Transcribed by Ana Sangadala September 4, 2014 Diagnosis of Oral Diseases Lecture 26- Saliva as a Diagnostic Tool by Dr. Malamud Slide 1- Oral Based Diagnostics: Past, Present, Future [Speaker-Dr. Malamud] Good Afternoon. Quick question. Quick question. Do we have any John Stewart fans here? Anyone who watches John Stewart? So my fantasy is, I would like to just sit here and do like hes doing and its 3 oclock and everybody goes YEAHH! Sorry I was a stand up comic in an earlier life actually. So were going to talk about the possibilities of using salivary testing in your practice in the next few years hopefully. Slide 2-Saliva Diagnostics: Lecture Overview So this is an overview of the lecture and for those of you who are doing other things, you should focus on the overview and then the last slide. And in between, you can order things on your iPhones or text message, watch movies, whatever. Im not fussy. So were gonna talk about whats out there. Why have a salivary test in the first place and the disconnect between the number of tests that are being developed for systemic diseases versus the number of tests that are being developed for oral diseases. A very interesting phenomenon. (Student asks a question).-Yeah, I actually dont know how anyone does that. I laugh, theres no volume on this. I can talk louder. Lets see if that works. TESTING. No it has something to do with my hands. Ok, so were going to talk about the fact that there are relatively few tests for oral diseases and many many more for systemic diseases. Thats an interesting statement about the field. Slide 3- Graph So, this is from PubMed and I just put in the term saliva in caries to see the number of publications. You see back here in 1970, were talking about 35 publications per year and out here, in 2013, were up to about 180 publications per year on salivary-the relationship between saliva and caries. That has to do with an awareness but also new developments in the technology that allow these tests to be done. Ill say at the outset that almost any molecule thats present in blood or urine, which are the typical test matrices, is also present somewhere in the oral cavity. It may be in saliva, maybe in the mucosa, maybe in the gingival fluid- its there. The issue that took some time to understand and then correct is that the levels of those molecules, whether its an antibody or a drug, or a particular protein, is usually 10-100 times less concentrated in the oral fluid than it is in the blood. So that means, as you needed to have amplification tests. Im sure you have all heard of the amplification for nucleic acids, which is PCR, and the amplification for proteins which is usually referred to as an ELISA. So if it is there, there are sensitive tests now that one can use to detect lower levels that are present. Slide 4-Why develop oral/salivary diagnostic tests? So why would we want to do this? Well, a lot of people dont like being stuck with even a finger prick. Certainly a blood draw. And infact, blood draws are very difficult at the two ends of the age spectrum. Young babies dont like it and infact if they

Transcribed by Ana Sangadala September 4, 2014 associate going to the doctor or the dentist with a shot, theyre crying as soon as they know theyre going there. In the elderly, you have two other problems. One is that the elderly have more diseases so they are going to the physician more often. Theyre having blood drawn more often and because of changes in the skin structure. Mostly, the toughening of the collagen fibers, it gets more and more difficult to draw blood from a geriatric patient. In those two extremes, an oral sample would be very much desired. Its cost effective. You dont need a phlebotomist. People can actually collect their own. If you go to CVS or any pharmacies, there are a whole series of oral tests that you can find there including a pregnancy test, HIV test, cholesterol test. You go home, you swab your oral cavity, put it into a solution, and it either turns a color or it doesnt. You dont need a trained phlebotomist. In the field, if youre in small villages and particularly in many countries, there are taboos in the religion about taking blood. But, nobody seems to object to having their mouths swabbed. Of course there are special populations, I mentioned the pediatric and the geriatric, obviously also the people with blood diseases: hemophilia. You would not like to draw blood. Slide 5-Widely Used Oral Tests So, the poster child for an oral test is the oral thermometer. Most of you are too young to remember but when I was growing up, it was a rectal thermometer. And that was not a pleasant experience. When it was demonstrated that you got the exact same result with an oral thermometer as a rectal thermometer, you can imagine that the sales of rectal thermometers went way down. They still exist. You can find them around the corner. The pharmacy still has rectal thermometers. They still have some use, particularly in infants who might bite on an oral thermometer. HIV antibody testing is very common now using a swab. The most common test here is called OraQuick and what it detects is antibodies to HIV. You get a result within 15 minutes. Its starting to be done in the dental offices, dental clinics. We had a study here, actually a pilot study, in A1 and almost nobody, when we told them it was a free test, almost nobody said I dont want one. As opposed to asking for a urine sample, I think they would go to a different dental clinic. There are good tests for blood alcohol. It turns out that alcohol is a small molecule, ethyl alcohol, that can cross the membrane very easily. So if you have a few shots of whiskey or a couple of beers, your blood alcohol goes up. Because the oral cavity is so well vascularized, your oral level of blood alcohol goes up. Your 1:1 correlation between your blood level and your oral level, so in a case stop, instead of the policeman getting out and drawing a line, they either do a breathalyzer or they do a oral swab and that same type of test is used for the recreational drugs. Marijuana, heroine, cocaine. Interesting observation: a colleague of mine did a study in the Netherlands some years ago and the police would pull people over if they were driving erratically. The first thing they did was give them an alcohol test, and almost all of them were negative. They gave them the test for recreational drugs, almost all of them were positive. And so, if marijuana becomes over the counter as it is in Oregon and Washington, I suspect that the police will start using a test for marijuana, an oral test, which is once again, as good as a blood test. A variety of steroid hormones and strep throat tests are done. But frankly, the largest use of the oral cavity in

Transcribed by Ana Sangadala September 4, 2014 diagnostics is in forensics. Youve seen it on the tv shows. They can take a sample off of a glass that somebody was drinking, off of a cigarette bud, or with a swab, and theres enough DNA there to be able to identify an individual. Most of the banking of DNA samples is actually done with oral swabs because if you try and do a blood draw on somebody you have just arrested, they would be very unhappy. You would have to train the police actually on how to do a blood draw. Slide 6-Potential Oral-Based Diagnostics So, these are some of the diagnostic tests that are being developed currently for a whole series of different indications. In our lab upstairs, were working with the nursing school on biomarkers for behavior, like depression for example. It turns out that we collect samples from blood and saliva and for some reason, which we dont understand yet, the saliva is a better predictor, has more of the biomarkers that are associated with depression than blood. It can be used for diabetes, and I put caries and periodontal in bold because thats what were going to focus on for the rest of the talk since we are the dental school. Slide 7-Role of the Dental Professional in Oral based testing I just point out that I prefer the term oral based testing to saliva because its not always saliva thats being tested. In the forensic, for example, its the swab. For most of the pathogens, its a swab. Its a stick with a blotter on the end. You just rub it across your buccal surface and under the tongue and that collects a DNA sample and any adherent bacteria or viruses. For HPV, you use a wire brush and scrape off some epithelial cells, so I think oral is a better term. And then, oral diagnostics refers to looking at carried, periodontal disease, oral cancer, mucosal lesions, versus systemic diseases such as cancer, infectious diseases, and diabetes. It turns out that these tests are being done. Oral tests are being done by almost everybody except the dental community, which is very interesting. In emergency clinics, where theres free testing for sexually transmitted diseases, its nurses and physicians assistants. In the emergency room, its doctors and nurses. Its first responders that do oral based testing rather than taking blood. But very few dental settings are doing this yet. Well get into it because what Ive learned in going out and lecturing is the resistance comes from the over 50 crowd because theyve got a practice, they talk about scope of the practice, why they became dentists. Theyre afraid that if they started testing for systemic diseases, that it will take time, they wont get reimbursed, people might stay away from them. They just dont want to tell people bad news. We try and educate people about, starting with dental students, is that mostly youre not diagnosing. Youre screening. So when you take a blood pressure, youve all learned to take blood pressure. In the school, we do it routinely. In dental practices, its used sporadically. If you take a blood pressure and its elevated, you dont tell the person Oh my god, youve got hypertension, you say you have high blood pressure, you need to see a physician or a cardiologist and I can give you a referral. The same thing with glucose testing or hemoglobin A1c for diabetes. We are trying to increase this. We have several trials going on here in the school because you get the same answer with an oral sample as you get with the finger stick. Once again, if you did it, and it was a high glucose or more importantly, a high

Transcribed by Ana Sangadala September 4, 2014 hemoglobin A1c, you dont say youve got diabetes, you say, this is high, you need to go see a specialist in this. What youre doing is youre playing a role in the overall health of the patient by identifying something that might be a problem. Slide 8-Saliva-based Tests for Caries Moving on to caries. You think it would be simple. Its not for a variety of reasons and its the same with periodontal disease. These are not caused by a single pathogen. The process, so in other words, the flu or HIV or Ebola now is caused by a virus. So, it would be easy to have a definitive definition if you have the flu virus and you have a temperature, you have the flu. If youre sick and vomiting and feeling bad and you have Ebola, you can test for the virus in this country. Unfortunately, they do not yet have the test in places where its really needed. In the case of caries and periodontal disease, theyre multifactorial and youve heard this before. Its not just strep mutans that causes caries and its not just AA that causes periodontal diseases. Its an interaction between host and pathogen and diet, environment, and so we know for example that the top 2 are very important. Caries, as Im sure youve heard, is a surface demineralization accelerated by the presence of low pH. So, if somebody drinks a lot of Coca-cola, or I guess at NYU, its pepsi-cola, thats got a pH of about 2. If you put a tooth, if you put an extracted tooth, into a glass of coke at the beginning of the semester and take a look at it at the end of the semester, youre going to see a lot of dissolution. So, pH is a big factor. What controls pH is number one, what you eat, but number two, your saliva. Your saliva has buffering ability and also just the flow of saliva, if you have adequate flow, youre constantly bathing the tooth surface, so food is being washed off and sticky food that remains on the enamel surface is a great nutrient for the bugs that are going to cause the acid demineralization of the tooth. So, pH, buffer capacity, salivary flow rate, are all players. The major bacteria involved are Strep mutans and lactobacilli, but its looking more and more like others that produce acid can also be bad. I suspect youve talked about the CARE test. Has someone talked about that? Dr. Wolf? So theres like a profile of things that you can measure. In combination, they can serve as an indication of someone who is more likely to have caries than others, but its not a rigid test. Were going to look at the recent observations that if you take a population of people that are caries free, they are 25 years old and they have no caries, and an alternative population, of 25 year olds with 15 restorations. You have caries active and caries free. If you study those people and say how are they different, you can learn, we think, some biomarkers that could tell you whos likely to get more caries and maybe needs to be seen every 4 months as opposed to whos unlikely to get caries and maybe only needs to be seen every 9 months or once a year. The insurance companies are very interested in this. Ill have more to say about that later. Slide 9-Salivary Tests for Caries Ok, so this field is moving slowly. One of the problems is if you approach, and I hate to keep picking people over 50, particularly since I am over 50, and you tell them that there is a new molecular test for caries, theyre going to say I dont need that. I can tell by probing, I can tell by my x-rays, why do I need this? So there is resistance

Transcribed by Ana Sangadala September 4, 2014 but the fact that there are caries free and caries active suggests that there is a genetic component. As you will see, there is some good data to show that it is true. There are a couple of approaches that could be used based on genetics that might be able to segregate the pediatric population for example into those that need to be seen more often and those that do not. Slide 10-CARE test One of the tests that is being developed at the University of Southern California by a husband and wife team, the name is Denny. They call their test the CARE test. Its a little bit complicated but Im going to walk you through it. Slide 11- The Scientific Principle Behind the Care Test You remember of course from biochemistry, what an oligosaccharide is. Its a chain of sugars. These sugar chains are found on salivary proteins and they can, depending on the protein and the sugar, they can control the relative amount of bacterial clearance versus adherence. If theres a soluble protein that has carbohydrate on it that binds to bacteria in the oral cavity, it clumps the bacteria, you swallow them, and its cleared. If that protein or another protein is on the tooth surface, it attracts bacteria and the bacteria stick to the tooth and once theyre on the tooth, if theres sucrose around, they will metabolize it, they produce acid, you get acid demineralization. So the idea that the Dennys had was the that the ideal way to do this test would be to take a group of children and follow them over time, but that would take over 20 years before you could see. So they did a clever thing, and that is, they studied older people between the ages of 25 and 34 and what they wanted to see is what was the composition of those oligosaccharides in the people that had a lot of caries versus the people that had few caries. Since these sugars are genetically determined, just like blood group substance. Blood group substance is a specific protein with specific sugars on it. If you are Type A or Type B or Type O, thats genetically determined. Well, thats the same thing for the rest of the salivary proteins. Slide 12-Lectin-based CARE test So the way to analyze it is by using lectins. Lectin is a protein that generally comes from plant. It has specificity for certain sugars. The plant uses it to protect itself from being attacked by insects or infections. So there are lectins that recognize different sugars. The glycoproteins contain two types of carbohydrates. They are either N linked, which means they are attached to asparagine. Or they are O linked and attached to serine and threonine. As I mentioned before, some of them are doing bacterial adherence and some are doing bacterial clearance. The pattern on those proteins is genetically determined. You can determine what it is using a laboratory assay using lectins. So if you light up with these five lectins, you might be caries prone and if you light up with these other four lectins, you might be caries resistant. Slide 13-Hypothetical Basis of CARE test

Transcribed by Ana Sangadala September 4, 2014 This is a cartoon. And what were showing here is a, this is the tooth surface. Somebody that has a high risk for caries has on their tooth surface a series of proteins that have sugars on them that attract bacteria. A person thats caries free has, it could be the same protein, or it could be another protein, but its in solution. These bugs clump, you swallow them, and these bugs adhere and when theyre fed sucrose, they create an acid environment. Thats the principle behind the test that the Dennys are developing. So what their data looks like(changes slide without finishing sentence). Slide 14-Correlation of Caries History with Specified Oligosaccharide So they took a group, a large group of adults, with different levels of caries. So this is on the y-axis, its decayed and filled teeth. On this assay, its the oligosaccharide that were associated with increased caries. So, the people down here had very low levels as based on this lectin assay of the glycoproteins that are associated with binding bacteria to the teeth. As it went up, its a beautiful linear relationship. As it got up to the people, these are the 24-34 year olds with many fillings and decay. They had a very high level of lectin binding and so they are going forward with this actually. Delta dental, which is very heavy into insurance, is investing in this because they are the ones that stand to really make money off it. They will save. If you could schedule your patients so that the ones with active caries came in more often and the ones that have the resistance came in less often, it would be economically sound. The insurance would go down, so thats why theyre interested in it. Slide 15-The Goal So, they are up to several thousand. They are doing this at multiple sites with multiple children and trying to accumulate enough data to go to the FDA to get approval for a test that would predict the likelihood of increased caries. Slide 16-Salivary proteins/peptides: caries free/caries active Other investigators have taken different approaches. Theyve looked at either salivary proteins or peptides. Peptides are little bits of salivary proteins that exist. What theyve found, again, by studying caries active versus caries free is a series of proteins and peptides that are associated with increased caries. This is just a list of the most common ones. Slide 17-Reverse Phase Chromatography of Saliva Peptide Pools This is a mass spec pattern and you see they had over 100 people. Half with caries, and half without caries. They did a profile of all the peptides. If you look at these two patterns without knowing what anything is, you see some similarities but you also see some differences. This one really stands out. This inversion here. Small, big-big, small. So when they see something like that, it becomes a clue that it could be a molecule that, again, could be part of a marker. A number of people have taken that approach for both caries and periodontal disease. Slide 18-Future for Caries Tests

Transcribed by Ana Sangadala September 4, 2014 In some, its likely, its unlikely, that there will be a one, a specific test looking at just one thing. Most likely, its going to be a composite because its a multifactorial disease. If you have, just for example, if you have the right saliva in terms of these proteins or the oligosaccharides, but you have the wrong pH, thats going to compensate for and make it worse. So likely, it will be a test that measures a number of things, so it could be the lectins, plus the peptides, plus the pH, plus salivary flow. The idea is that if we can nail down to a small enough number that there will be a test that will let you predict before theres caries that somebody is likely to have caries. Thats the goal. It is challenging and I think by the time youre out of dental school, they wont be here yet, but they will be farther ahead. I want to shift now to periodontal disease. Slide 19-Identification of Pathogen and Host-Response Markers Correlated with Periodontal Disease Even though this is a cariology course So there are a series of papers from this, the key person in this group is Will Giannobile at the University of Michigan. He has been, actually he is the editor of the journal of dental research and he has a large group of investigators in his lab that have been looking at a couple of things. Theyre looking at potential markers of periodontal disease. Once again, the over 50 dentists say I dont need that, I can just probe. Umm.maybe. But, so theyre looking for markers of periodontal disease. More interestingly, theyre looking at markers that tell you if a pocket or an individual is going to progress or remain stable. The early papers, they were just trying to identify the markers. Slide 20-Positive and Negative Predictive Values of Specific Thresholds of Selected Salivary Biomarkers and Plaque Biofilm Pathogens There are series of markers. And once again, its not black and white. You will see a tendency, so these are groups of forty and the number that didnt have versus had. Youll see that for some, the nos are higher and for some, the yess are higher, meaning there is some difference. But no one of these could tell you anything. So we talk about a positive predictive and a negative predictive of no versus yes. Its the statistical analysis. It works on a population, but if youre a single patient, it doesnt really give you enough information to go ahead with. Slide 21-No Title This is now, I think, more interesting. Its a later paper of theirs. What this looks at is progression, so they had about 100 subjects to start with and there was an initial diagnosis of serious periodontal disease, moderate, essentially no periodontal disease. This means that in this group over one year, 2/3 of them progressed and 1/3 didnt. In this group, it was about even. And in the stable group, most of them were stable and did not progress. And so, what they did was looked at a whole series of things. The two things that strike me immediately are if you look at serum, it doesnt tell you anything. Serol (sp?) moderately different. If you look at salivary biomarkers or bacteria, big differences. As you see, in the case of those that progressed the fastest, they have the highest levels of the biomarkers and the highest levels ofthese are the most common periodontal pathogens. That makes

Transcribed by Ana Sangadala September 4, 2014 perfect sense. Intermediate-its less. And these are fairly high and it may be that these are actually controlling this. In the staple, its very low and very low. It does suggest that if you get the right mix, that youll be able to have something that says to the individual, you need to come in very often. You need to use chlorohexidine, or you need to use this or that because youre likely. Youve got a few small pockets, but they look twice over a 1 year period. But this is going to progress rapidly. Or, you just need to be more careful with your brushing and flossing, so how aggressive to treat a given patient. Once again, were not quite there, but I think that the odds are pointing to it. Slide 22-Spit in the Eye I want to finish with a very interesting story that I learned about a couple of years ago and is now mushroomed into an industry. Weve known for a long time that there is a similarity between saliva and tears. Most of the protective molecules that are present in saliva are also present in tears. And the anatomy of the lacrimal gland has close resemblance to the anatomy of the salivary gland. And, so, in some diseases like Sjogrens, youve heard of Sjogrens I presume, autoimmune disease, prevalent in women. That affects simultaneously both the salivary glands and the eyes. However, there are a number of other conditions that only affect the eye. As I heard the story, it was in China, and it was a Chinese dentist speaking with a Chinese ophthalmologist. They went out for drinks after the meetings and they started talking about similarities of problems and the ophthalmologist mentioned that he has a lot of patients with dry eyes but I dont think they have any salivary problems. So they had the idea of transplanting part of the submandibular and in some cases, the entire submandibular. Taking it our from here, and putting it here, and having the duct, the tear duct, now be the salivary gland duct. It sounds wild. HA. Slide 23- Surgical Autologous Gland Transfer Treatment of Severe Keratoconjunctivitis Sicca This is a picture of the surgery. This is the, here they took the whole submandibular gland. By the way, what happens is, at least in animals, but I think in people too. If you remove one salivary gland, the other one grows to compensate. Its called compensatory hyperplasia. The same thing happens with the kidney. If you take out one kidney, the other kidney grows. If you take out two thirds of the liver, it grows. You cant do it with brain yet, but that would be neat. But several of the paired organs, if you take out one, the body senses and it turns on the growth of the other one. So the salivary gland is not impacted by this, but it is now producing salivary flow and proteins into the eye. Slide 24- Subjective findings for submandibular gland transplantation This is the data. This is early data from a five year study. What you see is, they measured a series of things. Visual acuity, you can see, it goes up over time, its sustained for 5 years. This is asking the patient how they feel kind of thing. They have a test. You can see thats better. Whether they need artificial tears or not and the number of times that they have to use it. So it looks like, it looks like it would work. So recently, I did a recent literature search and there are now a series of

Transcribed by Ana Sangadala September 4, 2014 papers that indicate there are 2 problems. In some cases, the secretion of the salivary gland is to great and so these people are tearing constantly. I guess it would be good for some things, but so the solution that they worked out is, they go back in and take out part of the gland. That cuts down the salivary flow. The second problem is that occasionally the duct gets clogged. By the way, that happens in the salivary gland also. You get blockage in the duct because of the high calcium phosphate concentration can crystalize out as stones. Its not clear if its the same people that had it in the salivary gland now have it in they eye or if theres something different about the eye environment that encourages that. But a percentage of people, they have to go back and clean out the duct. Its not widely used in this country, but it is in Asia and Europe. A number of European docs are doing this. The rationale is that dry eye, although it sounds trivial, is a major, major quality of life issue. Removing one submandibular gland has zero impact on your ability to chew, swallow, no increase in caries, periodontal disease. There doesnt seem to be any side effects. Anyways, its sort of a sideline but I found it an interesting observation. Slide 25-Why should dental professionals be interested in oral diagnostics? Why am I taking the time to tell you about this? Well, some of us in the dental community are concerned that we have the unique opportunity to do some really exciting things and its being taken over by almost every other health profession except the dentists. The line I use is that the oral cavity is really the domain of the dentist. You know more about it than anybody else and a physician just a small anecdote: When I was at the University of Pennsylvania before I came here, there was a very good infectious disease doc that got a grant to evaluate a compound for treatment of oral candidiasis. He got the grant and he started to do the study and then he realized that he didnt recognize what oral candidiasis. And so I got a call and he said, Do you have any colleagues that work on this? So they had to come over and actually show them, because its not as obvious as it seems. You havent seen much of this yet, but there are simple tests to tell the difference between a white oral lesion and oral candidiasis, but your average physician doesnt know that. So the oral cavity, you guys and girls are going to be the experts in this. And if this field evolves, you should be in charge. The second thing that I always point out is that you need, in order to do prevention and therapy, you need to know diagnosis. You cant treat a patient if you dont know what they have. So diagnostics play a very important role. The other thing is that healthcare is changing very, very rapidly. Even before the Obamacare, the health, who delivers the healthcare is just changing very rapidly. So there are nurses for example in the pharmacies who are giving flu shots. There are pharmacists in the pharmacies that are giving flu shots. And yet, a dentist is not yet at this point allowed to give a flu shot, which is amazing. So, what many of us see and particularly with the exciting thing thats going to happen in January. Its that the nursing school is actually moving here. Have any of you spent time in the nursing clinic? Anybody here? No? You will have the opportunity. At this point, its only about a dozen at a time, but when they move here, theres going to be more space and whats happening is that the nurses are spending time in 1A and helping with a number of issues that dentists are uncomfortable discussing with the

Transcribed by Ana Sangadala September 4, 2014 patient. The dentists are spending time in the nursing clinic learning about things like if you have a headache, the dentist thinks of TMJ and thats an illogical but there are many other things that cause headaches. So a nurse and a dentist working together can actually do a much better job of diagnosis. I think the most important thing is in the United States, there are 20 million people every year. With the only healthcare specialists they see is the dentist. Its very interesting because you can avoid seeing a doc, youve got a cold, you can avoid going to the doc because it goes away. If you have an endodontic involvement or anything in the oral cavity with pain, you cant ignore it. So, people are going to the dentist. Many people are going to the dentist and never see anybody else. And people are generally going to the dental clinic more often than they go, its usually an annual check up with the physician or biannual, but its a 6 month check up with the dentist. So the ability to play a role in what we call triage, not diagnosing, but screening and hooking up someone with high blood pressure, high blood glucose, pain in the chest. When you ask the question How are you feeling? and the patient says Well, I have a lot of pain in my chest. Thats an opportunity for you to say You really need to see a cardiologist, just for example. So learning about these diseases in conjunction with the nurses, which is going to be increasing starting in January is going to be a good thing. And the other point is, that I mentioned before, if you ask your patient for a urine sample, they would probably get another dentist. But if you ask the patient, can I swab your mouth, I mean youre in there anyway. In fact youre actually ejecting the salvia for the whole hour that theyre in the chair. So to take a little bit for a sample, I mean theyre not going to be surprised. Youre a dentist. And not to belittle the fact that you do need to make a living and if youre in a competitive area and you have, for example, to the patient, free testing for flu, infectious disease, blood pressure, glucose, I think that it could differentiate the practice that would encourage patients that might go elsewhere to come to you. So, I am done and I am more than willing to answer questions in class or after. Anybody have a question? Something I didnt say? Something that doesnt make sense? Well, I cant tell you how nice it was to be here with you.