Usefulness of a single-parameter tool for the prediction of large vessel occlusion in acute stroke.

BACKGROUND: In acute stroke, large vessel occlusion (LVO) should be promptly identified to guide patient's transportation directly to comprehensive stroke centers (CSC) for mechanical thrombectomy (MT). In many cases, prehospital multi-parameter scores are used by trained emergency teams to identify patients with high probability of LVO. However, in several countries, the first aid organization without intervention of skilled staff precludes the on-site use of such scores. Here, we assessed the accuracy of LVO prediction using a single parameter (i.e. complete hemiplegia) obtained by bystander's telephone-based witnessing. PATIENTS AND METHODS: This observational, single-center study included consecutive patients who underwent intravenous thrombolysis at the primary stroke center and/or were directly transferred to a CSC for MT, from January 1, 2015 to March 1, 2020. We defined two groups: patients with initial hemiplegia (no movement in one arm and leg and facial palsy) and patients without initial hemiplegia, on the basis of a bystander's witnessing. RESULTS: During the study time, 874 patients were included [mean age 73 years (SD 13.8), 56.7% men], 320 with initial hemiplegia and 554 without. The specificity of the hemiplegia criterion to predict LVO was 0.88, but its sensitivity was only 0.53. CONCLUSION: Our results suggest that the presence of hemiplegia as witnessed by a bystander can predict LVO with high specificity. This single criterion could be used for decision-making about direct transfer to CSC for MT when the absence of emergency skilled staff precludes the patient's on-site assessment, especially in regions distant from a CSC.

Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease.

Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84-/- mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications.

Shortening time to reperfusion after transfer from a primary to a comprehensive stroke center.

BACKGROUND: This study assessed whether a quality improvement (QI) process to streamline transfer from a primary stroke center (PSC) to a comprehensive stroke center (CSC) could reduce the delay of reperfusion by mechanical thrombectomy (MT). METHODS: From 2015 to 2017, a QI process was implemented with specific interventions to reduce door-in-to-door-out (DIDO) time in a high volume PSC, and speed up interhospital transfer and inhospital processes at the CSC. Clinical characteristics and time metrics were compared in the QI (2015-2017; n = 157) and pre-QI cohorts (2012-2014; n = 121). RESULTS: During the QI process, the median symptom onset to reperfusion time was reduced by 50 minutes (367 vs 417 minutes in the pre-QI cohort, p < 0.04), with a substantial 40-minute DIDO reduction (78 vs 118 minutes, p < 0.01), related to the faster administration of IV thrombolysis (median door-to-needle time: 49 vs 82 minutes, p = 0.0001). The door-to-door time was shortened (170 vs 205 minutes, p = 0.002), but not the transfer time (92 vs 87 minutes, p = 0.5). The QI process had no effect on the prehospital phase (77 vs 76 minutes, p = 0.83) and on the time from MRI imaging at the PSC to reperfusion (252 vs 288 minutes, p = 0.12). The rate of modified Rankin Scale score 0-2 at 90 days was comparable in the pre-QI and QI cohorts. CONCLUSIONS: A QI process can reduce the reperfusion therapy delay in a distant CSC; however, we could not demonstrate that it can also improve the outcome of patients who undergo MT.

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway.

Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We previously showed that 2-(3-pentylphenyl)acetic acid (PBI-4050) is a dual G protein-coupled receptor GPR40 agonist/GPR84 antagonist that exerts antifibrotic, anti-inflammatory, and antiproliferative action. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The antifibrotic effect of PBI-4050 was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation-induced liver fibrosis rodent models. Treatment with PBI-4050 suppressed CCl4-induced serum aspartate aminotransferase levels, inflammatory marker nitric oxide synthase, epithelial to mesenchymal transition transcription factor Snail, and multiple profibrotic factors. PBI-4050 also decreased GPR84 mRNA expression in CCl4-induced injury, while restoring peroxisome proliferator-activated receptor γ (PPARγ) to the control level. Collagen deposition and α-smooth muscle actin (α-SMA) protein levels were also attenuated by PBI-4050 treatment in the bile duct ligation rat model. Transforming growth factor-ß-activated primary HSCs were used to examine the effect of PBI-4050 and its mechanism of action in vitro. PBI-4050 inhibited HSC proliferation by arresting cells in the G0/G1 cycle phase. Subsequent analysis demonstrated that PBI-4050 signals through a reduction of intracellular ATP levels, activation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), and blockade of mammalian target of rapamycin (mTOR), resulting in reduced protein and mRNA levels of α-SMA and connective tissue growth factor and restored PPARγ mRNA expression. Our findings suggest that PBI-4050 may exert antifibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway in stellate cells, and PBI-4050 may be a promising agent for treating liver fibrosis.

Target Door-to-Needle Time for Tissue Plasminogen Activator Treatment with Magnetic Resonance Imaging Screening Can Be Reduced to 45 min.

OBJECTIVE: The purpose of this study was to demonstrate that the median door-to-needle (DTN) time for intravenous tissue plasminogen activator (tPA) treatment can be reduced to 45 min in a primary stroke centre with MRI-based screening for acute ischaemic stroke (AIS). METHODS: From February 2015 to February 2017, the stroke unit of Perpignan general hospital, France, implemented a quality-improvement (QI) process. During this period, patients who received tPA within 4.5 h after AIS onset were included in the QI cohort. Their clinical characteristics and timing metrics were compared each semester and also with those of 135 consecutive patients with AIS treated by tPA during the 1-year pre-QI period (pre-QI cohort). RESULTS: In the QI cohort, 274 patients (92.5%) underwent MRI screening. While the demographic and baseline characteristics were not significantly different between cohorts, the median DTN time was significantly lower in the QI than in the pre-QI cohort (52 vs. 84 min; p < 0.00001). Within the QI cohort, the median DTN time for each semester decreased from 65 to 44 min (p < 0.00001) and the proportion of treated patients with a DTN time ≤45 min increased from 25 to 58.9% (p < 0.0001). Overall, DTN time improvement was associated with a better outcome at 3 months (patients with a modified Rankin Scale score between 0 and 2: 61.8% in the QI vs. 39.3% in the pre-QI cohort; p < 0.0001). CONCLUSIONS: A QI process can reduce the DTN within 45 min with MRI as a screening tool.

A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84.

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.