To Treat or Not to Treat: Importance of Functional Dependence in Deciding Intravenous Thrombolysis of “Mild Stroke” Patients

Intravenous thrombolysis (IVT) in patients with a low National Institutes of Health Stroke Scale (NIHSS) score of 0–5 remains controversial. IVT should be used in patients with mild but nevertheless disabling symptoms. We hypothesize that response to IVT of patients with “mild stroke” may depend on their level of functional dependence (FD) at hospital admission. The aims of our study were to investigate the effect of IVT and to explore the role of FD in influencing the response to IVT. This study was a retrospective analysis of a prospectively collected database, including 389 patients stratified into patients receiving IVT (IVT+) and not receiving IVT (IVT −) just because of mild symptoms. Barthel index (BI) at admission was used to assess FD, dividing subjects with BI score < 80 (FD+) and with BI score ≥ 80 (FD−). The efficacy endpoints were the rate of positive disability outcome (DO+) (3-month mRS score of 0 or 1), and the rate of positive functional outcome (FO+) (mRS score of zero or one, plus BI score of 95 or 100 at 3 months). At the multivariate analysis, IVT treatment was an independent predictor of DO+ (OR 3.12, 95% CI 1.34−7.27, p = 0.008) and FO+ (OR: 4.70, 95% CI 2.38−9.26, p = 0.001). However, FD+ IVT+ patients had a significantly higher prevalence of DO+ and FO+ than those FD+ IVT–. Differently, IVT treatment did not influence DO+ and FO+ in FD– patients. In FD+ patients, IVT treatment represented the strongest independent predictor of DO+ (OR 6.01, 95% CI 2.59–13.92, p = 0.001) and FO+ (OR 4.73, 95% CI 2.29–9.76, p = 0.001). In conclusion, alteplase seems to improve functional outcome in patients with “mild stroke”. However, in our experience, this beneficial effect is strongly influenced by FD at admission.

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How do treatment times impact on functional outcome in stroke patients undergoing thrombectomy in Germany? Results from the German Stroke Registry

International Journal of Stroke ◽

10.1177/1747493020985260 ◽

2021 ◽

pp. 174749302098526

Author(s):

Juliane Herm ◽

Ludwig Schlemm ◽

Eberhard Siebert ◽

Georg Bohner ◽

Anna C Alegiani ◽

...

Keyword(s):

Functional Outcome ◽

Odds Ratio ◽

Intravenous Thrombolysis ◽

Stroke Patients ◽

Poor Functional Outcome ◽

Stroke Registry ◽

Primary Stroke Center ◽

Comprehensive Stroke Center ◽

Stroke Center ◽

Center Time

Background Functional outcome post-stroke depends on time to recanalization. Effect of in-hospital delay may differ in patients directly admitted to a comprehensive stroke center and patients transferred via a primary stroke center. We analyzed the current door-to-groin time in Germany and explored its effect on functional outcome in a real-world setting. Methods Data were collected in 25 stroke centers in the German Stroke Registry-Endovascular Treatment a prospective, multicenter, observational registry study including stroke patients with large vessel occlusion. Functional outcome was assessed at three months by modified Rankin Scale. Association of door-to-groin time with outcome was calculated using binary logistic regression models. Results Out of 4340 patients, 56% were treated primarily in a comprehensive stroke center and 44% in a primary stroke center and then transferred to a comprehensive stroke center (“drip-and-ship” concept). Median onset-to-arrival at comprehensive stroke center time and door-to-groin time were 103 and 79 min in comprehensive stroke center patients and 225 and 44 min in primary stroke center patients. The odds ratio for poor functional outcome per hour of onset-to-arrival-at comprehensive stroke center time was 1.03 (95%CI 1.01–1.05) in comprehensive stroke center patients and 1.06 (95%CI 1.03–1.09) in primary stroke center patients. The odds ratio for poor functional outcome per hour of door-to-groin time was 1.30 (95%CI 1.16–1.46) in comprehensive stroke center patients and 1.04 (95%CI 0.89–1.21) in primary stroke center patients. Longer door-to-groin time in comprehensive stroke center patients was associated with admission on weekends (odds ratio 1.61; 95%CI 1.37–1.97) and during night time (odds ratio 1.52; 95%CI 1.27–1.82) and use of intravenous thrombolysis (odds ratio 1.28; 95%CI 1.08–1.50). Conclusion Door-to-groin time was especially relevant for outcome of comprehensive stroke center patients, whereas door-to-groin time was much shorter in primary stroke center patients. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03356392 . Unique identifier NCT03356392

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Abstract TP64: Negative-FLAIR Vascular Hyperintensities Serves as a Marker of Chronic Major Arterial Occlusion in Acute Stroke

Stroke ◽

10.1161/str.47.suppl_1.tp64 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Junya Aoki ◽

Kentaro Suzuki ◽

Yuki Sakamoto ◽

Arata Abe ◽

Satoshi Suda ◽

...

Keyword(s):

Acute Stroke ◽

Arterial Occlusion ◽

Intravenous Thrombolysis ◽

Multivariate Regression Analysis ◽

Artery Occlusion ◽

Carotid Artery Occlusion ◽

National Institutes Of Health ◽

Chronic Occlusion ◽

Fluid Attenuated Inversion Recovery

Introduction: Because acute fluid-attenuated inversion recovery vascular hyperintensities (FVH) represent disordered blood flow, FVH has been considered as a marker of major arterial occlusions. Contrary, the role of absence of FVH (negative-FVH) is unknown. Hypothesis: We hypothesized that negative-FVH may indicate chronic occlusion. Thus, we investigated the clinical characteristics and neuroimaging findings in patients with negative-FVH and major arterial occlusion. Methods: Consecutive acute stroke patients within 24 hours of onset and major arterial occlusion on magnetic resonance angiography (MRA) were studied. All patients were examined using serial angiography to evaluate the presence of recanalization. Patients were classified into two groups (NF: group without FVH, F: group with FVH). Results: Seventy-two patients (49 [68%] males, 76 [66-83] years) were enrolled. Thirty-six (50%) patients were treated with acute recanalization therapy, including the intravenous thrombolysis or endovascular therapy. On admission, 10 patients were NF group and 62 were F group. Initial National Institutes of Health Stroke Scale (NIHSS) score was 4 (2-8) in NF group and 10 (4-21) in F group (p=0.012). The rate of internal carotid artery occlusion was similar between NF and F group (20% vs. 29%, p=0.716). Serial angiography studies revealed that recanalization was achieved in only 1 (10%) of the 10 patients with NF group and 49 (79%) of the 62 patients with F group during hospitalization (p<0.001). When all patients divided into 2 groups based on the presence or absence of recanalization, patients with recanalization were younger (p=0.023), had higher NIHSS (p=0.008), earlier admission (p=0.014), higher prevalence of atrial fibrillation (p=0.010), and frequently treated with acute recanalization therapy (p=0.040). When multivariate regression analysis was conducted, that Negative-FVH (odds ratio 0.061, 95% CI 0.06-0.620, p=0.018) was a negative independent factor associated with recanalization during hospitalization. Conclusions: Negative-FVH was independently associated with no recanalization during hospitalization. Negative-FLAIR may present not acute occlusion but chronic occlusion.

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Intravenous Thrombolysis Benefits Mild Stroke Patients With Large-Artery Atherosclerosis but No Tandem Steno-Occlusion

Frontiers in Neurology ◽

10.3389/fneur.2020.00340 ◽

2020 ◽

Vol 11 ◽

Author(s):

Dapeng Wang ◽

Lulu Zhang ◽

Xiaowei Hu ◽

Juehua Zhu ◽

Xiang Tang ◽

...

Keyword(s):

Intravenous Thrombolysis ◽

Large Artery ◽

Stroke Patients ◽

Mild Stroke

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Intravenous thrombolysis pretreatment and other predictors of infarct in a new previously unaffected territory (INT) in ELVO strokes treated with mechanical thrombectomy

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2019-014935 ◽

2019 ◽

Vol 12 (2) ◽

pp. 142-147 ◽

Cited By ~ 2

Author(s):

Nitin Goyal ◽

Georgios Tsivgoulis ◽

Jason J Chang ◽

Konark Malhotra ◽

Juan Goyanes ◽

...

Keyword(s):

Regression Models ◽

Mechanical Thrombectomy ◽

Independent Predictor ◽

Intravenous Thrombolysis ◽

Functional Independence ◽

Posterior Circulation ◽

National Institutes Of Health ◽

Special Focus ◽

Vessel Occlusion ◽

Logistic Regression Models

IntroductionOne uncommon complication of mechanical thrombectomy (MT) is an infarct in a new previously unaffected territory (infarct in new territory (INT)).ObjectiveTo evaluate the predictors of INT with special focus on intravenous thrombolysis(IVT)pretreatmentbefore MT.MethodsConsecutive patients with emergent large vessel occlusion (ELVO) treated with MT during a 5-year period were evaluated. INT was defined using standardized methodology proposed by ESCAPE investigators. The predictors of INT and its impact on outcomes were investigated.ResultsA total of 419 consecutive patients with ELVO received MT (mean age 64±15 years, 50% men, median baseline National Institutes of Health Stroke Scale score 16 points (IQR 11–20), 69% pretreated with IVT). The incidence of INT was lower in patients treated with combination therapy (IVTandMT) than in patients treated with MT alone, respectively (10% vs 20%; p=0.011). The INT group had more patients with posterior circulation occlusions than the group without INT (28% vs 10%, respectively; p<0.001). The rates of 3-month functional independence were lower in patients with INT (30% vs 50%; p=0.007). IVT pretreatment was not independently related to INT (OR=0.75; 95% CI 0.32 to 1.76), and INT did not emerge as an independent predictor of 3-month functional independence (OR=0.69; 95% CI 0.29 to 1.62) on multivariable logistic regression models. Location of posterior circulation occlusion was independently associated with a higher odds of INT (OR=3.33; 95% CI 1.43 to 7.69; p=0.005).ConclusionsIVT pretreatment is not independently associated with a lower likelihood of INT in patients with ELVO treated with MT. Patients with ELVO with posterior circulation occlusion are more likely to have INT after MT.

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Endovascular Therapy versus Thrombolysis in Patients with Mild Strokes and Large Vessel Occlusions within the Anterior Circulation

Interventional Neurology ◽

10.1159/000489708 ◽

2018 ◽

Vol 7 (6) ◽

pp. 431-438 ◽

Cited By ~ 2

Author(s):

Andreas Kastrup ◽

Freimuth Brunner ◽

Helmut Hildebrandt ◽

Christian Roth ◽

Michael Winterhalter ◽

...

Keyword(s):

Intravenous Thrombolysis ◽

Clinical Results ◽

National Institutes Of Health ◽

Large Vessel ◽

Intracranial Hemorrhages ◽

Anterior Circulation ◽

Treatment Groups ◽

Good Outcome ◽

Discharge Rates

Background: In patients with large vessel occlusions, endovascular treatment (ET) has been shown to be superior to intravenous thrombolysis (IVT) in recent trials. However, it is currently unclear if patients with mild strokes also benefit from ET. Methods: We compared the discharge rates of good outcome (modified Rankin scale [mRS] ≤2), very good outcome (mRS 0–1), symptomatic intracranial hemorrhages (SICH), and infarct sizes in patients with mild strokes (admission National Institutes of Health Stroke Scale ≤10) and distal intracranial carotid artery, M1, and M2 occlusions during two time periods. Results: From 1/2008 to 10/2012 160 patients (mean age: 72 ± 12 years) were treated with IVT, and from 11/2012 to 11/2016 145 patients (mean age: 71 ± 13 years,) received ET with or without IVT. The clinical results were comparable between both treatment groups (59% after ET vs. 56% after IVT, p = 0.5 for an mRS 0–2) and (38% after ET vs. 32% after IVT, p = 0.3 for an mRS 0–1). In the subgroup of patients with an mRS ≤6, the early outcome did not differ significantly between ET and IVT either. The rates of SICH as well as the infarct sizes were not significantly different after ET compared with IVT. Conclusion: Compared with IVT, the routine use of ET did not significantly improve the early clinical or radiological outcome in patients with mild strokes and anterior circulation large vessel occlusions. Further randomized trials are urgently needed to determine the role of ET in this cohort.

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Functional Outcome of Hemorrhagic Transformation after Thrombolysis for Ischemic Stroke: A Prospective Study

Cerebrovascular Diseases Extra ◽

10.1159/000440737 ◽

2015 ◽

Vol 5 (3) ◽

pp. 103-106 ◽

Cited By ~ 5

Author(s):

Mariam Annan ◽

Marie Gaudron ◽

Jean-Philippe Cottier ◽

Xavier Cazals ◽

Maelle Dejobert ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Outcome ◽

Intravenous Thrombolysis ◽

Hemorrhagic Transformation ◽

University Hospital ◽

3 Tesla ◽

Stroke Severity ◽

Increased Risk ◽

3 Tesla Mri

Background/Aims: Hemorrhagic transformation (HT) is usually taken into account when symptomatic, but the role of asymptomatic HT is not well known. The aim of our study was to evaluate the link between HT after thrombolysis for ischemic stroke and functional outcome at 3 months, with particular emphasis on asymptomatic HT. Methods: Our study was performed prospectively between June 2012 and June 2013 in the Stroke Unit of the University Hospital Center of Tours (France). All patients treated with intravenous thrombolysis were consecutively included. HT was classified on susceptibility-weighted imaging (SWI) with 3-tesla MRI at 7 ± 3 days after treatment. We evaluated functional outcome at 3 months using the modified Rankin Scale (mRS). Dependency was defined as an mRS score of ≥3. Results: After 1 year, 128 patients had received thrombolytic therapy for ischemic stroke, of whom 90 patients underwent both 3-tesla MRI and SWI at day 7. Fifty-two had HT, including 8 symptomatic cases. At 3 months, 68% of those patients were dependent compared to 31% of patients without HT [OR 4.6 (1.9-11.4), p = 0.001]. In asymptomatic HT, the rate was 62% [OR 3.5 (1.4-8.9), p = 0.007], but did not reach significance after adjustment for stroke severity. Discussion: Our study found no statistically significant effect of HT on outcome after adjustment for initial stroke severity. However, the innocuousness of HT is not certain, and only few studies have already highlighted the increased risk of dependency. Using 3-tesla MRI with SWI allows us to increase the detection rate of small hemorrhage. Conclusion: HT after thrombolysis is very frequent on SWI, but the initial stroke severity is an important predictor to assess the role of HT for patient outcome.

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Impact of Delirium and Its Motor Subtypes on Stroke Outcomes

Stroke ◽

10.1161/strokeaha.120.026425 ◽

2021 ◽

Vol 52 (4) ◽

pp. 1322-1329

Author(s):

Ivã Taiuan Fialho Silva ◽

Pedro Assis Lopes ◽

Tiago Timotio Almeida ◽

Saint Clair Ramos ◽

Ana Teresa Caliman Fontes ◽

...

Keyword(s):

Functional Outcome ◽

Functional Dependence ◽

Confusion Assessment Method ◽

Assessment Method ◽

Modified Rankin Scale ◽

Stroke Patients ◽

Risk Of Death ◽

Increased Risk ◽

And Behavior ◽

The Relationship

Background and Purpose: Delirium is an acute and fluctuating impairment of attention, cognition, and behavior. Although common in stroke, studies that associate the clinical subtypes of delirium with functional outcome and death are lacking. We aimed to evaluate the influence of delirium occurrence and its different motor subtypes over stroke patients’ prognosis. Methods: Prospective cohort of stroke patients with symptom onset within 72 hours before research admission. Delirium was diagnosed by Confusion Assessment Method for the Intensive Care Unit, and its motor subtypes were defined according to the Richmond Agitation-Sedation Scale. The main outcome was functional dependence or death (modified Rankin Scale>2) at 90 days comparing: delirium versus no delirium patients; and between motor subtypes. Secondary outcomes included modified Rankin Scale score >2 at 30 days and 90-day-mortality. Results: Two hundred twenty-seven patients were enrolled. Delirium occurred in 71 patients (31.3%), with the hypoactive subtype as the most frequent, in 41 subjects (57.8%). Delirium was associated with increased risk of death and functional dependence at 30 and 90 days and higher 90-day mortality. Multivariate analysis showed delirium (odds ratio, 3.28 [95% CI, 1.17–9.22]) as independent predictor of modified Rankin Scale >2 at 90 days. Conclusions: Delirium is frequent in stroke patients in the acute phase. Its occurrence—specifically in mixed and hypoactive subtypes—seems to predict worse outcomes in this population. To our knowledge, this is the first study to prospectively investigate differences between delirium motor subtypes over functional outcome three months poststroke. Larger studies are needed to elucidate the relationship between motor subtypes of delirium and functional outcomes in the context of acute stroke.

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Meta-analysis of the Smoker’s Paradox in Acute Ischemic Stroke Patients Receiving Intravenous Thrombolysis or Endovascular Treatment

Nicotine & Tobacco Research ◽

10.1093/ntr/ntz094 ◽

2019 ◽

Vol 21 (9) ◽

pp. 1181-1188 ◽

Cited By ~ 1

Author(s):

Peng Zhang ◽

Zhen-Ni Guo ◽

Xin Sun ◽

Yingkai Zhao ◽

Yi Yang

Keyword(s):

Ischemic Stroke ◽

Endovascular Treatment ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Functional Outcomes ◽

Meta Analysis ◽

Intravenous Thrombolysis ◽

Cochrane Library ◽

Stroke Patients ◽

Good Functional Outcome

Abstract Introduction The existence of the smoker’s paradox is controversial and potential mechanisms have not been explained. We aimed to explore the association between cigarette smoking and functional outcome at 3 months in patients with acute ischemic stroke who were treated with intravenous thrombolysis (IVT) or endovascular treatment (EVT). Methods This meta-analysis was conducted in accordance with the PRISMA guidelines. Studies exploring the association between smoking and good functional outcome (modified Rankin Scale score ≤ 2) following IVT or EVT were searched via the databases of PubMed, Embase, and the Cochrane Library from inception to August 8, 2018. Information on the characteristics of included studies was independently extracted by two investigators. Data were pooled using a random-effects or fixed-effects meta-analysis according to the heterogeneity of included studies. Results Among 20 identified studies, 15 reported functional outcomes following IVT, and five reported functional outcomes following EVT. Unadjusted analyses showed that smoking increased the odds of good functional outcomes with a pooled odds ratio (OR) of 1.48 (95% confidence interval [CI]: 1.36–1.60) after IVT and 2.10 (95% CI: 1.47–3.20) after EVT. Of IVT studies, only eight reported outcomes adjusted for covariates and none of the EVT studies reported adjusted outcomes. After adjustment, the relation between smoking and good functional outcome following IVT lost statistical significance (OR 1.14 [95% CI: 0.81–1.59]). Conclusion Our meta-analysis suggested that smoking was not associated with good functional outcome (mRS ≤ 2) at 3 months in patients with acute ischemic stroke who were treated with intravenous thrombolysis. Implications The existence of the smoker’s paradox is controversial. A previous letter by Plas et al. published in 2013 reported a positive result for the association between smoking and good functional outcome at 3 months in acute ischemic stroke patients who received intravenous thrombolysis (IVT). However, a major limitation of their meta-analysis was that the process of data synthesis was based on unadjusted data. Therefore, we conducted this meta-analysis to investigate the association based on adjusted data and a larger sample size. Our meta-analysis suggested that smoking was not associated with good functional outcome after adjusting for covariates.

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Comparison of outcome and interventional complication rate in patients with acute stroke treated with mechanical thrombectomy with and without bridging thrombolysis

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2015-012236 ◽

2016 ◽

Vol 9 (3) ◽

pp. 229-233 ◽

Cited By ~ 62

Author(s):

Ralph Weber ◽

Hannes Nordmeyer ◽

Jeffrie Hadisurya ◽

Markus Heddier ◽

Michael Stauder ◽

...

Keyword(s):

Acute Stroke ◽

Functional Outcome ◽

Mechanical Thrombectomy ◽

Independent Predictor ◽

Intravenous Thrombolysis ◽

Favorable Outcome ◽

Complication Rates ◽

Modified Rankin Scale

BackgroundNo randomized trial has investigated the effect of mechanical thrombectomy (MT) alone in patients with acute stroke. There are conflicting results as to whether prior intravenous thrombolysis (IVT) facilitates subsequent MT, and data in patients treated with MT alone owing to contraindications to IVT are limited.ObjectiveTo compare consecutive patients treated with MT alone or with preceding IVT in a large tertiary neurointerventional center, with special emphasis on contraindications to IVT.MethodsRetrospective analysis of 283 consecutive patients with acute ischemic stroke treated with MT in a tertiary neurovascular center over 14 months. Data on characteristics of periprocedural times, recanalization rate, complications, and long-term functional outcome were collected prospectively.ResultsInformation on prior IVT and functional outcome was available in 250 patients. Mean (SD) follow-up period was 5.7 (5.1) months and 105 (42%) patients received both IVT and MT. No significant differences were found in successful recanalization rates (Thrombolysis in Cerebral Infarction (TICI) 2b/3, 73.8% vs 73.1, p=0.952), complication rates, and long-term favorable outcome (modified Rankin Scale 0–2, 35.2% vs 40%, p=0.444) between patients receiving MT plus IVT and those receiving MT alone. A favorable outcome in patients directly treated with MT alone who were eligible for IVT was achieved in 48.2%. Thrombectomy was safe and resulted in a favorable outcome in 32% of patients with absolute contraindications to IVT.ConclusionsPreceding use of IVT was not an independent predictor of favorable outcome in patients with acute stroke treated with MT and complication rates did not differ whether or not IVT was used. MT is safe and achieved a favorable outcome in one-third of patients with stroke ineligible for IVT.

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Abstract WP262: Intravenous Thrombolysis in Acute Ischemic Stroke Patients With Infective Endocarditis

Stroke ◽

10.1161/str.51.suppl_1.wp262 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Mangala Gopal ◽

Sushil Lakhani ◽

Vivien Lee

Keyword(s):

Ischemic Stroke ◽

Infective Endocarditis ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Intravenous Thrombolysis ◽

Stroke Patients ◽

Medical Risk ◽

Good Functional Outcome ◽

Intravenous Tissue Plasminogen Activator ◽

The Mean

Introduction: Infective endocarditis (IE) is considered to be an absolute contraindication for intravenous tissue plasminogen activator treatment (IVtPA) in acute ischemic stroke. However during the hyperacute stroke evaluation, the exclusion of IE may be difficult. Methods: We reviewed consecutive patients hospitalized at our comprehensive stroke center from January 1, 2014 to March 31, 2019 with acute ischemic stroke who received IVtPA and identified patients who were diagnosed with infective endocarditis. Data was abstracted on demographics, medical history, clinical presentation, last known normal (LKN) time, initial National Institutes of Health Stroke Scale (NIHSS), neuroimaging, culture results, and 90 day modified Rankin Scale (mRS). Good functional outcome was defined as mRS ≤ 2. Results: Among 1022 acute ischemic stroke patients who received IVtPA, 5 patients (0.5%) were ultimately diagnosed with IE. Among the 5 patients with IE, the mean age was 53.4 years (range, 25-74) and 3 (60%) were female. The majority, 4 (80%) were white. Medical risk factors for IE were present in 3 (60%) and included intravenous drug use (1) and dialysis (2). Initial NIHSS was 4.6 (range, 1 to 8). Fever was present on initial presentation in only 1 patient (102.7 F). All patients met criteria for IVtPA and there were no protocol violations. The mean time from LKN to IVtPA was 3.0 hours (range, 1.9 to 4.4). Vascular imaging showed MCA occlusion in 4 (80%) and no occlusion in 1 (20%). One patient underwent endovascular thrombectomy with Thrombolysis in cerebral infarction scale 2A recanalization. Two patients (40%) developed hemorrhagic complications, including 1 patient who developed subarachnoid hemorrhage on Hospital Day #2 due to mycotic cerebral aneurysm. The blood culture results included MRSE (1), Streptococci viridans (2) and negative (2). TEE in all patients showed vegetations on the mitral valve. No patients had good functional outcome, and the mean 3 months mRS was 4.8 (range, 3 to 6). Conclusions: In a large series of acute ischemic stroke patients who received IVtPA, undiagnosed IE is rare (0.5%). Fever was not commonly present during initial evaluation. Despite affecting younger patients with initial mild deficits, patients with IE had poor functional outcomes.

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