Effectiveness of metformin pretreatment for stroke severity: A propensity score matching study.

BACKGROUND AND OBJECTIVE: Metformin pretreatment might have neuroprotective effects. We aimed to determine the therapeutic effects of the antidiabetic medication metformin on ischemic stroke severity and discharge outcomes. METHODS: We analyzed data on 1303 ischemic stroke patients who were on antidiabetic medications from the Massachusetts General Hospital (MGH) Advanced Comprehensive Stroke Center dataset (n = 8943, 2012-2022). We applied propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses to investigate the effect of current usage of metformin (versus alternate antidiabetic treatment) on acute stroke clinical severity and discharge outcomes. RESULTS: Of the 1303 patients who were on antidiabetic medications at the time of stroke admission, 730 (56%) were taking metformin. Metformin users were younger and more frequently had hypertension, whereas less frequently had prior CAD, AFib, and chronic kidney disease. The clinical features and laboratory values of the two groups were evenly distributed after PSM. Metformin-treated patients had statistically significant lower stroke severity on admission [National Institutes of Health Stroke Scale (NIHSS) (median, interquartile range) 3.0 (1.0-8.0) vs. 4.0 (2.0-11.3), p = 0.011], better functional independence at discharge (modified Rankin scale score 0-2, 36.3% vs. 25.4%, p < 0.001) and less in-hospital mortality (4.5% vs. 11.3%, p = 0.018). IPTW analysis results were consistent with PSM results. CONCLUSIONS: Among diabetic patients with acute ischemic stroke, metformin appears to confer neuroprotection. Our results extend previous findings to the general stroke population. Stroke patients with diabetes mellitus who were treated with metformin prior to stroke, even when combined with additional antidiabetic medications, experienced less severe strokes upon admission and had better functional outcomes during hospitalization.

Site-specific N-alkylation of DNA oligonucleotide nucleobases by DNAzyme-catalyzed reductive amination.

DNA and RNA nucleobase modifications are biologically relevant and valuable in fundamental biochemical and biophysical investigations of nucleic acids. However, directly introducing site-specific nucleobase modifications into long unprotected oligonucleotides is a substantial challenge. In this study, we used in vitro selection to identify DNAzymes that site-specifically N-alkylate the exocyclic nucleobase amines of particular cytidine, guanosine, and adenosine (C, G and A) nucleotides in DNA substrates, by reductive amination using a 5'-benzaldehyde oligonucleotide as the reaction partner. The new DNAzymes each require one or more of Mg2+, Mn2+, and Zn2+ as metal ion cofactors and have kobs from 0.04 to 0.3 h-1, with rate enhancement as high as ∼104 above the splinted background reaction. Several of the new DNAzymes are catalytically active when an RNA substrate is provided in place of DNA. Similarly, several new DNAzymes function when a small-molecule benzaldehyde compound replaces the 5'-benzaldehyde oligonucleotide. These findings expand the scope of DNAzyme catalysis to include nucleobase N-alkylation by reductive amination. Further development of this new class of DNAzymes is anticipated to facilitate practical covalent modification and labeling of DNA and RNA substrates.

Left atrial appendage closure in patients with atrial fibrillation and acute ischaemic stroke despite anticoagulation.

BACKGROUND: The occurrence of acute ischaemic stroke (AIS) while using oral anticoagulants (OAC) is an increasingly recognised problem among nonvalvular atrial fibrillation (NVAF) patients. We aimed to elucidate the potential role of left atrial appendage closure (LAAC) for stroke prevention in patients with AIS despite OAC use (AIS-despite-OAC). METHODS: We retrospectively collected baseline and follow-up data from consecutive NVAF patients who had AIS-despite-OAC and subsequently underwent endovascular LAAC, between January 2015 and October 2021. The primary outcome measure was the occurrence of AIS after LAAC, and the safety outcome was symptomatic intracerebral haemorrhage (ICH). RESULTS: 29 patients had LAAC specifically because of AIS-despite-OAC. The mean age at the time of the procedure was 73.4±8.7, 13 were female (44.82%). The mean CHA2DS2-VASc score was 5.96±1.32, with an expected AIS risk of 8.44 per 100 patient-years. 14 patients (48%) had two or more past AIS-despite-OAC. After LAAC, 27 patients (93.10%) were discharged on OAC which was discontinued in 17 (58.62%) after transoesophageal echocardiogram at 6 weeks. Over a mean of 1.75±1.0 years follow-up after LAAC, one patient had an AIS (incidence rate (IR) 1.97 per 100 patient-years). One patient with severe cerebral microangiopathy had a small ICH while on direct OAC and antiplatelet 647 days after LAAC. CONCLUSIONS: LAAC in AIS-despite-OAC patients demonstrated a low annual AIS recurrence rate in our cohort (1.97%) compared with the expected IR based on their CHA2DS2-VASc scores (8.44%) and to recent large series of AIS-despite-OAC patients treated with OAC/aspirin only (5.3%-8.9%). These hypothesis-generating findings support randomised trials of LAAC in AIS-despite-OAC patients.

Left atrial appendage closure for patients with atrial fibrillation at high intracranial haemorrhagic risk.

BACKGROUND AND OBJECTIVES: Although left atrial appendage closure (LAAC) is performed in patients with non-valvular atrial fibrillation (NVAF) at increased risk of intracranial haemorrhage (ICH), outcome data are scarce. We assessed the detailed neurological indications for LAAC and outcomes after LAAC in high ICH risk patients. METHODS: Study population included consecutive patients with NVAF who underwent LAAC in a single hospital network between January 2015 and October 2021 because of prior ICH or the presence of high ICH risk imaging markers on brain MRI (cerebral microbleeds (CMBs)). Primary safety and efficacy outcome measures were the occurrence of ICH and thromboembolic events, respectively, after LAAC. RESULTS: Among 146 patients with NVAF who underwent LAAC for high ICH risk, 122 had a history of ICH, while 24 presented with high ICH risk imaging markers only. Mean age was 75.7±7.61, 42 (28.8%) were women. Mean CHA2DS2-VASc score was 5.23±1.52. Of 122 patients with ICH history, 58 (47.5%) had intraparenchymal haemorrhage (IPH), 40 (32.8%) had traumatic ICH (T-ICH) and 18 (14.7%) had non-traumatic subdural haemorrhage. Of 85 patients with brain MRIs including necessary sequences, 43 (50.6%) were related to cerebral amyloid angiopathy and 37 (43.5%) to hypertensive microangiopathy. While 70% of patients were discharged on oral anticoagulants (OAC), 92% were not taking OAC at 1 year. Over 2.12 years mean follow-up, one patient had recurrent non-traumatic IPH (incidence rate (IR) 0.32 per 100 patient-years), five had T-ICH (IR 1.61 per 100 patient-years) and six had an ischaemic stroke (IR 1.94 per 100 patient-years). CONCLUSIONS: Among patients with NVAF at high ICH risk, LAAC demonstrated a low risk of recurrent ICH or ischaemic stroke compared with previously published data. LAAC in high ICH risk populations should be considered in clinical practice per FDA approval and recent guidelines.

DNAzyme-Catalyzed Site-Specific N-Acylation of DNA Oligonucleotide Nucleobases.

We used in vitro selection to identify DNAzymes that acylate the exocyclic nucleobase amines of cytidine, guanosine, and adenosine in DNA oligonucleotides. The acyl donor was the 2,3,5,6-tetrafluorophenyl ester (TFPE) of a 5'-carboxyl oligonucleotide. Yields are as high as >95 % in 6 h. Several of the N-acylation DNAzymes are catalytically active with RNA rather than DNA oligonucleotide substrates, and eight of nine DNAzymes for modifying C are site-specific (>95 %) for one particular substrate nucleotide. These findings expand the catalytic ability of DNA to include site-specific N-acylation of oligonucleotide nucleobases. Future efforts will investigate the DNA and RNA substrate sequence generality of DNAzymes for oligonucleotide nucleobase N-acylation, toward a universal approach for site-specific oligonucleotide modification.

Safety and Feasibility of an Emergency Department-to-Outpatient Pathway for Patients With TIA and Nondisabling Stroke.

Background and Objectives: Evaluation of transient ischemic attack/nondisabling ischemic strokes (TIA/NDS) in the emergency department (ED) contributes to capacity issues and increasing health care expenditures, especially high-cost duplicative imaging. Methods: As an institutional quality improvement project, we developed a novel pathway to evaluate patients with TIA/NDS in the ED using a core set of laboratory tests and CT-based neuroimaging. Patients identified as 'low risk' through a safety checklist were discharged and scheduled for prompt outpatient tests and stroke clinic follow-up. In this prespecified analysis designed to assess feasibility and safety, we abstracted data from patients consecutively enrolled in the first 6 months. Results: We compared data from 106 patients with TIA/NDS enrolled in the new pathway from April through September 2020 (age 67.9 years, 45% female), against 55 unmatched historical controls with TIA encountered from April 2016 through March 2017 (age 68.3 years, 47% female). Both groups had similar median NIHSS scores (pathway and control 0) and ABCD2 scores (pathway and control 3). Pathway-enrolled patients had a 44% decrease in mean ED length of stay (pathway 13.7 hours, control 24.4 hours, p < 0.001) and decreased utilization of ED MRI-based imaging (pathway 63%, control 91%, p < 0.001) and duplicative ED CT plus MRI-based brain and/or vascular imaging (pathway 35%, control 53%, p = 0.04). Among pathway-enrolled patients, 89% were evaluated in our stroke clinic within a median of 5 business days; only 5.5% were lost to follow-up. Both groups had similar 90-day rates of ED revisits (pathway 21%, control 18%, p = 0.84) and recurrent TIA/ischemic stroke (pathway 1%, control 2%, p = 1.0). Recurrent ischemic events among pathway-enrolled patients were attributed to errors in following the safety checklist before discharge. Discussion: Our TIA/NDS pathway, implemented during the initial outbreak of COVID-19, seems feasible and safe, with significant positive impact on ED throughput and ED-based high-cost duplicative imaging. The safety checklist and option of virtual telehealth follow-up are novel features. Broader adoption of such pathways has important implications for value-based health care.

Defining the substrate scope of DNAzyme catalysis for reductive amination with aliphatic amines.

Amines can be alkylated using various reactions, such as reductive amination of aldehydes. In this study, we sought DNAzymes as catalytic DNA sequences that promote reductive amination with aliphatic amines, including DNA-anchored peptide substrates with lysine residues. By in vitro selection starting with either N40 or N20 random DNA pools, we identified many DNAzymes that catalyze reductive amination between the DNA oligonucleotide-anchored aliphatic amino group of DNA-C3-NH2 (C3 = short three-carbon tether) and a DNA-anchored benzaldehyde group in the presence of NaCNBH3 as reducing agent. At pH 5.2, 6.0, 7.5, or 9.0 in the presence of various divalent metal ion cofactors including Mg2+, Mn2+, Zn2+ and Ni2+, the DNAzymes have kobs up to 0.12 h-1 and up to 130-fold rate enhancement relative to the DNA-splinted but uncatalyzed background reaction. However, analogous selection experiments did not lead to any DNAzymes that function with DNA-HEG-NH2 [HEG = long hexa(ethylene glycol) tether], or with short- and long-tethered DNA-AAAKAA and DNA-HEG-AAAKAA lysine-containing hexapeptide substrates (A = alanine, K = lysine). Including a variety of other amino acids in place of the neighboring alanines also did not lead to DNAzymes. These findings establish a practical limit on the substrate scope of DNAzyme catalysis for N-alkylation of aliphatic amines by reductive amination. The lack of DNAzymes for reductive amination with any substrate more structurally complex than DNA-C3-NH2 is likely related to the challenge in binding and spatially organizing those other substrates. Because other reactions such as aliphatic amine N-acylation are feasible for DNAzymes with DNA-anchored peptides, our findings show that the ability to identify DNAzymes depends strongly on both the investigated reaction and the composition of the substrate.

Asymptomatic carotid artery stenosis: a summary of current state of evidence for revascularization and emerging high-risk features.

Carotid artery stenosis is a leading cause of ischemic stroke. While management of symptomatic carotid stenosis is well established, the optimal approach in asymptomatic carotid artery stenosis (aCAS) remains controversial. The rapid evolution of medical therapies within the time frame of existing landmark aCAS surgical revascularization trials has rendered their findings outdated. In this review, we sought to summarize the controversies in the management of aCAS by providing the most up-to-date medical and surgical evidence. Subsequently, we compile the evidence surrounding high-risk clinical and imaging features that might identify higher-risk lesions. With this, we aim to provide a practical framework for a precision medicine approach to the management of aCAS.

Predictors of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease: A Prespecified Secondary Analysis of the STROKE AF Randomized Clinical Trial.

Importance: The Stroke of Known Cause and Underlying Atrial Fibrillation (STROKE AF) trial found that approximately 1 in 8 patients with recent ischemic stroke attributed to large- or small-vessel disease had poststroke atrial fibrillation (AF) detected by an insertable cardiac monitor (ICM) at 12 months. Identifying predictors of AF could be useful when considering an ICM in routine poststroke clinical care. Objective: To determine the association between commonly assessed risk factors and poststroke detection of new AF in the STROKE AF cohort monitored by ICM. Design, Setting, and Participants: This was a prespecified analysis of a randomized (1:1) clinical trial that enrolled patients between April 1, 2016, and July 12, 2019, with primary follow-up through 2020 and mean (SD) duration of 11.0 (3.0) months. Eligible patients were selected from 33 clinical research sites in the US. Patients had an index stroke attributed to large- or small-vessel disease and were 60 years or older or aged 50 to 59 years with at least 1 additional stroke risk factor. A total of 496 patients were enrolled, and 492 were randomly assigned to study groups (3 did not meet inclusion criteria, and 1 withdrew consent). Patients in the ICM group had the index stroke within 10 days before insertion. Data were analyzed from October 8, 2021, to January 28, 2022. Interventions: ICM monitoring vs site-specific usual care (short-duration external cardiac monitoring). Main Outcomes and Measures: The ICM device automatically detects AF episodes 2 or more minutes in length; episodes were adjudicated by an expert committee. Cox regression multivariable modeling included all parameters identified in the univariate analysis having P values <.10. AF detection rates were calculated using Kaplan-Meier survival estimates. Results: The analysis included the 242 participants randomly assigned to the ICM group in the STROKE AF study. Among 242 patients monitored with ICM, 27 developed AF (mean [SD] age, 66.6 [9.3] years; 144 men [60.0%]; 96 [40.0%] women). Two patients had missing baseline data and exited the study early. Univariate predictors of AF detection included age (per 1-year increments: hazard ratio [HR], 1.05; 95% CI, 1.01-1.09; P = .02), CHA2DS2-VASc score (per point: HR, 1.54; 95% CI, 1.15-2.06; P = .004), chronic obstructive pulmonary disease (HR, 2.49; 95% CI, 0.86-7.20; P = .09), congestive heart failure (CHF; with preserved or reduced ejection fraction: HR, 6.64; 95% CI, 2.29-19.24; P < .001), left atrial enlargement (LAE; HR, 3.63; 95% CI, 1.55-8.47; P = .003), QRS duration (HR, 1.02; 95% CI, 1.00-1.04; P = .04), and kidney dysfunction (HR, 3.58; 95% CI, 1.35-9.46; P = .01). In multivariable modeling (n = 197), only CHF (HR, 5.06; 95% CI, 1.45-17.64; P = .05) and LAE (HR, 3.32; 1.34-8.19; P = .009) remained significant predictors of AF. At 12 months, patients with CHF and/or LAE (40 of 142 patients) had an AF detection rate of 23.4% vs 5.0% for patients with neither (HR, 5.1; 95% CI, 2.0-12.8; P < .001). Conclusions and Relevance: Among patients with ischemic stroke attributed to large- or small-vessel disease, CHF and LAE were associated with a significantly increased risk of poststroke AF detection. These patients may benefit most from the use of ICMs as part of a secondary stroke prevention strategy. However, the study was not powered for clinical predictors of AF, and therefore, other clinical characteristics may not have reached statistical significance. Trial Registration: ClinicalTrials.gov Identifier: NCT02700945.

Frequency, predictors and cardiovascular outcomes associated with transthoracic echocardiographic findings during acute ischaemic stroke hospitalisation.

OBJECTIVE: To characterise the clinical utility of transthoracic echocardiography (TTE) at the time of acute ischaemic stroke (AIS). BACKGROUND: The utility of obtaining a TTE during AIS hospitalisation is uncertain. METHODS: We studied AIS hospitalisations at a single centre (2002-2016). TTE abnormalities were classified as findings associated with: high stroke risk (Category I), cardiac events (Category II) and of unclear significance (Category III). We performed logistic regressions to predict Category I, II and III abnormalities. The odds of 1 year recurrent stroke hospitalisation captured by ICD 9 and 10 codes as a function of Category I, II and III abnormalities were assessed. Improvement in predictive capacity for 1 year recurrent ischaemic stroke hospitalisation beyond stroke risk factors was evaluated by net reclassification improvement. RESULTS: There were 5523 AIS hospitalisations. Nearly 81% of admission TTEs were abnormal (18.7% Category I, 32.7% Category II, 72.8% Category III). Older patients with coronary artery disease, atrial fibrillation, hypertension, diabetes, and patent intracranial and extracranial vessels were likely to have an abnormal TTE. Category I finding was associated with lower odds of 1-year recurrent stroke hospitalisation (OR 0.54, 95% CI 0.30 to 0.96). Category I data significantly improved the predictive value for 1-year recurrent ischaemic stroke hospitalisation beyond stroke risk factors (net reclassification improvement 0.1563, 95% CI 0.0465 to 0.2661). CONCLUSIONS: TTE abnormalities associated with stroke and cardiac event risk were commonly detected during AIS hospitalisation. Detection of Category I TTE findings reduced the risk of recurrent stroke, potentially due to neutralisation of the cardioembolic source by targeted therapy, indicating the clinical utility of TTE.

Epigenetic MRI: Noninvasive imaging of DNA methylation in the brain.

Both neuronal and genetic mechanisms regulate brain function. While there are excellent methods to study neuronal activity in vivo, there are no nondestructive methods to measure global gene expression in living brains. Here, we present a method, epigenetic MRI (eMRI), that overcomes this limitation via direct imaging of DNA methylation, a major gene-expression regulator. eMRI exploits the methionine metabolic pathways for DNA methylation to label genomic DNA through 13C-enriched diets. A 13C magnetic resonance spectroscopic imaging method then maps the spatial distribution of labeled DNA. We validated eMRI using pigs, whose brains have stronger similarity to humans in volume and anatomy than rodents, and confirmed efficient 13C-labeling of brain DNA. We also discovered strong regional differences in global DNA methylation. Just as functional MRI measurements of regional neuronal activity have had a transformational effect on neuroscience, we expect that the eMRI signal, both as a measure of regional epigenetic activity and as a possible surrogate for regional gene expression, will enable many new investigations of human brain function, behavior, and disease.

Preoperative antithrombotic treatment in acutely symptomatic carotid artery stenosis.

OBJECTIVES: Early recurrence of cerebral ischemia in acutely symptomatic carotid artery stenosis can precede revascularization. The optimal antithrombotic regimen for this high-risk population is not well established. Although antiplatelet agents are commonly used, there is limited evidence for the use of anticoagulants. We sought to understand the safety and efficacy of short-term preoperative anticoagulants in secondary prevention of recurrent cerebral ischemic events from acutely symptomatic carotid stenosis in patients awaiting carotid endarterectomy (CEA). MATERIALS AND METHODS: A retrospective query of a prospective single institution registry of carotid revascularization was performed. Patients who presented with acute ischemic stroke or transient ischemic attack (TIA) attributable to an ipsilateral internal carotid artery stenosis (ICA) were included. Antiplatelet (AP) only and anticoagulation (AC) treatment arms were compared. The primary outcome was a composite of preoperative recurrent ischemic stroke or TIA. The primary safety outcome was symptomatic intracranial hemorrhage. RESULTS: Out of 443 CEA patients, 342 were in the AC group and 101 in the AP group. Baseline characteristics between groups (AC vs AP) were similar apart from age (71±10.5 vs 73±9.5, p=0.04), premorbid modified Rankin scale (mRS) score (1.0±1.2 vs 1.4±1.3, p=0.03) and stroke as presenting symptom (65.8 vs 53.5%, p=0.02). Patients in the AC group had a lower incidence of recurrent stroke/TIA (3.8 vs 10.9%, p=0.006). One patient had symptomatic intracranial hemorrhage in the AC group, and none in the AP group. In multivariate analysis controlling for age, premorbid mRS, stroke severity, degree of stenosis, presence of intraluminal thrombus (ILT) and time to surgery, AC was protective (OR 0.30, p=0.007). This effect persisted in the cohort exclusively without ILT (OR 0.23, p=0.002). CONCLUSIONS: Short term preoperative anticoagulation in patients with acutely symptomatic carotid stenosis appears safe and effective compared to antiplatelet agents alone in the prevention of recurrent cerebral ischemic events while awaiting CEA.

Cardiovascular Risk Factors Affect Specific Segments of the Intracranial Vasculature in High-Resolution (HR) Vessel Wall Imaging (VWI).

OBJECTIVES: Luminal-based imaging have identified different risk factors for extracranial and intracranial atherosclerosis (ICAS), but these techniques are known to underestimate the true extent of the disease. High-resolution (HR) vessel wall imaging (VWI) has recently gained recognition as a valuable tool in the assessment of ICAS. The aim of this study is to determine the association between cardiovascular risk factors and specific intracranial vessel segment involvement using HR-VWI. MATERIALS AND METHODS: From January 2017 to January 2020, consecutive patients ≥ 18 years-old undergoing HR-VWI of the brain were identified. Patients with history of primary or secondary vasculitis, reversible cerebral vasoconstriction syndrome, or moya-moya were excluded. The presence of vessel wall thickening and enhancement were assessed in the perpendicular plane for each vessel segment by two neuroradiologists. Univariate and multivariate analyses were performed to assess associations between imaging findings and cardiovascular risk factors. Interrater reliability was calculated. RESULTS: Seventy-one patients (39 men; mean age: 55.9 years) were included. Vessel wall enhancement was seen in 39/71 (55%). A total number of 105 vessel segments demonstrated abnormal enhancement and 79/105 (75%) had an eccentric pattern. Eccentric vessel wall enhancement was independently associated with age >65 years-old in the ICA (OR 9.0, CI 2.1 - 38.2, p < 0.01) and proximal MCA (OR 4.0, CI 1.2 - 13.2, p = 0.02), and with hyperlipidemia in the posterior circulation (OR 44.0, CI2.9-661.0, p<0.01). CONCLUSION: There is a significant association between eccentric vessel wall enhancement of the ICA and proximal MCA in patients with age > 65; and of the proximal posterior circulation (basilar - PCA1) with hyperlipidemia.

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation with warfarin or edoxaban: An in-depth analysis from the ENGAGE AF-TIMI 48 randomized trial.

Intracranial hemorrhage (ICH) is a known risk of oral anticoagulation; delineating ICH attributes may provide nuanced guidance regarding atrial fibrillation management. We evaluated ICH characteristics and outcomes from Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), a randomized trial that compared two edoxaban regimens (higher-dose edoxaban regimen 60/30 mg (HDER), lower-dose edoxaban regimen 30/15 mg (LDER)) with warfarin in patients with atrial fibrillation. Patients who suffered ICH vs those who did not were compared and independent predictors of ICH were calculated. We also assessed ICH subtype and etiology. Of 21,105 randomized patients, 322 (1.53%) had ≥ 1 ICH for a total of 368 events. Intraparenchymal hemorrhage (HDER: HR 0.52 [95% CI 0.35-0.77], LDER: HR 0.22 [0.13-0.38]) and subdural hematoma (HDER: HR 0.29 [0.15-0.55], LDER: HR 0.26 [0.13-0.50]) were lower with both HDER and LDER vs warfarin. Subarachnoid hemorrhage frequency was similar in the HDER vs warfarin groups but lower in LDER. Compared to warfarin, edoxaban was associated with lower risk of spontaneous ICH (HDER: HR 0.47 [0.31-0.69], LDER: HR 0.34 [0.22-0.53]) and traumatic ICH (HDER: HR 0.32 [0.17-0.61], LDER: HR 0.31 [0.16-0.59]). In multivariable analysis, randomization to warfarin, increased age, and risk of falling remained independent predictors of ICH. In ENGAGE AF-TIMI 48, ICH was decreased in edoxaban-treated patients compared to warfarin-treated patients, including ICH of both spontaneous and traumatic causes. Both edoxaban regimens lowered intraparenchymal and subdural hemorrhages compared to warfarin. Patient characteristics and medical history may help guide anticoagulation management.

Treatment Approaches and Outcomes for Acute Anterior Circulation Stroke Patients with Tandem Lesions.

OBJECTIVES: Endovascular thrombectomy (EVT) has revolutionized stroke care for large vessel occlusions (LVOs). However, over half treated remain functionally disabled or die. Patients with tandem lesions, or severe stenosis/occlusion of the cervical internal carotid artery (ICA) with intracranial LVO, may have technical EVT challenges and worse outcomes. We sought to compare treatments and outcomes for patients with anterior circulation tandem lesions versus isolated LVOs. MATERIALS AND METHODS: Consecutive tandem lesion and isolated intracranial LVO patients were identified at a single center. Demographics, medical history, presentations, treatments, and outcomes were collected and analyzed. RESULTS: From 381 EVT patients, 62 had tandem lesions related to atherosclerosis (74%) or dissection (26%). Compared to isolated intracranial LVOs, they were younger (63 vs 70, p = 0.003), had less atrial fibrillation (13% vs 40%, p < 0.0001), less adequate reperfusion (TICI 2b-3, 58% vs 82%, p < 0.0001), more intracranial hemorrhage (ICH, 13% vs 5%, p = 0.037), but similar 90-day functional independence (mRS 0-2, 34% vs 43%, p = 0.181). The cervical ICA was treated before intracranial EVT (57%), after (13%), not acutely (22%), or was inaccessible (8%). Acute cervical ICA treatments were stenting (57%) or angioplasty alone (13%). Neither acute stenting nor order of treatment was associated with outcomes (TICI 2b-3, ICH, or 90-day mRS 0-2). Among acutely stented, neither alteplase nor antiplatelets were associated with outcomes or stent patency. CONCLUSIONS: Tandem lesions were associated with less reperfusion, more ICH, but similar 90-day functional independence. No treatment approach was associated with outcomes. These data illustrate the technical challenges of tandem lesion treatment and underscore the importance of developing new approaches.

DNAzymes for amine and peptide lysine acylation.

DNAzymes were previously identified by in vitro selection for a variety of chemical reactions, including several biologically relevant peptide modifications. However, finding DNAzymes for peptide lysine acylation is a substantial challenge. By using suitably reactive aryl ester acyl donors as the electrophiles, here we used in vitro selection to identify DNAzymes that acylate amines, including lysine side chains of DNA-anchored peptides. Some of the DNAzymes can transfer a small glutaryl group to an amino group. These results expand the scope of DNAzyme catalysis and suggest the future broader applicability of DNAzymes for sequence-selective lysine acylation of peptide and protein substrates.