scholarly journals 2B, 2C, or 3

Stroke ◽  
2020 ◽  
Vol 51 (6) ◽  
pp. 1790-1796
Author(s):  
Natalie E. LeCouffe ◽  
Manon Kappelhof ◽  
Kilian M. Treurniet ◽  
Hester F. Lingsma ◽  
Guang Zhang ◽  
...  

Background and Purpose— A score of ≥2B on the modified Thrombolysis in Cerebral Infarction scale is generally regarded as successful reperfusion after endovascular treatment for ischemic stroke. The extended Thrombolysis in Cerebral Infarction (eTICI) includes a 2C grade, which indicates near-perfect reperfusion. We investigated how well the respective eTICI scores of 2B, 2C, and 3 correlate with clinical outcome after endovascular treatment. Methods— We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry, a prospective, nationwide registry of endovascular treatment in the Netherlands. We included patients with a proximal intracranial occlusion of the anterior circulation for whom final antero-posterior and lateral digital subtraction angiography imaging was available. Our primary outcome was the distribution on the modified Rankin Scale at 90 days per eTICI grade. We performed (ordinal) logistic regression analyses, using eTICI 2B as reference group, and adjusted for potential confounders. Results— In total, 2807/3637 (77%) patients met the inclusion criteria. Of these, 17% achieved reperfusion grade eTICI 0 to 1, 14% eTICI 2A, 25% eTICI 2B, 12% eTICI 2C, and 32% eTICI 3. Groups differed in terms of age ( P <0.001) and occlusion location ( P <0.01). Procedure times decreased with increasing reperfusion grades. We found a positive association between reperfusion grade and functional outcome, which continued to increase after eTICI 2B (adjusted common odds ratio, 1.22 [95% CI, 0.96–1.57] for eTICI 2C versus 2B; adjusted common odds ratio, 1.33 [95% CI, 1.09–1.62] for eTICI 3 versus 2B). Conclusions— Our results indicate a continuous relationship between reperfusion grade and functional outcome, with eTICI 3 leading to the best outcomes. Although this implies that interventionists should aim for the highest possible reperfusion grade, further research on the optimal strategy is necessary.

Stroke ◽  
2019 ◽  
Vol 50 (8) ◽  
pp. 2057-2064 ◽  
Author(s):  
Bruna G. Dutra ◽  
Manon L. Tolhuisen ◽  
Heitor C.B.R. Alves ◽  
Kilian M. Treurniet ◽  
Manon Kappelhof ◽  
...  

Background and Purpose— Thrombus imaging characteristics have been reported to be useful to predict functional outcome and reperfusion in acute ischemic stroke. However, conflicting data about this subject exist in patients undergoing endovascular treatment. Therefore, we aimed to evaluate whether thrombus imaging characteristics assessed on computed tomography are associated with outcomes in patients with acute ischemic stroke treated by endovascular treatment. Methods— The MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, and observational study in all centers performing endovascular treatment in the Netherlands. We evaluated associations of thrombus imaging characteristics with the functional outcome (modified Rankin Scale at 90 days), mortality, reperfusion, duration of endovascular treatment, and symptomatic intracranial hemorrhage using univariable and multivariable regression models. Thrombus characteristics included location, clot burden score (CBS), length, relative and absolute attenuation, perviousness, and distance from the internal carotid artery terminus to the thrombus. All characteristics were assessed on thin-slice (≤2.5 mm) noncontrast computed tomography and computed tomography angiography, acquired within 30 minutes from each other. Results— In total, 408 patients were analyzed. Thrombus with distal location, higher CBS, and shorter length were associated with better functional outcome (adjusted common odds ratio, 3.3; 95% CI, 2.0–5.3 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted common odds ratio, 1.15; 95% CI, 1.07–1.24 per CBS point; and adjusted common odds ratio, 0.96; 95% CI, 0.94–0.99 per mm, respectively) and reduced duration of endovascular procedure (adjusted coefficient B, −14.7; 95% CI, −24.2 to −5.1 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted coefficient B, −8.5; 95% CI, −14.5 to −2.4 per CBS point; and adjusted coefficient B, 7.3; 95% CI, 2.9–11.8 per mm, respectively). Thrombus perviousness was associated with better functional outcome (adjusted common odds ratio, 1.01; 95% CI, 1.00–1.02 per Hounsfield units increase). Distal thrombi were associated with successful reperfusion (adjusted odds ratio, 2.6; 95% CI, 1.4–4.9 for proximal M1 occlusion compared with internal carotid artery occlusion). Conclusions— Distal location, higher CBS, and shorter length are associated with better functional outcome and faster endovascular procedure. Distal thrombus is strongly associated with successful reperfusion, and a pervious thrombus is associated with better functional outcome.


Stroke ◽  
2021 ◽  
Author(s):  
Manon Kappelhof ◽  
Manon L. Tolhuisen ◽  
Kilian M. Treurniet ◽  
Bruna G. Dutra ◽  
Heitor Alves ◽  
...  

Background and Purpose: Thrombus perviousness estimates residual flow along a thrombus in acute ischemic stroke, based on radiological images, and may influence the benefit of endovascular treatment for acute ischemic stroke. We aimed to investigate potential endovascular treatment (EVT) effect modification by thrombus perviousness. Methods: We included 443 patients with thin-slice imaging available, out of 1766 patients from the pooled HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set of 7 randomized trials on EVT in the early window (most within 8 hours). Control arm patients (n=233) received intravenous alteplase if eligible (212/233; 91%). Intervention arm patients (n=210) received additional EVT (prior alteplase in 178/210; 85%). Perviousness was quantified by thrombus attenuation increase on admission computed tomography angiography compared with noncontrast computed tomography. Multivariable regression analyses were performed including multiplicative interaction terms between thrombus attenuation increase and treatment allocation. In case of significant interaction, subgroup analyses by treatment arm were performed. Our primary outcome was 90-day functional outcome (modified Rankin Scale score), resulting in an adjusted common odds ratio for a one-step shift towards improved outcome. Secondary outcomes were mortality, successful reperfusion (extended Thrombolysis in Cerebral Infarction score, 2B–3), and follow-up infarct volume (in mL). Results: Increased perviousness was associated with improved functional outcome. After adding a multiplicative term of thrombus attenuation increase and treatment allocation, model fit improved significantly ( P =0.03), indicating interaction between perviousness and EVT benefit. Control arm patients showed significantly better outcomes with increased perviousness (adjusted common odds ratio, 1.2 [95% CI, 1.1–1.3]). In the EVT arm, no significant association was found (adjusted common odds ratio, 1.0 [95% CI, 0.9–1.1]), and perviousness was not significantly associated with successful reperfusion. Follow-up infarct volume (12% [95% CI, 7.0–17] per 5 Hounsfield units) and chance of mortality (adjusted odds ratio, 0.83 [95% CI, 0.70–0.97]) decreased with higher thrombus attenuation increase in the overall population, without significant treatment interaction. Conclusions: Our study suggests that the benefit of best medical care including alteplase, compared with additional EVT, increases in patients with more pervious thrombi.


Stroke ◽  
2020 ◽  
Vol 51 (6) ◽  
pp. 1781-1789 ◽  
Author(s):  
Robert-Jan B. Goldhoorn ◽  
Rob A. van de Graaf ◽  
Jan M. van Rees ◽  
Hester F. Lingsma ◽  
Diederik W.J. Dippel ◽  
...  

Background and Purpose— The use of oral anticoagulants (OAC) is considered a contra-indication for intravenous thrombolytics as acute treatment of ischemic stroke. However, little is known about the risks and benefits of endovascular treatment in patients on prior OAC. We aim to compare outcomes after endovascular treatment between patients with and without prior use of OAC. Methods— Data of patients with acute ischemic stroke caused by an intracranial anterior circulation occlusion, included in the nationwide, prospective, MR CLEAN Registry between March 2014 and November 2017, were analyzed. Outcomes of interest included symptomatic intracranial hemorrhage and functional outcome at 90 days (modified Rankin Scale score). Outcomes between groups were compared with (ordinal) logistic regression analyses, adjusted for prognostic factors. Results— Three thousand one hundred sixty-two patients were included in this study, of whom 502 (16%) used OAC. There was no significant difference in the occurrence of symptomatic intracranial hemorrhage between patients with and without prior OACs (5% versus 6%; adjusted odds ratio, 0.63 [95% CI, 0.38–1.06]). Patients on OACs had worse functional outcomes than patients without OACs (common odds ratio, 0.57 [95% CI, 0.47–0.66]). However, this observed difference in functional outcome disappeared after adjustment for prognostic factors (adjusted common odds ratio, 0.91 [95% CI, 0.74–1.13]). Conclusions— Prior OAC use in patients treated with endovascular treatment for ischemic stroke is not associated with an increased risk of symptomatic intracranial hemorrhage or worse functional outcome compared with no prior OAC use. Therefore, prior OAC use should not be a contra-indication for endovascular treatment.


Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3742-3745
Author(s):  
Johanna Ospel ◽  
Manon Kappelhof ◽  
Adrien E. Groot ◽  
Natalie E. LeCouffe ◽  
Jonathan M. Coutinho ◽  
...  

Background and Purpose: Ischemic brain tissue damage in patients with acute ischemic stroke, as measured by the Alberta Stroke Program Early CT Score (ASPECTS) may be more impactful in older than in younger patients, although this has not been studied. We aimed to investigate a possible interaction effect between age and ASPECTS on functional outcome in acute ischemic stroke patients undergoing endovascular treatment, and compared reperfusion benefit across age and ASPECTS subgroups. Methods: Patients with ischemic stroke from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; March 2014–November 2017) were included. Multivariable ordinal logistic regression was performed to obtain effect size estimates (adjusted common odds ratio) on functional outcome (modified Rankin Scale score) for continuous age and granular ASPECTS, with a 2-way multiplicative interaction term (age×ASPECTS). Outcomes in four patient subgroups based on age (< versus ≥ median age [71.8 years]) and baseline ASPECTS (6–10 versus 0–5) were assessed. Results: We included 3279 patients. There was no interaction between age and ASPECTS on modified Rankin Scale ( P =0.925). The highest proportion of modified Rankin Scale 5 to 6 was observed in patients >71.8 years with baseline ASPECTS 0 to 5 (68/107, 63.6%). There was benefit of reperfusion in all age-ASPECTS subgroups. Although the adjusted common odds ratio was lower in patients >71.8 years with ASPECTS 0 to 5 (adjusted common odds ratio, 1.60 [95% CI, 0.66–3.88], n=110), there was no significant difference from the main effect ( P =0.299). Conclusions: Although the proportion of poor outcomes following endovascular treatment was highest in older patients with low baseline ASPECTS, outcomes did not significantly differ from the main effect. These results do not support withholding endovascular treatment based n a combination of high age and low ASPECTS.


Stroke ◽  
2021 ◽  
Author(s):  
Marie Louise E. Bernsen ◽  
Agnetha A.E. Bruggeman ◽  
Josje Brouwer ◽  
Bart J. Emmer ◽  
Charles B.L.M. Majoie ◽  
...  

Background and Purpose: Whereas a clear benefit of endovascular treatment for anterior circulation stroke has been established, randomized trials assessing the posterior circulation have failed to show efficacy. Previous studies in anterior circulation stroke suggest that advanced thrombectomy devices were of great importance in achieving clinical benefit. Little is known about the effect of thrombectomy techniques on outcomes in posterior circulation stroke. In this study, we compare first-line strategy of direct aspiration to stent retriever thrombectomy for posterior circulation stroke. Methods: We analyzed data of patients with a posterior circulation stroke who were included in the Multicentre Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry between March 2014 and December 2018, a prospective, nationwide study, in which data were collected from consecutive patients who underwent endovascular treatment for ischemic stroke in the Netherlands. We compared patients who underwent first-line aspiration versus stent retriever thrombectomy. Primary outcome was functional outcome according to the modified Rankin Scale. Secondary outcomes were reperfusion grade, complication rate, and procedure duration. Associations between thrombectomy technique and outcome measures were estimated with multivariable ordinal logistic regression analyses. Results: Overall, 71 of 205 patients (35%) were treated with aspiration, and 134 (65%) with stent retriever thrombectomy. Patients in the aspiration group had a lower pc-ASPECTS on baseline computed tomography, and general anesthesia was more often applied in this group. First-line aspiration was associated with better functional outcome compared with stent retriever thrombectomy (adjusted common odds ratio for a 1-point improvement on the modified Rankin Scale 1.94 [95% CI, 1.03–3.65]). Successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2B) was achieved more often with aspiration (87% versus 73%, P =0.03). Symptomatic hemorrhage rates were comparable (3% versus 4%). Procedure times were shorter in the aspiration group (49 versus 69 minutes P <0.001). Conclusions: In this retrospective nonrandomized cohort study, our findings suggest that first-line aspiration is associated with a shorter procedure time, better reperfusion, and better clinical outcome than stent retriever thrombectomy in patients with ischemic stroke based on large vessel occlusion in the posterior circulation.


Stroke ◽  
2019 ◽  
Vol 50 (8) ◽  
pp. 2147-2155 ◽  
Author(s):  
Rob A. van de Graaf ◽  
Vicky Chalos ◽  
Adriaan C.G.M. van Es ◽  
Bart J. Emmer ◽  
Geert J. Lycklama à Nijeholt ◽  
...  

Background and Purpose— Intravenous administration of heparin during endovascular treatment for ischemic stroke may improve outcomes. However, risks and benefits of this adjunctive therapy remain uncertain. We aimed to evaluate periprocedural intravenous heparin use in Dutch stroke intervention centers and to assess its efficacy and safety. Methods— Patients registered between March 2014 and June 2016 in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke), including all patients treated with endovascular treatment in the Netherlands, were analyzed. The primary outcome was functional outcome (modified Rankin Scale) at 90 days. Secondary outcomes were successful recanalization (extended Thrombolysis in Cerebral Infarction ≥2B), symptomatic intracranial hemorrhage, and mortality at 90 days. We used multilevel regression analysis to evaluate the association of periprocedural intravenous heparin on outcomes, adjusted for center effects and prognostic factors. To account for possible unobserved confounding by indication, we analyzed the effect of center preference to administer intravenous heparin, defined as percentage of patients treated with intravenous heparin in a center, on functional outcome. Results— One thousand four hundred eighty-eight patients from 16 centers were analyzed, of whom 398 (27%) received intravenous heparin (median dose 5000 international units). There was substantial between-center variability in the proportion of patients treated with intravenous heparin (range, 0%–94%). There was no significant difference in functional outcome between patients treated with intravenous heparin and those without (adjusted common odds ratio, 1.17; 95% CI, 0.87–1.56), successful recanalization (adjusted odds ratio, 1.24; 95% CI, 0.89–1.71), symptomatic intracranial hemorrhage (adjusted odds ratio, 1.13; 95% CI, 0.65–1.99), or mortality (adjusted odds ratio, 0.95; 95% CI, 0.66–1.38). Analysis at center level showed that functional outcomes were better in centers with higher percentages of heparin administration (adjusted common odds ratio, 1.07 per 10% more heparin, 95% CI, 1.01–1.13). Conclusions— Substantial between-center variability exists in periprocedural intravenous heparin use during endovascular treatment, but the treatment is safe. Centers using heparin more often had better outcomes. A randomized trial is needed to further study these effects.


Stroke ◽  
2019 ◽  
Vol 50 (11) ◽  
pp. 3156-3163 ◽  
Author(s):  
Heitor C. Alves ◽  
Kilian M. Treurniet ◽  
Ivo G.H. Jansen ◽  
Albert J. Yoo ◽  
Bruna G. Dutra ◽  
...  

Background and Purpose— The location of the thrombus as observed on first digital subtraction angiography during endovascular treatment may differ from the initial observation on initial noninvasive imaging. We studied the incidence of thrombus dynamics, its impact on patient outcomes, and its association with intravenous thrombolytics. Methods— We included patients from the MR CLEAN registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke) with an initial target occlusion on computed tomography angiography located in the intracranial internal carotid artery, M1, or M2. The conventional angiography target occlusion was defined during endovascular treatment. Thrombus dynamics were classified as growth, stability, migration, and resolution. The primary outcome was functional outcome at 90 days (modified Rankin Scale). The secondary outcomes were successful and complete reperfusion (extended treatment in cerebral infarction scores of 2b-3 and 3, respectively). Results— The analysis included 1349 patients. Thrombus migration occurred in 302 (22%) patients, thrombus growth in 87 (6%), and thrombus resolution in 39 (3%). Intravenous treatment with alteplase was associated with more thrombus migration (adjusted odds ratio, 2.01; CI, 1.29–3.11) and thrombus resolution (adjusted odds ratio, 1.85; CI, 1.22–2.80). Thrombus migration was associated with a lower chance of complete reperfusion (adjusted odds ratio, 0.57; CI, 0.42–0.78) and successful reperfusion (adjusted odds ratio, 0.74; CI, 0.55–0.99). In the subgroup of patients with M1 initial target occlusion, thrombus migration was associated with better functional outcome (adjusted common odds ratio, 1.49; CI, 1.02–2.17), and there was a trend towards better functional outcome in patients with thrombus resolution (adjusted common odds ratio, 2.23; CI, 0.93–5.37). Conclusions— In patients with acute ischemic stroke, thrombus location regularly changes between computed tomography angiography and digital subtraction angiography. Administration of intravenous alteplase increases the chance of thrombus migration and resolution. Thrombus migration is associated with better functional outcome but reduces the rate of complete reperfusion.


Neurology ◽  
2020 ◽  
Vol 95 (2) ◽  
pp. e131-e139 ◽  
Author(s):  
Adrien E. Groot ◽  
Kilian M. Treurniet ◽  
Ivo G.H. Jansen ◽  
Hester F. Lingsma ◽  
Wouter Hinsenveld ◽  
...  

ObjectiveTo explore clinical outcomes in older adults with acute ischemic stroke treated with endovascular thrombectomy (EVT).MethodsWe included consecutive patients (2014–2016) with an anterior circulation occlusion undergoing EVT from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry. We assessed the effect of age (dichotomized at ≥80 years and as continuous variable) on the modified Rankin Scale (mRS) score at 90 days, symptomatic intracranial hemorrhage (sICH), and reperfusion rate. The association between age and mRS was assessed with multivariable ordinal logistic regression, and a multiplicative interaction term was added to the model to assess modification of reperfusion by age on outcome.ResultsOf the 1,526 patients, 380 (25%) were ≥80 years of age (referred to here as older adults). Older adults had a worse functional outcome than younger patients (adjusted common odds ratio [acOR] for an mRS score shift toward better outcome 0.31, 95% confidence interval [CI] 0.24–0.39). Mortality was also higher in older adults (51% vs 22%, adjusted odds ratio 3.12, 95% CI 2.33–4.19). There were no differences in proportion of patients with mRS scores of 4 to 5, sICH, or reperfusion rates. Successful reperfusion was more strongly associated with a shift toward good functional outcome in older adults than in younger patients (acOR 3.22, 95% CI 2.04–5.10 vs 2.00, 95% CI 1.56–2.57, pinteraction = 0.026).ConclusionOlder age is associated with an increased absolute risk of poor clinical outcome, while the relative benefit of successful reperfusion seems to be higher in these patients. These results should be taken into consideration in the selection of older adults for EVT.


Stroke ◽  
2021 ◽  
Author(s):  
Noor Samuels ◽  
Rob A. van de Graaf ◽  
Carlijn A.L. van den Berg ◽  
Simone M. Uniken Venema ◽  
Kujtesa Bala ◽  
...  

Background and Purpose: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and after intravenous alteplase can be extrapolated to endovascular treatment (EVT) for stroke due to large artery occlusion in the anterior circulation. We evaluated the associations between systolic BP (SBP) in the first 6 hours following EVT and functional outcome as well as symptomatic intracranial hemorrhage. Methods: Patients of 8 MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry centers, with available data on SBP in the 6 hours following EVT, were analyzed. We evaluated maximum, minimum, and mean SBP. Study outcomes were functional outcome (modified Rankin Scale) at 90 days and symptomatic intracranial hemorrhage. We used multivariable ordinal and binary regression analysis to adjust for important prognostic factors and studied possible effect modification by successful reperfusion. Results: Post-EVT SBP data were available for 1161/1796 patients. Higher maximum SBP (per 10 mm Hg increments) was associated with worse functional outcome (adjusted common odds ratio, 0.93 [95% CI, 0.88–0.98]) and a higher rate of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.17 [95% CI, 1.02–1.36]). The association between minimum SBP and functional outcome was nonlinear with an inflection point at 124 mm Hg. Minimum SBP lower and higher than the inflection point were associated with worse functional outcomes (adjusted common odds ratio, 0.85 per 10 mm Hg decrements [95% CI, 0.76–0.95] and adjusted common odds ratio, 0.81 per 10 mm Hg increments [95% CI, 0.71–0.92]). No association between mean SBP and functional outcome was observed. Successful reperfusion did not modify the relation of SBP with any of the outcomes. Conclusions: Maximum SBP in the first 6 hours following EVT is positively associated with worse functional outcome and an increased risk of symptomatic intracranial hemorrhage. Both lower and higher minimum SBP are associated with worse outcomes. A randomized trial to evaluate whether modifying post-intervention SBP results in better outcomes after EVT for ischemic stroke seems justified.


PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0249093
Author(s):  
Sabine L. Collette ◽  
Maarten Uyttenboogaart ◽  
Noor Samuels ◽  
Irene C. van der Schaaf ◽  
H. Bart van der Worp ◽  
...  

Objective The effect of anesthetic management (general anesthesia [GA], conscious sedation, or local anesthesia) on functional outcome and the role of blood pressure management during endovascular treatment (EVT) for acute ischemic stroke is under debate. We aimed to determine whether hypotension during EVT under GA is associated with functional outcome at 90 days. Methods We retrospectively collected data from patients with a proximal intracranial occlusion of the anterior circulation treated with EVT under GA. The primary outcome was the distribution on the modified Rankin Scale at 90 days. Hypotension was defined using two thresholds: a mean arterial pressure (MAP) of 70 mm Hg and a MAP 30% below baseline MAP. To quantify the extent and duration of hypotension, the area under the threshold (AUT) was calculated using both thresholds. Results Of the 366 patients included, procedural hypotension was observed in approximately half of them. The occurrence of hypotension was associated with poor functional outcome (MAP <70 mm Hg: adjusted common odds ratio [acOR], 0.57; 95% confidence interval [CI], 0.35–0.94; MAP decrease ≥30%: acOR, 0.76; 95% CI, 0.48–1.21). In addition, an association was found between the number of hypotensive periods and poor functional outcome (MAP <70 mm Hg: acOR, 0.85 per period increase; 95% CI, 0.73–0.99; MAP decrease ≥30%: acOR, 0.90 per period; 95% CI, 0.78–1.04). No association existed between AUT and functional outcome (MAP <70 mm Hg: acOR, 1.000 per 10 mm Hg*min increase; 95% CI, 0.998–1.001; MAP decrease ≥30%: acOR, 1.000 per 10 mm Hg*min; 95% CI, 0.999–1.000). Conclusions Occurrence of procedural hypotension and an increase in number of procedural hypotensive periods were associated with poor functional outcome, whereas the extent and duration of hypotension were not. Randomized clinical trials are needed to confirm our hypothesis that hypotension during EVT under GA has detrimental effects.


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