Dr. James Nichols: Thank you for your interest. And this was actually some case studies that were produced by our residents

We had a pediatric endocrine fellow who comes through every January. And then we also have our resident in pathology

So, I want to go through basically three cases with ketosis due to different causes, kind of review ketone bodies and the pathophysiology of diabetes, diabetic ketoacidosis, and then identify some of the clinical utility of beta-hydroxybutyrate as an analyte in the laboratory

So, the first case I want to cover is actually pediatric, a 13-year-old Caucasian female. She's overweight, has no past medical history, a family history of type 1 diabetes, and she's going to her primary care practitioner with a two-week history of polydipsia, polyuria, a 20-pound weight loss

She seems to not--her big complaint to the primary care practitioner was she couldn't get enough to drink. She was waking up several times at night to urinate

And at the physician's office, she had a capillary glucose of about 444 milligrams per deciliter. And a urinalysis done at the physician's office the physician's office was four-plus ketones

So, she was transferred to our emergency department, and her pH was low. She was acidotic, had a high serum glucose. Her bicarb was very low. So, her anion gap was up

She had a high beta-hydroxybutyrate. It was 8.46. And the normal range for those of you who aren't familiar with it is zero to 0.27 millimoles per liter. So, this was orders of magnitude above the normal range

And her sodium was 137, 141 when you correct it for hyperglycemia

Now, the second case we want to talk about is an African-American female, 58-year old, no previous history of diabetes. She shows up in the emergency room with one week history of fatigue, polyuria, polydipsia, blurry vision

Again, her capillary glucose, glucose meter, was 300. Her hemoglobin A1c was 16.1 percent. And again, this was a little bit of a higher anion gap, not as high as the last one, was 33. But, her ketones and glucose were plus four by dipstick. And the beta-hydroxybutyrate was in the 6.86 range, again, very elevated

Then we have case three here. This is a 57-year-old Caucasian male. He has poorly controlled type 2 diabetes he's been diagnosed with

His past history of reflux esophagitis, alcohol abuse, cirrhosis, he comes to the emergency room with vomiting blood, abdominal pain. He has a recent history of increased alcohol consumption, has not been eating or taking his insulin. I guess he just forgot, as he was drinking

So, his pH was borderline at the low, again in the acidotic range, but borderline in the norm--low normal. Glucose was elevated, but not as elevated as the previous ones. Bicarb was very low, anion gap, super high

Lactate was up. Beta-hydroxybutyrate you can see was elevated about 10 times the normal limit. A blood alcohol of 209, which is quite impressive, and ketones was two-plus

So, it just kind of brings home as you look at these pictures and the similarities between three different cases, three different people showing up in the emergency room with similar and dissimilar analytes, they all kind of surround the ketone bodies. And in all of these cases, these patients had elevated ketone bodies

So, what is a ketone body? Well, it's actually a--there are three of them. They are water soluble compounds produced by byproducts when fatty acids are actually metabolized or broken down by the liver, beta-hydroxybutyrate, acetoacetate, and acetone

Acetone is volatile. Beta-hydroxybutyrate and acetoacetate are not

So, they are stable in serum. After processed, you don't have to remember to keep the cap on. They're not ethanol, in other words

Normally, when the body breaks down ketones, they break them down into CO2 and H2O. But, the buildup of ketones causes an acid imbalance. And that's where you get the ketone bodies, both--ketone bodies, actually, if you look at this--oops, let me go back here. Guess I don't have a pointer

If you look at the beta-hydroxybutyrate, it's butyric acid. So, that gives you the acid that is the unbound or unrecognized in the anion gap. So, it is one of the elements that is causing the increased anion gap along with the acetic acid

If it's not diagnosed and treated, ketoacidosis can be fatal

I do want to point out that, in normal patients, acetoacetate-to-beta-hydroxybutyrate ratio is normally about one to one. But, when you go into ketoacidosis, acetoacetate to beta-hydroxybutyrate is about a one-to-six ratio, meaning beta-hydroxybutyrate outnumbers acetoacetate and acetone by about a six-to-one ratio

Beta-hydroxybutyrate, in other words, is favored in the ketosis states

So, I want to point out here that actually these are byproducts of metabolites. And whether you're actually in the absence or presence of insulin, if you're in the presence of insulin, you actually are building and putting yourself into basically an anabolic type of state

You're digesting glucose. Insulin allows glucose to go into the cells and be actively utilized. And in the liver, you're actually in a state of gluconeogenesis, meaning that you're taking glucose, and you're storing it for long-time use so that when you go into a starvation or when you are not eating, you can then breakdown those stored glucose and continue to have glucose for the brain metabolism

But, when you are in a starvation situation and your glucose can't be utilized because you are not taking in a lot of carbohydrates, you're basically in an absence of insulin, and you're no longer utilizing glucose as your primary energy source

You're actually utilizing fatty acids. And it is the breakdown of the fatty acids that leads to the beta-hydroxybutyrate

So, you can see from a TCA cycle, free fatty acids comes into acetyl CoA. And if you have oxygen, if you're in a catabolic state and actually metabolizing all of this well, you actually will breakdown those fatty acids to CO2 and H2O with a byproduct of ATP that can be used for energy stores

But, if you don't have and you've overwhelmed the TCA cycle, which can happen as you're going in and using fatty acid stores, instead, you breakdown acetyl CoA into HMGCoA and eventually into acetoacetate and beta-hydroxybutyrate

So, what is diabetes? Diabetes is actually chronic high blood sugar. It's--in long-term risk of putting glucose and binding glucose to your proteins, you actually can have cardiovascular problems. You can have protein issues that cause blindness, circulatory problems

So, all of these, the retinopathy, the nephropathy, the neuropathies, all of these are microvascular complications of proteins that have been glycosylated over a long period of time

In type 1, primarily pediatric, you're diagnosed as a child, it's previously termed insulin-dependent or juvenile-onset diabetes. This is an immune-mediated type of cause

In other words, your pancreatic cells that release and store insulin and release it upon a meal, that's damaged by antibody action, so an autoimmune type of reaction against those cells

So, you don't have enough insulin in the body, and that's where the problem is coming from, as opposed to type 2, which is called non-insulin-dependent diabetes or adult onset

This is where your cells become refractory to insulin because you have a constant state of high glucose. You're constantly pumping out a lot of insulin. Your cells become refractory to it. So, in other words, eventually, your pancreas shuts down and stops producing and releasing the insulin

So, it is a different cause. But, both of these are due to an imbalance in insulin and a response to insulin

Diabetic ketoacidosis is a life-threatening complication of untreated diabetes. Insulin deficiency and stress hormones combine to cause DKA

And it was once the leading cause of death amongst type 1 diabetics, primarily seen in type 1 diabetics, although type 2 can also show DKA

Still a very high mortality rate, particularly even in developed nations, like America, 5 to 10 percent of patients showing up in the ED who have DKA can end up in a fatal problem

It's characterized by a kind of trifecta of hyperglycemia, acetosis, and ketone bodies

Now, ketone bodies, as I mentioned before, in DKA, beta-hydroxybutyrate accounts for about 75 percent of the ketones, outnumbers acetoacetate and acetone by about a six-to-one ratio. Greater than about 0.0--this should be 0.027 millimoles per liter is abnormal

Historically, ketoacidosis is diagnosed, monitored in urine and serum with nitroprusside, the urine-based test. But, there's a problem with urine-based tests. They're not as--while they may be equally sensitive, they're not as specific to beta-hydroxybutyrate as a direct analyte would be

The Ketostix, the Acetest, and again there's been problems in marketing the Acetest and getting this Acetest, which is also driving a lot of physicians to be using more the direct marker, the beta-hydroxybutyrate

But, the problem is they're colorimetric. They're kind of semiqualitative at best. And you get that one-plus, two-plus, three-plus, four-plus type of reading

The other problem with this is that they don't--they're more specific for acetoacetate, and they don't detect beta-hydroxybutyrate

So, they're not really detecting the predominant ketone body in DKA

And these are what they look like. I think many of you are familiar with these and have used these in the laboratory. The nitroprusside reaction I show at the top actually forms this colored compound that is purple. So, it changes from a clear compound, a kind of yellowish to a bright purple in the presence of acetoacetate

And they're marketed under a number of different names, Acetest, the Keto-Diastix. You have the tablets that you can add serum or urine to in a test tube, or you also have the Multistix types of formats, where it is one of the pads on a multianalyte urine dipstick

Now, ketone bodies in severe ketoacidosis, I mentioned about that beta-hydroxybutyrate-acetoacetate ratio shifting. And the problem when you use dipsticks, it depends at what stage the person comes in because, if they're in diabetic ketoacidosis, the beta-hydroxybutyrate is going to far outweigh the acetoacetate

And then remember the metabolic pathway. As it reverses and as beta-hydroxybutyrate goes down, you're going to see this rise in acetoacetate. So, there is almost a leg as during treatment where you may actually see a rise in the dipstick response and a decrease in the beta-hydroxybutyrate, which more directly prevails treatment, the rehydration, the removal of the acidosis situation

That's why I mention here that the fall of acetoacetate lags behind the improvement in ketoacidosis

Drugs can also cause a false positive nitroprusside test

Now, the different methodologies that you can actually measure, I mentioned about nitroprusside, but there's the several limitations

You can have false negatives because it doesn't detect the primary ketone body beta-hydroxybutyrate. And you can have false positives with drugs like L-Dopa, Captopril, other ACE inhibitors that patients may be on if they're diabetic and they have high blood pressure

Gas chromatography, capillary electrophoresis, very specific for beta-hydroxybutyrate, but how many of us actually really have gas chromatography and capillary electrophoresis ready to go in the core laboratory

It's not real simple, not amenable to point-of-care-type of strategies

And then you have the enzymatic. It's rapid, has minimal cross reactivity with interfering drugs, and you can perform it in an automated analyzer-type format in the main laboratory, or you can perform it on point-of-care testing devices. And there's a variety of those that are available now

The enzymatic methods I can tell you have a comparable sensitivity. It's about 98 percent sensitive to nitroprusside methods. But, it's far superior in specificity

Here, it's 79 percent versus 39--35 percent for the nitroprusside test

Varying formats, as I mentioned, you can have smaller meters that can be deployed outside of the laboratory, and you have the liquid reagents that can be put onto the analyzers

And again, ketosis is generally around that 0.3 millimolar per liter range

Now, I want to finish kind of wrap up with this with--I'll come back to the cases. But, I kind of want to summarize and leave you with some of the recommendation from professional consensus societies

The American Diabetes Association, in their guidelines that were released in January 2004, mentioned that blood ketone testing that quantifies beta-hydroxybutyric acid or beta-hydroxybutyrate, the predominant ketone body, are available and are preferred over urine ketone testing for diagnosis and for monitoring treatment of ketoacidosis and that home tests for beta-hydroxybutyrate are also available

And in 2011, they updated this in diabetes care. And their recommendations at that point in time said that blood ketone determinations that rely on the nitroprusside reaction should be used only as an adjunct to the diagnosis of DKA. They should never be used to monitor DKA treatment, again because acetoacetate is not reflective of the rehydration and the reversal of the acidosis in these situations. It lags behind beta-hydroxybutyrate in the metabolic pathway

And specific measurement of beta-hydroxybutyric acid in blood can be used for diagnosis and for monitoring of the treatment

So, let's go back, and let's just summarize how these cases resolved. The first case was actually a case of diabetic ketoacidosis. This was the 13-year old who showed up to her primary care practitioner complaining of thirst and frequent urination

She was positive for islet cell antibodies, which means that this confirmed a type 1 diabetes. So, she was having an autoimmune response to her pancreatic cells

She received IV insulin. They transitioned her then in the hospital to subcutaneous insulin, and she had improved glycemia at that point. She was discharged home from the hospital with extensive diabetic education and teaching

And on a two-month follow up after this, she's a healthy adolescent girl, teenager. Her hemoglobin A1c decreased from 11.3 at admission to now eight. So, she's improving and on the right pathway

Her average two-week capillary glucose was 99 with the subcue insulin. And the take-home message here is that diabetes diagnosis and education is vital as a key part to the treatment and prevention of another DKA episode

So, this was her first foray into the emergency room. And that was where she was diagnosed with the type 1. And she didn't have the symptomology before that age

Case two, this is a patient that presented with diabetic ketoacidosis as well but without evidence of latent autoimmune diabetes in adults, what's sometimes called LADA

The patient was negative for antiglutamic acid decarboxylase antibody test, which is a kind of marker for this syndrome of latent autoimmune diabetes in adults

So, what they're actually trying to figure out, the endocrinologists, is this diabetes because of patient's lifestyle, simply their genetics together with overeating, lack of exercise, and that use of alcohol, or is this an autoimmune response against their pancreatic cells because they have to treat them very differently? And they have different risks and prognosis

So, part of this testing here, the negative antiglutamic acid decarboxylase is to sift through some of these autoimmune versus type 2 diabetes

This patient improved with multiple daily injections of insulin, was finally weaned and stopped because they kept going into fasting hypoglycemic episodes. So, they were getting too much insulin, actually. And they were responding with this

And it was almost as if their cells shocked back and came back and started responding again to insulin once they kind of gave her a little bit of a help for a couple of weeks

Within six months, her hemoglobin A1c improved from 16.2, which is rather impressive, down to 6.2. So, she's almost now within the normal range without insulin and with just diet control

Her diagnosis was glucose toxicity of beta cells with euglycemia--that means normal glycemic--endogeneous insulin secretion improved. So, once they normalized her glucose, her insulin started coming back, and her beta cells started pumping back out the insulin

She was diagnosed with what we call ketosis-prone diabetes or what's called atypical diabetes. And it's typical of African Americans from a particular part of New York, Flatbush actually and was sometimes called Flatbush syndrome or Flatbush diabetes

It's diabetes type 1B. And it's typical of the non-Caucasian population

So, it was interesting. I didn't know about this. Our resident didn't realize this. It came from one of our pediatric endocrine fellows, who mentioned that this particular syndrome is rather common actually and was identified in that population in New York

The prognosis really depends on their beta cell reserve and how functioning their islet cells are. So, the presence of islet cell antibodies is a really bad prognosis with this because it means it's progressing more to a type 1 diabetes

So, most undergo long-term improvement, insulin--total independence from insulin. But, some will reflex back into these types of DKA episodes. And those are the ones that have continued risk of relapse and may eventually go into insulin dependence

And the final case, I'll wrap up with a case of metabolic ketoacidosis overlaid on lactic acidosis caused by alcoholic ketoacidosis, starvation ketoacidosis, and maybe a component of diabetic ketoacidosis because this was the type 2 patient who was drinking, not taking their insulin, and not eating either

The treatment actually was with hydration. They started giving back insulin. And that resolved the acidosis within about 24 hours. And then the lactate levels eventually came back and declined

The patient was eventually transitioned to glargine insulin prior to discharge. So, they switched their insulin. They got the patient eating. They got them hydrated, and it pretty much resolved. But, the patient is diagnosed type 2. So, they need to take better care of themselves. And if they are going to drink a lot, they need to eat along with it and take their insulin

So, with summary, I want to say, in the past, urine dipstick nitroprusside has historically been utilized to screen and monitor for diabetic ketoacidosis. It's still widely marketed method. But, it's qualitative, and it has a number of potential interferences

The present is really plasma or serum beta-hydroxybutyrate levels. They give more a direct quantitative measurement of blood ketones, can provide a better method of diagnosis and management of the ketosis from any cause, whether it's starvation, whether it's diabetic ketoacidosis, or it's another cause

Clinical applications of beta-hydroxybutyrate for screening, diagnosis of ketosis in the setting of DKA, alcoholic ketoacidosis, or starvation-induced ketosis are some of the applications

So, with that, I think I'll wrap it up and open it up for questions

Yes

Unidentified Man: Do you think there's a mindset in the ER that is using--they're using nitroprusside that they're thinking, "Well, here's acetoacetate. There's a six-to-one ratio. So, the beta-hydroxybutyrate is such"

Dr. James Nichols: You know, again, it comes--it has to be used in conjunction with the symptomology and what's going on. And I think a lot of the mentality is that it's part of a multidipstick. So, I'm screening the patient for multiple things without having to try and figure out exactly what's going on with the patient

And in fact, there are some EDs I know that are dipping every person who walks in the ED simply because it's a screening method. They're looking for something that's abnormal. And in many instances, the physicians don't even follow up with that

There was a study out of Australia I believe several years ago, where it was customary policy that any patient admitted to the hospital got a urine dipstick. And they asked, "How many of those physicians actually followed up on the abnormal results from those dipsticks?

And more than two-thirds of them never knew that they had an abnormal result from the dipstick. And the third that did realize about it, it was inconsequential. And it led them kind of down a wrong pathway because it wasn't a test that was part of their overall diagnostic scheme

They started chasing results, in other words. And there were more problems with false positives on that dipstick than there was with true positives

So, I think, you know, that's something to think about in terms of just doing blind screening of testing

We had, for instance--I can tell you with glucose meters, one of our--if you read the fine print on the glucose meter package inserts, all manufacturers, you should not be doing capillary glucose testing in patients that are in DKA with or without ketosis in patients with severe dehydration, in patients in shock or circulatory insufficiency, which kind of rules out a lot of the intensive care patients because they all have circulatory insufficiency and problems

But, the big problem was, in our ED, they wanted to move patients quicker through the ED. So, they thought, if we dip everyone with a dipstick and we get a glucose meter reading on them, it'll speed their triage

And we warned them about the probability that they're going to get a misleading glucose in these types of patients with DKA

So, we did a study and looked at them. And in fact, it was not so much the patients in DKA as it was the hyperosmolar nonketotic types of conditions that were coming in where we got widely different and discrepant results that misled the physician and the treatment of those patients

One patient I can remember was like 1,800 glucose in the main lab. And their glucose meter was like in the two to 300 range. And it never changed from the two to 300 for the next like three days of treatment until the patient got rehydrated and they got them out of that dehydration state

And they couldn't do it right away because you can send those patients into shock and kill them. You have to kind of gradually wean them back onto insulin, continue with the glucose infusion and a lot of hydration and monitor their electrolytes quite readily

So, I think it's a mentality. It's an old mindset. It's there. It was convenient. They think it's cheap. They don't understand kind of--you know, and I'm screening for a dozen different things all at once. But, it's not always the most effective as to go right to the test that you really need

Yes

Unidentified Woman: So, in your study, it means that a glucose capillary, it is acceptable for DKA patients

Dr. James Nichols: It was not, you know? And we warned them not to use it on DKA patients in the emergency room as a general screening method

If they specifically know that this patient has circulatory insufficiency and they run into problems with--they're going to run into problems with the glucose meter. So, trust the main laboratory or use a different device. Use something like an i-STAT or an IRMA, or a blood-gas analyzer that's down there that looks at it more by a biosensor type of technology for the glucose rather than the test strip

And that was independent of manufacturer. We looked at a couple of different manufacturers, showed that same discrepancies

Unidentified Woman: Is the reference range for the beta-hydroxybutyrate the same for a diabetic as a nondiabetic

Dr. James Nichols: Now, that's interesting because what you say, I don't know that there's been a lot of research in this. And I say that because I'm going to talk about an off-label use of the beta-hydroxybutyrate

I was at Hopkins. And there's Lennox-Gastaut syndrome, which is pediatric refractory epilepsy. These patients are on multiple medications or have tried multiple anti-epileptics to control their seizures

And the thing that seems to help these patients, it's interesting, is actually keeping them on a ketogenic diet, meaning sort of like the Atkins diet, so low carbs, high fat, and keep them in a range of ketosis that's not so high as they're in this like diabetic ketoacidotic range, but it was like in that normal to two range

And they actually utilized the beta-hydroxybutyrate method back at Hopkins back in the '90s I know when I was there to titrate these patients' diets to keep them in that particular range

So, I think what you're saying is, yes, there may be different ranges for different types of patients. But, no, you don't expect that a diabetic should be running a normal ketosis if they're keeping their diet normal, if they're exercising, if they're taking their insulin, and that that probably is not a normal situation

At which point do they get into danger? That's the question

I think usually they don't show up in the ED until they get to such an extreme event that then it's very, very high by then

But, does anyone know what they normally run? Is it normal for a diabetic who's asymptomatic to be running higher ketones than a nondiabetic patient? I don't know. And I'm sure it depends on their diets because I've seen advertisements

Again, this is non-FDA labeled. I'm not going to advocate that you do this

But, I've seen advertisements for the dipsticks, the nitroprusside or whatever, to monitor your ketosis to make sure that you're in this kind of anabolic type of state where you're actually metabolizing fats really well as a dietary aid for people on like the Atkins or these high-fat, low-carb-type diets

That's not an approved method. And I don't think there's a target range there. So, I wouldn't advocate that. But, certainly, it is monitoring beta-hydroxybutyrate from any cause is basically the bottom line that we're getting at

And then it's kind of the physician's responsibility and you as the laboratory to help the physician understand where's that coming from

Unidentified Man: I would--it's a general question. Coming from Europe and [unintelligible], when you're talking there to kind of customers and physicians about BHB, you get kind of a blank expression. It's not a commonly known or commonly used assay for ketoacidosis

So, in the U.S., the American Diabetes Association [unintelligible] this methodology, or--and how do they manage to get the message across to physicians or pathologists

Dr. James Nichols: Well, you have to remember that the American Diabetes Association is predominantly endocrinologist. And endocrinologists know the laboratory better than any other physicians other than the pathologists who work in the laboratory

So, they're very attuned to those types of tests. So, I don't know how well they have gotten it out to the general practitioner

I think it's our responsibility to talk it up in our institutions and tell them about the benefits and disadvantages of each of the tests and what some of the applications are for it

Unidentified Woman: And we just don't offer these screening tests

Dr. James Nichols: That's the other side of it

Unidentified Woman: [Unintelligible] and it worked for us. [Unintelligible]

Dr. James Nichols: That's another alternative

Unidentified Woman: Yeah

Dr. James Nichols: Yeah

Unidentified Man: Well, [unintelligible] I mean, obviously, with the nationwide shortage of the Acetest, whatever, there's been a shift here. And to her point there about having placement and saying, "This is what you get now--.

Dr. James Nichols: --Um-hmm--

Unidentified Man: --That test, I'm just curious what percentage of people have gone that route [unintelligible] to say, "This is what we're going to do in the future. Forget the Acetest or whatever screening. It's just going--the BHB offer.

Dr. James Nichols: I really don't know. We have dipsticks, obviously, for urine there. We have not run the Acetest for many years because we've had this for the serum side of it

We have not done away with the dipsticks simply because they have other advantages. You know, they look for nitrite, for infections, and--

Unidentified Man: --But, on a serum-based test, you're not going to run the dipstick, right

Dr. James Nichols: No, we do not run it on the serum. I'm talking about the urine

Unidentified Man: Right

Unidentified Man: To give a bit of an answer to his question, last year, we had about [unintelligible] using beta-hydroxybutyrate [unintelligible] was on a slide [unintelligible]. So, we've seen a [unintelligible]. And we think [unintelligible]

Unidentified Man: All right. Thanks. I apologize. I wasn't here early enough to see that

Unidentified Man: That's okay. No, no

Dr. James Nichols: Any other questions? Well, I thiank you for your attention and--

Unidentified Man: --One more, Doctor

Dr. James Nichols: Oh, one more? Yes

Unidentified Woman: I just have a question. How would you correlate the range between the meters [unintelligible]

Dr. James Nichols: You're talking about the meters that give beta-hydroxybutyrate and a central laboratory method

Unidentified Woman: Yes

Dr. James Nichols: And again, I think it depends on the methodology. In general, they correlate fairly well. But, again, you're going to have to look at it at each individual and then depending on the core platform because there may be some slight matrix differences, depending on a Beckmann analyzer or Roche analyzer and Abbott analyzer. That would be expected

And I think you might be able to tell by looking at the cap [sp] survey a little bit

I don't advocate that because many of those cap samples, the proficiency samples, are stabilized control-type material. And because of that, they get matrix of that based on the different analyzers

So, you're probably best when you bring it in if you are running both methods to make sure that you run a correlation between the two initially and then periodically to make sure that that stays the same correlation

But, you see, it's so sensitive to beta-hydroxybutyrate in terms of the range of physiological that minor changes of 0.1 or 0.2 biases are not a big deal and can easily be used to train patients up or down, whether they're getting worse or they're getting better during treatment

Unidentified Woman: How often do you recommend checking this in a patient that's in DKA as you're monitoring their progress

Dr. James Nichols: Um-hmm

Unidentified Woman: How often do you recommend [unintelligible]

Dr. James Nichols: I would think that they would want to run it particularly at the early stage while they're rehydrating them, probably once or twice a day easily and, if they are not certain what's happening with the patient, to recheck it again

Do we get that from our physicians? No, not always. I'll be quite honest. You know, sometimes they do it at the beginning for diagnosis, and then they never monitor it again because they monitor their glucose. And they monitor their electrolytes to see if they're rehydrating

So, they sort of go with that approach rather than using this. And I think it's still because it's very new to them

Well, thank you very much for your attention. I hope you have a great rest of the conference