IMPORTANCE: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. OBJECTIVE: To determine whether 0.40 mg/kg ...of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria. INTERVENTIONS: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy. MAIN OUTCOMES AND MEASURES: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale mRS score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death. RESULTS: All 300 patients who were randomized (mean age, 72.7 years; 141 47% women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% 95% CI, −8.9% to −8.9%; adjusted risk ratio, 1.03 95% CI, 0.66-1.61; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 17% vs 22 15%; unadjusted risk difference, 2.7% 95% CI, −5.6% to 11.0%) or symptomatic intracranial hemorrhage (7 4.7% vs 2 1.3%; unadjusted risk difference, 3.3% 95% CI, −0.5% to 7.2%). CONCLUSIONS AND RELEVANCE: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03340493
BACKGROUND AND PURPOSE—In malignant infarction, brain edema leads to secondary neurological deterioration and poor outcome. We sought to determine whether swelling is associated with outcome in ...smaller volume strokes.
METHODS—Two research cohorts of acute stroke subjects with serial brain MRI were analyzed. The categorical presence of swelling and infarct growth was assessed on diffusion-weighted imaging (DWI) by comparing baseline and follow-up scans. The increase in stroke volume (ΔDWI) was then subdivided into swelling and infarct growth volumes using region-of-interest analysis. The relationship of these imaging markers with outcome was evaluated in univariable and multivariable regression.
RESULTS—The presence of swelling independently predicted worse outcome after adjustment for age, National Institutes of Health Stroke Scale, admission glucose, and baseline DWI volume (odds ratio, 4.55; 95% confidence interval, 1.21–18.9; P<0.02). Volumetric analysis confirmed that ΔDWI was associated with outcome (odds ratio, 4.29; 95% confidence interval, 2.00–11.5; P<0.001). After partitioning ΔDWI into swelling and infarct growth volumetrically, swelling remained an independent predictor of poor outcome (odds ratio, 1.09; 95% confidence interval, 1.03–1.17; P<0.005). Larger infarct growth was also associated with poor outcome (odds ratio, 7.05; 95% confidence interval, 1.04–143; P<0.045), although small infarct growth was not. The severity of cytotoxic injury measured on apparent diffusion coefficient maps was associated with swelling, whereas the perfusion deficit volume was associated with infarct growth.
CONCLUSIONS—Swelling and infarct growth each contribute to total stroke lesion growth in the days after stroke. Swelling is an independent predictor of poor outcome, with a brain swelling volume of ≥11 mL identified as the threshold with greatest sensitivity and specificity for predicting poor outcome.
Ischemia-reperfusion (I/R) injuries are implicated in a large array of pathological conditions such as myocardial infarction, cerebral stroke, and hepatic, renal, and intestinal ischemia, as well as ...following cardiovascular and transplant surgeries. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands such as low-molecular hyaluronic acid, fibronectin, heat shock protein 70, and heparin sulfate were all found to be cleaved in the inflamed tissue and to activate TLR2 and TLR4, initiating an inflammatory response even in the absence of pathogens and infiltrating immune cells. In this review, we discuss the contribution of TLR activation in hepatic, renal, cerebral, intestinal, and myocardial I/R injuries. A greater understanding of the role of TLRs in I/R injuries may aid in the development of specific TLR-targeted therapeutics to treat these conditions.
C3a is a key complement activation fragment, yet its neutrophil-expressed receptor (C3aR) still has no clearly defined role. In this study, we used a neutrophil-dependent mouse model of intestinal ...ischemia-reperfusion (IR) injury to explore the role of C3aR in acute tissue injuries. C3aR deficiency worsened intestinal injury, which corresponded with increased numbers of tissue-infiltrating neutrophils. Circulating neutrophils were significantly increased in C3aR ⁻/⁻ mice after intestinal ischemia, and C3aR ⁻/⁻ mice also mobilized more circulating neutrophils after granulocyte colony-stimulating factor infusion compared with WT mice, indicating a specific role for C3aR in constraining neutrophil mobilization in response to intestinal injury. In support of this role, C3aR ⁻/⁻ mice reconstituted with WT bone marrow reversed IR pathology back to WT levels. Complement C5a receptor (C5aR) antagonism in C3aR ⁻/⁻ mice also rectified the worsened pathology after intestinal IR injury but had no effect on circulating neutrophils, highlighting the opposing roles of C3a and C5a in disease pathogenesis. Finally, we found that using a potent C3a agonist to activate C3aR in vivo reduced neutrophil mobilization and ameliorated intestinal IR pathology in WT, but not C3aR ⁻/⁻, mice. This study identifies a role for C3aR in regulating neutrophil mobilization after acute intestinal injury and highlights C3aR agonism as a potential treatment option for acute, neutrophil-driven pathologies.
About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre ...case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors.
We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity.
During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4).
Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.
This study examined the theoretical relationships between consumers' perceived benefits, place attachment and future visit intentions (FVI) at nature-based recreation and tourism areas, utilizing ...importance and performance concepts. The desired benefits and perceived attained benefits of consumers were treated as an antecedent to place attachment and FVI in structural models. Results of two separate structural models tests using responses from 934 visitors at the Ocala National Forest in Florida, USA, confirmed that place attachment fully mediates the relationship between benefits desired and FVI, while place attachment partially mediates the relationship between benefits attained and FVI. The former verifies the significant role of place attachment, and the latter validates the importance of place attachment as well as recreation benefit attainment in predicting visitors' FVI. These findings suggest that both benefits desired and benefits attained are important predictors of place attachment and behavioral intentions. Accordingly, tourism and recreation planners and managers need to provide visitors with recreation opportunities, which maximize visitors' ability to attain recreation benefits, such as nature exploration, physical fitness and escape. These managerial initiatives would result in increasing visitors' emotional attachments and intentions to revisit.
Eph/Ephrin Signaling in Injury and Inflammation Coulthard, Mark G; Morgan, Michael; Woodruff, Trent M ...
The American journal of pathology,
11/2012, Letnik:
181, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The Eph/ephrin receptor–ligand system plays an important role in embryogenesis and adult life, principally by influencing cell behavior through signaling pathways, resulting in modification of the ...cell cytoskeleton and cell adhesion. There are 10 EphA receptors, and six EphB receptors, distinguished on sequence difference and binding preferences, that interact with the six glycosylphosphatidylinositol-linked ephrin-A ligands and the three transmembrane ephrin-B ligands, respectively. The Eph/ephrin proteins, originally described as developmental regulators that are expressed at low levels postembryonically, are re-expressed after injury to the optic nerve, spinal cord, and brain in fish, amphibians, rodents, and humans. In rodent spinal cord injury, the up-regulation of EphA4 prevents recovery by inhibiting axons from crossing the injury site. Eph/ephrin proteins may be partly responsible for the phenotypic changes to the vascular endothelium in inflammation, which allows fluid and inflammatory cells to pass from the vascular space into the interstitial tissues. Specifically, EphA2/ephrin-A1 signaling in the lung may be responsible for pulmonary inflammation in acute lung injury. A role in T-cell maturation and chronic inflammation (heart failure, inflammatory bowel disease, and rheumatoid arthritis) is also reported. Although there remains much to learn about Eph/ephrin signaling in human disease, and specifically in injury and inflammation, this area of research raises the exciting prospect that novel therapies will be developed that precisely target these pathways.
While numerous studies have examined the developmental trajectory of task-based neural oscillations during childhood and adolescence, far less is known about the evolution of spontaneous cortical ...activity during this time period. Likewise, many studies have shown robust sex differences in task-based oscillations during this developmental period, but whether such sex differences extend to spontaneous activity is not understood.
Herein, we examined spontaneous cortical activity in 111 typically-developing youth (ages 9–15 years; 55 male). Participants completed a resting state magnetoencephalographic (MEG) recording and a structural MRI. MEG data were source imaged and the power within five canonical frequency bands (delta, theta, alpha, beta, gamma) was computed. The resulting power spectral density maps were analyzed via vertex-wise ANCOVAs to identify spatially-specific effects of age, sex, and their interaction.
We found robust increases in power with age in all frequencies except delta, which decreased over time, with findings largely confined to frontal cortices. Sex effects were distributed across frontal and temporal regions; females tended to have greater delta and beta power, whereas males had greater alpha. Importantly, there was a significant age-by-sex interaction in theta power, such that males exhibited decreasing power with age while females showed increasing power with age in the bilateral superior temporal cortices.
These data suggest that the strength of spontaneous activity undergoes robust change during the transition from childhood to adolescence (i.e., puberty onset), with intriguing sex differences in some cortical areas. Future developmental studies should probe task-related oscillations and spontaneous activity in parallel.
Many scientific researchers aspire to engage policy in their writing, but translating scientific research and findings into policy discussion often requires an understanding of the institutional ...complexities of legal and policy processes and actors. To examine how researchers have undertaken that challenge, we developed a set of metrics and applied them to articles published in one of the principal academic publication venues for science and policy-Science magazine's Policy Forum. We reviewed each Policy Forum article published over a five-year period (2011-15), 220 in all. For each article, we assessed the level of policy content based on presence of a stated policy proposal or position and identification of the relevant policy actors and actions, and recorded attributes such as field of science, field of policy, number of references to legal and policy sources, number of authors from law and policy institutions, and number of citations. We find that a handful of science fields dominate publication frequency, but that all fields have produced publications with high policy engagement. Of the attributes, number of references to law and policy sources is correlated positively with level of engagement, whereas number of law and policy authors was fairly constant across all depths of engagement. Surprisingly, level of policy engagement was negatively correlated with the number of citations an article subsequently received. We offer possible explanations for these results and thoughts for authors, editors, and research institutions interested in facilitating robust engagement of policy in scientific writing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract We analyze the evolution of massive (log 10 M ⋆ / M ⊙ > 10) galaxies at z ∼ 1–4 selected from JWST Cosmic Evolution Early Release Survey (CEERS). We infer the physical properties of all ...galaxies in the CEERS NIRCam imaging through spectral energy distribution (SED) fitting with dense basis to select a sample of high-redshift massive galaxies. Where available we include constraints from additional CEERS observing modes, including 18 sources with MIRI photometric coverage, and 28 sources with spectroscopic confirmations from NIRSpec or NIRCam WFSS. We sample the recovered posteriors in stellar mass from SED fitting to infer the volume densities of massive galaxies across cosmic time, taking into consideration the potential for sample contamination by active galactic nuclei. We find that the evolving abundance of massive galaxies tracks expectations based on a constant baryon conversion efficiency in dark matter halos for z ∼ 1–4. At higher redshifts, we observe an excess abundance of massive galaxies relative to this simple model, resulting in a shallower decline of observed volume densities of massive galaxies. These higher abundances can be explained by modest changes to star formation physics and/or the efficiencies with which star formation occurs in massive dark matter halos, and are not in tension with modern cosmology.
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