scholarly journals Age and Acute Ischemic Stroke Outcome in North American Patients With COVID‐19

2021 ◽  
Author(s):  
Adam A. Dmytriw ◽  
Mahmoud Dibas ◽  
Clemens M. Schirmer ◽  
Fabio Settecase ◽  
Manraj K. S. Heran ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Young Patients ◽  
The United States ◽  
Secondary Outcome ◽  
Modified Rankin Scale ◽  
Ischemic Event ◽  
Intravenous Tissue Plasminogen Activator ◽  
Younger Age

Background Acute ischemic stroke (AIS) in the context of COVID‐19 has received considerable attention for its propensity to affect patients of all ages. We aimed to evaluate the effect of age on functional outcome and mortality following an acute ischemic event. Methods and Results A prospectively maintained database from comprehensive stroke centers in Canada and the United States was analyzed for patients with AIS from March 14 to September 30, 2020 who tested positive for SARS‐CoV‐2. The primary outcome was Modified Rankin Scale score at discharge, and the secondary outcome was mortality. Baseline characteristics, laboratory values, imaging, and thrombectomy workflow process times were assessed. Among all 126 patients with COVID‐19 who were diagnosed with AIS, the median age was 63 years (range, 27–94). There were 35 (27.8%) patients with AIS in the aged ≤55 years group, 47 (37.3%) in the aged 56 to 70 group, and 44 (34.9%) in the aged >70 group. Intravenous tissue plasminogen activator and thrombectomy rates were comparable across these groups, ( P =0.331 and 0.212, respectively). There was a significantly lower rate of mortality between each group favoring younger age (21.9% versus 45.0% versus 48.8%, P =0.047). After multivariable adjustment for possible confounders, a 1‐year increase in age was significantly associated with fewer instances of a favorable outcome of Modified Rankin Scale 0 to 2 (odds ratio [OR], 0.95; 95 CI%, 0.90–0.99; P =0.048) and higher mortality (OR, 1.06; 95 CI%, 1.02–1.10; P =0.007). Conclusions AIS in the context of COVID‐19 affects young patients at much greater rates than pre‐pandemic controls. Nevertheless, instances of poor functional outcome and mortality are closely tied to increasing age.

Sex-Related Differences in Management and Outcome of Acute Ischemic Stroke in Eligible Patients to Thrombolysis

2019 ◽  
Vol 47 (3-4) ◽  
pp. 196-204 ◽  
Author(s):  
Laurie Fraticelli ◽  
Julie Freyssenge ◽  
Clément Claustre ◽  
Marielle Buisson ◽  
Magali Bischoff ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Urban Landscape ◽  
Real Life ◽  
Rural Landscape ◽  
Response To Treatment ◽  
Ischemic Time ◽  
Intravenous Tissue Plasminogen Activator ◽  
Prehospital Management

Background: Literature has highlighted sex-based differences in the natural course of stroke and in response to treatment with intravenous tissue plasminogen activator (tPA). Objectives: We aimed to compare the management and outcome of acute ischemic stroke (AIS) among women and men on a French registry based on a federated network of emergency physicians and neurologists. Method: We included 2,790 patients received tPA between 2010 and 2016 from the stroke centers in the RESUVal area. We provided age-adjusted analysis and multivariate models for determining the role of sex in the outcome measures. Results: After age-adjustment, women presented more moderate to severe stroke at admission with more proximal occlusions. Among tPA eligible patients, the therapeutic strategy and in-hospital hemorrhagic complications were proportionally identical whatever the sex. The total ischemic time from onset symptom to thrombolysis did not differ from women to men. Age-adjusted 3-month mortality did not differ between women and men, and the determinants of mortality were age (relative risk [RR] 1.56 [1.37–1.78], p < 0.0001), proximal occlusion (RR 2.5 [1.88–3.33], p < 0.0001), and at least one complication (RR 2.43 [1.89–3.13], p < 0.0001). The determinants of poor functional outcome at 3 months were the sex (RR 1.22 [1.01–1.48] for women, p = 0.0385) and the occurrence of onset symptom in rural landscape (RR 1.26 [1.03–1.55], p = 0.0219) compared to urban landscape. Conclusions: We provided an exhaustive overview and real-life professional practices conditions in thrombolyzed AIS. Despite a later prehospital management in neurovascular units and more severe strokes at admission, women and men had both similar outcomes at hospital discharge and in 3-month survival, but women were associated to worst functional outcome at 3 months.

scholarly journals Effect of Statin Administration After Onset of Acute Ischemic Stroke With Large Vessel Occlusion: Insights From RESCUE‐Japan Registry 2

2020 ◽  
Vol 9 (23) ◽  
Author(s):  
Kazutaka Uchida ◽  
Shinichi Yoshimura ◽  
Hirotoshi Imamura ◽  
Nobuyuki Ohara ◽  
Nobuyuki Sakai ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Large Vessel ◽  
Modified Rankin Scale ◽  
Large Vessel Occlusion ◽  
Odds Ratios ◽  
Vessel Occlusion ◽  
Statin Group ◽  
Younger Age

Background Statins have been associated with reduced recurrence and better functional outcomes in patients with acute ischemic stroke. However, the effect of statins in patients with acute large vessel occlusion (LVO) is not well scrutinized. Methods and Results RESCUE (Recovery by Endovascular Salvage for Cerebral Ultra‐Acute Embolism)‐Japan Registry 2, a physician‐initiated registry, enrolled 2420 consecutive patients with acute LVO who were admitted to 46 centers across Japan within 24 hours of onset. We compared patients with and without statin use after acute LVO onset (statin group and nonstatin group, respectively) in terms of the modified Rankin scale at 90 days. We estimated that the odds ratios for the primary outcome was modified Rankin scale and we estimated the odds ratios for a 1‐scale lower modified Rankin scale adjusting for confounders. After excluding 12 patients without LVO and 9 patients without follow‐up, the mean age of 2399 patients was 75.9 years; men accounted for 55% of patients. Statins were administered to 447 (19%) patients after acute LVO onset. Patients in the statin group had more atherothrombotic cerebral infarctions (34.2% versus 12.1%, P <0.0001), younger age (73.4 years versus 76.5 years, P <0.0001), and lower median National Institutes of Health Stroke Scale on admission (14 versus 17, P <0.0001) than the nonstatin group. The adjusted common OR of the statin group for lower modified Rankin scale was 1.29 (95% CI, 1.04–1.37; P =0.02). The mortality at 90 days was lower in the statin group (4.7%) than the nonstatin group (12.5%; P <0.0001). The adjusted OR of the statin group relative to the nonstatin group for mortality was 0.36 (95% CI, 0.21–0.62; P =0.02). Conclusions Statin administration after acute LVO onset is significantly associated with better functional outcome and mortality at 90 days.

scholarly journals Effect of Interhospital Transfer on Endovascular Treatment for Acute Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (4) ◽  
pp. 923-930 ◽  
Author(s):  
Esmee Venema ◽  
Adrien E. Groot ◽  
Hester F. Lingsma ◽  
Wouter Hinsenveld ◽  
Kilian M. Treurniet ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endovascular Treatment ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Functional Independence ◽  
Modified Rankin Scale ◽  
Interhospital Transfer ◽  
Primary Stroke Center ◽  
Transferred Patients ◽  
Stroke Center

Background and Purpose— To assess the effect of inter-hospital transfer on time to treatment and functional outcome after endovascular treatment (EVT) for acute ischemic stroke, we compared patients transferred from a primary stroke center to patients directly admitted to an intervention center in a large nationwide registry. Methods— MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, observational study in all centers that perform EVT in the Netherlands. We included adult patients with an acute anterior circulation stroke who received EVT between March 2014 to June 2016. Primary outcome was time from arrival at the first hospital to arterial groin puncture. Secondary outcomes included the 90-day modified Rankin Scale score and functional independence (modified Rankin Scale score of 0–2). Results— In total 821/1526 patients, (54%) were transferred from a primary stroke center. Transferred patients less often had prestroke disability (227/800 [28%] versus 255/699 [36%]; P =0.02) and more often received intravenous thrombolytics (659/819 [81%] versus 511/704 [73%]; P <0.01). Time from first presentation to groin puncture was longer for transferred patients (164 versus 104 minutes; P <0.01, adjusted delay 57 minutes [95% CI, 51–62]). Transferred patients had worse functional outcome (adjusted common OR, 0.75 [95% CI, 0.62–0.90]) and less often achieved functional independence (244/720 [34%] versus 289/681 [42%], absolute risk difference −8.5% [95% CI, −8.7 to −8.3]). Conclusions— Interhospital transfer of patients with acute ischemic stroke is associated with delay of EVT and worse outcomes in routine clinical practice, even in a country where between-center distances are short. Direct transportation of patients potentially eligible for EVT to an intervention center may improve functional outcome.

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

Stroke ◽  
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.

scholarly journals Combined Effect of Age and Baseline Alberta Stroke Program Early Computed Tomography Score on Post-Thrombectomy Clinical Outcomes in the MR CLEAN Registry

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3742-3745
Author(s):  
Johanna Ospel ◽  
Manon Kappelhof ◽  
Adrien E. Groot ◽  
Natalie E. LeCouffe ◽  
Jonathan M. Coutinho ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endovascular Treatment ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Odds Ratio ◽  
Modified Rankin Scale ◽  
Common Odds Ratio ◽  
Significant Difference ◽  
Main Effect ◽  
Mr Clean

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.

Middle Cerebral Artery M2 Thrombectomy in the STRATIS Registry

Stroke ◽  
2021 ◽  
Author(s):  
Mouhammad A. Jumaa ◽  
Alicia C. Castonguay ◽  
Hisham Salahuddin ◽  
Ashutosh P. Jadhav ◽  
Kaustubh Limaye ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Scale Score ◽  
Cerebral Artery ◽  
Mechanical Thrombectomy ◽  
Modified Rankin Scale ◽  
Good Functional Outcome ◽  
First Choice

Background and Purpose: The safety and benefit of mechanical thrombectomy in the treatment of acute ischemic stroke patients with M2 segment middle cerebral artery occlusions remain uncertain. Here, we compare clinical and angiographic outcomes in M2 versus M1 occlusions in the STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) Registry. Methods: The STRATIS Registry was a prospective, multicenter, nonrandomized, observational study of acute ischemic stroke large vessel occlusion patients treated with the Solitaire stent-retriever as the first-choice therapy within 8 hours from symptoms onset. Primary outcome was defined as functional disability at 3 months measured by dichotomized modified Rankin Scale. Secondary outcomes included reperfusion rates and rates of symptomatic intracranial hemorrhage. Results: A total of 984 patients were included, of which 538 (54.7%) had M1 and 170 (17.3%) had M2 occlusions. Baseline demographics were well balanced within the groups, with the exception of mean baseline National Institutes of Health Stroke Scale score which was significantly higher in the M1 population (17.3±5.5 versus 15.7±5.0, P ≤0.001). No difference was seen in mean puncture to revascularization times between the cohorts (46.0±27.8 versus 45.1±29.5 minutes, P =0.75). Rates of successful reperfusion (modified Thrombolysis in Cerebral Infarction≥2b) were similar between the groups (91% versus 95%, P =0.09). M2 patients had significantly increased rates of symptomatic ICH at 24 hours (4% versus 1%, P =0.01). Rates of good functional outcome (modified Rankin Scale score of 0–2; 58% versus 59%, P =0.83) and mortality (15% versus 14%, P =0.75) were similar between the 2 groups. There was no difference in the association of outcome and onset to groin puncture or onset to successful reperfusion in M1 and M2 occlusions. Conclusions: In the STRATIS Registry, M2 occlusions achieved similar rates of successful reperfusion, good functional outcome, and mortality, although increased rates of symptomatic ICH were demonstrated when compared with M1 occlusions. The time dependence of benefit was also similar between the 2 groups. Further studies are needed to understand the benefit of mechanical thrombectomy for M2 occlusions. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02239640.

Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial

Stroke ◽  
2021 ◽  
Author(s):  
Iris Lettow ◽  
Märit Jensen ◽  
Eckhard Schlemm ◽  
Florent Boutitie ◽  
Fanny Quandt ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Ischemic Stroke ◽  
Adverse Events ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Fatal Outcome ◽  
Modified Rankin Scale ◽  
Unique Identifier ◽  
Serious Adverse Events ◽  
Link Type

Background and Purpose: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). Methods: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE. Results: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0–1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21–0.61], P <0.001). Higher age ( P =0.04) and male sex ( P =0.01) were predictors for the occurrence of SAE. Conclusions: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01525290 and https://eudract.ema.europa.eu ; Unique identifier: 2011-005906-32.

Abstract 3994: Obese Patients Receiving Intravenous Thrombolysis in Acute Ischemic Stroke Have lower Rates of Intracerebral hemorrhage and Mortality

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Ameer Hassan ◽  
Mikayel Grigoryan ◽  
Saqib Chaudhry ◽  
Adnan Qureshi
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Multivariate Logistic Regression Analysis ◽  
Intravenous Thrombolysis ◽  
International Classification Of Diseases ◽  
The United States ◽  
Obese Patients ◽  
Stroke Patients ◽  
Intravenous Tissue Plasminogen Activator ◽  
Classification Of Diseases

Background: The current recommended dose of intravenous tissue plasminogen activator (IV rt-PA) for ischemic stroke patients weighing >100 kg is fixed at 90 mg and thus obese patients receive less than the recommend 0.9mg/kg dosage. We hypothesized that obese patients receive a lower dose of thrombolytics and they will have a lower rates of intracerebral hemorrhages (ICH), but lower rates of clinical benefit from IV rt-PA. Objective: To determine the relationship between obesity and clinical outcomes among acute ischemic stroke patients receiving IV rt-PA. Methods: Data were obtained from all states within the United States that contributed to the Nationwide Inpatient Sample. All patients admitted to US hospitals between 2002 and 2009 with a primary discharge diagnosis of stroke treated with IV thrombolysis (identified by the International Classification of Diseases, Ninth Revision procedure codes) were included. We analyzed whether the presence of obesity was associated with clinical outcome and ICH with multivariate logistic regression analysis after adjusting for potential confounders. Results: Of the 84,727 patients with ischemic stroke treated with IV rt-PA, 5,437 (6.4%) had concurrent obesity. The ICH rates between obese and non-obese patients was 4.3% versus 6.1% (p=0.005). After adjusting for age, sex, hypertension, diabetes mellitus, renal failure, hospital teaching status, and ICH, the presence of obesity was not associated with increased rates of self-care (odds ratio [OR] 0.929, 95% confidence interval [CI] 0.815-1.063, p=0.27), but was associated with decreased rates of mortality (OR 0.78, 95% CI 0.61 - 0.94, p=0.045) at discharge. Conclusion: Obese patients undergoing IV t-PA treatment for acute ischemic stroke appear to have lower rates of ICHs and mortality presumably due to lower weight adjusted thrombolytic dose.

scholarly journals Genome-wide association meta-analysis of functional outcome after ischemic stroke

Neurology ◽  
2019 ◽  
Vol 92 (12) ◽  
pp. e1271-e1283 ◽  
Author(s):  
Martin Söderholm ◽  
Annie Pedersen ◽  
Erik Lorentzen ◽  
Tara M. Stanne ◽  
Steve Bevan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Outcome ◽  
Scale Score ◽  
Genetic Variants ◽  
The United States ◽  
Genome Wide Association ◽  
Modified Rankin Scale ◽  
Brain Functions ◽  
Suggestive Association ◽  
Genome Wide

ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0–2 vs 3–6 and 0–1 vs 2–6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10−8.ResultsWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0–2 vs 3–6, p = 5.3 × 10−9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10−5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1).ConclusionsIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

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