Remote Ischemic Postconditioning vs. Physical Exercise After Stroke: an Alternative Rehabilitation Strategy?

You'll just have to ask your doctor what remote ischemic postconditioning is. My google searches came up with no easy explanation.

 

Remote Ischemic Postconditioning vs. Physical Exercise After Stroke: an Alternative Rehabilitation Strategy?

• Xiaokun Geng,
• Qingzhu Wang,
• Hangil Lee,
• Christian Huber,
• Melissa Wills,
• Kenneth Elkin,
• Fengwu Li,
• Xunming Ji &
• Yuchuan Ding 

Molecular Neurobiology (2021)Cite this article

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Abstract

There remain debates on neuroprotection and rehabilitation techniques for acute ischemic stroke patients. Therapeutic physical exercise following stroke has shown promise but is challenging to apply clinically. Ischemic conditioning, which has several clinical advantages, is a potential neuroprotective method for stroke rehabilitation that is less understood. In the present study, the rehabilitative properties and mechanisms of physical exercise and remote ischemic postconditioning (RIPostC) after stroke were compared and determined. A total of 248 adult male Sprague-Dawley rats were divided into five groups: (1) sham, (2) stroke, (3) stroke with intense treadmill exercise, (4) stroke with mild treadmill exercise, and (5) stroke with RIPostC. Focal ischemia was evaluated by infarct volume and neurological deficit. Long-term functional outcomes were represented through neurobehavioral function tests: adhesive removal, beam balance, forelimb placing, grid walk, rota-rod, and Morris water maze. To further understand the mechanisms underlying neurorehabilitation and verify the presence thereof, we measured mRNA and protein levels of neuroplasticity factors, synaptic proteins, angiogenesis factors, and regulation molecules, including HIF-1α, BDNF, TrkB, and CREB. The key role of HIF-1α was elucidated by using the inhibitor, YC-1. Both exercise intensities and RIPostC significantly decreased infarct volumes and neurological deficits and outperformed the stroke group in the neurobehavioral function tests. All treatment groups showed significant increases in mRNA and protein expression levels of the target molecules for neurogenesis, synaptogenesis, and angiogenesis, with intermittent further increases in the RIPostC group. HIF-1α inhibition nullified most beneficial effects and indicative molecule expressions, including HIF-1α, BDNF, TrkB, and CREB, in both procedures. RIPostC is equally, or superiorly, effective in inducing neuroprotection and rehabilitation compared to exercise in ischemic rats. HIF-1α likely plays an important role in the efficacy of neuroplasticity conditioning, possibly through HIF-1α/BDNF/TrkB/CREB regulation.

Introduction

Stroke is the fifth leading cause of death and the leading cause of disability worldwide [1]. Over the past two decades, the economic and disease burden of stroke has increased dramatically and is anticipated to continue growing due to aging populations and shifting dependency ratios [2]. Meanwhile, the development of neuroprotective and rehabilitative strategies remains a challenge in improving the quality of life in post-stroke patients after initial life-saving measures.

The effect of physical exercise in neuroprotection and rehabilitation following ischemic stroke has been extensively studied and is recommended for all post-stroke patients [3]. Physical exercise mitigates many detrimental consequences of stroke, including memory loss [4], neurological impairment [5], and motor function [6]. However, there is significant variability in the extent of neuroprotection conferred by exercise, depending on the time of initiation, the dosage, and the type of activity [7]. While there is ample recent evidence to support the ability of physical exercise to promote recovery through increased neuroplasticity, a key component of successful rehabilitation [8], a number of obstacles still remain in implementing post-stroke exercise in stroke rehabilitation. Stroke patients are generally refractory to physical activity and are likely to face challenges in complying with post-stroke exercise plans, especially in the earlier post-stroke period [9], which can impair rehabilitation potential during the most salient stages of disease progression. Given patients’ varying forms and extent of disability after a stroke, it also remains a challenge to research and implement a standardized treatment plan for stroke patients. Patients’ amenability to physical activity may vary depending on age, motivation, and other factors. Moreover, recent clinical trials of stroke patients undergoing early physical exercise did not show consistent rehabilitative benefits and instead revealed that very early exercise rehabilitation, such as within 24 h of the stroke, may worsen the post-stroke prognosis [10]. In order to bridge these challenges in the continuum of post-stroke rehabilitation and care, there is growing interest in alternative rehabilitation options, namely ischemic conditioning.

Ischemic conditioning leverages the neuroplastic and neuroprotective benefits of temporary and controlled ischemia for therapeutic benefit [11]. A variety of ischemic conditioning methods have been employed, including ischemic preconditioning (IPreC, exposure to moderate hypoxia prior to an ischemic event) and ischemic postconditioning (IPostC, exposure to moderate hypoxia after an ischemic event) [12]. IPostC has been shown to increase cerebral perfusion, prevent neuronal cell death, and improve cognitive function, notably in spatial learning and memory impairment, in ischemic brains [13,14,15,16]. Remote ischemic postconditioning (RIPostC) is a conditioning method that induces brief, focal hypoxia in the limbs using blood pressure cuffs [17]. It has been employed in a variety of clinical situations for diverse therapeutic goals [18]. RIPostC may confer neuroprotection through multiple mechanisms, including enhanced cerebral perfusion, formation of cerebral collaterals, and increased tolerance to cerebral ischemia [19, 20]. As a result, it has been shown to improve motor function recovery [21], reduce infarct size [22], and minimize cerebral injury by attenuating apoptosis [23, 24]. Furthermore, it is a passive therapeutic measure for the patient and its use is not dependent on his or her level of motivation or post-stroke disability. As an attractive option to augment or replace post-stroke physical exercise, ischemic conditioning may confer neurorehabilitation to stroke patients with high disease burdens. However, RIPostC is yet to be thoroughly studied in the setting of stroke rehabilitation.

The present study aimed to determine whether RIPostC following ischemic stroke can be an effective alternative or augmentative rehabilitation strategy to physical exercise. In order to comprehensively understand and compare the efficacy of exercise and ischemic conditioning, this study further elucidated the important molecular regulations of neurorehabilitative mechanisms. We measured various proteins and biochemical pathways known to be involved in rehabilitation of the ischemic brain in order to assess the benefit of RIPostC. To assess neuroplasticity, we measured neural microtubule proteins (Tau), growth associated protein 43 (GAP-43) and synaptic proteins (postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN)); for angiogenesis, we measured vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang-1), and Angiopoietin-2 (Ang-2); and for neuroplasticity regulation, we measured brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP-response-element binding protein (CREB), and nerve growth factor (NGF). We further elucidated the key role of hypoxia-inducible factor 1α (HIF-1α) underlying the rehabilitative mechanism by using the inhibitor, YC-1.

 

Implementation Strategies and Outcomes for Occupational Therapy in Adult Stroke Rehabilitation: A Scoping Review

Absolutely nothing here tells me your rehabilitation outcomes. Useless. Did you get any of the patients even minutely close to 100% recovery?

 Implementation Strategies and Outcomes for Occupational Therapy in Adult Stroke Rehabilitation: A Scoping Review

J. Edward Murrell (  ed21@uab.edu )
UAB: University of Alabama at Birmingham https://orcid.org/0000-0002-4204-8075
Janell L. Pisegna
The Ohio State University School of Health and Rehabilitation Sciences
Lisa A. Juckett
The Ohio State University School of Health and Rehabilitation Sciences

J. Edward Murrell, Janell L. Pisegna, Lisa A. Juckett
DOI:
10.21203/rs.3.rs-229354/v1
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LICENSE:
This work is licensed under a CC BY 4.0 License. Read Full License

Abstract

Background

Every year, millions of people worldwide experience a stroke. Given the degree of physical, cognitive, visual, and behavioral impairments post-stroke, stroke survivors often encounter occupational therapy practitioners in the rehabilitation practice settings. Although evidence-based occupational therapy practices have been well-established in the stroke literature, it remains unclear what strategies have been used to promote these practices' effective implementation in the real-world context. The present review identifies these strategies and the extent to which researchers have measured implementation outcomes.

Methods

A scoping review protocol was developed to assess the breadth and depth of occupational therapy literature examining implementation strategies and outcomes in the stroke rehabilitation field. Four electronic databases and two peer-reviewed implementation science journals were searched to identify studies meeting inclusion criteria. Two reviewers applied the inclusion parameters and consulted with a third reviewer, as needed, to achieve consensus. The Expert Change guided synthesis of review findings for Implementing Change project and the Implementation Outcomes Framework.  

Results

The initial search yielded 1219 studies, and 26 were included in the final review. A total of 48 out of 73 discrete implementation strategies were deployed in the included studies. The most used implementation strategies were “distribute educational materials,” “assess for readiness and identify barriers and facilitators,” and “conduct educational outreach visits.” “Adoption” was the most frequently measured implementation outcome, while “cost” was not measured in any included studies. Eleven studies reported findings to support the effectiveness of their implementation strategy or strategies; eleven studies reported inconclusive findings, and four studies found that their strategies did not lead to improved implementation outcomes.  

Conclusions

This scoping review identified occupational therapy literature examining implementation strategies and outcomes in the context of stroke rehabilitation. With the growth of the stroke survivor population, the occupational therapy profession must identify effective strategies that promote the uptake of evidence-based practices into routine stroke care. (So you don't even care whether or not your therapies are effective?) Occupational therapy researchers and practitioners are encouraged to collaborate to develop and deploy implementation strategies responsive to known implementation barriers and facilitators in the stroke rehabilitation setting.

A usability study in patients with stroke using MERLIN, a robotic system based on serious games for upper limb rehabilitation in the home setting

But is it better than all these other games?

• arm-training games (2 posts)

• exergames (3 posts)

• games (20 posts)

• gaming devices (7 posts)

• video games (82 posts)

• virtual reality games (7 posts)

A usability study in patients with stroke using MERLIN, a robotic system based on serious games for upper limb rehabilitation in the home setting

• Silvia Guillén-Climent,
• Ainara Garzo,
• María Nieves Muñoz-Alcaraz,
• Pablo Casado-Adam,
• Javier Arcas-Ruiz-Ruano,
• Manuela Mejías-Ruiz &
• Fernando Jesús Mayordomo-Riera 

Journal of NeuroEngineering and Rehabilitation volume 18, Article number: 41 (2021) Cite this article

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Abstract

Background

Neuroscience and neurotechnology are transforming stroke rehabilitation. Robotic devices, in addition to telerehabilitation, are increasingly being used to train the upper limbs after stroke, and their use at home allows us to extend institutional rehabilitation by increasing and prolonging therapy. The aim of this study is to assess the usability of the MERLIN robotic system based on serious games for upper limb rehabilitation in people with stroke in the home environment.

Methods

9 participants with a stroke in three different stages of recovery (subacute, short-term chronic and long-term chronic) with impaired arm/hand function, were recruited to use the MERLIN system for 3 weeks: 1 week training at the Maimonides Biomedical Research Institute of Cordoba (IMIBIC), and 2 weeks at the patients’ homes. To evaluate usability, the System Usability Scale (SUS), Adapted Intrinsic Motivation Inventory (IMI), Quebec User Evaluation of Satisfaction with assistive Technology (QUEST), and the ArmAssist Usability Assessment Questionnaire were used in the post-intervention. Clinical outcomes for upper limb motor function were assessed pre- and post-intervention.

Results

9 patients participated in and completed the study. The usability assessment reported a high level of satisfaction: mean SUS score 71.94 % (SD = 16.38), mean QUEST scale 3.81 (SD = 0.38), and mean Adapted IMI score 6.12 (SD = 1.36). The results of the ArmAssist Questionnaire showed an average of 6 out of 7, which indicates that MERLIN is extremely intuitive, easy to learn and easy to use. Regarding clinical assessment, the Fugl-Meyer scores showed moderate improvements from pre- to post-intervention in the total score of motor function (p = 0.002). There were no significant changes in the Modified Ashworth scale outcomes (p = 0.169).

Conclusions

This usability study indicates that home-based rehabilitation for upper limbs with the MERLIN system is safe, useful, feasible and motivating. Telerehabilitation constitutes a major step forward in the use of intensive rehabilitation at home.

Trial registration ClinicalTrials.gov, NCT04405609. Registered 06 January 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04405609

Background

Strokes are among the leading causes of death, physical disability and economic burden worldwide [1, 2]. The prevalence of people living with the effects of stroke has increased over the last few years, thus creating a higher demand for rehabilitation services [3]. The paralysis of the upper limbs is a common impairment after strokes, and only 10–20% of patients recover completely [4, 5]: for these patients, the main aim of arm rehabilitation is to recover lost functions [6]. Nowadays, the key aspects to make rehabilitation effective for people with stroke are considered to be intensity, repetition and using suitably challenging and function-oriented activities [7,8,9]. However, the increase in the number of people affected and the current limitation of health resources make it very difficult to provide services using a traditional approach.

Continuous advances in neuroscience and neurotechnology are transforming stroke rehabilitation [10]. At a time when the rehabilitation services resources are unable to meet the demand, robot-assisted rehabilitation and home-based telerehabilitation are gaining greater acceptance [11]. Robot-based neurorehabilitation systems provide a solution to increase the number of movements, involve safe, intensive rehabilitation exercises [12, 13] and have the advantage that the precise movements of the robot are able to measure the patients’ movements objectively [14, 15]. On the other hand, home-based telerehabilitation allows us to extend institutional rehabilitation by increasing and prolonging the therapy [16]. What is more, the combination of game-based telerehabilitation and robotic systems creates a motivating, engaging environment for patients [17]. The enjoyment patients derive from playing these so called ‘serious games’, designed specifically for the rehabilitation tasks, can greatly increase the quality and quantity of the therapy delivered [18].

MERLIN is a robotic system based on serious games for the upper limb tele rehabilitation in patients with a stroke. It is presented as an affordable and easy to use solution to allow the patient to carry out an intensive rehabilitation at home, with a continuous remote monitoring and communication with the therapist. The system is composed of an upper-limb rehabilitation robot and a software platform which guides and measures the patient’s movements and allows physicians to customize the therapeutic plan and to monitor the patients’ evolution.

The purpose of this manuscript is to present the usability validation of MERLIN system. In this study, we evaluate the ease to use, consistency and acceptance of the system have been evaluated. The research carried out also aims to demonstrate the feasibility of including the robotic therapy as a complement to a regular daily rehabilitation program.

 

 More at link.

 

Wine case carrying challenge

 It is impossible to carry a full 12 bottle case of wine, I may have the strength but not the coordination to balance it and walk at the same time. Breaking wine bottles would be a travesty. But I can carry 6 bottles at a time with all 6 on one end and thus can put the heavy end in the crook of my elbow. I can wedge the box with my body against the door frames with the box to be able to unlock the entry doors. Yesterday was a run to two wine stores to pick up 3 weeks of virtual wine tastings for 6 groups of people(Monastrell, Mondeuse, and Tavel), plus a number of orange wines from Georgia just to try.

 

Why to drink wine!

1. Social connections first of all.

2.Reservatrol

• resveratrol (54 posts)

The two lower ones with bottle caps are white/orange sparkling wines from Georgia and Slovenia

Primary motor cortex excitability during recovery after stroke: implications for neuromodulation

 Just the word, implications, means followup will be needed and no protocols were written and with NO STROKE LEADERSHIP OR STRATEGY, nothing will occur. Wasted research. What survivor cares about excitability? They want proven recovery results.

Primary motor cortex excitability during recovery after stroke: implications for neuromodulation

2015, Brain Stimulation
 Cathy M. Stinear a,b, 

Matthew A. Petoe a,b, 

Winston D. Byblow b,c,*
 

a Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
b Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
c Department of Sport & Exercise Science, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

 abstract

Background:
 Non-invasive brain stimulation techniques may be useful adjuvants to promote recovery after stroke. They are typically used to facilitate ipsilesional cortical excitability directly, or indirectly by suppressing contralesional cortical excitability and reducing interhemispheric inhibition from the contralesional to ipsilesional hemisphere. However, most of the evidence for this approach comes from studies of patients at the chronic stage of recovery.

Hypothesis:

 We hypothesized that corticomotor excitability and interhemispheric inhibition would initially be asymmetric, with greater interhemispheric inhibition from contralesional to ipsilesional M1.We also hypothesized that balancing of corticomotor excitability and interhemispheric inhibition would be associated with greater improvements in paretic upper-limb impairment and function.
Methods:
 We conducted a retrospective analysis of longitudinal data collected from 46 patients during the
 first six months after stroke. Transcranial magnetic stimulation was used to measure rest motor threshold, stimulus-response curves, and ipsilateral silent periods from the extensor carpi radialis muscles of both upper limbs. Analyses of variance and linear regression modeling were used to evaluate the effect of time on corticomotor excitability and interhemispheric inhibition in both hemispheres, and associations between these effects and improvements in paretic upper-limb impairment and function.
Results:
 All participants had subcortical damage and only two had motor cortex involvement. As expected, ipsilesional corticomotor excitability was initially suppressed and increased over time, and this increase was associated with improved upper-limb impairment and function. However, interhemispheric inhibition was symmetrical and stable over time, and there was no evidence for a decrease in contralesional corticomotor excitability.
Conclusions:
 Neuromodulation interventions applied during spontaneous recovery may be more beneficial if they facilitate ipsilesional corticomotor excitability directly.
 

banana bunch failure

 Removing one banana from a bunch one-handed comes very close to failure most of the time. I can't use the hip check method as proposed in One-Handed in a Two-Handed World (Second Edition) (Spiral-bound) by Tommye-K. Mayer. That would smash the bananas.  Hopefully your speech therapist trained you in the correct way to peel a banana by following the experts in that, chimpanzees. Peeling it the wrong way one-handed invariably results in a smashed banana. 

 

 

 

 

 

 

 

 

How To Peel A Banana Like A Monkey

Only 32 seconds long.

No Stroke Expertise? Specialist on Speed Dial Boosts Outcomes

 Oh God, 'better care'! The tyranny of low expectations in full display. Aren't you glad your doctors and researchers are OK with this lazy crapola? Massive amounts of chest thumping for what should be regular care. When you get to 100% recovery then you can celebrate, until then just shut up and do your job, which is 100% recovery in case you missed that goal.

No Stroke Expertise? Specialist on Speed Dial Boosts Outcomes

Stroke care compared between hospitals with and without telestroke technology

by Nicole Lou, Staff Writer, MedPage Today March 1, 2021

Stroke patients received better care(NOT RECOVERY!) at hospitals lacking on-site stroke expertise if they had telestroke capacity, according to large observational study.

Reperfusion treatment, through thrombolysis or thrombectomy, was more likely among acute ischemic stroke patients at telestroke centers compared with matched peers treated without either on-site or virtual capacity (6.8% vs 6.0%, RR 1.13, 95% CI 1.09-1.17), reported Ateev Mehrotra, MD, MPH, of Harvard Medical School, and colleagues in a paper published online in JAMA Neurology.

Telestroke made the biggest difference for rural patients and the lowest-volume hospitals (admitting fewer than two strokes per month), whereas higher-volume centers (averaging at least two strokes per week) showed no improvement in reperfusion therapy by telestroke capacity.

Approximately 30% of all hospitals emergency departments in the U.S. now use telestroke technology. Although low-volume and rural hospitals showed the greatest benefits of telestroke, they were least likely to have telestroke capacity in the study.

Better reimbursement or direct financial support may encourage these hospitals to adopt telestroke, Mehrotra's team suggested, noting that barriers to adoption may include insufficient financial investment, lack of high-speed internet in rural communities, and regulations that limit financial support from tertiary hospitals.

Mehrotra's group also showed higher reperfusion rates at telestroke centers among patients 85 years and older, for whom emergency medicine physicians may be uncomfortable using thrombolysis given the associated increased risk of intracerebral hemorrhage in the oldest age group.

Telestroke extends stroke expertise to hospitals without on-site stroke expertise, where emergency departments are staffed by people with less exposure to stroke care(NOT RECOVERY!) and thus lower comfort levels with reperfusion decisions. Remote consultations permit contact between a stroke specialist, the bedside care(NOT RECOVERY!) provider, and the patient.

Study investigators compiled Medicare data on acute stroke admissions in the U.S. in which the patient had first presented to a hospital without on-site stroke expertise in 2008-2017. They found 76,636 matched pairs of patients (57.7% women, mean age 78.8 years) going to hospitals with or without telestroke.

There was no evidence that stroke care(NOT RECOVERY!) had previously been superior at hospitals that eventually adopted telestroke.

Mortality rates at 30 days favored stroke patients at telestroke-capable hospitals (13.1% vs 13.6%, RR 0.96, 95% CI 0.94-0.99). However, the effect dissipated by 6 months (22.6% vs 23.0%, RR 0.98, 95% CI RR 0.97-1.00).

The two groups had similar healthcare costs (institutional spending $26,560 vs $26,524) and functional status (60.25 vs 60.22 days alive in the community after discharge) through 90 days.

"To our knowledge, this is the first study to demonstrate that telestroke is associated with a clinically meaningful reduction in mortality and improved use of reperfusion treatments with no increase in health care spending," Mehrotra and colleagues noted.

"Though cost-effective from the perspective of Medicare, it is important to emphasize that local hospitals must pay for telestroke capacity, and these payments are not captured in our data," they cautioned.

Other limitations of the study include unobserved confounding, the lack of data on symptom onset and other patient factors in Medicare records, and the reliance on community living as a proxy measure of functional outcome after stroke.

"Given the increasing prevalence of telestroke in EDs and current state of evidence, it is unlikely that a randomized clinical trial of telestroke vs placebo is feasible given the ethics of not offering patients effective stroke care(NOT RECOVERY!). Therefore, we believe this form of rigorous observational study is likely to be the best evidence available on the association of telestroke with treatment and outcomes for patients with acute ischemic stroke," study investigators wrote.

• 

  Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow

Disclosures

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

Mehrotra had no disclosures.

Study coauthors reported ties to Genentech, Life Image, the Massachusetts Department of Public Health, Penumbra, Diffusion Pharma, the Agency for Healthcare Research and Quality, Controlled Risk Insurance Company, and the American College of Emergency Physicians.

Primary Source

JAMA Neurology

Source Reference: Wilcock AD, et al "Reperfusion treatment and stroke outcomes in hospitals with telestroke capacity" JAMA Neurol 2021; DOI: 10.1001/jamaneurol.2021.0023.

 

First-in-Human Clinical Trial to Assess Gene Therapy for Alzheimer’s Disease

 Your doctor should have been trying for years to figure out how to get BDNF into the brain. Now they should be excitedly following this research because they may finally be able to help you with this. 

• BDNF (146 posts to August 2013)

First-in-Human Clinical Trial to Assess Gene Therapy for Alzheimer’s Disease

UC San Diego researchers will inject harmless virus carrying a restorative gene into participants’ brains, where earlier animal studies suggest it may slow, prevent or reverse progression of the neurological disorder

Researchers at University of California San Diego School of Medicine have launched a first-in-human Phase I clinical trial to assess the safety and efficacy of a gene therapy to deliver a key protein into the brains of persons with Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI), a condition that often precedes full-blown dementia.

The protein, called brain-derived neurotrophic factor or BDNF, is part of a family of growth factors found in the brain and central nervous system that support the survival of existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is particularly important in brain regions susceptible to degeneration in AD.

In previous published research, principal investigator Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, and colleagues described the prevention and reversal of brain cell degeneration and death in animal models.

Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine.

“We found that delivering BDNF to the part of the brain that is affected earliest in Alzheimer’s disease —the entorhinal cortex and hippocampus — was able to reverse the loss of connections and to protect from ongoing cell degeneration,” said Tuszynski. “These benefits were observed in aged rats, aged monkeys and amyloid mice.”

Amyloid mice are genetically engineered to inherit a mutation in the gene encoding the amyloid precursor protein, and as a result develop amyloid plaques — aggregates of misfolded proteins in the brain that are considered a hallmark characteristic of AD.

BDNF is normally produced throughout life in the entorhinal cortex, an important memory center in the brain and one of the first places where the effects of AD typically appear in the form of short-term memory loss. Persons with AD have diminished levels of BDNF.

But BDNF is not easy to work with. It is a large molecule and cannot pass through the blood-brain barrier. As a result, researchers will use gene therapy in which a harmless adeno-associated virus (AAV2) is modified to carry the BDNF gene and injected directly into targeted regions of the brain, where researchers hope it will prompt production of therapeutic BDNF in nearby cells.

The injections are precisely controlled to contain exposure to surrounding degenerating neurons since freely circulating BDNF can cause adverse effects, such as seizures.

The three-year-long trial will recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons serving as comparative controls over that period.

This is the first safety and efficacy assessment of AAV2-BDNF in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called nerve growth factor (NGF) found heightened growth, axonal sprouting and activation of functional markers in the brains of participants.

“The BDNF gene therapy trial in AD represents an advance over the earlier NGF trial,” said Tuszynski. “BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”

Despite billions of dollars of research investment and decades of effort, there are only two symptomatic treatments for AD. There is no cure or approved way to slow or stop progression of the neurological disorder that afflicts more than 5 million Americans and is the sixth leading cause of death in the United States.

Numerous clinical trials are ongoing to assess pharmaceutical remedies. Tuszynski said gene therapy, which debuted in 1980 and has been tested on multiple diseases and conditions, represents a different approach to a disease that requires new ways of thinking about the disease and new attempts at treatments.

“We hope to build on recent successes of gene therapy in other diseases, including a breakthrough success in the treatment of congenital weakness in infants (spinal muscular atrophy) and blindness (Leber Hereditary Optic Neuropathy, a form of retinitis pigmentosa),” Tuszynski said.

“BDNF gene therapy has the potential, unlike other AD therapies currently under development, to rebuild brain circuits, slow cell loss and stimulate cell function. We are looking forward to observing the effects of this new effort in patients with AD and MCI.”

For more information on this Phase I clinical trial, contact Michelle Mendoza at 858-822-7438 or email alphastemcellclinic@ucsd.edu

 

Do commonly prescribed antidepressants(SSRIs) increase the risk of bleeding stroke? NO

A while ago SSRIs were considered helpful in recovery.

Common antidepressant can help stroke patients improve movement and coordination Sept. 2015 

 

Antidepressants may help people recover from stroke even if they are not depressed Jan. 2013

  

 Have your doctor explain why  this discrepancy occurred between the upper two and this lower one.

 Then further research disproved that. 

 

Is there a suitable drug for stroke recovery?

The latest here:

Do commonly prescribed antidepressants(SSRIs) increase the risk of bleeding stroke? NO

There is good news for people who take antidepressants called selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants in the United States. A new preliminary study has found that they are not associated with an increased risk of intracerebral hemorrhage, the deadliest kind of stroke. The preliminary study released today, February 25, 2021, will be presented at the American Academy of Neurology’s 73^rd Annual Meeting being held virtually April 17 to 22, 2021.

An intracerebral hemorrhage is when a blood vessel bursts in the brain sending blood into the surrounding tissue. The most common causes are high blood pressure and head trauma, but some studies have also suggested that SSRIs may increase a person’s risk of this type of bleeding stroke.

“Selective serotonin reuptake inhibitors work by preventing reabsorption of the chemical serotonin, which regulates mood, into the cells, making more of it available in the brain,” said study author Mithilesh Siddu, MD, of the University of Miami in Florida and member of the American Academy of Neurology. “However, by interfering with serotonin, which also plays a role in blood clotting, SSRIs may increase the risk of bleeding. Therefore, to determine if these antidepressants increase the risk of bleeding strokes, we looked at a large population of people with stroke.”

For the study, researchers identified 127,915 people who had a stroke between 2010 to 2019. A total of 17,009 people had been prescribed antidepressants prior to their stroke and the other 110,906 had never had an SSRI prescription.

Researchers found that 11% of people who had been prescribed antidepressants had an intracerebral hemorrhage, compared to 14% of the people who had not. After adjusting for other factors that could affect stroke risk, such as age, high blood pressure and diabetes, researchers found that people who took antidepressants were just as likely to have an intracerebral hemorrhage as people not taking such medications.

“These findings are important, especially since depression is common after stroke and selective serotonin reuptake inhibitors are some of the first drugs considered for people,” said Siddu. “More research is needed to confirm our findings and to also examine if SSRIs prescribed after a stroke may be linked to risk of a second stroke.”

A limitation of the study was that some details regarding the length, dosage and type of antidepressants were not available to be included in the study.

To read more, click here

 

 

Early Post-Stroke Electroacupuncture Promotes Motor Function Recovery in Post-Ischemic Rats by Increasing the Blood and Brain Irisin

Early  as defined means they have no clue if spontaneous recovery caused all this recovery they measured instead of the electroacupuncture or irisin.

Early Post-Stroke Electroacupuncture Promotes Motor Function Recovery in Post-Ischemic Rats by Increasing the Blood and Brain Irisin

Authors Liu L, Zhang Q, Li M, Wang N, Li C, Song D, Shen X, Luo L, Fan Y, Xie H, Wu Y

Received 3 November 2020

Accepted for publication 25 January 2021

Published 1 March 2021 Volume 2021:17 Pages 695—702

DOI https://doi.org/10.2147/NDT.S290148

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Yuping Ning

Li Liu,^1,* Qun Zhang,^1,* Mingyue Li,² Nianhong Wang,¹ Ce Li,¹ Di Song,³ Xueyan Shen,¹ Lu Luo,¹ Yunhui Fan,¹ Hongyu Xie,¹ Yi Wu<sup>1

1</sup>Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; ²Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; ³Department of Rehabilitation Medicine, The Affiliated Sixth People’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hongyu Xie; Yi Wu
Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, People’s Republic of China
Email huangdaitian@163.com; 16111220064@fudan.edu.cn

Objective: Recent studies have shown that irisin, a novel peptide hormone derived from muscles, could be used as a potential therapeutic drug against ischemic stroke. Moreover, electroacupuncture (EA) is widely used in the treatment of ischemic stroke. Yet, whether irisin is involved in the EA neuroprotection remains unclear. The following study investigated the association between serum and peri-lesional cortex irisin and EA-induced post-stroke motor recovery in rats.
Methods: The middle cerebral artery occlusion (MCAO) method was used to induce ischemic stroke in rats. Rats were randomly divided into two groups: a middle cerebral artery occlusion (MCAO) group (MCAO rats without treatment) and an electroacupuncture (EA) group (MCAO rats treated with EA). On the 3rd day post-stroke, infarct volume, behavioral deficits, surviving neurons, irisin protein expression in peri-infarction cortex, muscle tissue, and serum were evaluated to identify the neuroprotective of EA in acute ischemic stroke.
Results: Compared with the MCAO group, the EA group showed better behavioral performance, a smaller cerebral infarct volume, more surviving neurons, and a significant increase in irisin expression in the peri-infarction cortex and serum (p< 0.05). However, no difference in irisin expression in the muscle tissue was found between the MCAO group and the EA group (p> 0.05).
Conclusion: EA promotes motor function recovery, reduces the volume of cerebral infarction, and alleviates neuronal death following ischemic stroke by enhancing the expression of irisin in both the blood and peri-lesional cortex.

Keywords: ischemic stroke, electroacupuncture, irisin

Introduction

Stroke is a leading cause of morbidity and mortality worldwide.¹ Acute thrombolytic therapy is the most effective treatment for patients suffering from ischemic stroke.² This kind of therapy is usually given within 4–6 hours after onset of an ischemic stroke, while its effectiveness beyond this time frame (>6 h) still remains debatable. Ischemic stroke is a complex inflammatory cascade. Cerebral ischemia can cause acute neuroinflammation and neuronal injury. In the subacute and chronic phases, cerebral ischemic inflammation can lead to glial cell proliferation, neuronal apoptosis, and brain tissue atrophy. These processes are associated with the impairment of nerve function.³

Recent studies have shown that irisin, cleaved from precursor fibronectin type III domain-containing protein 5 (FNDC5), could be used as a potential therapeutic drug against ischemic stroke. Emerging evidence has indicated that the serum levels of irisin could predict outcomes of patients with ischemic stroke.⁴ In addition, irisin can also promote neuronal cell survival⁵ and inhibit post-stroke inflammation, reducing cerebral infarction volume in MCAO models.⁶ Since irisin is released from skeletal muscle during exercise,⁷ any treatment that stimulates muscle contraction may be used as a potential therapy to increase the irisin post-stroke. However, it is still unclear whether peripheral or central irisin mediates the effects in the brain.

Previous studies have found that early EA can improve neurobehavioural functional recovery and reduce infarct volume by inhibiting the brain inflammation,⁸ oxidative stress,⁹ and promoting angiogenesis.¹⁰ Moreover, EA stimulation at peripheral limbs, for instance, at Zusanli (ST36) and Quchi (LI11) points, could also increase the serum factors, like brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF).¹¹ Recent studies found that long-term EA stimulation promotes the expression of FNDC5 in skeletal muscle of diet-induced obesity rats.¹² However, whether irisin is involved in EA neuroprotection remains unclear.

The aim of this study was to investigate the efficacy of EA stimulation at Zusanli (ST36) and Quchi (LI11) points on post-stroke recovery. In order to further explore the early EA neuroprotection mechanism, we analyzed different irisin concentrations in the muscle, serum, and pei-infarct cortex on the 3rd day of the post-ischemic stroke. We hypothesized that EA stimulates muscle contraction, increasing the skeletal muscle-originated irisin in either blood or the peri-lesional cerebral cortex, thus resulting in an infarct reduction (Figure 1).

 

Cellular Senescence in Brain Aging

 You'll have to ask your doctor how you get senolytics in your brain to eliminate senescent cells.

Cellular Senescence in Brain Aging

Ewa Sikora^1*, Anna Bielak-Zmijewska¹, Magdalena Dudkowska¹, Adam Krzystyniak¹, Grazyna Mosieniak¹, Malgorzata Wesierska² and Jakub Wlodarczyk³

• ¹Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland
• ²Laboratory of Neuropsychology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland
• ³Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

Introduction

As with other organs and systems, the functional capabilities of the brain decline progressively during aging. As we age, cognitive performance generally declines which manifests as decrements in learning and memory, attention, decision-making speed, sensory perception (vision, hearing, touch, smell, and taste), and motor coordination (reviewed in Mattson and Arumugam, 2018). Aging is the leading risk factor of age-related diseases (ARDs), including neurodegenerative disorders. The aging process and ARDs are considered as a sort of a continuum with two extremes. One is represented by centenarians, who largely avoided or postponed most ARDs and are characterized by decelerated aging. Individuals 60+, 70+, 80+ who suffered from one or more severe ARDs, represent another extremum and show signs of accelerated aging. In between, there are relatively healthy aged people (Franceschi et al., 2018). Thus, precise boundaries between “normal” and “pathological” aging do not exist, especially when molecular and cellular mechanisms at the roots of aging are considered. Particularly, little is known about healthy brain aging outside of the realm of neurogenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Nonetheless, we must remember that the current consensus in geroscience (Kennedy et al., 2014) considers AD as a more severe form of pathologies associated with normal aging. With age physical fitness and cognitive functions often decline in human and animals (Leal and Yassa, 2015). However, we must not forget that in nature exist animal species, such as naked mole rats, ocean quahog, rockfish and Greenland shark, and many others that exhibit negligible senescence and superior resistance to age-related diseases (Finch, 2009).

In humans, cognitive abilities can be divided into such domains as: processing speed, attention, memory, language, visuospatial abilities, and executive functioning (Harada et al., 2013). Similarly, animal behavior is based on attention and different kinds of memory. Age-associated deterioration of cognitive functions correlates with impaired motor coordination of both animals and humans, who lose their independence and experience a decrease in the quality of life. The age-related cognitive impairment is associated with changes in the central nervous system, mainly in the prefrontal cortex and hippocampus. These changes may lead to development of not only neurodegenerative diseases, but also psychiatric diseases, for example, depression and schizophrenias (Baker and Petersen, 2018). However, in agreement with the idea of a continuum of the aging process (Franceschi et al., 2018), healthy aging, free of mental disabilities, is not a rare exception.

Transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after the age of 40. Genes that play a role in synaptic function and neuronal plasticity that underlies learning and memory, were among those most significantly affected in the aging human cortex. Significantly reduced expression of several neurotransmitter receptors that play a key role in synaptic plasticity, including the GluR1 AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit, the NMDA (Nmethyl- D-aspartate) R2A receptor subunit, and subunits of the GABA receptor, was shown in people over 40. Moreover, the expression of genes that mediate synaptic vesicle release and recycling, involved in protein transport, involved in protein turnover, also showed reduced expression in the aged cortex. Interestingly, most of the age-downregulated genes showed significantly greater oxidative DNA damage in the aged cortex. In line with this, the aging of the human frontal cortex was associated with increased expression of genes that mediate stress responses and repair. Those included genes involved in protein folding, DNA damage repair, antioxidant defense, metal ion homeostasis, and neuroinflammation (Lu et al., 2004). Generally, the study of Lu et al. may suggest that the main culprit of aging could be cellular senescence of brain cells.

Actually, the hallmarks of aging that are common to neurons and other cells have been described recently (Mattson and Arumugam, 2018). They include: mitochondrial dysfunction, intracellular accumulation of oxidatively damaged proteins, nucleic acids, and lipids, dysregulated energy metabolism, impaired cellular “waste disposal” mechanisms (autophagy-lysosome and proteasome functionality), impaired adaptive stress response signaling, compromised DNA repair, dysregulated neuronal Ca²⁺ homeostasis, stem cell exhaustion, and inflammation. Since the brain function relies on the neuronal network connectivity, the effects of aging are manifested at the level of synaptic plasticity, as shown by the age-associated decline in the number of synapses and in aberrant synaptic transmission in several brain regions. Moreover, a landmark of the aged brain is an increased level of neuroinflammation generated by glial cells, which can contribute to alterations in neuronal/synaptic function (Lupo et al., 2019).

Very recently an outstanding progress in elucidating molecular changes associated with cognitive decline through genome-wide profiling of aging brain cells at different molecular levels, namely genomic, epigenomic, transcriptomic, and proteomic, has been made (Ximerakis et al., 2019). Although the research of the role of cellular senescence in the aging brain is still in its infancy the concept has been laid (Tan et al., 2014; Baker and Petersen, 2018; Kritsilis et al., 2018; Wengerodt et al., 2019) (Figure 1). Therefore, in these review, we will focus on cellular senescence of the brain and discuss recent studies, which have shown that elimination of senescent cells can lead to alleviation of brain associated age-related diseases in many genetically modified mouse models (reviewed by Sikora et al., 2019). Accordingly, we ask the question of whether elimination of senescent brain cells may lead to brain rejuvenation.

 

Reperfusion Treatment and Stroke Outcomes in Hospitals With Telestroke Capacity

'More likely' IS NOT WHAT THE FUCK THIS RESEARCH IS SUPPOSED TO BE ABOUT!  Since you didn't measure 100% recovery this was useless.

Reperfusion Treatment and Stroke Outcomes in Hospitals With Telestroke Capacity

Andrew D. Wilcock, PhD¹; Lee H. Schwamm, MD^2,3; Jose R. Zubizarreta, PhD^4,5,6; et al Kori S. Zachrison, MD, MSc^2,7; Lori Uscher-Pines, PhD⁸; Jessica V. Richard, BS⁴; Ateev Mehrotra, MD, MPH^4,9

Author Affiliations

JAMA Neurol. Published online March 1, 2021. doi:10.1001/jamaneurol.2021.0023

Key Points

Question  What is the association between telestroke capacity and care patterns and outcomes(You didn't measure 100% recovery?) for patients with acute ischemic stroke?

Findings  In this study including 153 272 patients treated for stroke, those who received care at hospitals with telestroke capacity had higher rates of reperfusion treatment and lower 30-day mortality compared with those treated at hospitals without telestroke. Increases in reperfusion treatment were largest in smaller hospitals, among rural residents, and among patients 85 years and older.

Meaning  Patients who present to hospitals with telestroke capacity were more likely to receive reperfusion treatment and have lower mortality.

Abstract

Importance  Telestroke is increasingly used in hospital emergency departments, but there has been limited research on its impact on treatment and outcomes.

Objective  To describe differences in care patterns and outcomes among patients with acute ischemic stroke who present to hospitals with and without telestroke capacity.

Design, Setting, and Participants  Patients with acute ischemic stroke who first presented to hospitals with telestroke capacity were matched with patients who presented to control hospitals without telestroke capacity. All traditional Medicare beneficiaries with a primary diagnosis of acute ischemic stroke (approximately 2.5 million) who presented to a hospital between January 2008 and June 2017 were considered. Matching was based on sociodemographic and clinical characteristics, hospital characteristics, and month and year of admission. Hospitals included short-term acute care and critical access hospitals in the US without local stroke expertise. In 643 hospitals with telestroke capacity, there were 76 636 patients with stroke who were matched 1:1 to patients at similar hospitals without telestroke capacity. Data were analyzed in July 2020.

Main Outcomes and Measures  Receipt of reperfusion treatment through thrombolysis with alteplase or thrombectomy, mortality at 30 days from admission, spending through 90 days from admission, and functional status as measured by days spent living in the community after discharge.

Results  In the final sample of 153 272 patients, 88 386 (57.7%) were female, and the mean (SD) age was 78.8 (10.4) years. Patients cared for at telestroke hospitals had higher rates of reperfusion treatment compared with those cared for at control hospitals (6.8% vs 6.0%; difference, 0.78 percentage points; 95% CI, 0.54-1.03; P < .001) and lower 30-day mortality (13.1% vs 13.6%; difference, 0.50 percentage points; 95% CI, 0.17-0.83, P = .003). There were no differences in days spent living in the community following discharge or in spending. Increases in reperfusion treatment were largest in the lowest-volume hospitals, among rural residents, and among patients 85 years and older.

Conclusions and Relevance  Patients with ischemic stroke treated at hospitals with telestroke capacity were more likely to receive reperfusion treatment and have lower 30-day mortality.

Full Text

 

Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage

 WHOM allows research into cost before telling us exactly how to 100% recover from this Intracranial Hemorrhage?  THIS is what is wrong with stroke, totally wrong focus of stroke research.  All because we have NO stroke strategy leading to 100% recovery, and that is because we have NO STROKE LEADERSHIP.

Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage

Andrew Micieli

,

Andrew M. Demchuk

,

Harindra C. Wijeysundera

Originally published1 Mar 2021https://doi.org/10.1161/STROKEAHA.120.031108Stroke. ;0

Abstract

Background and Purpose:

Andexanet was approved by the Food and Drug Administration in 2018 for reversal of life-threatening or uncontrolled bleeding associated with factor Xa anticoagulation; however, the cost-effectiveness of Andexanet compared with standard of care (ie, prothrombin complex concentrate, PCC) in patients with factor Xa–associated intracranial hemorrhage (ICrH) is unknown.

Methods:

Cost-effectiveness analysis using a Markov cohort decision analytic model with a lifetime horizon was completed to determine the costs and benefits of Andexanet compared with PCC for reversal of factor Xa–associated ICrH. The population of interest was patients living in Canada on chronic factor Xa inhibitors for prevention of ischemic stroke in nonvalvular atrial fibrillation or the prevention/treatment of venous thromboembolism, presenting with an ICrH. Outcomes of interest were life expectancy (measured in years), quality-adjusted life years (QALY), costs (reported in 2020 Canadian dollars), and the incremental cost-effectiveness ratio.

Results:

An overall reduction in fatal ICrH and increase in thromboembolic events was associated with Andexanet compared with PCC. Andexanet had the highest discounted life expectancy of 2.53 years and a discounted QALY of 1.55. PCC had a discounted life expectancy of 2.09 years and a discounted QALY of 1.28. The average discounted lifetime costs were $237 177 Canadian dollars for Andexanet and $177 871 Canadian dollars for PCC. The strategy of Andexanet had an incremental cost-effectiveness ratio was $219 652 per QALY gained compared with the comparator of PCC. The probabilistic sensitivity analyses demonstrated that Andexanet (at its current cost) was cost-effective in 19% of simulations using a willingness-to-pay threshold of $50 000/QALY and 33% of simulations at $150 000/QALY. A 1-way sensitivity analysis found that for the incremental cost-effectiveness ratio to be <$150 000/QALY gained, Andexanet high or standard dosing would require a price reduction to <$24 000 Canadian (at current baseline efficacy).

Conclusions:

Based on available evidence, Andexanet represents low value for reversal of factor Xa–associated ICrH; however, there is substantial uncertainty reflecting the currently available data. Further comparative evidence and costing data will become available in the future with randomized trials of Andexanet versus PCC.

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