Mahesh Jayaraman

• Doctor of Medicine
• Brown University

Background and purpose: The non-contrast CT (NCCT) appearance of liquid embolic material post-middle meningeal artery embolization (MMAE) for chronic subdural hematomas (cSDH) is poorly described. We aimed to categorize the spectrum of post-procedural liquid embolic distribution and determine whether embolic penetration impacts resorption. Materi...

Background Transradial access (TRA) is increasingly common in cerebrovascular intervention, but its safety and efficacy in mechanical thrombectomy (MT) in acute ischemic stroke remain unclear. Methods We reviewed a prospectively maintained single-institution stroke database including consecutive cases between January 1, 2016 and December 31, 2023....

Background Rapid reperfusion is an important predictor of neurologic recovery in acute ischemic stroke due to large vessel occlusion (AIS-LVO) treated with mechanical thrombectomy (MT). We present a single-institution retrospective observational study of the ThrOmbectomy withOut Flushes or AnestheSia Teams (TOOFAST) technique, which eliminates cont...

Introduction Stroke remains to be a significant cause of morbidity and mortality in the US, with an estimated 800,000 strokes occurring yearly. It is well understood that thorough follow‐up care and rehabilitation has a significant impact on long‐term outcomes after experiencing a stroke, and especially after undergoing mechanical thrombectomy for...

Background Surgeons are at high risk for malpractice claims, which can significantly impact physician quality of life and risk of burnout. There are few published data reporting the incidence, outcomes, and repercussions of malpractice lawsuits on neurointerventionalists. Methods A survey of senior members of the United States Society of Neurointe...

Introduction Rapid time to reperfusion is among the most important metrics predictive of good neurologic outcomes among acute ischemic stroke (AIS) patients who undergo mechanical thrombectomy (MT). There is considerable controversy regarding methods to streamline patient preparation for MT while maintaining procedural safety, with wide institution...

Introduction Ischemic stroke poses a significant morbidity and mortality burden in the United States. Risk factors, management paradigms, including the use of mechanical thrombectomy, and outcomes of ischemic stroke have evolved in recent years. An updated, population-level analysis of the burden of ischemic stroke is necessary. Methods Using the...

Background Management of aneurysmal subarachnoid hemorrhage (aSAH) evolved substantially over the past two decades with foundational changes to medical and surgical management. We sought to determine trends in management and outcomes including hospital discharges of patients who underwent aneurysm securement by reviewing the National Inpatient Samp...

Introduction/Purpose Previous research has suggested that patients with limited English proficiency may have decreased access to rapid and definitive care for acute ischemic stroke (AIS), though conflicting results have been reported regarding presentation, treatment, and outcomes. The objective of this study was to determine whether AIS patients’...

Introduction Transradial access is increasingly common in cerebrovascular intervention, but its safety and efficacy in mechanical thrombectomy (MT) in acute ischemic stroke remain unclear. We present a single-institution experience at a high-volume comprehensive stroke center comparing neurologic outcomes between transfemoral and transradial MT pro...

Background: The efficacy and safety of statins for secondary prevention in patients who have experienced a cardioembolic stroke are not well-defined. However, previous observational data reported hyperlipidemia as a risk factor for both ischemic and bleeding complications in patients with AF and previous stroke. Based on these premises, we conducte...

Background: Intracranial Atherosclerosis (ICAS) leads to stroke by perforator disease, artery to artery embolism, and impaired distal flow/perfusion. While medical treatment is likely to stabilize atherosclerotic plaques, it is unlikely to improve distal perfusion in the acute setting. We hypothesize that medically treated patients with symptomatic...

Introduction: Trials using advanced imaging have shown a benefit from intravenous thrombolysis in patients with wake-up stroke, but real-world data is limited. This study presents data on outcomes in patients presenting with wake-up stroke at a comprehensive stroke center comparing those who received thrombolysis to those who did not. Methods: In F...

Introduction: Intracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke worldwide. We assessed the clinical outcomes of endovascular treatment in acute large vessel occlusion (LVO) strokes caused by ICAD and compared them with large vessel occlusion strokes not associated with intracranial atherosclerosis (non-ICAD LVO). Meth...

Introduction: Mechanical Thrombectomy improves outcomes in patients with acute ischemic stroke due to large vessel occlusion. Nearly 15% of patients have a tandem extracranial and intracranial occlusion. There is limited data on in-hospital outcomes in patients with acute tandem lesions undergoing thrombectomy. Methods: We included patients hospita...

Purpose Diffusion-weighted imaging (DWI) lesion expansion after endovascular thrombectomy (EVT) is not well characterized. We used serial diffusion-weighted magnetic resonance imaging (MRI) to measure lesion expansion between 2 and 24 h after EVT. Methods In this single-center observational analysis of patients with acute ischemic stroke due to la...

Background Patients treated with mechanical thrombectomy (MT) for acute ischemic strokes from large vessel occlusion (LVO) have better outcomes with effective reperfusion. However, it is unknown which technique leads to better technical and clinical success. We aimed to determine which technique yields the most effective first pass reperfusion duri...

Background: Standard surgical treatment for vascular spinal tumors, including renal cell carcinomas and hemangiomas, may result in significant blood loss despite preoperative arterial tumor embolization. Methods: is is a retrospective review of 12 patients who underwent direct percutaneous polymethylmethacrylate embolization (DPPE) with or without...

Background The real-world performance of the Zoom aspiration system is not well studied as compared with preliminary trials. Objective To compare the real-world performance of the Zoom aspiration system with preliminary trials, using data from the NeuroVascular Quality Initiative-Quality Outcomes Database (NVQI-QOD). Methods We retrospectively re...

BACKGROUND American Heart Association guidelines specify infarct core volume as 1 determinant of eligibility for endovascular thrombectomy. Therefore, it is important to understand how time‐dependent infarct core growth translates to a patient's declining probability of thrombectomy eligibility. Modeling the probability that a patient with suspecte...

Introduction Ischaemic stroke patients with atrial fibrillation (AF) are at high risk of stroke recurrence despite oral anticoagulation therapy. Patients with cardiovascular comorbidities may take both antiplatelet and oral anticoagulation therapy (OAC/AP). Our study aims to evaluate the safety and efficacy of OAC/AP therapy as secondary prevention...

Background Atrial fibrillation (AF) and congestive heart failure often coexist due to their shared risk factors leading to potential worse outcome, particularly cerebrovascular events. The aims of this study were to calculate the rates of ischemic and severe bleeding events in ischemic stroke patients having both AF and reduced ejection fraction (r...

Background: The risk of early recurrence in medically treated patients with intracranial atherosclerotic stenosis (ICAS) may differ in clinical trials versus real-world settings. Delayed enrollment may contribute to lower event rates in ICAS trials. We aim to determine the 30-day recurrence risk in a real-world setting of symptomatic ICAS. Method...

Introduction: Up to 25% of strokes are recognized upon awakening. Recent studies have demonstrated that a “tissue clock” rather than a time clock can be used to identify patients who may benefit from intravenous thrombolytics (IVT) beyond 4.5 hours from last known well (LKW). Consistent access to hyperacute MRI limits many centers from treating wak...

Background: While optimizing medical treatment contributed to the low recurrence risk seen in SAMMPRIS medical arm, other factors such as delayed enrollment may have contributed to this low event rate. In this study, we aim to determine the 30-day recurrence risk in a real-world setting in patients with symptomatic intracranial atherosclerosis. Met...

Introduction: Data on predictors of early stroke recurrence in patients with symptomatic intracranial atherosclerotic disease (sICAD) is limited. We hypothesized that hypoperfusion delay predicts stroke recurrence within 90-days. Methods: We retrospectively collected all patients hospitalized with anterior circulation sICAD over 3 years (April 2019...

Introduction: It is well established that reduced door-to-needle (DTN) time leads to improved outcomes in acute ischemic stroke. Rhode Island Hospital is a Comprehensive Stroke Center focused on improving outcomes by seeking novel methods to improve the DTN to below the institutional goal of a median of < 30 minutes. Methods: We sought to reduce DT...

Background Delays to endovascular therapy (EVT) for stroke may be mitigated with direct field triage to EVT centers. We sought to compare times to treatment over a 5.5 year span between two adjacent states, one with field triage and one without, served by a single comprehensive stroke center (CSC). Methods During the study period, one of the two s...

Background Delays to endovascular therapy (EVT) for stroke may be mitigated with direct field triage to EVT centers. Objective To compare times to treatment over a five-and-a-half-year span between two adjacent states, one with field triage one without, served by a single comprehensive stroke center (CSC). Methods A single CSC serves our region o...

Background Transradial access has been described for mechanical thrombectomy in acute stroke, and proximal balloon occlusion has been shown to improve recanalization and outcomes. However, sheathed access requires a larger total catheter diameter at the access site. We aim to characterize the safety of sheathless transradial balloon guide catheter...

Intro: SARS-CoV-2 (COVID-19) infection is associated with acute ischemic stroke (AIS), which may be due to a prothrombotic state. Early reports have suggested high rates of reocclusion following mechanical thrombectomy (MT) with poor radiographic and clinical outcomes. We report our early experience using intra-procedural antithrombotics to addres...

Background In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding...

Introduction : Mechanical thrombectomy (MT) has become the standard of care in patients with large vessel occlusion after trials have demonstrated (MT) improved outcomes in acute ischemic stroke (AIS) as compared to medical therapy. Despite leading to high reperfusion rates, MT patients are at high risk for recurrent ischemic events and complicatio...

Introduction The carotid web is a compelling potential mechanism of embolic ischemic stroke. In this study, we aim to determine the prevalence of ipsilateral carotid web in a cohort of ischemic stroke patients and to perform a systematic review and meta-analysis of similar cohorts. Patients & methods We performed a retrospective, observational, co...

Background Determining infarct progression rate in acute ischemic stroke (AIS) is important for patient triage, treatment decision-making, and outcome prognostication. Objective To estimate infarct progression rate in patients with AIS with large vessel occlusion (LVO) and determine its predictors and impact on clinical outcome. Methods Data are...

A correction to this paper has been published: https://doi.org/10.1007/s00234-021-02735-6

Background and purpose: Infarct volume is an important predictor of clinical outcome in acute stroke. We hypothesized that the association of infarct volume and clinical outcome changes with the magnitude of infarct size. Materials and methods: Data were derived from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Throm...

Background and Purpose In patients with acute large vessel occlusion, the natural history of penumbral tissue based on perfusion time-to-maximum (T max ) delay is not well established in relation to late-window endovascular thrombectomy. In this study, we sought to evaluate penumbra consumption rates for T max delays in patients with large vessel o...

Background Intracranial hemorrhage is a known complication after endovascular treatment in patients with acute ischemic stroke due to large vessel occlusion, but the association between radiologic hemorrhage severity and outcome is controversial. Purpose To investigate the prevalence and impact on outcome of intracranial hemorrhage and hemorrhage s...

Purpose: The goal of this study was to determine whether the benefits of multiphase CTA (mCTA) over single-phase CTA (sCTA) for the detection of proximal cerebrovascular occlusions similarly extend to the distal cerebral vasculature. Methods: Four attending radiologists, two neuroradiologists and two emergency radiologists, contributed as readers...

Purpose: There is little data and lack of consensus regarding antiplatelet management for intracranial stenting due to underlying intracranial atherosclerosis in the setting of endovascular treatment (EVT). In this DELPHI study, we aimed to assess whether consensus on antiplatelet management in this situation among experienced experts can be achie...

Introduction: In patients with acute large vessel occlusion, the definition of penumbral tissue based on T max delay perfusion imaging is not well established in relation to late-window endovascular thrombectomy (EVT). In this study, we sought to evaluate penumbra consumption rates for T max delays in patients treated between 6 and 16 hours from la...

Background and purpose Brain infarct growth, despite successful reperfusion, decreases the likelihood of good functional outcome after ischemic stroke. In patients undergoing reperfusion, admission glucose is associated with poor outcome but the effect of glucose level on infarct growth is not well studied. Materials and Methods This is a secondar...

We report on the use of systemic heparinization following thrombolysis with intravenous tissue plasminogen activator (t-PA) for acute ischemic large vessel stroke, in the setting of COVID-19-induced hypercoagulability, with partial recanalization of the internal carotid artery. Off-label systemic heparinization was used within 12 hours of t-PA admi...

Background and purpose: There are only few data and lack of consensus regarding antiplatelet management for carotid stent placement in the setting of endovascular stroke treatment. We aimed to develop a consensus-based algorithm for antiplatelet management in acute ischemic stroke patients undergoing endovascular treatment and simultaneous emergen...

Background Large vessel occlusion (LVO) stroke is one of the most time-sensitive diagnoses in medicine and requires emergent endovascular therapy to reduce morbidity and mortality. Leveraging recent advances in deep learning may facilitate rapid detection and reduce time to treatment. Purpose To develop a convolutional neural network to detect LVOs...

Background and purpose: There is a paucity of data regarding antiplatelet management strategies in the setting of stent-assisted coiling/flow diversion for ruptured intracranial aneurysms. This study aimed to identify current challenges in antiplatelet management during stent-assisted coiling/flow diversion for ruptured intracranial aneurysms and...

Endovascular treatment is a highly effective therapy for acute ischemic stroke due to large vessel occlusion and has recently revolutionized stroke care. Oftentimes, ischemic core extent on baseline imaging is used to determine endovascular treatment-eligibility. There are, however, 2 fundamental issues with the core concept: First, computed tomogr...

Frequency and outcomes of mechanical thrombectomy (MT) in clinical practice for patients with severe pre-stroke disability are largely unknown. In this case series, we aim to describe the disability make-up and outcomes of 33 patients with severe pre-stroke disability undergoing MT. Patients with a permanent, severe, pre-stroke disability (modified...

The first part of this review provides a step-by-step guide to optimize endovascular therapy (EVT) for your patients, whereas the second part describes management strategies for frequently encountered challenging situations, which might require additional steps or modification of the thrombectomy approach.

The global pandemic of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to our healthcare system.1 As the number of identified COVID-19 patients exponentially increases, protocols for the safe delivery of care of both patients and providers a...

Background and Purpose— We aimed to compare functional and procedural outcomes of patients with acute ischemic stroke with none-to-minimal (modified Rankin Scale [mRS] score, 0–1) and moderate (mRS score, 2–3) prestroke disability treated with mechanical thrombectomy. Methods— Consecutive adult patients undergoing mechanical thrombectomy for an an...

Background The benefit of endovascular treatment (EVT) is highly time-dependent, and treatment delays reduce patients’ chances to achieve a good outcome. In this survey-based study, we aimed to evaluate current in-hospital EVT workflow characteristics across different countries and hospital settings, and to quantify the time-savings that could be a...

Objectives: CT angiography (CTA) is essential in acute stroke to detect emergent large vessel occlusions (ELVO) and must be interpreted by radiologists with and without subspecialized training. Additionally, grayscale inversion has been suggested to improve diagnostic accuracy in other radiology applications. This study examines diagnostic perform...

Clinical outcomes in patients with acute basilar occlusion (BAO) vary widely; several prognostic scores based on noninvasive imaging have been proposed. We aimed to compare the predictive value of several noninvasive neuroimaging scores in patients with BAO.

Background: There is limited data on predictors of sICH in patients who underwent mechanical thrombectomy. In this study, we aim to determine those predictors with external validation. Methods: We evaluated mechanical thrombectomy in a derivation cohort of patients at a comprehensive stroke center over a 30-month period. sICH was defined using the...

Introduction: Intravenous alteplase improves functional outcome in patients with acute ischemic stroke. While patients often have better outcomes, other patients may experience recurrent or worsening symptoms. We sought to determine the association between stroke subtype and neurologic deterioration in this study cohort. Methods: Data were abstract...

Background: Among thrombectomy techniques, Continuous Aspiration Prior to Intracranial Vascular Embolectomy (CAPTIVE) is associated with higher rates of recanalization. Initially, CAPTIVE was performed without a balloon guide catheter (BGC). We aimed to determine the association between BGC usage with final recanalization as well as first pass effe...

Background and Purpose: There is limited data on predictors of 30-day stroke or death in patients with symptomatic intracranial atherosclerosis (sICAS) undergoing stenting. We aim to determine these predictors. Methods: This is a post-hoc analysis SAMMPRIS including patients who underwent angioplasty/stenting. We determined associations between pat...

Introduction: Clinical outcomes in patients with acute basilar occlusion (BAO) vary widely; several prognostic scores based on noninvasive imaging have been proposed. We aimed to compare the predictive value of several noninvasive neuroimaging scores in patients with BAO. Methods: We performed a single-center retrospective cohort study including al...

Introduction: The insular cortex controls several aspects of vital function including autonomic regulation, and strokes affecting the insula have been associated with dysautonomia, cardiac dysfunction, and arrhythmias. Previous studies have shown an association between insular strokes, elevated troponin levels, and atrial fibrillation (AF). In this...

Background and Purpose: While studies have stratified cardioembolic (CE) stroke risk by qualitative left atrial appendage (LAA) morphology and biomarkers of atrial dysfunction, the quantitative properties that underlie these observations are not well established. Accordingly, we hypothesized that LAA volume and contrast density (attenuation) on com...

Introduction: Carotid web is a putative mechanism of cryptogenic ischemic stroke. We aimed to determine the prevalence of carotid web based on assigned stroke mechanism, and hypothesized that carotid webs would be found more frequently in younger cryptogenic stroke patients. Methods: We performed a single-center retrospective cohort study using ins...

Objective: Clinical predictors of ischemic stroke in the setting of atrial fibrillation (AF) have been identified, but there is limited data on predictors in the context of abnormal flow originating from the left atrial appendage. We hypothesize that reduced LAA flow velocity is associated with cerebrovascular ischemic events in patients with AF. M...

Background and Purpose: Early neurologic improvement (ENI) in patients treated with alteplase has been shown to correlate with functional outcome. However, the definition of ENI remains controversial and has varied across studies. Current definitions take into account the absolute difference between the admission and 24-hour NIHSS but this differen...

Background: Predictors of alteplase associated symptomatic intracranial hemorrhage (sICH) have been identified but there are very limited data on predictors of delayed sICH (> 24 hours from infusion). We hypothesize that asymptomatic hemorrhage on 24 hour brain imaging predicts delayed sICH and that delaying antithrombotic treatment in these patien...

Introduction: Spontaneous intracerebral hemorrhage (ICH) most commonly arises due to primary etiologies such as hypertensive or cerebral amyloid angiopathy (CAA), but may also occur due to underlying secondary causes such as vascular malformations or intracranial neoplasms. However, focal mass effect may potentially obscure underlying lesions on ne...

Background: The current AHA/ASA guidelines recommend only offering mechanical thrombectomy (MT) to patients without pre-stroke disability. We aimed to compare outcomes of acute ischemic stroke patients with none-to-minimal (modified Rankin score, mRS, 0-1) and moderate (mRS 2-3) pre-stroke disability treated with MT. Methods: Consecutive adult pati...

Background and purpose: While studies have stratified cardioembolic (CE) stroke risk by qualitative left atrial appendage (LAA) morphology and biomarkers of atrial dysfunction, the quantitative properties that underlie these observations are not well established. Accordingly, we hypothesized that LAA volume and contrast density (attenuation) on co...

Background and purpose: The role of collateral imaging in selecting patients for endovascular thrombectomy beyond 6 hours from onset has not been established. To assess the comparative utility of collateral imaging using multiphase CTA in selecting late window patients for EVT. Materials and methods: We used data from a prospective multicenter o...

Background and purpose: Early neurologic improvement (ENI) in patients treated with alteplase has been shown to correlate with functional outcome. However, the definition of ENI remains controversial and has varied across studies. We hypothesized that ENI defined as a percentage change in the National Institute of Health Stroke Scale (NIHSS) score...

PURPOSE The aim of this investigation was to quantitatively evaluate the effects of the addition of peak and delayed venous phase imaging to arterial phase CTA for the detection of distal ischemic strokes. Changes in sensitivity, specificity, time required to render a final decision, and subjective level of diagnostic confidence were quantified. M...

Background: Because of the overwhelming benefit of thrombectomy for highly selected trial patients with large vessel occlusion (LVO), some trial-ineligible patients are being treated in practice. Objective: To determine the safety and efficacy of thrombectomy in DAWN/DEFUSE-3-ineligible patients. Methods: Using a multicenter prospective observ...

Background and purpose: The 2018 AHA guidelines recommend perfusion imaging to select patients with acute large vessel occlusion (LVO) for thrombectomy in the extended window. However, the relationship between noncontrast CT and CT perfusion imaging has not been sufficiently characterized >6 hours after last known normal (LKN). Methods: From a m...

Introduction: Endovascular therapy is the standard of care for acute ischemic stroke due to large vessel occlusions. The ultimate goal is to achieve fast first pass complete reperfusion, since delayed and/or incomplete reperfusion increases complication rates and costs and deteriorates patient outcome. Achieving optimal results can sometimes be cha...

Background and Purpose— To identify the specific post-endovascular stroke therapy (EVT) peak systolic blood pressure (SBP) threshold that best discriminates good from bad functional outcomes (a priori hypothesized to be 160 mm Hg), we conducted a prospective, multicenter, cohort study with a prespecified analysis plan. Methods— Consecutive adult p...

Background and purpose There are limited data on predictors of 30-day stroke or death in patients with symptomatic intracranial atherosclerosis (sICAS) undergoing stenting. We aim to determine the factors associated with stroke or death at 30 days in the stenting arm of the SAMMPRIS trial. Methods This is a post-hoc analysis of the SAMMPRIS trial...

Background Endovascular therapy (EVT) for stroke improves outcomes but is time sensitive. Objective To compare times to treatment and outcomes between patients taken to the closest primary stroke center (PSC) with those triaged in the field to a more distant comprehensive stroke center (CSC). Methods During the study, a portion of our region allo...

Background There is limited data on predictors of symptomatic intracranial haemorrhage (sICH) in patients who underwent mechanical thrombectomy. In this study, we aim to determine those predictors with external validation. Methods We evaluated mechanical thrombectomy in a derivation cohort of patients at a comprehensive stroke centre over a 30-mon...

M2 segment occlusion of the middle cerebral artery is a potentially debilitating cause of stroke, and the data is unclear on the optimal method of treatment for these patients. FLAIR hyperintense vessels (FHV) on MRI have been postulated to be correlated with ischemic penumbra, and we sought to evaluate the incidence of this radiologic finding in p...

Background M2 segment occlusion of the middle cerebral artery is a potentially debilitating cause of stroke, and the data is unclear on the optimal method of treatment for these patients. FLAIR hyperintense vessels (FHV) on MRI have been postulated to be correlated with ischemic penumbra, and we sought to evaluate the incidence of this radiologic f...

Background Current guidelines recommend the use of perfusion imaging for selection of patients for endovascular thrombectomy (EVT) beyond six hours from onset. The role of collateral imaging in this time window is not established. Methods We used data from a prospective multi-center observational study where all stroke patients with suspected larg...

Background The aetiology of wall motion abnormalities (WMA) in patients with ischaemic stroke is unclear. We hypothesised that WMAs on transthoracic echocardiography (TTE) in the setting of ischaemic stroke mostly reflect pre-existing coronary heart disease rather than simply an isolated neurocardiogenic phenomenon. Methods Data were retrospective...

Background and Purpose— Left atrial enlargement has been shown to be associated with ischemic stroke, but the association with embolic stroke mechanisms remains unknown. We aim to study the associations between left atrial volume index (LAVI) and embolic stroke subtypes and atrial fibrillation (AF) detection on cardiac event monitoring in patients...

Introduction Atraumatic convexity subarachnoid hemorrhage is a subtype of spontaneous subarachnoid hemorrhage that often presents a diagnostic challenge. Common etiologies include cerebral amyloid angiopathy, vasculopathies, and coagulopathy; however, aneurysm is rare. Given the broad differential of causes of convexity subarachnoid hemorrhage, we...

Background and Purpose: Patients with ischemic stroke of cardioembolic origin are at risk of visceral (renal or splenic) infarction. We hypothesized that serum troponin level at time of ischemic stroke would be associated with presence of visceral infarction. Methods: Data were abstracted from a single center prospective stroke database over 18 mon...

BACKGROUND AND PURPOSE Studies have shown an association between infarct patterns and recurrent stroke in patients with symptomatic intracranial stenosis (sICAS) but there are limited data on associations with perfusion imaging mismatch profile. We aim to determine the association between infarct pattern, optimal mismatch profile definition, and re...