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Saccharomyces cerevisiae bearing engineered alginate and mannitol catabolic pathways can ferment sugars from brown macroalgae to produce ethanol, potentially allowing the use of brown macroalgae as a viable feedstock for the production of biofuels and renewable chemicals. Brown algae as a biofuel feedstock Brown macroalgae are seen as a viable feedstock for the production of biofuels, with the advantage that they can be farmed in coastal waters without using valuable arable land. However, the most abundant sugars in brown macroalgae are alginate, mannitol and glucan, and the full potential of this feedstock cannot be realized without extensive re-engineering of the alginate and mannitol catabolic pathways in Saccharomyces cerevisiae . In this paper the authors identify a 4-deoxy-L-erythro-5-hexoseulose uronate transporter in Asteromyces cruciatus brown algae and use it to develop a S. cerevisiae strain that can use the unique sugars in brown macroalgae for high-efficiency ethanol fermentation. With appropriate genetic modifications, this synthetic biology platform can be used to produce many other biofuels and renewable chemicals. The increasing demands placed on natural resources for fuel and food production require that we explore the use of efficient, sustainable feedstocks such as brown macroalgae. The full potential of brown macroalgae as feedstocks for commercial-scale fuel ethanol production, however, requires extensive re-engineering of the alginate and mannitol catabolic pathways 1 , 2 , 3 in the standard industrial microbe Saccharomyces cerevisiae . Here we present the discovery of an alginate monomer (4-deoxy- l -erythro-5-hexoseulose uronate, or DEHU) transporter from the alginolytic eukaryote Asteromyces cruciatus 4 . The genomic integration and overexpression of the gene encoding this transporter, together with the necessary bacterial alginate and deregulated native mannitol catabolism genes, conferred the ability of an S. cerevisiae strain to efficiently metabolize DEHU and mannitol. When this platform was further adapted to grow on mannitol and DEHU under anaerobic conditions, it was capable of ethanol fermentation from mannitol and DEHU, achieving titres of 4.6% (v/v) (36.2 g l −1 ) and yields up to 83% of the maximum theoretical yield from consumed sugars. These results show that all major sugars in brown macroalgae can be used as feedstocks for biofuels and value-added renewable chemicals in a manner that is comparable to traditional arable-land-based feedstocks.

Phosphorylation of the calcium transporting adenosinetriphosphatase of rabbit sarcoplasmic reticulum by La$\\sp{3+}\\cdot$ ATP and the dissociation of calcium from the phosphorylated enzyme formed from Mg$\\cdot$ATP were investigated with rapid-quench reaction techniques. Conditions for the experiments were 25$\\sp\\circ$C, 100 mM KCl and 40 mM MOPS, pH 7.0. The enzyme with bound calcium ($\\sp{\\rm c}$E$\\cdot$Ca$\\sb2$) is phosphorylated by 200 $\\mu$M ($\\gamma$-$\\sp{32}$P) La$\\cdot$ATP with an observed rate constant of k = 6.5 s$\\sp{-1}$. The reaction of the labeled phosphoenzyme (EP) with ADP in the presence of labeled ATP is biphasic; a burst of phosphoenzyme disappearance is followed by a slower first-order disappearance, which proceeds gives an equilibrium mixture of EP, EP$\\cdot$ADP and nonphosphorylated forms of the enzyme with bound ATP. The fraction of EP that reacts in the burst and the first-order rate constant for the slow phase increase proportionally with increasing concentrations of ADP. The kinetics of EP formation and disappearance are consistent with a rate-limiting conformational change in both directions. The conformational change converts $\\sp{\\rm c}$E$\\cdot$Ca$\\sb2\\cdot$La$\\cdot$ATP to the form of the enzyme that is activated for phosphoryl transfer, $\\sp{\\rm c}$E$\\cdot$Ca$\\sb2\\cdot$La$\\cdot$ATP, at 6.5 s$\\sp{-1}$, the analogous reaction with Mg$\\cdot$ ATP is faster with a rate constant of k = 220 s$\\sp{-1}$. The internalization of radiolabeled calcium into SR vesicles containing ambient ($\\sim$10 $\\mu$M) or 20 mM unlabeled calcium by the phosphoenzyme formed from Mg$\\cdot$ATP was measured using a quench of 7 mM ADP and 10 mM EGTA. Two Ca$\\sp{2+}$ ions are internalized into empty and loaded vesicles during a single turnover of the enzyme in a first-order reaction with a rate constant of k = $\\sim$30 s$\\sp{-1}$. The individual Ca$\\sp{2+}$ ions are internalized with the same rate constant; there is no indication of a biphasic reaction or inhibition by 20 mM lumenal calcium. The data are consistent with a rate-limiting conformational change that precedes rapid dissociation of the Ca$\\sp{2+}$ ions from the phosphoenzyme. The absence of inhibition by 20 mM lumenal calcium suggests that the ions may dissociate rapidly from independent sites on the phosphoenzyme. Alternatively, the Ca$\\sp{2+}$ ions could rapidly exchange their positions on the phosphoenzyme and dissociate sequentially from a single site.

Among patients receiving surgical or nonsurgical standard treatment for chronic subdural hematoma, adjunctive middle meningeal artery embolization reduced the risk of treatment failure within 180 days.

Stent retriever thrombectomy of large-vessel occlusion results in better outcomes than medical therapy alone. Alternative thrombectomy strategies, particularly a direct aspiration as first pass technique, while promising, have not been rigorously assessed for clinical efficacy in randomised trials. We designed COMPASS to assess whether patients treated with aspiration as first pass have non-inferior functional outcomes to those treated with a stent retriever as first line. We did a multicentre, randomised, open label, blinded outcome, core lab adjudicated non-inferiority trial at 15 sites (ten hospitals and four specialty clinics in the USA and one hospital in Canada). Eligible participants were patients presenting with acute ischaemic stroke from anterior circulation large-vessel occlusion within 6 h of onset and an Alberta Stroke Program Early CT Score of greater than 6. We randomly assigned participants (1:1) via a central web-based system without stratification to either direct aspiration first pass or stent retriever first line thrombectomy. Those assessing primary outcomes via clinical examinations were masked to group assignment as they were not involved in the procedures. Physicians were allowed to use adjunctive technology as was consistent with their standard of care. The null hypothesis for this study was that patients treated with aspiration as first pass achieve inferior outcomes compared with those treated with a stent retriever first line approach. The primary outcome was non-inferiority of clinical functional outcome at 90 days as measured by the percentage of patients achieving a modified Rankin Scale score of 0–2, analysed by intent to treat; non-inferiority was established with a margin of 0·15. All randomly assigned patients were included in the safety analyses. This trial is registered at ClinicalTrials.gov, number: NCT02466893. Between June 1, 2015, and July 5, 2017, we assigned 270 patients to treatment: 134 to aspiration first pass and 136 to stent retriever first line. A modified Rankin score of 0–2 at 90 days was achieved by 69 patients (52%; 95% CI 43·8–60·3) in the aspiration group and 67 patients (50%; 41·6–57·4) in the stent retriever group, showing that aspiration as first pass was non-inferior to stent retriever first line (pnon-inferiority=0·0014). Intracranial haemorrhage occurred in 48 (36%) of 134 in the aspiration first pass group, and 46 (34%) of 135 in the stent retriever first line group. All-cause mortality at 3 months occurred in 30 patients (22%) in both groups. A direct aspiration as first pass thrombectomy conferred non-inferior functional outcome at 90 days compared with stent retriever first line thrombectomy. This study supports the use of direct aspiration as an alternative to stent retriever as first-line therapy for stroke thrombectomy. Penumbra.

BackgroundThe PerfusiOn imaging Selection of Ischemic sTroke patIents for endoVascular thErapy (POSITIVE) trial was designed to evaluate functional outcome in patients with emergent large vessel occlusion (ELVO) presenting within 0–12 hours with pre-specified bifurcated arms of early and late window presentation, who were selected for endovascular thrombectomy with non-vendor specific commercially available perfusion imaging software. Recent trials demonstrating the benefit of thrombectomy up to 16–24 hours following ELVO removed equipoise to randomize late window ELVO patients and therefore the trial was halted.MethodsUp to 200 patients were to be enrolled in this FDA-cleared, prospective, randomized, multicenter international trial to compare thrombectomy and best medical management in patients with ELVO ineligible for or refractory to treatment with IV tissue plasminogen activator (IV-tPA) selected with perfusion imaging and presenting within 0–12 hours of last seen normal. The primary outcome was 90-day clinical outcome as measured by the raw modified Rankin Scale (mRS) with scores 5 and 6 collapsed (mRS shift analysis).ResultsThe POSITIVE trial suspended enrollment with the release of results from the DAWN trial and was stopped after the release of the DEFUSE 3 trial results. Thirty-three patients were enrolled (21 for medical management and 12 for thrombectomy). Twelve of the 33 patients were enrolled in the 6–12 hour cohort. Despite the early cessation, the primary outcome demonstrated statistically significant superior clinical outcomes for patients treated with thrombectomy (P=0.0060). The overall proportion of patients achieving an mRS score of 0–2 was 75% in the thrombectomy cohort and 43% in the medical management cohort (OR 4.00, 95% CI 0.84 to 19.2).ConclusionPOSITIVE supports the already established practice of delayed thrombectomy for appropriately selected patients presenting within 0–12 hours selected by perfusion imaging from any vendor. The results of the POSITIVE trial are consistent with other thrombectomy trials. The statistically significant effect on functional improvement, despite the small number of patients, reinforces the robust benefits of thrombectomy.Clinical trial registration NCT01852201

BackgroundThe Woven EndoBridge (WEB) device is approved in the USA for treatment of unruptured wide-neck bifurcation aneurysms. However, the safety and effectiveness of the WEB device in the treatment of ruptured intracranial aneurysms is not clear. We aim to evaluate the perioperative safety and effectiveness of the WEB device in patients with ruptured intracranial aneurysms.MethodsThis retrospective study, conducted at eight centers in the USA, included patients with ruptured intracranial aneurysms treated with the WEB device in the setting of subarachnoid hemorrhage (SAH). Safety outcomes included intraoperative complications such as vessel perforation, thromboembolic events, and postoperative hemorrhagic or thromboembolic complications based on radiologic imaging. The primary effectiveness outcome was adequate (complete and neck remnant) aneurysm occlusion, according to the Raymond–Roy classification.ResultsA total of 91 patients with 94 ruptured intracranial aneurysms were included (mean age 57.7±15.2 years; 68.1% women; 82.9% wide-necked). Aneurysms were located in the anterior communicating artery (42/94, 44.6%), middle cerebral artery (16/94, 17%), and basilar artery (15/94, 16%). Adequate occlusion was achieved in 48.8% (41/84) and 80.0% (40/50) at discharge and last follow-up (mean of 3.4 months), respectively. At discharge, procedural-related morbidity was 3.3% (3/91) and there was no procedure-related mortality. No re-rupture or delayed aneurysm rupture was observed.ConclusionsThis study demonstrates the perioperative safety and effectiveness of the WEB device for the treatment of patients with ruptured intracranial aneurysms in the setting of SAH, with low periprocedural morbidity and mortality. Long-term follow-up is warranted.

Abstract Background The Pipeline Flex (PED Flex; Medtronic, Dublin, Ireland) was designed to facilitate deployment and navigation compared to its previous iteration to reduce the rate of technical events and complications. OBJECTIVE To assess the neurological morbidity and mortality rates of the PED Flex at 30 d. Methods Information from 9 neurovascular centers was retrospectively obtained between July 2014 and March 2016. Data included patient/aneurysm characteristics, periprocedural events, clinical, and angiographic outcomes. Multivariate logistic regression was performed to determine predictors of unfavorable clinical outcome (modified Rankin Scale [mRS] > 2). Results A total of 205 patients harboring 223 aneurysms were analyzed. The 30-d neurological morbidity and mortality rates were 1.9% (4/205) and 0.5% (1/205), respectively. The rate of intraprocedural events without neurological morbidity was 6.8% (14/205), consisting of intraprocedural ischemic events in 9 patients (4.5%) and hemorrhage in 5 (2.4%). Other technical events included difficulty capturing the delivery wire in 1 case (0.5%) and device migration after deployment in another case (0.5%). Favorable clinical outcome (mRS 0-2) was achieved in 186 patients (94.4%) at discharge and in 140 patients (94.5%) at 30 d. We did not find predictors of clinical outcomes on multivariate analysis. Conclusion The 30-d rates of neurological morbidity and mortality in this multicenter cohort using the PED Flex for the treatment of intracranial aneurysms were low, 1.9% (4/205) and 0.5% (1/205), respectively. In addition, technical events related to device deployment were also low, most likely due to the latest modifications in the delivery system.

BackgroundThrombectomy for anterior large vessel occlusion less than 24 hours since last known well is now standard of care. Certain aspects of clinical trials may limit generalizability to ’real-world' practice.ObjectiveTo compare revascularization rates and outcomes for direct aspiration (ADAPT) and stent retriever thrombectomy following anterior acute ischemic stroke (AIS) in a real-life setting.MethodsData from the most recent 20 consecutive patients with AIS treated with mechanical thrombectomy between 2015 and 2016 were collected from 15 high-volume stroke centers across North America for a total of 300 cases. Patients with proximal anterior large vessel occlusions were dichotomized by primary treatment technique. Ordinal logistic regression assessed the effects of clinical variables on patient disability using 90-day modified Rankin Scale (mRS) scores.ResultsAdequate revascularization (Thrombolysis in Cerebral Infarction ≥2b) was ultimately achieved in 91.2% of first-line direct aspiration (ADAPT) cases with an average of 1.9±1.9 passes and in 87.5% of stent retriever cases with an average of 1.7±1.0 passes. Time from groin puncture to revascularization was shorter for ADAPT cases. The mean 90-day mRS score for both groups was 3.0±2.4. Number of passes using primary technique, and postintervention intracranial hemorrhage, were significant predictors of 90-day mRS scores after ADAPT, while age and preprocedure mRS score were predictive of outcomes following first-line stent retriever.ConclusionsOur data show similar adequate revascularization rates and 90-day functional outcomes for first-line direct aspiration and stent retrievers for anterior large vessel occlusion in a real-world setting. These results support the findings of other prospective trials evaluating the two techniques.

Abstract BACKGROUND Though the Pipeline Embolization Device (Medtronic) is approved for use in adults 22 yr and older, the high efficacy and long-term durability of the device is attractive for treatment of intracranial aneurysms in younger patients who often have aneurysms less amenable to traditional endovascular treatments. OBJECTIVE To report technical, angiographic, and clinical outcomes in patients aged 21 or below undergoing flow-diversion treatment for intracranial aneurysms. METHODS Retrospective review across 16 institutions identified 39 patients aged 21 or below undergoing 46 treatment sessions with Pipeline Embolization Device placement between 2012 and 2018. A total of 50 intracranial aneurysms were treated. Details regarding patient demographics, aneurysm characteristics, treatment considerations, clinical outcomes, and aneurysm occlusion were obtained and analyzed in a multicenter database. RESULTS A total of 70% of patients were male. Nonsaccular morphology was seen in half of identified aneurysms. Six aneurysms were giant, and five patients were treated acutely after ruptured presentation. Eight patients were younger than 10 yr of age. Complete aneurysm occlusion was seen in 74% of treated aneurysms. Three aneurysms (6%) were retreated. A total of 83% of patients had a modified Rankin Scale scores of ≤2 at last clinical follow-up. There were 2 early mortalities (4.3%) in the immediate postprocedure period because of rerupture of a treated ruptured aneurysm. No recanalization of a previously occluded aneurysm was observed. CONCLUSION Flow-diversion treatment is a safe and effective treatment for intracranial aneurysms in patients younger than 22 yr. Rates of complete aneurysm occlusion and adverse events are comparable for rates seen in older patients. Graphical Abstract Graphical Abstract

IntroductionThe Woven EndoBridge Intrasaccular Therapy (WEB-IT) Study is a pivotal, prospective, single-arm, investigational device exemption study designed to evaluate the safety and effectiveness of the WEB device for the treatment of wide-neck bifurcation aneurysms.MethodsOne-hundred and fifty patients with wide-neck bifurcation aneurysms were enrolled at 21 US and six international centers. Angiograms from the index procedure, and 6-month and 1-year follow-up visits were all reviewed by a core laboratory. All adverse events were reviewed and adjudicated by a clinical events adjudicator. A data monitoring committee provided oversight during the trial to ensure subject safety.ResultsOne-hundred and forty-eight patients received the WEB implant. One (0.7%) primary safety event occurred during the study—a delayed ipsilateral parenchymal hemorrhage—on postoperative day 22. No primary safety events occurred after 30 days through 1 year. At the 12-month angiographic follow-up, 77/143 patients (53.8%) had complete aneurysm occlusion. Adequate occlusion was achieved in 121/143 (84.6%) subjects.ConclusionsThe prespecified safety and effectiveness endpoints for the aneurysms studied in the WEB-IT trial were met. The results of this trial suggest that the WEB device provides an option for patients with wide-neck bifurcation aneurysms that is as effective as currently available therapies and markedly safer.Trial registration number NCT02191618