BackgroundWhether pretreatment with intravenous thrombolysis prior to mechanical thrombectomy (IVT+MTE) adds additional benefit over direct mechanical thrombectomy (dMTE) in patients with large ...vessel occlusions (LVO) is a matter of debate.MethodsThis study-level meta-analysis was presented in accord with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled effect sizes were calculated using the inverse variance heterogeneity model and displayed as summary Odds Ratio (sOR) and corresponding 95% confidence interval (95% CI). Sensitivity analysis was performed by distinguishing between studies including dMTE patients eligible for IVT (IVT-E) or ineligible for IVT (IVT-IN). Primary outcome measures were functional independence (modified Rankin Scale≤2) and mortality at day 90, successful reperfusion, and symptomatic intracerebral hemorrhage.ResultsTwenty studies, incorporating 5279 patients, were included. There was no evidence that rates of successful reperfusion differed in dMTE and IVT+MTE patients (sOR 0.93, 95% CI 0.68 to 1.28). In studies including IVT-IN dMTE patients, patients undergoing dMTE tended to have lower rates of functional independence and had higher odds for a fatal outcome as compared with IVT+MTE patients (sOR 0.78, 95% CI 0.61 to 1.01 and sOR 1.45, 95% CI 1.22 to 1.73). However, no such treatment group effect was found when analyses were confined to cohorts with a lower risk of selection bias (including IVT-E dMTE patients).ConclusionThe quality of evidence regarding the relative merits of IVT+MTE versus dMTE is low. When considering studies with lower selection bias, the data suggest that dMTE may offer comparable safety and efficacy as compared with IVT+MTE. The conduct of randomized-controlled clinical trials seems justified.
Background
Polymerized allergens conjugated to non‐oxidized mannan (PM‐allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM‐allergoids are ...readily taken up by DCs and induce Treg cells. This first‐in‐human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM‐allergoid (PM‐HDM) administered subcutaneously (SC) or sublingually (SL).
Methods
In a randomized, double‐blind, double‐dummy, placebo‐controlled trial, 196 subjects received placebo or PM‐HDM at 500, 1000, 3000, or 5000 mannan‐conjugated therapeutic units (mTU)/mL in 9‐arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers.
Results
No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups.
Conclusions
PM‐HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.
This first‐in‐human study evaluates safety and optimal dose of PM‐HDM in SCIT and SLIT. PM‐HDM is safe and shows dose‐dependent clinical efficacy outcomes in SCIT and SLIT. A dose‐response in specific IgG4 to HDM is observed in SCIT, but not SLIT.Abbreviations: AIT, allergy immunotherapy; PM‐HDM, polymerized house dust mite allergoids conjugated with mannan; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy
OBJECTIVE:To investigate the effect of endovascular treatment on cognitive function as a prespecified secondary analysis of the REVASCAT (Endovascular Revascularization With Solitaire Device Versus ...Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours) trial.
METHODS:REVASCAT randomized 206 patients with anterior circulation proximal arterial occlusion stroke to Solitaire thrombectomy or best medical treatment alone. Patients with established dementia were excluded from enrollment. Cognitive function was assessed in person with Trail Making Test (TMT) Parts A and B at 3 months and 1 year after randomization by an investigator masked to treatment allocation. Test completion within 5 minutes, time of completion (seconds), and number of errors were recorded.
RESULTS:From November 2012 to December 2014, 206 patients were enrolled in REVASCAT. TMT was assessed in 82 of 84 patients undergoing thrombectomy and 86 of 87 control patients alive at 3 months and in 71 of 79 patients undergoing thrombectomy and 72 of 78 control patients alive at 1 year. Rates of timely TMT-A completion were similar in both treatment arms, although patients undergoing thrombectomy required less time for TMT-A completion and had higher rates of error-free TMT-A performance. Thrombectomy was also associated with a higher probability of timely TMT-B completion (adjusted odds ratio 3.17, 95% confidence interval 1.51–6.66 at 3 months; and adjusted ratio 3.66, 95% confidence interval 1.60–8.35 at 1 year) and shorter time for TMT-B completion. Differences in TMT completion times between treatment arms were significant in patients with good functional outcome but not in those who were functionally dependent (modified Rankin Scale score >2). Poorer cognitive outcomes were significantly associated with larger infarct volume, higher modified Rankin Scale scores, and worse quality of life.
CONCLUSIONS:Thrombectomy improves TMT performance after stroke, especially among patients who reach good functional recovery.
CLINICALTRIALS.GOV IDENTIFIER:NCT01692379.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for patients with stroke from acute anterior circulation proximal arterial occlusion, thrombectomy improves performance on the TMT at 3 months.
BACKGROUND AND PURPOSE—The standard outcome measure in stroke research is modified Rankin scale (mRS) evaluated by local blinded investigators. We aimed to assess feasibility and reliability of 2 ...central adjudication methods of mRS in the setting of a randomized endovascular stroke trial.
METHODS—This is a secondary analysis derived from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) trial cohort. Primary outcome was distribution of mRS at 90 days. Local evaluation was done by certified investigators masked to treatment assignment using structured face-to-face interviews. In addition, central assessment was performed by 2 independent raters via structured phone interview (n=120) and via video recordings of the face-to-face interviews with local investigators (n=106). Interrater agreement was evaluated using kappa and discordance statistics. Sensitivity analyses for the primary end point using different adjudication approaches were performed. Correlation between mRS obtained with each modality and 24-hour follow-up infarct volumes was studied.
RESULTS—Using local evaluation as the reference, higher agreement rates were noted with central video than with central phone evaluations (kw 0.92 0.88–0.96 versus 0.77 0.72–0.83). Discrepancies in mRS scoring between local and central raters (phone- and video-based) were similar in both treatment allocation arms. Sensitivity analyses showed benefit of endovascular treatment irrespective of adjudication method, but higher odds ratios were observed with local evaluations. Final infarct volume was similarly correlated with mRS across all 3 evaluation modalities.
CONCLUSIONS—Central adjudication of mRS is feasible, reducing interrater variability and avoiding potential problems related to lack of blinding. Our findings may have implications in the planning of future randomized acute stroke trials, especially in those including nonpharmacological interventions.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01692379.
Summary Background The REVASCAT trial and other studies have shown that the neurovascular thrombectomy improves outcomes at 90 days post stroke. However, whether the observed benefit is sustained in ...the long term remains unknown. We report the results of the prespecified 12-month analysis of the REVASCAT trial. Methods Patients with acute ischaemic stroke who could be treated within 8 h of symptom onset were randomly assigned to medical therapy (including intravenous alteplase when eligible) and neurovascular thrombectomy with Solitaire FR or medical therapy alone. The main secondary outcome measure at 1 year follow-up was disability, measured using the modified Rankin Scale (mRS), ranging from 0 (no symptoms) to 6 (death) with categories 5 (severe disability) and 6 (death) collapsed into one category (severe disability or death), analysed as the distribution of the mRS. Additional prespecified secondary outcome measures included health-related quality of life measured with the EuroQol five dimensions questionnaire (EQ-5D) utility index (ranging from −0·3 to 1, higher values indicate better quality of life), the rate of functional independence (mRS 0–2), and cognitive function measured with the Trail Making Test (reported elsewhere). Treatment allocation was open label but endpoints at 12 months were assessed by masked investigators. The trial was registered at ClinicalTrials.gov , number NCT01692379. Findings From Nov 24, 2012, to Dec 12, 2014, 206 patients were randomly assigned to medical therapy plus endovascular treatment (n=103) or medical treatment alone (n=103), at four centres in Catalonia, Spain. At 12 months post randomisation, based on 205 of 206 outcomes available at 12 months, thrombectomy reduced disability over the range of the mRS (common adjusted odds ratio aOR 1·80, 95% CI 1·09–2·99), and improved functional independence (mRS=0–2; 45 44% of 103 patients vs 31 30% of 103 patients; aOR 1·86, 95% CI 1·01–3·44). Health-related quality of life was superior in the thrombectomy group (mean EQ-5D utility index score, 0·46 SD 0·38 in the thrombectomy group vs 0·33 0·33 in the control group, difference 0·12 95% CI 0·03–0·22; p=0·01). 1-year mortality was 23% (24 of 103 patients) in the thrombectomy group versus 24% (25 of 103 patients) in the control group. Interpretation At 12 months follow-up, neurovascular thrombectomy reduced post-stroke disability and improved health-related quality of life, indicating sustained benefit. These findings have important clinical and public health implications for evaluating the cost-effectiveness of the intervention in the long term. Funding Fundació Ictus Malaltia Vascular through an unrestricted grant from Medtronic.
La presente investigación propone la existencia de una Querella de la novela, una pequeña «guerre littéraire» de por lo menos treinta años de duración (1670-1700) en la que Antiguos y Modernos ...disputaron acerca del sentido y el valor del género novelesco en el primer campo literario francés. Frente a la idea del auge de la novela a partir del surgimiento de una única obra inaugural, ya sea el Lazarillo, el Quijote, La princesse de Clèves o Robinson Crusoe, esta tesis sostiene, en primer lugar, que la invención teórica del género fue a la vez causa y resultado de diversas controversias, cuyo análisis se plantea en los términos de una querella, equiparable a la Querelle du théâtre, la des inscriptions, la du merveilleux o la du sublime, con las que mantiene diversos puntos de contacto. En segundo lugar, que hubo una profunda relación de participación entre esta querella y la contemporánea Querella en torno a los Antiguos y los Modernos, en la que la novela fue confrontada con el modelo clásico de la épica, así como con los paradigmas antiguos de la tragedia y de la historia. Y, por último, que en el proceso de emergencia de la novela, marcado ideológica y retóricamente por la Querella, el género no sólo fue aducido como emblema de lo nuevo, sino que, a pesar de su consabida modernidad, encontró su fundamentación teórica y la base para su legitimación en la autoridad y las razones de los Antiguos. Asimismo, el estudio del discurso novelesco francés del siglo XVII revela que, desde las primeras poéticas barrocas hasta las teorizaciones de la nouvelle o nouvelle historique, la novela tendió a definirse primordialmente como una forma de escritura de la historia.
This thesis proposes the existence of a Quarrel of the novel, a “guerre littéraire” lasting at least thirty years (1670-1700) in which the Ancients and Moderns clashed over the meaning and value of the novelistic genre in early modern France. Against the notion of the rise of the novel from the emergence of a single founding work, whether Lazarillo, Don Quijote, La princesse de Clèves or Robinson Crusoe, I contend, firstly, that the theoretical invention of the genre was at once the cause and result of various controversies, which are analysed in terms of a a quarrel, comparable to the Querelle du théâtre, des inscriptions, du merveilleux or du sublime, with which it shares a number of features. Secondly, I argue that there was a fundamental interplay between this dispute and the concurrent Quarrel of the Ancients and Moderns, in which the novel was set in opposition to the classical model of the epic and the ancient paradigms of tragedy and history. Finally, I show that in the emergence of the novel, informed ideologically and rhetorically by the Quarrel, the genre was not only considered emblematic of the the new but also, and despite its overt modernity, discovered its legitimacy and theoretical roots in the authority and reasons of the Ancients. Examination of the French novelistic discourse of the seventeenth century also reveals that, from the earliest baroque poetics to the theoretical treatises on the nouvelle or nouvelle historique, the novel was defined fundamentally as a form of historical writing.
Extubation and emergence from anesthesia may lead to systemic and cerebral hemodynamic changes that endanger neurosurgical patients. We aimed to compare systemic and cerebral hemodynamic variables ...and cough incidence in neurosurgery patients emerging from general anesthesia with the standard procedure (endotracheal tube ETT extubation) or after replacement of the ETT with a laryngeal mask airway (LMA).
Forty-two patients undergoing supratentorial craniotomy under general anesthesia were included in a randomized open-label parallel trial. Patients were randomized (sealed envelopes labeled with software-generated randomized numbers) to awaken with the ETT in place or after its replacement with a ProSeal LMA. We recorded mean arterial pressure as the primary endpoint and heart rate, middle cerebral artery flow velocity, regional cerebral oxygen saturation, norepinephrine plasma concentrations, and coughing.
No differences were found between groups at baseline. All hemodynamic variables increased significantly from baseline in both groups during emergence. The ETT group had significantly higher mean arterial pressure (11.9 mm Hg; 95% confidence interval CI, 2.1-21.8 mm Hg) (P=0.017), heart rate (7.2 beats/min; 95% CI, 0.7-13.7 beats/min) (P=0.03), and rate-pressure product (1045.4; 95% CI, 440.8-1650) (P=0.001). Antihypertensive medication was administered to more ETT-group patients than LMA-group patients (9 42.9% vs. 3 14.3% patients, respectively; P=0.04). The percent increase in regional cerebral oxygen saturation was greater in the ETT group by 26.1% (95% CI, 9.1%-43.2%) (P=0.002), but no between-group differences were found in MCA flow velocity. Norepinephrine plasma concentrations rose in both groups between baseline and the end of emergence: LMA: from 87.5±7.1 to 125.6±17.3 pg/mL; and ETT: from 118.1±14.1 to 158.1±24.7 pg/mL (P=0.007). The differences between groups were not significant. The incidence of cough was higher in the ETT group (87.5%) than in the LMA group (9.5%) (P<0.001).
Replacing the ETT with the LMA before neurosurgical patients emerge from anesthesia results in a more favorable hemodynamic profile, less cerebral hyperemia, and a lower incidence of cough.
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