Abstract WP294: Deferoxamine Treatment Improves Outcomes After Embolic Stroke in Diabetic Rats

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
John Paul Valenzuela ◽  
Guangkuo Dong ◽  
Yasir Abdul ◽  
Rebecca Ward ◽  
...  
Keyword(s):  
Iron Chelation ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Embolic Stroke ◽  
High Risk Population ◽  
Excess Iron ◽  
Male Wistar Rats ◽  
Poor Outcomes ◽  
Cerebral Ischemic

Diabetes increases the risk of hemorrhagic transformation (HT) after a cerebral ischemic event, a major factor limiting the use of tissue plasminogen activator (tPA) for stroke patients. We previously showed that increased HT is associated with poorer recovery in diabetes. In the current study, we hypothesized that excess iron contributes to poor recovery and that iron chelation with deferoxamine (DFX) will improve the neurological recovery after embolic stroke in diabetes. Diabetes was induced with high fat diet and low dose streptozotocin injection (30 mg/kg) in male Wistar rats. Both control and diabetes animals were subjected to embolic stroke with middle cerebral artery occlusion and sacrificed 2 weeks after the surgery. DFX (100 mg/kg) or vehicle was given every 12 h for 7 days after stroke. The composite score (Bederson’s score and beam walk), adhesive removal (ART) and novel object recognition (NOR) were assessed at day 1, 3, 7 and 14 after the surgery. DFX reduced mortality in diabetes. Diabetic animals displayed poor outcomes. By Day 14, DFX reduced motor and cognitive deficits in diabetes but not in controls. These results suggest that iron chelation therapy may improve outcomes after ischemic stroke in this high risk population.

Abstract WMP81: Low Dose tPA Worsens The Short Term Outcomes After Thromboembolic Stroke In Both Male And Female Diabetic Animals

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
John Paul Valenzuela ◽  
Guangkuo Dong ◽  
Rebecca Ward ◽  
Susan C Fagan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Functional Outcome ◽  
Low Dose ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Male And Female

Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tPA treatment. We previously showed that low dose tPA decreased infarct size and improved functional outcome in both male and female control rats with embolic stroke. In the current study, we hypothesized that low dose tPA will also improve the functional recovery after the embolic stroke in both male and female animals with diabetes. Diabetes was induced in age matched male and female Wistar rats with high fat diet and low dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with middle cerebral artery occlusion. The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. The blood flow has increased in the tPA treated animals in the first 1 to 1.5 hr after treatment. The infarct size and edema was not significantly different in untreated animals, but HT was greater in female diabetic rats. The tPA treatment worsened HT in both genders with no change in infarct size. Decline in ART was worsened with tPA treatment in both sexes. Our data suggest that the low dose tPA after ischemic stroke has detrimental effects on the cerebrovascular recovery and functional outcome in both male and female animals with diabetes.

scholarly journals Expression of Urotensin II During Focal Cerebral Ischemic in Diabetic Rats

2014 ◽  
Vol 41 (4) ◽  
pp. 498-503 ◽  
Author(s):  
Lin Tian ◽  
Yunqian Li ◽  
Wei Hua ◽  
Ying Jia ◽  
Min Zhou ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cerebral Ischaemia ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Focal Cerebral Ischaemia ◽  
Urotensin Ii ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Ischaemic Brain ◽  
Cerebral Ischemic

Background:The objective of this study was to explore the expression of urotensin II (UII), its receptor (GPR14), and vascular endothelial growth factor (VEGF), as well as their associations in the ischaemic brains of rats with focal cerebral ischaemia, under normal and diabetic conditions.Methods:Diabetes mellitus (DM) was induced by injection of streptozotocin (STZ) into Sprague—Dawley rats. Focal cerebral ischaemia was induced by middle cerebral artery occlusion (MCAO) four weeks after DM onset by STZ. Rats (n=80) were divided into four groups: normal control, DM, MCAO, and DM/MCAO. Immunohistochemistry and reverse-transcriptase-polymerase chain reaction (RT-PCR) were used to detect the expression of UII, GPR14 and VEGF in the diabetic and ischaemic brain.Results:Expression of UII and GPR14 was increased at mRNA and protein levels in the DM and MCAO group compared with controls. In the DM/MCAO group, expression of UII and GPR14 was increased significantly in the ischaemic brain, and was accompanied by a significantly increased VEGF expression.Conclusion:Diabetes mellitus was seen to aggravate brain lesions after ischaemia, and UII may have an important role.

scholarly journals 3533 Delayed Administration Of Angiotensin Receptor (AT2R) Agonist C21 Downregulates Diabetes Induced Pro-Inflammatory Microglia Activation To Improve Cognitive & Functional Recovery Post Stroke: Therapeutic Indications For The Treatment Of Vascular Cognitive

2019 ◽  
Vol 3 (s1) ◽  
pp. 7-7
Author(s):  
Ladonya Jackson ◽  
Guangkuo Dong ◽  
Susan Fagan ◽  
Adviye Ergul
Keyword(s):  
Cognitive Function ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Post Stroke ◽  
Set Inclusion ◽  
Angiotensin Type 2 Receptor ◽  
Male Wistar Rats ◽  
Study Population ◽  
Adhesive Removal ◽  
Cerebral Artery Occlusion

OBJECTIVES/SPECIFIC AIMS: The study aim was to 1) elucidate mechanisms contributing to the evolution of PSCI using a clinically relevant model of diabetes, a major risk factor for stroke and cognitive impairment, and 2) develop angiotensin type 2 receptor (AT2R) agonism as a therapeutic target. METHODS/STUDY POPULATION: Diabetes was induced in male Wistar rats by a HFD & low dose streptozotocin combination. At 12-14 weeks of age a total of 69 control & diabetic rats were subjected to 1 hr middle cerebral artery occlusion (MCAO) or Sham surgery. 3 days post-MCAO, rats that met the pre-set inclusion criteria were administered C21 or saline in drinking water at a dose of 0.12 mg/kg/day Adhesive removal task (ART) & 2-trial Ymaze were utilized to test sensorimotor & cognitive function at baseline as well as 1, 2, 4 and 8 weeks post-stroke. At week 8 post-stroke cell suspensions from freshly harvested brains were analyzed by flow cytometry utilizing antibodies against cell surface markers for M1 (CD11b+/CD45 low/ CD86+/TNFa+), M2 (CD11b+/CD45 low/ CD206+/IL-10+), and residential microglia (CD11b+/CD45+/ TMEM119+). RESULTS/ANTICIPATED RESULTS: Control rats progressively recovered from stroke-induced functional deficits by week 8, while diabetics still remained impaired (P< 0.05). 8 weeks post-MCAO only diabetic rats exhibited a decline in sensorimotor (P< 0.05) and cognitive function (P< 0.05) compared to Shams. Delayed administration of C21 on D2 post-stroke halted the decline and improved sensorimotor (P< 0.05) and cognitive function (P< 0.01). Flow cytometric analyses indicate that 8 post-stroke vehicle diabetics had an elevated M1/M2 ratio within the ipsilateral prefrontal cortex and hippocampus (P< 0.01, 0.01). They also had a larger percentage of non-residential microglia/macrophages, indicative of compromised blood brain barrier (BBB) integrity. Treatment with C21 significantly lowered the M1/M2 ratio (P< 0.05) and improved the BBB integrity. DISCUSSION/SIGNIFICANCE OF IMPACT: Taken together this study suggests that the use of comorbid disease models such as diabetes, may allow for more translational evaluations of PSCI. Higher translational relevance may also lead to a higher number of successful clinical trials and more FDA approved stroke therapies. It also suggests that C21 may serve as a potential therapeutic to modulate the development of PSCI.

scholarly journals Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy

2021 ◽  
Vol 14 (10) ◽  
pp. 983
Author(s):  
Mohd. Salman ◽  
Saifudeen Ismael ◽  
Lexiao Li ◽  
Heba A. Ahmed ◽  
Michelle A. Puchowicz ◽  
...  
Keyword(s):  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Embolic Stroke ◽  
Interacting Protein ◽  
Knock Out ◽  
Thioredoxin Interacting Protein ◽  
Associated Proteins ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion ◽  
Neurovascular Damage

We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive days to induce diabetes. Four-weeks after confirming HG, mice were subjected to embolic middle cerebral artery occlusion (eMCAO) followed by tissue plasminogen activator (tPA)-reperfusion (10 mg/kg at 3 h post-eMCAO). After the neurological assessment, animals were sacrificed at 24 h for neurovascular stroke outcomes. There were no differences in cerebrovascular anatomy between the strains. Infarct size, edema, and HT as indicated by hemoglobin (Hb)-the content was significantly higher in HG-WT mice, with or without tPA-reperfusion, compared to normoglycemic WT mice. Hyperglycemic EC-TXNIP KO mice treated with tPA tended to show lower Hb-content, edema, infarct area, and less hemorrhagic score compared to WT hyperglycemic mice. EC-TXNIP KO mice showed decreased expression of inflammatory mediators, apoptosis-associated proteins, and nitrotyrosine levels. Further, vascular endothelial growth factor-A and matrix-metalloproteinases (MMP-9/MMP-3), which degrade junction proteins and increase blood-brain-barrier permeability, were decreased in EC-TXNIP KO mice. Together, these findings suggest that vascular-TXNIP could be a novel therapeutic target for neurovascular damage after stroke.

Abstract WP275: Hemorrhagic Transformation in Large Cerebral Infarction of Rats Pretreated With Dabigatran or Warfarin

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Sunho An ◽  
Il Kwon ◽  
Jayoung Kim ◽  
Joonsang Yoo ◽  
Kijeong Lee ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Gelatin Zymography ◽  
International Normalized Ratio ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Slice Thickness ◽  
Mri Findings ◽  
Double Blind ◽  
Male Wistar Rats ◽  
Magnetic Resonance Imaging Mri

Introduction: Dabigatran is effective in preventing stroke and reduces the risk of intracerebral hemorrhage when comparing with warfarin in patients with atrial fibrillation. However, it is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is also less frequent in dabigatran users than warfarin users. Hypothesis: We hypothesized that intracerebral HT would occur less frequently following large cerebral infarction in rats pretreated with dabigatran than those with warfarin. We also compared the change of matrix metalloproteinases (MMPs), which play a key role in HT. Methods: We performed randomized, double-blind experiments comparing warfarin and dabigatran in rats. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or normal saline for 7 days, male wistar rats were subjected to permanent middle cerebral artery occlusion (MCAO) using a nylon thread. After 22 hours of MCAO, magnetic resonance imaging (MRI) was undergone (9.4T MR scanner, slice thickness = 0.5 mm). Operative procedures and assessment of MRI findings were performed by investigators who were blind to the group information. The presence of HT was assessed on gradient recalled-echo and infarction volume was measured on diffusion-weighted image. The MMP-2 and MMP-9 activities in brain tissues (obtained 24 hours after MCAO) were investigated using gelatin zymography. Results and Conclusions: Of the 33 rats with MRI, HT was observed less frequently in the dabigatran group than the warfarin group (placebo 14% [2/14], dabigatran 0% [0/10], and warfarin 100% [9/9], p < 0.001 [dabigatran vs warfarin]). The volume of infarction was similar between the groups (placebo 432.45 ± 78.35 mm3, dabigatran 432.42 ± 60.27 mm3, and warfarin 446.55 ± 73.55 mm3). MMP-2 and MMP-9 activities were not different between the groups. In the placebo, dabigatran, and warfarin groups, mean international normalized ratio were 1.38 ± 0.13, 1.73 ± 0.20, and 4.72 ± 2.92, respectively; mean activated partial thromboplastin times were 30.20 ± 7.49, 31.14 ± 7.02, and 55.06 ± 24.05, respectively. The risk of HT after large cerebral infarction was remarkably reduced in rats pretreated with dabigatran. MMPs did not seem to play a major role in reduced risk of HT.

scholarly journals Effects of Apocynin on Heart Muscle Oxidative Stress of Rats with Experimental Diabetes: Implications for Mitochondria

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 335
Author(s):  
Estefanía Bravo-Sánchez ◽  
Donovan Peña-Montes ◽  
Sarai Sánchez-Duarte ◽  
Alfredo Saavedra-Molina ◽  
Elizabeth Sánchez-Duarte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Sensitivity ◽  
Cardiac Tissue ◽  
Diabetic Rats ◽  
Oxidase Inhibitor ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Transport Chain ◽  
Male Wistar Rats

Diabetes mellitus (DM) constitutes one of the public health problems today. It is characterized by hyperglycemia through a defect in the β-cells function and/or decreased insulin sensitivity. Apocynin has been tasted acting directly as an NADPH oxidase inhibitor and reactive oxygen species (ROS) scavenger, exhibiting beneficial effects against diabetic complications. Hence, the present study’s goal was to dissect the possible mechanisms by which apocynin could mediate its cardioprotective effect against DM-induced oxidative stress. Male Wistar rats were assigned into 4 groups: Control (C), control + apocynin (C+A), diabetes (D), diabetes + apocynin (D+A). DM was induced with streptozotocin. Apocynin treatment (3 mg/kg/day) was applied for 5 weeks. Treatment significantly decreased blood glucose levels and insulin resistance in diabetic rats. In cardiac tissue, ROS levels were higher, and catalase enzyme activity was reduced in the D group compared to the C group; the apocynin treatment significantly attenuated these responses. In heart mitochondria, Complexes I and II of the electron transport chain (ETC) were significantly enhanced in the D+A group. Total glutathione, the level of reduced glutathione (GSH) and the GSH/ oxidized glutathione (GSSG) ratio were increased in the D+A group. Superoxide dismutase (SOD) and the glutathione peroxidase (GSH-Px) activities were without change. Apocynin enhances glucose uptake and insulin sensitivity, preserving the antioxidant defense and mitochondrial function.

Activation of astroglial CB1R mediates cerebral ischemic tolerance induced by electroacupuncture

2021 ◽  
pp. 0271678X2199439
Author(s):  
Cen Yang ◽  
Jingjing Liu ◽  
Jingyi Wang ◽  
Anqi Yin ◽  
Zhenhua Jiang ◽  
...  
Keyword(s):  
Endocannabinoid System ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Protective Mechanisms ◽  
Promising Therapeutic Approach ◽  
Subsequent Activation ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion ◽  
The Brain

There are no effective treatments for stroke. The activation of endogenous protective mechanisms is a promising therapeutic approach, which evokes the intrinsic ability of the brain to protect itself. Accumulated evidence strongly suggests that electroacupuncture (EA) pretreatment induces rapid tolerance to cerebral ischemia. With regard to mechanisms underlying ischemic tolerance induced by EA, many molecules and signaling pathways are involved, such as the endocannabinoid system, although the exact mechanisms have not been fully elucidated. In the current study, we employed mutant mice, neuropharmacology, microdialysis, and virus transfection techniques in a middle cerebral artery occlusion (MCAO) model to explore the cell-specific and brain region-specific mechanisms of EA-induced neuroprotection. EA pretreatment resulted in increased ambient endocannabinoid (eCB) levels and subsequent activation of ischemic penumbral astroglial cannabinoid type 1 receptors (CB1R) which led to moderate upregulation of extracellular glutamate that protected neurons from cerebral ischemic injury. These findings provide a novel cellular mechanism of EA and a potential therapeutic target for ischemic stroke.

scholarly journals Neuroprotective mechanisms of erythropoietin in a rat stroke model

2020 ◽  
Vol 11 (1) ◽  
pp. 48-59
Author(s):  
Martin Juenemann ◽  
Tobias Braun ◽  
Nadine Schleicher ◽  
Mesut Yeniguen ◽  
Patrick Schramm ◽  
...  
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Cerebral Edema ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Human Erythropoietin ◽  
Male Wistar Rats ◽  
Cerebral Artery Occlusion

AbstractObjectiveThis study was designed to investigate the indirect neuroprotective properties of recombinant human erythropoietin (rhEPO) pretreatment in a rat model of transient middle cerebral artery occlusion (MCAO).MethodsOne hundred and ten male Wistar rats were randomly assigned to four groups receiving either 5,000 IU/kg rhEPO intravenously or saline 15 minutes prior to MCAO and bilateral craniectomy or sham craniectomy. Bilateral craniectomy aimed at elimination of the space-consuming effect of postischemic edema. Diagnostic workup included neurological examination, assessment of infarct size and cerebral edema by magnetic resonance imaging, wet–dry technique, and quantification of hemispheric and local cerebral blood flow (CBF) by flat-panel volumetric computed tomography.ResultsIn the absence of craniectomy, EPO pretreatment led to a significant reduction in infarct volume (34.83 ± 9.84% vs. 25.28 ± 7.03%; p = 0.022) and midline shift (0.114 ± 0.023 cm vs. 0.083 ± 0.027 cm; p = 0.013). We observed a significant increase in regional CBF in cortical areas of the ischemic infarct (72.29 ± 24.00% vs. 105.53 ± 33.10%; p = 0.043) but not the whole hemispheres. Infarct size-independent parameters could not demonstrate a statistically significant reduction in cerebral edema with EPO treatment.ConclusionsSingle-dose pretreatment with rhEPO 5,000 IU/kg significantly reduces ischemic lesion volume and increases local CBF in penumbral areas of ischemia 24 h after transient MCAO in rats. Data suggest indirect neuroprotection from edema and the resultant pressure-reducing and blood flow-increasing effects mediated by EPO.

scholarly journals A novel voxel-wise lesion segmentation technique on 3.0-T diffusion MRI of hyperacute focal cerebral ischemia at 1 h after permanent MCAO in rats

2017 ◽  
Vol 38 (8) ◽  
pp. 1371-1383 ◽  
Author(s):  
Chi-Hoon Choi ◽  
Kyung Sik Yi ◽  
Sang-Rae Lee ◽  
Youngjeon Lee ◽  
Chang-Yeop Jeon ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Region Of Interest ◽  
Artery Occlusion ◽  
Lesion Segmentation ◽  
Ischemic Lesion ◽  
Segmentation Technique ◽  
Apparent Diffusion ◽  
Relative Threshold ◽  
Cerebral Ischemic

To assess hyperacute focal cerebral ischemia in rats on 3.0-Tesla diffusion-weighted imaging (DWI), we developed a novel voxel-wise lesion segmentation technique that overcomes intra- and inter-subject variation in apparent diffusion coefficient (ADC) distribution. Our novel technique involves the following: (1) intensity normalization including determination of the optimal type of region of interest (ROI) and its intra- and inter-subject validation, (2) verification of focal cerebral ischemic lesions at 1 h with gross and high-magnification light microscopy of hematoxylin-eosin (H&E) pathology, (3) voxel-wise segmentation on ADC with various thresholds, and (4) calculation of dice indices (DIs) to compare focal cerebral ischemic lesions at 1 h defined by ADC and matching H&E pathology. The best coefficient of variation was the mode of the left hemisphere after normalization using whole left hemispheric ROI, which showed lower intra- (2.54 ± 0.72%) and inter-subject (2.67 ± 0.70%) values than the original. Focal ischemic lesion at 1 h after middle cerebral artery occlusion (MCAO) was confirmed on both gross and microscopic H&E pathology. The 83 relative threshold of normalized ADC showed the highest mean DI (DI = 0.820 ± 0.075). We could evaluate hyperacute ischemic lesions at 1 h more reliably on 3-Tesla DWI in rat brains.

Abstract 1122‐000125: Underlying ICAD is Associated with Worse Outcome in Acute Large Vessel Occlusion Undergoing Endovascular Therapy

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Sonam Thind ◽  
Ali Mansour ◽  
Scott Mendelson ◽  
Elisheva Coleman ◽  
James Brorson ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Intravenous Thrombolysis ◽  
Fold Increase ◽  
Large Vessel ◽  
High Risk Population ◽  
Large Vessel Occlusion ◽  
Vessel Occlusion ◽  
Nihss Score ◽  
Intracranial Atherosclerotic Disease ◽  
Poor Outcomes

Introduction : Acute large vessel occlusion (LVO) can be secondary to thromboembolism or underlying intracranial atherosclerotic disease (ICAD). Data on the management of LVO due to underlying ICAD are scarce. We hypothesized that patients with ICAD would have worse clinical outcomes following mechanical thrombectomy (MT) than those without ICAD. Methods : We performed a retrospective analysis of consecutive patients who underwent MT for LVO in a large academic comprehensive stroke center between 01/2018 and 05/2021. Presence of underlying ICAD at the site of LVO was determined by the treating interventionalist. We compared outcomes including in‐hospital mortality and 90‐day modified Rankin Scale (mRS) between those with and without underlying ICAD, adjusting for relevant covariates using logistic regression. Results : Among 195 patients (mean age 67.4+15.1 years, 56.9% female, 81% black, median NIHSS score 15), underlying ICAD was present in 39 (20.0%). Stent‐retrievers were used 196 patients with only 3 having rescue stent placement. There were no significant differences in baseline factors amongst the two groups except diabetes was more common (69.2% vs. 49.7%, p = 0.028) and intravenous thrombolysis provided less often (17.9% vs. 36.5%, p = 0.027) in those with ICAD. TICI 2B or higher was achieved in 82.1% of ICAD compared with 94.3% of non‐ICAD patients (p = 0.012). Mortality was more common (50.0% vs. 30.8%, p = 0.025) and good functional outcome (mRS 0–2) at 90 days was less common (10.8% vs. 30.0%, p = 0.002) in the ICAD group. Adjusting for age, diabetes, intravenous thrombolysis, baseline NIHSS score, and final TICI score, underlying ICAD was an independent predictor of mRS 0–2 at 90 days (OR 4.5, 95% CI 1.4‐14.2, p = 0.010). Conclusions : Underlying ICAD is associated with 4.5‐fold increase in poor functional outcome in patients with LVO undergoing traditional MT. Further research is needed to understand factors associated with poor outcomes investigate alternative interventional approaches and medical management in this high‐risk population.

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