CPU activity decreased rapidly within 3 h, while CPU + CPUi levels were still elevated at 7 h. CPU activity or CPU + CPUi levels were similar in in situ and peripheral samples. No correlation between CPU or CPU + CPUi and NIHSS or thrombus localization was found. The CPU system was rapidly activated and deactivated following thrombolysis and thrombectomy in stroke patients, suggesting that a CPU inhibitor would have to be administered during rtPA infusion and over the next few hours. The high CPU generation variability suggests that some patients may not respond to the treatment. EudraCT number 2017-002760-41.

Geographic dissemination of endovascular stroke thrombectomy in Catalonia within the 2011-2015 period.

INTRODUCTION: Endovascular thrombectomy was recently established as a new standard of care in acute ischemic stroke patients with large artery occlusions. Using small area health statistics, we sought to assess dissemination of endovascular thrombectomy in Catalonia throughout the period 2011-2015. PATIENTS AND METHODS: We used registry data to identify all endovascular thrombectomies for acute ischemic stroke performed in Catalonia within the study period. The SONIIA registry is a government-mandated, population-based and externally audited data base that includes all reperfusion therapies for acute ischemic stroke. We linked endovascular thrombectomy cases identified in the registry with the Central Registry of the Catalan Public Health Insurance to obtain the primary care service area of residence for each treated patient, age and sex. We calculated age-sex standardized endovascular thrombectomy rates over time according to different territorial segmentation patterns (metropolitan/provincial rings and primary care service areas). RESULTS: Region-wide age-sex standardized endovascular thrombectomy rates increased significantly from 3.9 × 100,000 (95% confidence interval: 3.4-4.4) in 2011 to 6.8 × 100,000 (95% confidence interval: 6.2-7.6) in 2015. Such increase occurred in inner and outer metropolitan rings as well as provinces although highest endovascular thrombectomy rates were persistently seen in the inner metropolitan area. Changes in endovascular thrombectomy access across primary care service areas over time were more subtle, but there was a rather generalized increase of standardized endovascular thrombectomy rates. DISCUSSION: This study demonstrates temporal and territorial dissemination of access to endovascular thrombectomy in Catalonia over a 5-year period although variation remains at the completion of the study. CONCLUSION: Mapping of endovascular thrombectomy is essential to assess equity and propose actions for access dissemination.

Tuberculin immunotherapy: its history and lessons to be learned.

The use of tuberculin for the therapy of tuberculosis was attempted more than 100 years ago and abandoned because of its adverse reactions. In this historical review we point out that some of the intensive efforts to avoid the reactions were based on the best scientific rationale available at that time. Balancing the dosage and intervals of tuberculin delivery with clinical and laboratory monitoring of patients achieved a limited success, with implications, toward current research in the field. The role of economical and social aspects at that time is also a lesson to be learned toward current approaches to tuberculosis control.