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Foliar fungal endophytes are known to alter plant physiology, but the mechanisms by which they do so remain poorly understood. We focused on how plant gene expression was altered by six fungal strains that generated "water-saver" and "water-spender" drought physiologies in a C4 grass, Panicum hallii. Water-saver physiologies have lower plant water loss, improved wilt resistance, and higher survival compared to water-spender strategies. We expected fungi within each functional group would have similar effects on P. hallii, and this was largely true for plant physiology, but not for plant gene expression. When we focused only on genes that were differentially expressed relative to fungus-free controls, we found surprisingly little overlap in plant differentially expressed genes or gene regulatory pathways across the fungal treatments, including within and between the water-saver and water-spender strategies. Nevertheless, using lasso regression we identified a small subset of genes that predicted 39% and 53% of the variation in plant wilt resistance and water loss, respectively. These results suggest that fungal effects on plant transcription may identify how they extend the plant phenotype, and the comparison across multiple fungi allows us to differentiate broadly fungal-responsive plant genes vs. those plant genes that respond only to single fungal taxa. The genes identified here could be targeted for future study to understand their function and, ultimately, represent candidates for precision breeding efforts to increase plant drought tolerance.

Soil moisture is a major driver of microbial activity and thus, of the release of carbon (C) into the Earth's atmosphere. Yet, there is no consensus on the relationship between soil moisture and microbial respiration, and as a result, moisture response functions are a poorly constrained aspect of C models. In addition, models assume that the response of microbial respiration to moisture is the same for all ecosystems, regardless of climate history, an assumption that many empirical studies have challenged. These gaps in understanding of the microbial respiration response to moisture contribute to uncertainty in model predictions. We review our understanding of what drives microbial moisture response, highlighting evidence that historical precipitation can influence both responses to moisture and sensitivity to drought. We present two hypotheses, the ‘climate history hypothesis’, where we predict that baseline moisture response functions change as a function of precipitation history, and the ‘drought legacy hypothesis’, in which we suggest that the intensity and frequency of historical drought have shaped microbial communities in ways that will control moisture responses to contemporary drought. Underlying mechanisms include biological selection and filtering of the microbial community by rainfall regimes, which result in microbial traits and trade-offs that shape function. We present an integrated modelling and empirical approach for understanding microbial moisture responses and improving models. Standardized measures of moisture response (respiration rate across a range of moistures) and accompanying microbial properties are needed across sites. These data can be incorporated into trait-based models to produce generalized moisture response functions, which can then be validated and incorporated into conventional and microbially explicit ecosystem models of soil C cycling. Future studies should strive to analyse realistic moisture conditions and consider the role of environmental factors and soil structure in microbial response. Microbes are the engines that drive C storage and are sensitive to changes in rainfall. A greater understanding of the factors that govern this sensitivity could be a key part of improving predictions of soil C dynamics, climate change and C-climate feedbacks. Read the free Plain Language Summary for this article on the Journal blog.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Introduction: One of the most feared complications of carotid revascularization, including carotid artery stenting (CAS), is peri-procedural ischemic stroke. Several studies suggest that the use of a distal embolic protection device (EPD), as well as over-sized pre- and post-stenting balloon angioplasty, may increase the risk of dislodgement of atheromatous plaque in patients undergoing CAS. The CREST trial, that mandated the use of an EPD, had a peri-procedural ischemic stroke rate of 4.1%. We hypothesize that our technique of stenting without the use of an EPD and sub-maximal angioplasty will have a low risk of peri-procedural complications. Methods: A retrospective review was conducted of consecutive cases of ICA stenting without use of an embolic protection device between January 2012 and June 2020 at a Canadian stroke centre. Data was extracted from the patient electronic medical record and Picture Archives and Communications Systems (PACS). Both symptomatic and asymptomatic CAS cases were included. Results: A total of 220 patients were included in the study, with a median age of 70 years (range 39-93 years), and 83 patients (38%) were female. The vast majority of patients were symptomatic (216 patients [98%]). A large portion of patients had a contralateral ICA occlusion or near occlusion (56 patients [25%]). In the majority of cases, a Precise Cordis RX carotid stent (Cordis) was placed. There were four patients with peri-procedural ischemic strokes (1.8%), with two occurring 8-30 days after stenting. There was one case of acute stent occlusion associated with an ischemic stroke. Two patients (less than 1%) had hyperperfusion syndrome after CAS. Median length of stay following the procedure was one day. Conclusions: In this single centre series, the peri-procedural risks of CAS without using an EPD are low. The ischemic stroke rate is less than 2%, lower than what has been reported in large randomized controlled trials using embolic protection.

Background: Distal posterior inferior cerebellar artery (PICA) aneurysms are uncommon intracranial vascular lesions. The coincidence of these aneurysms and Arteriovenous malformation (AVM) is even more rare. Since 1956, a total of 57 cases of distal PICA aneurysms associated with AVM have been reported with clear and adequate description. None of these reports describe a giant prenidal aneurysm at this particular location. The paucity of natural history data as well as lack of consensus about treatment strategies in such cases present a significant challenge that requires an individualized management approach.Case Description: A 68-year-old male presented with recurrent episodes of nausea and vomiting precipitated by physical exertion and change of head position. An MRI of the brain demonstrated a giant partially thrombosed right posterior inferior cerebellar artery (PICA) aneurysm with mass effect on the floor of the fourth ventricle. A conventional cerebral angiogram revealed a giant (3.1 x 3.1 x 2.8cm) distal right PICA pre-nidal aneurysm with two smaller distal PICA aneurysms. An AVM (Spetzler-Martin Grade 1) supplied by the right PICA as well as the right superior cerebellar artery (SCA) was also identified on cerebral angiography (not seen on an MRI). Endovascular coil embolization with parent vessel sacrifice was performed to occlude the giant aneurysm. Due to the asymptomatic nature, low risk of rupture, and the patient's age, AVM treatment was deferred.Conclusion: This paper presents the first case of a giant PICA aneurysm associated with cerebellar AVM. For PICA aneurysm-AVM complexes, meticulous evaluation of the morphology, associated anatomy, and comparative risk analysis for both lesions are key for treatment planning. Distal PICA aneurysms can be treated safely with parent vessel occlusion, particularly in the case of prenidal aneurysms.

Posterior circulation strokes (PCS) comprise a relatively small number of overall ischemic strokes; however, they carry a high level of morbidity and mortality. Clinicians must have a strong index of suspicion as presenting symptoms may be ambiguous and can occur in a smoldering fashion. Once recognized, acute intervention with thrombolytics or thrombectomy must be initiated immediately. The data are relatively sparse for systemic thrombolysis, local intra-arterial thrombolysis, and mechanical thrombectomy (MT) for PCS treatment compared to anterior circulation strokes (ACS), but if the vessel is not recanalized, outcomes are irrevocably poor. Multiple case series and reviews have demonstrated systemic and intra-arterial thrombolysis as promising recanalization methods for PCS. Furthermore, with the recent publications of the successful MT trials, MT has become the vogue option for treatment of PCS large-vessel occlusions (LVO). While current guidelines establish strict time criteria for treatment of ischemic strokes, there is some growing evidence that time should not limit treatment for PCS LVOs, given that the lack of treatment would result in a poor outcome. Optimizing triage and transport to appropriate centers, new-generation devices and neuroprotectants will be the next frontier in comprehensive acute PCS management.

Introduction: The optimal treatment strategy for symptomatic extra-cranial internal carotid artery (ICA) occlusion remains unknown. A radiographic classification of ICA occlusions has been proposed to help predict technical feasibility and the risk of complications with revascularization. The classification includes 4 main types (A-D) based on the morphology of the ICA stump (A having a tapered stump, B having a non-tapered stump, C and D having no stump) as well as the presence of reconstitution of flow in the intracranial ICA (C having reconstitution of the ICA within the cavernous and/or petrous segment and D having no reconstitution). In this study, we assess the predictive value of this classification scheme in understanding clinical phenotype and post-stenting complications. Methods: A retrospective review of a prospectively maintained database was conducted of clinical and radiological data from patients undergoing attempted angioplasty and stenting of complete symptomatic cervical ICA occlusion without tandem intracranial occlusion. Results: Seventy-two patients were included in the study, with a mean age of 63 years and 36% female gender. Classification type was as follows: 36% (type A), 25% (type B), 32% (type C) and 7% (type D). Revascularization was successful in 66/72 (92%) of patients. Clinical fluctuation prior to revascularization was most frequent in type A occlusions (p=0.02) and least frequent in type B occlusion (p=0.02). Only 8% of patients had peri-procedural intracerebral hemorrhage and the highest frequency occurred in group D (p=0.05). In a multivariate analysis, lower age, lower pre-treatment NIH Stroke Scale and favorable Alberta Stroke Program Early CT Score were predictors of higher modified Rankin Scale at 3 months (p=0.025, 0.004, 0.049, respectively). Conclusions: Radiographic classification of ICA occlusions can help classify patient phenotypes and potentially predict the technical safety of angioplasty and stenting. Prospective studies are warranted to confirm these findings.

Background: Favorable clinical outcomes after acute ischemic stroke (AIS) in the setting of a symptomatic large vessel occlusion (LVO) are reliant upon fast and high quality recanalization. Recent data suggests that modified first pass effect mFPE (mTICI ≥ 2b after one attempt of thrombectomy) is a strong predictor of favorable outcome; however, the patient specific features that favor mFPE are poorly understood. In this study, we aim to understand the rate of mFPE in fast versus slow progressors of early infarct growth before recanalization. Methods: A retrospective review of all patients presenting with AIS due to LVO treated with endovascular thrombectomy (ET) at a single comprehensive stroke center between November 2014 and February 2017 was performed. The following data was collected: patient demographic features, imaging characteristics and procedural details (mTICI, thrombectomy attempts). Ischemic core volume before ET was analyzed using automated software (RAPID, IschemaView, Inc). Patients were stratified based on infarct growth and defined as follows: fast progressor (last known well-LKW 50ml), slow progressors (LKW >6hours, core Results: Of 98 patients with available baseline core imaging, 8% (n=8) were fast progressors, 42% (n=41) were slow progressors, and the remaining 50% were intermediate progressors (n=49). mFPE rates were significantly higher in slow progressors compared to fast progressors (p = 0.02). Rates of successful recanalization (mTICI ≥ 2b) were lower in fast progressors compared to the slow and intermediate progressors (p = 0.073). Conclusion: Higher rates of successful recanalization and mFPE were observed in slow progressors of infarct growth. These results indicate that early recognition of LVO stroke phenotypes may aid in future device and technique selection for ET.

Background: NMDA receptor encephalitis (NMDARE) is associated with pre-existing psychiatric symptoms and seizure disorders. It is not typically associated with elevated ICP. Diagnostically, EEG findings in NMDARE are characteristic as are the pathological features of ovarian teratomas associated with this disease. We report a patient who tested positive for NMDARE however presented with features not known to be associated with the disease including elevated ICP, atypical EEG findings and grossly atypical features on pathological section. Results: A 26 year old woman presented with psychiatric symptoms and status epilepticus. On examination, she was found to have papilledema and eleveated ICP on measurement. Her imaging and EEG demonstrated atypical findings, not consistent with NMDARE. CT scan of the abdomen demonstrated an adnexal mass. CSF studies eventually tested positive for NMDARE and following removal of her ovarian teratoma, the pathology demonstrated atypical findings for lesions associated with NMDARE classically. Conclusions: NMDARE is a new entity, which has historically shown a typical clinical course. Our case demonstrates a previously undescribed presentation of NMDARE with elevated ICP, atypical EEG findings and unique pathology of the associated ovarian teratoma.