Let’s Talk LMCC
Glucose Abnormalities

S01E01

Meryem Talbo, Alice Cheng, Katherine Lan, Esther Kang, Susan Wang, for the McGill Journal of Medicine1
Published online: May 5, 2023

1McGill University
mjm.med@mcgill.ca

Abstract

Welcome to the McGill Journal of Medicine (MJM) LMCC review. This podcast series was created to aid medical students studying for the Canadian Medical Council (MCC)’s licensing exam. Each episode is created based on specific LMCC objectives and is divided into 2 parts. In part one we provide an overview of the topic with the help of experts in the field, followed by Part 2 where we review LMCC styled questions to help consolidate knowledge. In this episode, we welcome our expert advisor, Dr. Alice Cheng, Endocrinologist and Associate Professor at the University of Toronto to speak on LMCC Objective 37-1: Glucose Abnormalities. This episode was written by Meryem Talbo and Dr. Alice Cheng, edited by Esther Kang, Katherine Lan and Susan Wang. Please see our website www.mjmmed.com for more information, including a link to show notes.

     

Content overview

0:00 Introduction;

0:34 Episode Overview;

1:17 Part 1: Overview of concepts - Defining normal blood glucose;

1:49 Symptoms of hyperglycemia and hypoglycemia;

4:35 States of hyperglycemia - transient/stress hyperglycemia;

6:33 Diagnosing hypoglycemia ;

10:30 Differentiating the types of Diabetes Mellitus: Type 1 diabetes, Type 2 diabetes, gestational diabetes and monogenic diabetes;

18:55 Less common causes of hyperglycemia ;

21:49 Diagnosis of diabetes mellitus ;

25:42 Part 2: Sample LMCC Questions;

30:43 Outro;

Glossary

Links and papers

Transcript

0:00 EK: Welcome to the MJM LMCC review. My name is Esther Kang and I am excited to introduce this new podcast series that was created to aid medical students studying for the Canadian licensing exam. Each episode is created based on specific LMCC objectives and is divided into 2 parts. We first provide an overview of the topic with the help of experts in the field then review the LMCC style questions to help consolidate the information. Please join us for our first episode, tackling part one of diabetes with our host, Meryem Talbo and her generous expert advisor, Doctor Alice Chang.

0:34 MT: Welcome to the McGill Journal of Medicine LMCC Review Podcast Series. In our first 2 episodes we will present an overview of the MCSS objectives 37-1 and 37-2 with our special guest, Dr. Alice Cheng - Endocrinologist and Associate Professor at the University of Toronto. This episode was written by Meryem Talbo, and edited by Susan Wang and Esther Kang.

Now, first and foremost, I would like to welcome and thank Dr. Cheng for sharing her time with us today. For more information on Dr. Cheng’s work you can visit the link in this episode’s description (https://www.researchgate.net/scientific-contributions/Alice-YY-Cheng-2049763810 and https://www.themededpledge.com/) and I also recommend you follow her on twitter (@AliceYYCheng)

AC: Thanks very much for having me, Meryem, it’s a pleasure to be here.

1:17 MT: Dr. Cheng, we often toss around the term "normal blood glucose levels" How would you define this?

AC: Well according to the Medical Council of Canada as well as Diabetes Canada, normal blood sugars or blood glucose levels are considered between 4 to 6 mmol/L in the fasted state and up to 11 mmol/L when the sample’s taken either randomly or in a non-fasting state. Anything outside of these ranges would be considered either hypo- or hyperglycemia.

1:49 MT: And can you tell us, what are the most common symptoms of each?

AC: Well, the kind of symptoms that someone will experience will very much depend on exactly how high or how low the sugars are, and it will also depend on that person’s, uh, how used to they are, if you will, to the high or to the low sugars.

So for example, you might have someone living with diabetes who chronically has elevated blood sugars, in which case in very high blood sugar, they may not have any symptoms versus someone who's not used to having high blood sugars, in the same glucose level, they may become very symptomatic and similarly on the other end of the spectrum for hypoglycemia

In general, though, if we're talking about symptoms of hyperglycemia - these would include things like polyurea, which is frequent urination, polydipsia, which is increased fluid intake because of thirst, they may have fatigue, they may have blurry vision and in the circumstance where there's actually insulin deficiency, which we’ll talk about later, they could also experience weight loss. So the big things are polyurea, polydipsia, blurry vision and fatigue.

On the other side of the coin, for hypoglycemia, then there’s sort of two sets of symptoms someone might experience. They usually begin with the autonomic symptoms. Now the autonomic symptoms are sort of the symptoms we have, the fight or flight kind of symptoms, or the symptoms we have if we realize we forgot to study for an exam, or the alarm just went off and we’re freaking out a little bit. It’s those kinds of symptoms. So it’s symptoms like tremor, palpitations, feeling anxious, breaking out into a sweat, hunger, and there may be things like paresthesia, which is that pins and needles feeling. That's sort of in the beginning with autonomic symptoms, and then if the hypoglycemia worsens, one can then get neuroglycopenic symptoms. Now neuroglycopenic symptoms are exactly as the words suggest, “neuro” is brain, “glycol” is sugar and “penic” is lack thereof. So it’s brain lacking sugar symptoms. And the brain lacking sugar symptoms are things like dizziness, weakness, drowsiness, confusion, or altered mental state.

Now in terms of whether or not hyper- or hypoglycemia could lead to loss of consciousness or even be life-threatening, the answer is yes but in the extremes, so if the blood sugar is very low, usually well under 2.8mmol/L, then yes there's a possibility of lost consciousness or seizure and even death, or if its very high, which is typically above 33.3mmol/L, then there is the possibility again of decreased level of consciousness and then perhaps getting into a coma and even death.

4:35 MT: You mentioned diabetes when talking about hypo- and hyperglycemia. Can you tell us in what other contexts can hyperglycemia happen other than diabetes?

AC: So you’re right Meryem, it’s typically found in diabetes. However, some people can have what’s called “transient hyperglycemia”, which is where, exactly as it sounds, the high blood sugars are limited in time. And it’s usually during acute periods of stress, such as infections, trauma, or surgery. And sometimes we refer to this as “stress hyperglycemia”. And it’s usually due to the increased hormones that can be secreted in times of stress, especially infection, with increased cortisol, catecholamines, glucagon, growth hormone, and all of this leading to increased insulin resistance and then impacting gluconeogenesis and glycogenolysis.

MT: So when do clinicians have to be concerned about transient or stress hyperglycemia in the hospital and why?

AC: Uncontrolled hyperglycemia, in the context of critical illness, has been linked with worse outcomes and can be used as a marker of disease severity. So we know that people who develop higher blood sugars while they’re sick in hospital tend to do worse than those who have lower sugar. It’s not that the high sugar causes the bad outcomes, but there definitely is an association. And we do know that when people have higher blood sugars in hospital, that can impact things like wound healing, increase the risk of infections, and can also affect sort of electrolyte disturbances and, potentially, dehydration. And then of course, if it’s long-term, then there are micro- and macrovascular complications but really, when we’re talking about the transient stress hyperglycemia in hospital, our concern has to do with the immediate time, which are things around healing and the risk of infection.

6:33 MT: Now, what about the other side of what I like to call “the glycemia continuum”. So you briefed us on the symptoms and the significance of hyperglycemia, now I’m curious to know, how is hypoglycemia diagnosed?

AC: So, when we think about hypoglycemia, I like to joke about things that are common in medical jeopardy games and this is one of the things that are very common in medical jeopardy games, and that is Whipple’s Triad. Now clearly Dr. Whipple, Professor Whipple, did a lot of things because there are a lot of things that are named after him, but Whipple’s Triad is used to make the clinical diagnosis of hypoglycemia and it consists of three things: 1) symptoms consistent with hypoglycemia or low blood sugar, and specifically the neuroglycopenic symptoms, 2) you need to actually have a low sugar, so it’s usually a low plasma glucose that’s measured with a blood draw as opposed to poking the finger, typically below 2.8 mmol/L, and then there needs to be 3) resolution of those symptoms after someone takes in carbohydrates and raises that plasma glucose. So three things: you have to have symptoms of hypo, you have to actually have low sugar, and then it has to get better after you take in sugar. So those are the three things that define Whipple’s Triad.

MT: Taking all these points into account, what would be your diagnostic approach to a patient presenting with hypoglycemia?

AC: So when someone presents with hypoglycemia, I usually like to think of it in several categories right. So one category would be “is it fasting hypoglycemia or non-fasting hypoglycemia”, cause that’s sort of one way to differentiate potential causes, and then the other big group to think about would be “medication-induced hypoglycemia”. Now the most common cause of hypoglycemia is usually medications, it’s usually someone living with diabetes who’s taking medications that can cause hypoglycemia, such as insulin or sulfonylurea. And then if they take too much of either, and have not consumed enough carbohydrates to account for it, then they can get a low blood sugar. That’s by far the most common cause. The other potential causes would be things that either, because of increased insulin secretion, or because of something disrupting the usual glucose cycle, something affecting your ability to make glucose. So what are the things that can increase glucose secretion? Well, one of those things are medications that I just mentioned, like insulin or sulfonylureas, or someone could have an insulinoma where they actually have a tumor that is making insulin, which would then cause an inappropriate increase in insulin. But then what are the things that could impact your body not being able to make enough insulin? Well then it could be things like excessive alcohol intake, which would then affect-, usually there’s very little oral intake when one is binging on alcohol at the same time and then that of course can impact whether the liver has enough glucose stores to push out, and then alcohol itself can also disrupt the normal glucose cycle. Or it could be a situation where someone has marked liver failure, so then there’s no glucose storages in there or significant kidney failure can also affect it. And then there’s also situations where there may be excess burning of glucose, let’s say, so something like sepsis could account for things like that. So we usually need to think about “is it a situation where there’s too much insulin?” or a situation where there’s too little production or availability of glucose, and then “is there a situation where there’s excess burning of glucose?”. So those are the things that we would think about in that kind of scenario.

10:30 MT: Alright, so now that we have covered the general concepts of glucose abnormalities, namely hypoglycemia and hyperglycemia, we can maybe delve into more diabetes-specific topics, so can you tell us more about specific diabetes types, how many are there and what are the different characteristics of the most common diagnoses?

AC: So if we think about diabetes, the most common types of diabetes that we’ll see will be type 1 diabetes, type 2 diabetes, gestational diabetes, by far the most common are these three, and then there are much less common forms such as monogenic diabetes and other secondary causes, which we’ll get to.

So if we think about type 1 and type 2 diabetes, the most common one is type 2 diabetes. Type 2 diabetes makes up about 90% of the individuals that we see living with diabetes. In the case of type 2 diabetes, the scenario is one of insulin resistance coupled with a pancreas that’s not able to make enough insulin to compensate. So the insulin resistance means that their body is resistant to insulin, so you need a lot more insulin in order for the organs to do what they’re supposed to do when insulin is around. Now initially, the pancreas can compensate - put out more insulin to overcome that resistance. But eventually the pancreas poops out and is not able to make enough insulin, so then you have a relative insulin deficiency, which is why type 2 diabetes is characterized by insulin resistance coupled with relative insulin deficiency. Type 1 diabetes, in contrast, which makes up 10% of the diabetes cases we typically see. In type 1 diabetes, it is an usually autoimmune disorder whereby there is absolute insulin deficiency. So the pancreas is damaged by the autoimmune process, therefore not able to make insulin at all. In that scenario, you can see that it’s critical that that person receive insulin as therapy because they’re not able to make any. So those are the two most common types of diabetes. 90% type 2, insulin resistance with relative deficiency of insulin, and then 10% type 1 diabetes, which is more absolute deficiency of insulin because of an autoimmune process destroying the pancreas.

12:59: Now gestational diabetes is the other common form of diabetes you may see and that one’s easy to remember - that is diabetes diagnosed in pregnancy. Now remember, pregnancy is an insulin resistance state. As the placenta enters into sort of the second trimester, into the third trimester, it’s making hormones which increase insulin resistance. Now again, if your pancreas was 100% normal, it could compensate for that by pushing out more insulin. But if your pancreas was not 100% normal or was already kind of tired, it’s not able to overcome that resistance. Then you end up with high blood sugars in pregnancy and that’s called gestational diabetes. But because it’s as a result of the placenta, upon delivery of the baby and the placenta, that diabetes usually goes away. So that’s gestational diabetes. So those are the three most common types: type 1, type 2, and gestational diabetes.

13:55: Now there’s a much less common form, that’s called monogenic diabetes, which is worth mentioning. It’s worth mentioning because the treatment of monogenic diabetes can be quite different and can be quite life-changing for patients when it’s identified because they’re finally on the right stuff. Now monogenic diabetes is caused by a very specific genetic defect of beta cell function. Typically, it’s an autosomal dominant kind of inheritance pattern so there’s usually a strong family history and typically the patient’s presenting at under the age of 25. And it’s worth identifying those individuals because, depending on the type of monogenic diabetes they have, they may be treated with just sulfonylurea and have fantastic control or some people may not require treatment at all. So it is worthwhile trying to identify those people when it’s possible to do so. Now, part of the question was also, okay, so if these are the more common types then how do we differentiate? And I wish I had an easy answer to that, cause when it’s textbook then it’s an easy differentiator but in reality, there can be a lot of gray-zone. So we can look at things like age of onset. Classically, type 1 diabetes presents at a younger age in children, adolescents, and occasionally in young adults. Type 2 diabetes classically presents as an adult, however there’s a lot of gray-zone now because we’re certainly seeing type 2 diabetes presenting in children and presenting in adolescents, and that is coupled with the obesity epidemic that we’re also seeing in children and adolescents. So it’s not-, it’s no longer very clear-cut. But classically, young patient type 1, older patient type 2. And then for monogenic diabetes typically presenting before the age of 25. Now there’s one form of monogenic, though, that’s worth highlighting. If a baby presents under the age of 6 months with diabetes, then there’s a high likelihood that they have a form of monogenic diabetes that can be easily treated with just sulfonylurea pills. So that’s one form where if you hear about someone diagnosed before the age of, 6 months of age, they should be checked for that monogenic form.

16:23: Other factors we could look at: body weight, again classically, type 1 diabetes lower BMI, type 2 diabetes higher BMI. Not an absolute rule by any means, in fact we’re seeing a lot more people living with type 1 diabetes who also have overweight or obesity, which I think is just a function of society, and sometimes you will find someone with type 2 diabetes who’s on the leaner side. But classically, it would be leaner type 1, larger would be type 2.

16:54: Are there any specific tests that could be done to sort of help us differentiate? Yes. So things like islet autoantibodies, for example anti-GAD antibodies, which is anti-glutamic acid decarboxylase antibodies, or anti-islet cell antibodies. Those are found in type 1 diabetes and not found in type 2 diabetes, so that can be a helpful differentiator. The C-peptide test is a measure of endogenous insulin production, so only the stuff you make yourself, not the stuff you take from outside. And if the C-peptide is very low, that fits with the pancreas not working anymore and more type 1, versus being very high, which is what you’d expect in type 2 diabetes because the pancreas is working really hard to overcome that resistance but it just can make enough. But the absolute amount of insulin being made is actually still high so the C-peptide can be helpful.

17:54: And then the other thing that we could think about would be family history. So, in type 2 diabetes there’s usually a strong family history, in monogenic diabetes there is a strong family history, in type 1 diabetes there may not be. Ethnicity can sometimes be helpful but again, there’s a lot of gray-zone there. And then, finally, we can-, if we’re sort of finding out from someone, they’ve already been diagnosed a long time ago, is asking about how they presented. So if they presented with a marked hyperglycemia, maybe needing hospitalization and went straight to insulin therapy, that story, to me, usually rings like type 1 diabetes. Versus the person who was diagnosed years ago who’s put on some pills and then stayed on pills for a while and then eventually went on insulin, that to me sounds like someone living with type 2 diabetes. So sometimes you’re working backwards because you’re meeting them, they’re already on insulin, and you’re trying to figure out “do you have type 1/type 2” then that piece of history can sometimes be helpful.

18:55 MT: Thank you, Dr. Cheng, for this really nice summary of the common types of diabetes that can be encountered in the clinic. I was actually wondering if there are other less common causes or types of diabetes that you can maybe elaborate on.

AC: For sure. There are some less common causes but ones that we should be aware of, and I should point out there’s actually a fantastic appendix in the Diabetes Canada Clinical Practice Guidelines which is a whole table looking at the etiologic classification of diabetes. And on there you’re going to see listings for things like pancreatic disease. So if someone had their pancreas taken out or chronic pancreatitis where their pancreas is essentially destroyed for other reasons, then that could also result in diabetes. Or things like cystic fibrosis.

19:40: There are also endocrinopathies that can result in marked insulin resistance, such as Cushing’s Syndrome. So in Cushing’s Syndrome, that is a syndrome of excess cortisol either because of a pituitary tumor that’s pushing out ACTH and stimulating cortisol production or because of a tumor in the adrenals making cortisol under no regulation, or a cancer, usually a metastatic cancer of some sort that is creating something that looks like ACTH and is pushing the adrenals to work harder. So in that situation of Cushing’s Syndrome, and actually, I should add one more: the other potential cause is someone taking steroids from outside. So in that situation, though, they present clinically the same, which is very high cortisol levels in the body which then results in insulin resistance which could then result in presenting with diabetes.

20:40: Another endocrinopathy that’s very common would be polycystic ovarian syndrome, where it’s essentially insulin resistance in a woman of reproductive age and therefore it’s not surprising to also see diabetes in that situation. Or things like acromegaly, where there’s excess growth hormone, can also result in an insulin resistance state.

21:05: And then, finally, there’s other medications that we may give people that can induce insulin resistance and possibly diabetes, such as steroids, as I’ve alluded to, but also some of the anti-rejection medications we give in the transplant or immunosuppressants, like tacrolimus or cyclosporin, can cause that. Or certain vasopressors that we may give that are like catecholamines and that can also create insulin resistance. So there are definitely other causes. A lot less common, certainly in the outpatient space, but something to be aware of.

MT: Yes, thank you Dr. Cheng for mentioning the appendix and actually, to our listeners, you can find the link to the appendix as well as other resources for further reading in the episode’s description.

21:49: And now to conclude the first part, can you, Dr. Cheng, please summarize for us, how is diabetes diagnosed and what are the key metrics and values that physicians need to include in their assessment and diagnosis?

AC: So the diagnosis of diabetes is clearly outlined, again, in the Diabetes Canada Clinical Practice Guidelines. Specifically, Chapter 3 has the content that you’re looking for. And the diagnosis of diabetes is based on high blood sugars, defined as either a fasting plasma glucose of 7 mmol/L or greater OR a 2h plasma glucose after a 75 g oral glucose tolerance test of 11.1 mmol or greater, or finally a random plasma glucose of 11.1 mmol or greater. So therefore the potential tests one could have is a fasting glucose, an A1C, an oral glucose tolerance test, or a random glucose. So many ways in which one can diagnose diabetes. Now one thing to bear in mind is that, if the person is symptomatic of their hyperglycemia - and recall that’s polyuria, polydipsia, blurry vision, fatigue - if they’re symptomatic, and you’ve got one abnormal blood test, that’s good enough to make the call that you’ve got diabetes. If however, they’re asymptomatic, so they have no symptoms of hyperglycemia and you’re just doing a random test or screening for diabetes and you find an abnormal result, then you really should do a repeat confirmatory test in a timely fashion in order to officially make the diagnosis of diabetes. Now if someone is quite sick, so their-, they’ve got symptoms of hyperglycemia, they’re losing weight, they’re decompensating, then obviously you’re not going to send them away and say “go do another blood test in a week” cause they’re obviously unwell. Then that single abnormal test is enough to make the call. So that’s in the case of diabetes, be it type 1 or type 2.

23:58: What about gestational diabetes? So remember, gestational diabetes is diabetes diagnosed in pregnancy. The diagnostic criteria are different and there are two different approaches that one can take to make the diagnosis. The preferred approach is with-, starting off with the screening test, which is a 50 g glucose challenge test. So the woman comes to the lab - could be fasted, could be fed, does not matter. She gets 50 g of glucose and then sugar is checked an hour later. And then if it’s abnormal, then she goes on to the confirmatory test which is a 75 g oral glucose tolerance test where she comes to the lab fasting, gets a blood sample, gets the 75 g of glucose, gets another blood sample at 1h and at 2h. And the specific numbers are-, you can look those up. That’s sort of the two-step approach which is the approved or preferred approach, if you will, from Diabetes Canada. There is an alternate approach, though, which saves women time, which is a single step of going straight to the 75 g OGTT (oral glucose tolerance test). But in that case, the criteria for diagnosis are a little bit lower because you’re kind of wanting to capture a few more people cause you don’t have that initial screen. So the one option is the two-step test, the other option is a one-step test. Either one could be used to make the diagnosis of GDM.

MT: Thank you Dr. Cheng for covering these key concepts to help us better understand the different clinical aspects of glucose abnormalities as well as the introduction to the different types of diabetes and how they’re diagnosed.

25:42: Now it's very clear from what we covered here today that the maintenance of glucose within normal levels is quite essential for health and any disturbances can be quite dangerous both in the short and long term. So to help us in consolidating the information presented today we will now go over a couple questions starting with our first case:

26:03: So we have a 45 year-old male patient who comes for his routine check up. His friend was recently diagnosed with diabetes and he is worried that he might also have it. How would you evaluate this patient? What kind of symptoms would you look for? How would you proceed and what would your plan for follow up and management include?

AC: So for this patient, as with all patients, we should start with the history, physical, followed by appropriate lab tests. So on history, I would be interested in whether or not he’s experiencing symptoms of hyperglycemia now, such as polyuria, polydipsia, fatigue, blurry vision. I’d also be interested in his ethnicity, interested in whether there’s a family history of diabetes. On physical exam: his height, his weight, and therefore his BMI and his waist circumference would be helpful information. As well as his vital signs, including his blood pressure, which would then also help me determine his vascular risk. Most importantly, though, we’re talking about lab tests to help determine “does he in fact have diabetes?”. And your options here are either a fasting plasma glucose or a hemoglobin A1C. Now, either of them could be used to make the diagnosis. The fasting glucose has the disadvantage of needing to be fasting and then the A1C has the advantage of you don’t have to be fasting. However there are some limitations sometimes to the A1C if someone has an existing hemoglobinopathy, for example. Then the A1C may not be reliable. Then of course I’d bring him back so that we could review the results of his screening test, either for fasting glucose or the A1C. And the results may come back either normal, pre-diabetes, or diabetes. So if it comes back normal, then, typically, screening would happen again about-, at 3 year intervals. If someone has a lot of risk factors then you might choose to do it annually. If he in fact has pre-diabetes, which means a fasting glucose between 6.1-6.9 or an A1C that’s sort of 6.1-6.4%, then he’s sort of in the waiting room for diabetes as I like to refer to it. He would need to be counseled, of course, about healthy lifestyles and attempt to try to get out of that waiting room and reverse back into normal glycemia. But in someone with pre-diabetes, I would personally rescreen for diabetes at 6 month intervals to see if they progressed in diabetes. If the diabetes diagnosis is made, then of course treatment needs to be initiated. And in someone with existing diabetes, we typically follow up at 3-6 month intervals depending on their level of control because then we can assess their A1C at a 3-6 month interval as well and then, of course, make other necessary adjustments at that time.

28:51 MT: For our second case, we have a 36 year-old woman who comes for her first pregnancy visit. Along with her dating ultrasound and blood tests, she asks when she should get screened for gestational diabetes and what that entails. How would you counsel your patient?

AC: So typically we screen for gestational diabetes between 24-28 weeks gestation. However, in women who have significant risk factors, such as previous GBM, strong family history of type 2 diabetes, coming from certain ethnicities, perhaps pre-pregnancy obesity, then there are certain scenarios where we may choose to screen earlier and that could be done before 20 weeks of gestation. Now the screening could either be two steps or one step. You could either just screen with a 50 g glucose challenge test, which has the advantage of simplicity since she could be fasted or not fasted, and then if the threshold is crossed then do a confirmatory 75 g oral glucose tolerance test. Alternatively, if it’s really hard for her to come in for two separate tests, you could go straight to the 75 g oral glucose tolerance test and then use different cutoffs. So you can look up the different numbers, however, the concept is either a two step screen vs, followed by confirmation, or go straight to the 75 g and use a different set of cutoffs.

30:18 MT: Thank you very much Dr. Cheng for this summary, and indeed, you can find more information such as the different diagnostic tests, their targets, key clinical numbers, and more on the Clinical Practice Guidelines of Diabetes Canada which are accessible online and we put the link in the episode description notes for you. As well as the full list of our references can be found in those notes.

AC: Thank you very much.

30:43 EK: We hope you enjoyed this episode. As mentioned by our host, for details about the LMCC objectives, diabetes resources and information about our expert advisor Dr. Cheng, please check out the episode descriptions below and stay tuned for our next episode continuing with Part 2 of the Diabetes Review.



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