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Behavioral Symptoms in Alzheimer's Disease: Getting Into Focus With Agitation

  • Authors: Anton Porsteinsson, MD; Larry Culpepper, MD, MPH; Alireza Atri, MD, PhD
  • CME / ABIM MOC Released: 1/20/2023
  • Valid for credit through: 1/20/2024
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Target Audience and Goal Statement

This activity is intended for neurologists, psychiatrists, primary care professionals (including primary care physicians, nurse practitioners, physician assistants, and geriatricians), psychologists, and other healthcare professionals as well as patients/care partners involved in the care of patients with AAD.

The goal of this activity is for learners to be better able to recognize AAD, current therapeutic approaches in the management of AAD, and clinical investigational therapies.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Appropriate clinical tools for the evaluation of patients for AAD
    • Factors involved in the selection of a currently available treatment for the management of AAD
  • Demonstrate greater confidence in their ability to
    • Diagnose AAD


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  • Anton Porsteinsson, MD

    William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine
    University of Rochester School of Medicine and Dentistry
    Rochester, New York


    Anton Porsteinsson, MD, has the following relevant financial relationships:
    Consultant or advisor for: ACADIA Pharmaceuticals, Inc.; Athira; Biogen; Cognitive Research Corporation, Eisai, Inc.; Functional Neuromodulation, Ltd.; IQVIA; Lundbeck, Inc.; MapLight Therapeutics; Merck; MJH Life Sciences; Novartis
    Research funding from: Alector; Athira; Biogen; Biohaven Pharmaceuticals; Cassava; Eisai, Inc.; Genentech/Roche; Lilly; Vaccinex

  • Larry Culpepper, MD, MPH

    Professor of Family Medicine
    Boston University School of Medicine
    Boston, Massachusetts


    Larry Culpepper, MD, MPH, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie Inc.; ACADIA Pharmaceuticals, Inc.; Allergan; Eisai, Inc.; Supernus Pharmaceuticals, Inc.; Takeda Pharmaceuticals
    Owns stock (privately owned) in: M-3 Information, LLC
    Other: Receive payment from Physicians Postgraduate Press as Editor in Chief of the Primary Care Companion for CNS Diseases

  • Alireza Atri, MD, PhD

    Institute Director
    Banner Sun Health Research Institute
    Sun City, Arizona


    Alireza Atri, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: ACADIA Pharmaceuticals Inc.; Biogen; Eisai, Inc.; Lundbeck, Inc.; Novo Nordisk; Qynapse; Roche/Genentech
    Research funding from: Athira; Biohaven Pharmaceuticals; Eisai, Inc.; Lilly; Vivoryon


  • Frances McFarland, PhD, MA

    Medical Education Director, Medscape, LLC


    Frances McFarland, PhD, MA, has no relevant financial relationships.

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    Associate Director, Accreditation and Compliance, Medscape, LLC


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Behavioral Symptoms in Alzheimer's Disease: Getting Into Focus With Agitation

Authors: Anton Porsteinsson, MD; Larry Culpepper, MD, MPH; Alireza Atri, MD, PhDFaculty and Disclosures

CME / ABIM MOC Released: 1/20/2023

Valid for credit through: 1/20/2024


Activity Transcript

Anton Porsteinsson, MD: Hello. I'm Anton Porsteinsson, the William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine at the University of Rochester School of Medicine and Dentistry in Rochester, New York. Welcome to this program titled, "Behavioral Symptoms in Alzheimer's Disease: Getting Into Focus With Agitation."

Joining me today are my colleagues: Larry Culpepper, who is professor of family medicine at Boston University, and Alireza Atri, who is a cognitive neurologist and director of the Banner Sun Health Research Institute in Sun City, Arizona. Welcome.

During the next half hour or so, we'll discuss the diagnostic criteria of AD-associated agitation, the epidemiology and burden of AAD, pathophysiology, how do we evaluate and diagnose AAD, current approaches to management, and investigational therapies.

I'll start with how we define agitation. Agitation is really a cornucopia of symptoms. Back in 2015, the International Psychogeriatric Association created a work group to come up with a provisional consensus definition of agitation, and that has really served as a foundation to make sure that when we are describing agitation, we're talking about the same thing. So let's explore the provisional consensus definition.

One of the critical criteria is that the patient must meet criteria for cognitive impairment or dementia syndrome, such as Alzheimer's disease. The patient must exhibit at least one of the behaviors that is associated with emotional distress, is shown persistently or frequently for at least two weeks, and the behavior represents a change from their usual behavior. We look for excessive motor activity, verbal aggression, sometimes we see physical aggression. The behaviors need to be severe enough to produce excess disability that is beyond what the cognitive impairment or dementia brings to the table. So this could include significant impairment in interpersonal relationships, other aspects of social functioning, and the ability to perform or participate in daily living activities. Now the behavior cannot be solely attributable to another psychiatric disorder, to suboptimal care conditions, to a medical condition, or the physiological effects of a substance, although often comorbid conditions are present.

It is important to note that agitation is not identical to aggression. Agitation may often include aggressive behaviors, and that combination is often the type of agitation that is most distressing to care partners in particular. But it can also occur without aggression, for example, with pacing, rocking, repetitious behavior or resistance to collaborating with the care partner.

Now the provisional definition of AD-associated agitation currently it's being updated by an IPA associated work group and we expect to see a publication of the updated definition within the next year.

So how common is agitation among patients with Alzheimer's disease? Why is it important? Larry, what do we know about the burden of AD-associated agitation?

Larry Culpepper, MD, MPH: Well, what we know is that 76% of patients with Alzheimer's disease display agitation, and 60% even in mild cognitive impairment stage of Alzheimer's disease, and the patients with agitations have more severe behavioral problems in general, have more depressive symptoms. And it increases with severity over time. It worsens patients' daily function, it worsens their quality of life. It also leads to more rapid disease progression. And we find excess morbidity and more hospital stays in those Alzheimer's patients that display agitation.

It does have higher care partner burden and that is evidenced by their stress and depression levels, and by their having lower employment earnings. It affects us as healthcare providers as well. We have a higher number of consultations for these patients and families, and these patients often have a higher rate of spending time in psychiatric wards. In terms of direct healthcare costs, what we find is that the care of these patients when they have agitation is about $20,000, whereas the same patients without agitation, it's a little over $9000, $9200. So agitation is a common phenomenon in dementia and some psychiatric illnesses as well, but historically we've seldom addressed it as a distinct entity.

Dr Porsteinsson: Thank you Larry. With that in mind, Ali, what do we know about the etiology and pathophysiology underlying agitation?

Alireza Atri, MD, PhD: It could be a manifestation of multiple things, certainly of the underlying disease itself, AD, that affects structures and function in a certain way, but it could also be a manifestation of medical illness, a physical discomfort, of drugs or medication side effects, emotional or psychological distress or needs not being met, or environmental stressors. So it's very multifactorial and in some cases it comes down to we can't figure it out and put it down to the effect of the disease on ultimately behavioral systems in the brain.

As far as pathophysiology goes, I would say it's even less understood. We have some evidence from imaging and other structural studies that, there are structural and functional deficits that occur in regions that oftentimes overlap very early on, even with AD pathology. There are neurochemical changes and imbalance oftentimes. So we think about lower cholinergic activity in the frontal lobes or the temporal lobes, but oftentimes there's some balance with other chemicals. So it's not just in isolation that, cholinergic activity goes down and that's the sole cause. For example, lower serotonin activity and metabolites have been noted in other areas, including the frontal lobes.

There are a number of different hypotheses. Some of them have to do with, potentially agitation being an emotional hyperreactive state, putting individuals in a state where they're misinterpreting threats. Part of it could be that it's basically undercutting behavioral networks in the frontal lobes causing behavioral disinhibition. And part of it is, again, if individuals have issues with perception or with language, again, they can become in a hyperaroused state or misinterpret stimuli.

So the underlying mechanisms, even though not completely understood, may be different from the cause of agitation or psychosis potentially in other neuropsychiatric illnesses. And in that way, some of the treatments for AD may have to be more specific than that's used in other medical and psychiatric conditions.

Dr Porsteinsson: Thanks, Ali. But this leads us to management. What should we think about?

There can be a lot of different things going on, which really requires kind of a comprehensive approach, and Helen Kales, Constas Lyketsos, and Laura Gitlin came up with a standardized approach that is often referred to as DICE, D-I-C-E. And the acronym stands for, describe the problematic behavior, investigate the possible causes, create a plan for management, and evaluate, so that you can assess the benefit from the intervention and adapt it.

So let me start with the "describe" part of DICE. When you're describing what's going on, you have to have a discussion with the care partner or the family member, the person that might be the professional provider here and understand what is going on. Input from the patient matters if they can contribute. So you need to find details about the behavior, what is really going on. This is kind of who, what, when, and where. You need to identify the context, the triggers, and underlying modifiable factors. You got to identify the most distressing or problematic behavior. And it helps to assess the care partner's understanding of dementia, what they think is going on. It helps to understand the how well they appreciate neuropsychiatric symptoms. And they don't attribute this just to the patient trying to be difficult.

Larry, can you tell us more about the assessment and maybe what a primary care physician might think about?

Dr Culpepper: Sure. And probably a key issue, particularly for primary care, is remembering that agitation is not simply aggression. That, involved in the concept of agitation are actually, going back to the provisional definition, a number of other persistent behaviors. And what we find is that we really need to manage these in large part because of the increased impairment that leads to institutionalization and so forth. So we really need to assess these patients, understand the dimensions of agitation, and then craft management accordingly.

So in terms of the assessment, we've already discussed about a lot of the other clinical factors that might go into it. So we need to go back and reassess in terms of, are there comorbidities that might be contributing to these? Beyond that, we need to assess the dimensions of symptomatology that the patient is displaying and not only the severity of the symptoms, but the distress it's causing to them and to the care partner. So the NPI questionnaire is a very helpful tool. And certainly those of us in primary care, we may not remember all of the dimensions that we would have value in assessing. And so the NPI can guide us through these. It's very quick and it covers the key elements.

So what we do is rule out conditions, but we also then need to investigate. And when we get to the investigate component of DICE, we're looking at certainly patient factors. We also need to look at care partner factors. So what are the quality of the relationships with the patient? Are there sticking points that we can go back over with the partner in terms of their understanding. So communication style, are they being abrupt with a patient, angry with a patient in a way that just simply increases the anxiety and the agitation? And finally, we need to understand the culture context of the patient and family, so that we understand what are management strategies that might be acceptable or not acceptable to them.

And finally, we do need to look at the environment. Yes, we've already mentioned stimulation. Safety issues, is a patient who is agitated more prone to get up and wander for instance? Can we establish predictable routines that the patient can begin to comprehend and work with and thus decrease their anxiety? And finally, are there pleasurable activities that we can engage the patient in, which in a positive way tends to calm down the agitation?

And we need to recognize that this often is a team sport. We may need to involve others. That may be, for instance, visiting nurse service or elder care program individuals who can really work with a family and assess their ability to manage. If a patient's already in a nursing home, we may need to engage with the nursing staff, not only the daytime staff, but the evening and night staff, in terms of assessing the conditions affecting the patient. So finally, we need to recognize that as we move through that, we'll often come to a point where obtaining input from a specialist can be very valuable. So a geriatrician, a neurologist, an Alzheimer's disease specialist, all may be very helpful to engage in the further assessment of patients, particularly if we're looking at a patient who we can project is going to require a change in institutional level of care at some point in the future. Obtaining early input from these other members of our team may be helpful in stabilizing the patients before we come to a crisis point.

Dr Porsteinsson: With that in mind, Ali, what kinds of things does a specialist like a cognitive neurologist address in their evaluation?

Dr Atri: Yeah, I think Larry covered it really well. I don't think that we have a massive high-tech approach. I think we have potentially a little bit more leeway and expertise and time to unpack some of these issues that Larry was mentioning, do it using instruments to measure them and really to, again, go into this DICE approach in a more comprehensive way.

So just around sleep for example, imagine how irritated and irritable or maybe agitated you may get if you're not sleeping well for several nights in a row. And this may not be recognized. So people say, "Oh yeah, they go to bed at this time and they get up this time." Well, are they observed? Are they actually sleeping during that time or not? Is there something else going on? So they're coming in getting their sleep interrupted, and maybe during the day they're falling asleep and they're being woken up and they're getting agitated. So we delve into those and we use instruments.

And we try to refine things. So sometimes we're told that the patient is really depressed and it turns out that there's actually apathy involved instead of depression. Sometimes they're becoming aggressive because they're being separated and they're being anxious. So refining those and then really understanding the impact and the burden. So we can use the NPI for part of the impact. There's also the Zarit Burden Inventory, the ZBI, that we use to look at caregiving burden and stress. There are other instruments that are shorter and more broad, like the Quick Dementia Rating Scale, QDRS. It has some behavioral questions on it and then you have to refine it.

On the exam side, things like looking at the level of consciousness or arousal. Could this be really a subclinical delirium or the medicines depressing their cognition? Is there asterixis for example? So simple things we look for. Certainly doing a neurobehavioral status exam, assessing again from the patient's anxiety and depression. Really no major tests, I think, oftentimes by the time they're referred to us, that there may be some tests on board, but if not, absolutely we want to make sure their hydration's okay. So I usually do a CBC for infection. I do a Chem-20 with LFTs. I will add on a thyroid and a B12 and a homocysteine. But I also look for C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as a suggestion of there may be something inflammatory, infectious may be going on. Of course, the urinalysis (UA) has been done oftentimes, sometimes the chest x-ray, occasionally you'll see the neurologist will think about doing an electroencephalogram (EEG) or something like that, thinking about sleep or a sleep study in some cases. But oftentimes this does not require like another magnetic resonance imaging (MRI scan), another head computed tomography (CT scan), or something like that.

Dr Porsteinsson: Thanks Ali. Thanks Larry. I think you've pointed very clearly that the investigation part of DICE needs to be handled thoughtfully and carefully. And if there's something there that we find, that we aim to reverse it.

So let's say that we've established that agitation is present. Well how do we manage it? And basically that's where we hit the C in DICE, which is to create a plan for treatment. And creating a plan for treatment calls for some collaboration between the clinician, the care partner, and again, if possible, the patient. So after your investigation, primarily as a first step, use non-pharmacological approaches. So the patient may have some needs that are unmet, there are considerations for the care partners such as, can we educate and support the care partner? At the same time, we've got to be certain that we ensure safety. If there is aggression involved we want to make sure that nobody gets hurt. We want to simplify the environment if there's overstimulation, we want to enhance the environment if there's under stimulation. So the care plan needs to be patient centered.

Let's look at some of the non-pharmacological interventions that we ought to always apply. And there have been studies looking at this, and non-pharmacological interventions can be particularly useful in milder to moderate stage of agitation. Structured social interaction, what we call brief psychosocial therapy, which included interaction with a care assistant for up to 30 minutes a day under the supervision of a therapist, was shown to be helpful. Reminiscence treatment, again, it has to be patient centered, focused on their interest. It can be something that you build between the care partner and the patient to look at times in their lives that the patient still may well remember. Music therapy actually can be very positive for both the patient and the care partner. It's effective particularly when interactive, when people kind of get into it, so clapping, singing, dancing, and you got to be thoughtful about what kind of music does this person like. Bright light therapy, surprisingly showed low or no clinical benefit, aromatherapy wasn't superior to placebo. Therapeutic touch, well that actually seemed to work for non-aggressive behaviors but wasn't helpful if there was physical or verbally agitated, aggressive behavior.

So if you apply non-pharmacological interventions, they may help they may be partially helpful or they in some situations may not help at all. So when we need to go to pharmacological treatments, Ali, what are our options?

Dr Atri: Well, unfortunately they're limited, because there isn't any FDA-approved medications for these indications. And research in this is difficult for a number of reasons. But generally the way I think about it is, how acute is the problem? And if we have to pull the trigger of a medication, how much time do we have? If there's psychosis immediately and there's a safety issue to somebody, then we have to think about actually even hospitalization in some cases or going with medications that have black box warnings. And if we're doing that, we have to do it in a time limited way, monitor closely.

If I can get away with temporizing things for now, I always think about the FDA-approved medications of cholinesterase inhibitors and memantine. They actually have some effects on behavioral symptoms, including agitation. There's data that suggests that, particularly the combination of memantine on top of the cholinesterase inhibitors. But again, that's not a medicine you're going to give acutely and get a result. So I explain that to patients and families as almost like a pot that is going to boil at some point and you're turning the temperature down a little bit. The other things that are used are selective serotonin reuptake inhibitors (SSRIs).

People have used neuroleptics, various data for that for harm benefit, things like gabapentin, prazosin, carbamazepine, quetiapine, and the various other antipsychotics. But the one that has an approval from the European Medicines Agency for, again, very short-term use for severe and refractory sort of aggression, agitation, and psychosis is risperidone. And again, does it work for everybody? Not necessarily.

I always think of it as, above all, do no harm and safety and tolerability. And the issue with the antipsychotics, and that is also true for the atypicals, is parkinsonism. So extrapyramidal symptoms, sedation, rigidity, falls, prolongation of QT, and that's why there's been a black box warning, that suggest that with patients with dementia-related psychosis, there's an increased risk of death with these medicines and oftentimes it's cardiac or stroke risk. And the longer they're on it, the greater that risk over time.

So that's all to say that there's risk involved, but sometimes we have to pull the trigger because not doing something also involves risk. These patients and families, they're on a knife edge. So if the aggression and agitation goes far enough, they can fall, they can hurt somebody. So really this involves a very careful deliberation and discussion with families in a patient-centered way. If you have to do it, you start it low, you tell them that in the beginning it's possible to overshoot, to make them sedated, you'll pull back. Get the consent, you document that consent actually about the treatment decisions, and you go from there and kind of monitor it. Some people do it after a week with a phone call. Some people bring people in within a few weeks, but generally within a few months you have to periodically check, do some check-ins.

Ultimately things like benzodiazepines I would avoid. Sometimes in the hospital they give them in really emergency situations. But I would say avoid benzos if you can. It actually can also cause a delirium of itself.

So measuring the response, seeing if you've kind of turned the flame down and hopefully things aren't boiling as much, and see if you can taper and withdraw. But that really depends on the patients and families. In some cases you'll do that and very clearly the behaviors will come back, and they're so severe and disturbing that they could lead to, again, a spouse being harmed or the patient having to be institutionalized.

Things like citalopram, [in a] JAMA publication a few years ago, about 40% of individuals who had marked agitation had improvement, but just the act of being in a trial meant that there was a 26% placebo response. So that 14% difference, maybe a number needed to treat was 7 to 1. Primary care clinicians know how to use this, oftentimes they'll add this on. But again, it can suppress cognition a little bit, especially at higher doses. It could prolong the QT interval. So I'll put a plug in for a new study with escitalopram. That's being actually studied right now in the S-CitAD study, to see if we can get better results with that.

There are small studies with prazosin, which is an alpha blocker. It could have some effects on blood pressure. So it'd have to be managed a certain way. One of the first-line things sometimes I will suggest is to give a little bit of acetaminophen. There have been studies from the UK that sometimes just that may be calming enough, they may have pain that's unrecognized and they can't voice. So maybe a small trial of that. Again, you're not going to do that if someone is floridly aggressive, hitting people. This is a kind of lower levels. And then there're the anticonvulsants. Many of those trials, people have put them empirically, but a lot of them haven't really panned out. And cannabinoids are being tried now too.

So the bottom line is that, it's a bit of a trial and error. There's off-label use with serious side effects that have to be monitored. This is an area of absolute need to have something that could have some efficacy for some people, and for some people that could be the difference, that's huge. But we need to have things that are also safe.

Dr Porsteinsson: Thanks Ali. This brings us to investigational therapies, and there are several medications that are currently in late stage development. Brexpiprazole is a partial serotonin 5-HT1A and dopamine D2 receptor agonist, that also has 5-HT2A and noradrenaline alpha 1B and alpha 2C receptor antagonist. It is already on the market for the treatment of schizophrenia and as an adjunctive treatment for depression. But it has been studied in 3 different studies for patients with agitation and aggression in Alzheimer's disease.

We also have studies that have looked at dextromethorphan. And most of us know dextromethorphan as a part of a cough suppressant, but if you give DM associated with a metabolism inhibitor, that basically blocks the metabolism through the cytochrome P450 system. And we can either use quinidine or bupropion. We have studies that have had mixed outcomes for dextromethorphan quinidine or the deuterated version of that. But for dextromethorphan bupropion, we have both a positive phase 2/3 trial where the combination of dextromethorphan bupropion was superior to bupropion alone, and superior to placebo. We are also looking at cannabinoid such as nabilone and others that seem to have the possibility of promise. And Ali was very gracious to mention the S-CitAD study that is ongoing right now looking at escitalopram for the same indication.

So let's bring this all together. And let me start with you Larry. Can I ask you to share key points on the evaluation of patients with agitation associated with Alzheimer's disease, and the creation of a treatment plan?

Dr Culpepper: Sure. So I think there're several key issues. One is to recognize that agitation is more than just aggression, and that we need to look at the level of anxiety. We need to look at, particularly from a primary care perspective, what led to this? Was there a sudden change or has this been growing over time? Because if it's a sudden change, then we need to look further at what either pathological process is contributing to that sudden change, or we need to look at the caregiver and the environment, and has there been a significant change there that we can manage? So certainly, that type of assessment can lead us directly to identifying an intervention.

I think the other key is to recognize that, while the primary care provider often has early and ongoing contact with these patients, it's really a team sport. And so bringing in our other team members, in terms of the specialty evaluation, and particularly at where we need help in terms of not only diagnosing, but in terms of thinking about more advanced management strategies, either non-pharmacologic or pharmacologic. Because as we've just gone through, there's a lot of development in this area that our patients may benefit from. So those would be keys that I would provide as take homes for primary care.

Dr Porsteinsson: Thanks Larry. And you were talking about pharmacological treatment. Ali, can I ask you about the main considerations in selecting pharmacological treatment?

Dr Atri: Yeah. Try not to. So very early on having these discussions about psychoeducation and triggers, so important to try to head it off as opposed to being reactive. But if you have to, the first thing to do is to simplify and get rid of the bad ones. And if you have to add something, you have to know that there's nothing the FDA approved. So this is a big area of need. Think about doing no harm, safety and tolerability. Consider extrapyramidal symptoms (EPS), sedation, falls, and of course risk of mortality being increased with some of these medicines.

It has to be personalized, has to be matching the profile and the urgency. What is the urgency that's going on? Can you wait? Or this is an immediate safety issue, because the patients and families are on a knife edge. And that's a very, very complex discussion. But always try to do the education first. Get them on background medicines the cholinesterase and memantine. And then you can think about things like atypical antipsychotics like risperidone or SSRIs or other things that will be off-label.

You really have to make sure the care partner is taken care of and understanding the impact of this. No matter what you instill, you're going to have to monitor the temperature of the patient, the care partner, and what these pharmacological things are doing. So start low, go slow, monitor, and try to taper if you can. Sometimes you can, sometimes you will stay on them.

Dr Porsteinsson: And thanks, Ali. I think you hit 2 important highlights. One is that this is an area of tremendous need, and that there is no FDA-approved pharmacological treatment for agitation and aggression in Alzheimer's disease.

So let me close with some key themes. I'm optimistic because we have better understanding of the neurobiology of agitation and aggression. We have greater consensus on the diagnosis. So, when we think that somebody has agitation and aggression, I think we're more speaking the same language than we used to. And on the research end, we have much-improved trial designs and better scales and outcome measures. And this has led to some exciting new options in late-state development that hold actual promise both on efficacy as well as safety. And I'm particularly thinking of brexpiprazole and dextromethorphan bupropion. So I think that the next year, 2023, may show us a very significant step forward in overall evaluation, management, and treatment of patients with AAD.

So Larry, Ali, I really appreciate the great discussion that we've had. For the audience, thank you for participating in this activity and please continue on to answer the questions that follow, and complete the evaluation.

This transcript has not been copyedited.

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