I’m excited to be joined by Dr. Geoffrey Sher for today’s article. Dr. Sher is an internationally renowned expert in the field of ART. He trained under the fathers of IVF, Dr. Patrick Steptoe and Robert Edwards in the UK. He came to the United States in 1982 to establish the first private non-university-based IVF program, the fourth IVF clinic in the nation. He then expanded his presence to include 10 IVF centers throughout the country before founding Sher Fertility Solutions with offices in New York City and Las Vegas in 2020.
Over a career spanning almost 40 years, he’s been influential in the birth of over 17,000 IVF babies. He’s published over 200 scientific papers and abstracts, and is the author of several books, including IVF, In Vitro Fertilization, the A.R.T. of Making Babies. More recently, he wrote Unexplained IVF Failure and Recurrent Pregnancy Loss: The Immunologic Link, which is available as a free download on his website or by calling his office at 702-533-2691.
Dr. Aimee: What drew you to the field of fertility medicine?
Dr. Geoffrey Sher: I was faculty at the University of North Carolina and Victor Lewis, the secretary of the Royal Fertility Society came to visit me in Chapel Hill. He said to me, “There’s a guy out here who is a very good friend of mine called Patrick Steptoe, and Bob Edwards his associate, and they started doing this thing called IVF. Would you be interested?” I had been doing infertility work in South Africa before I moved to the United States in the late 1970s, so I took him up on his offer, and I went to the United Kingdom, and I worked with Steptoe and Edwards.
It was a very new field. We were putting eggs and sperm together hoping that a baby would occur, and it happened maybe one in 10 times if we were lucky. But I learned the process. It was all being done through surgery. We used to do egg retrievals with laparoscopy. I came back to the United States and opened the first private IVF program in the country in 1982.
Dr. Aimee: How has your practice changed over time? You told us a little bit about how you were doing egg retrievals through laparoscopy. Can you describe the changes that you’ve seen?
Dr. Geoffrey Sher: We were the first people using injectable fertility drugs. At the time, we were using purely gonadotropins. In those days, it was a drug called Pergonal. Most everybody else was using other oral fertility drugs. We went purely with injectable fertility drugs. Everybody thought we were crazy, but at the end of the day, the success rates proved that we weren’t.
We moved on into doing IVF with purely injectable fertility drugs and laparoscopically. Eventually, things changed, and ultrasound guided egg retrievals became the vogue, so we got moving there and we just moved on. My first practice was in Reno, Nevada. Then we opened in Sacramento, after that we opened in San Francisco, and California Pacific Medical Center. There is still a program in San Francisco which I opened; it looks out over the Bay. Went from there to Santa Rosa, Los Angeles, Torrance, Dallas, then to Chicago, New York, Pennsylvania, and all over.
Dr. Aimee: I want to dig into today’s topic, immunologic implantation dysfunction, IID, unexplained IVF failure and recurrent pregnancy loss. You have so much information about this on your website, but I also just want to dig a little bit deeper here on today’s show. What is IID?
Dr. Geoffrey Sher: First of all, 75-80% of all pregnancies that fail or are miscarried early on, fail because there is something wrong with the human embryo. Usually, it’s a chromosomal abnormality, but it can be other things. It’s usually an irregularity in the chromosome number, we call it aneuploidy, that causes the embryo to be lost.
In 2004 we were the first to introduce PGS/PGT-A into the field of IVF. There have been an estimated 17,000 to 20,000 births from selecting embryos in this way, of which approximately 700- come from us alone, so we’ve done a lot of that. We were very much involved in the evolution of these technologies.
25% of failure to conceive or retain a pregnancy do not relate to the embryo itself being abnormal, but rather to the implantation base being non-receptive. I call it the seed-soil relationship. You can’t put a good seed in a bad soil, and you can’t put a bad seed in a good soil. The soil is the uterine lining. The seed is the embryo.
If a woman experiences repeated pregnancy losses or fails to get pregnant once egg competency and chromosome abnormality issues are ruled out (a major determinant for an egg to turn into an embryo and reach blastocyst stage), it’s obviously, through a simple process of elimination, likely to be related to the soil, not the seed, and the soil is the uterine lining.
While there are numerous possible factors that affect implantation, there are but three that account for more than 80% of implantation dysfunction.
One of these reasons is an anatomical factor, any kind of irregularity in the uterus contour. Therefore, I do hysteroscopies and saline ultrasounds to confirm regularity of the cavity and get rid of any irritation that could possibly reject an embryo.
The second is the thickness of the uterine lining. The uterine lining needs to be at least 8 millimeters, ideally over 9, 8 to 9 being kind of a gray zone. We published that for the first time in 1989.
Dr. Aimee: I love it. That’s exactly what I tell people, my limit is 9, but then people say, “Lining doesn’t matter, the thickness doesn’t matter.”
Dr. Geoffrey Sher: It matters a great deal.
Dr. Aimee: I agree.
Dr. Geoffrey Sher: I don’t even do embryo transfers to the uterus if the lining is less than 8mm by the time of egg retrieval or on the day that progesterone injections commence in embryo recipient cycles (e.g., FET). To address this, we came up some years back with vaginal Viagra and all kinds of things, but that’s for a different day.
The third factor is immunologic. To set the scene for that, 80% of miscarriages are sporadic, in other words, it’s just part of being a human:10-15% of pregnancies are going to miscarry. Maybe you have a pregnancy and a baby or two, and then you miscarry again. 80% of those are still due to the embryo being abnormal, but in 20% of cases it is not that, it’s due to a rejection of the embryo from the uterine wall.
If a woman repeatedly miscarries over and over (recurrent pregnancy loss-RPL), the chances are 75% likely that it not because of the embryo, but rather, because of an implantation dysfunction, where something wrong with the implantation process prevents the embryo from gaining a proper grip into the wall of the uterus.
Dr. Aimee: How do you have this dysfunction, what kinds of tests should someone ask their doctor for? And how does someone get help from you to figure this out?
Dr. Geoffrey Sher: The basic things that we all do. We do a sonohysterogram or a hysteroscopy on everybody within a year or 18 months of doing a transfer to make sure the uterus is normal. We check the thickness of the uterine lining, which in my opinion, is critically important. In other words, it must be at least 8 millimeters, preferably over 9 millimeters with a trilaminar appearance.
Clearly, if the uterine lining is fine, there is nothing in the uterine cavity, you know you’re putting back embryos into the uterus that are likely to be “competent”, chromosomally normal, and the patient is still not getting pregnant or she’s miscarrying, the most likely explanation is implantation failure. Then you dig into immunologic factors, because if it’s not the anatomical contour of the uterine cavity and it’s not the thickness of the lining, then through a process of elimination, it is highly likely to be an immunologic factor that you have to look into.
We were among the first people in the world to start giving treatment for immunologic factors that affected implantation in IVF. We started by using Heparin. That helped in some cases but not in the vast majority. We then moved on to IVIG, which works but is very expensive. Today, we use intralipid infusion along with oral steroids, virtually to the exclusion of all else.
The important thing to understand is that there is a very complex and magnificent interaction of immunologic factors that determine the immunocompetence of the uterus.
They’re all brought about through uterine lymphocytes. About 75% of the lymphocytes in the uterine lining are natural killer (NK) cells. These are large lymphocytes that journey from the bone marrow to the uterine lining every month and there they proliferate under the effect of estrogen. These natural killer cells are vital for orderly implantation of the embryo’s root system. . They can and sometimes do function abnormally. When this happens, immunologic implantation dysfunction (IID) often occurs.
There’s another family of cells that only comprises 10-15% of the uterine lymphocyte population. These are T cells. Together, activated natural killer cells (NKa) and activated T-cells will often lead to the failure of an embryo to implant. Why? Because they both release substances called TH-1 and TH-2 cytokines. TH-2 cytokines are humoral, they attract the roots of the embryo into the wall of the uterus to form what is going to become the placenta. The TH1 cytokines cause those very same cells to undergo self-suicide, or apoptosis. This culls down the root system allowing placental attachment to be confined to the inner aspect of the uterine wall while promoting optimal respiratory, endocrinological, and nutritional needs of the growing conceptus. For orderly implantation and placentation to occur, you need a balance between TH1 and TH2 cytokines.
Now, there are certain conditions where TH1 cytokines predominate resulting in so many of embryo’s root-cells (the trophoblast) being destroyed that the conceptus cannot survive. In such cases the embryo is often lost before the woman even knows she’s pregnant. In other cases, the impact is more gradual, and the pregnancy is lost after a few days as a chemical pregnancy or miscarries after a few weeks. Sometimes the pregnancy will continue to grow, but ultimately, when the placenta has lost its potential to function optimally (placental insufficiency, intrauterine growth retardation) development slows down and the baby can die in-utero.
For all of these reasons, it is extremely important to quantify, identify, typify, and address an immunologic implantation dysfunction, upfront. Simply stated, orderly natural killer cells activity where there is a balance between TH-1 and TH-2 cytokine activity is imperative for normal pregnancy.
The first thing is to make the diagnosis. If the embryo is deemed to be “competent”, the uterine cavity is of regular contour and there are no endometrial lining issues then through a process of elimination, it becomes likely that you are dealing with an immunologic implantation dysfunction. , Then, by and large it comes down to natural killer cell activity and T cell activation, and you need to address these factors. The required testing costs around $1000-$3000. While testing can be expanded to include many more parameters (often costing upward of $6000), this is in my opinion, usually unnecessary…
Remember, it is not the blood concentration of natural killer cells that matters. In fact, the higher the blood concentration of NK cells around, the better. After all, they play a major role in orchestrating orderly implantation. It is NK cell “activation” (i.e., the TH-1 production) that matters. In fact, in certain conditions such as endometriosis the concentration of blood NK cells is often below normal, yet NK cell activation is increased in ⅓ of such cases. So, if you have natural killer cells that are activated, you have a problem on your hands. I order the performance of the blood K-562 target cell test to measure NK cell activation. But you can also measure TH-1 and TH-2 cytokines in the uterine lining or blood. There are only three or four places in the country that can do the K-562 target cell test with sufficient reliability. I use Reprosource Reproductive Immunology Reference Laboratory, Boston, MA for my patients.
Simultaneously, I also assess blood antiphospholipid antibodies (APA) and an immunophenotype to look at the spread of all the lymphocytes. Antinuclear antibodies can also be tested for. In my opinion however, if there is no activation of natural killer cells (NKa) it is very unlikely that a serious underlying immunologic implantation dysfunction exists.
Dr. Aimee: You mentioned the word suspicious. When you’re seeing an IVF patient and you’re suspicious that this might be present, what makes you suspicious if a patient hasn’t had a miscarriage or a biochemical pregnancy? Is there something about her history that you’re thinking I should do this workup even before I do an embryo transfer? What kind of patient population are you doing that with?
Dr. Geoffrey Sher: You’re looking at two causes of natural killer cell cytokinopathies, s. One is autoimmune, IID and the other is alloimmune IID. Autoimmune is by far the most common (>80%).
In the autoimmune IID variety, it’s almost as if, when the embryo reaches the endometrial environment, it “steps into a proverbial NKa minefield” and gets destroyed no matter what happens. The autoimmune IID is most seen in women who have a personal or family history of autoimmune diseases such as – Lupus, Rheumatoid Arthritis, Hypothyroidism, Scleroderma, Celiac Disease, Multiple Sclerosis etc. There are almost certainly other conditions that we don’t even know about, but the bottom line is that when there is IID, it is not always traceable to an underlying autoimmune condition.
I was giving a lecture at Monash University, Melbourne, Australia, several years ago when a lady who had ailed 23 embryo transfers, approached me. She had an underlying thyroid autoimmune condition (Hashimoto’s Disease) where in 50% of cases there is NK cell activation (I published this in 1998). We tested her and confirmed that she had NKa. She came to the USA where I treated her. This lady was 42y of age and had very severely diminished ovarian reserve. I retrieved two eggs, she propagated two embryos, both of which were transferred, she had a baby after her 1st IVF attempt with me.
As I stated earlier, one-third of women with endometriosis have a secondary autoimmune underpinning with natural killer cell activation. This occurs regardless of the severity of the endometriosis. It can even occur before endometriosis becomes visible through a laparoscope, and possibly even before a positive BCL6 test raises a suspicion of the condition
Dr. Aimee: That brings up a question that I know some of my patients will have. If you let’s say test them and you treat the natural killer cells, do you see a drop in the BCL6 level? I’m just wondering.
Dr. Geoffrey Sher: I don’t know the answer to that question. There is no data!
Separately, 50-60% of women who have endometriosis will have antiphospholipid antibodies (APA), if the testing is sufficiently sensitive and specific. Unfortunately, most reference laboratories cannot deliver on this. That is why I send the blood of my patients to a Reproductive Immunology Reference laboratory such as ReproSource, Boston, MA.
Dr. Aimee: Yes. I’m thinking about a particular patient. I’ll investigate her natural killer cell activity now. Maybe I’ll have her reach out to you for that evaluation to make sure that it’s as thorough as possible. Then maybe we’ll repeat a biopsy after treatment. Because I know her BCL6 is elevated.
Dr. Geoffrey Sher: That makes it very much more likely that she has endometriosis, of course.
Dr. Aimee: Right. She’s had the laparoscopy, she’s been treated, and now we’re preparing for a transfer, but we’ve worked really hard to get this one embryo for her.
Dr. Geoffrey Sher: The bottom line is that with endometriosis you don’t have a “primary “autoimmune condition like Lupus or Rheumatoid or thyroid, but you probably have a secondary or “reactionary” autoimmune process, That is why, APA tests done in conventional Reference Laboratories, such Quest or LabCorp commonly only measure for APA’s associated with “primary autoimmune conditions such as lupus erythematosus, rheumatoid arthritis, hypothyroidism etc., largely focus on measuring lupus anticoagulant (LA) and anti- cardiolipins etc. , which are not sufficient when it comes to testing for IID. They do not test for all 21 different types of APA’s spanning IGG, IGM, and IGA and they certainly do not adequately assay natural killer cell activity.
In my opinion, it’s not that APAs themselves that cause a problem, even though it is believed that they can attach to the embryos root system and compromise its functionality. Rather it is that detection of certain types of APA is linked to natural killer cell activation (NKa), and those are the ones that we must focus on.
Dr. Aimee: It is. I think that in medical schools and in fellowship programs across the country we’re trained to think that IID is not a big deal. Then now through all these years of my practice, I feel like it was a shame that we didn’t spend more time on that, but I think that you’re right. So, I feel like our minds are now opening and I can see a trend among all my colleagues, and the trend is that we really feel like we’re doing patients a disservice now in not bringing up an immunologic factor for situations like you’re presenting here.
Dr. Geoffrey Sher: I mentioned earlier there are two types of immunologic issues. The one issue I already addressed is autoimmune IID butt there is another variety of IID known as alloimmune IID.
We do not have the time to fully go into alloimmune IID here, but it is also associated with NK cell activation. Here, rather than presenting with failure to achieve a pregnancy (as occurs with autoimmune-IID), alloimmune IID often presents as recurrent pregnancy loss (RPL) or secondary recurrent pregnancy loss. . It is also quite common with this variety of IID, that the affected woman will have a baby and thereafter, either fail to conceive (secondary infertility) or experience RPL.
Alloimmune IID, is due to both partners sharing certain genetic similarities. Bear in mind that for an embryo to propagate a viable, healthy pregnancy, it must not share certain transplant genes (DQ alpha/HLA) with the recipient. When such genetic matching occurs AND in addition there is NK cell activation, only then is that pregnancy at risk. There must be both a genetic matching, plus NKa, for the problem to exist. Since it often takes repeated exposures of the woman’s uterine NK cells to a genetically matching embryo for NK cells to become activated, it should not come as a surprise that women with alloimmune IID often give a history of having had one or two successful pregnancies before presenting with RPL or secondary infertility.
People don’t realize that technically, an embryo shouldn’t take in the woman’s uterus. Remember, in most cases, we differ immunologically from one another and therefore, in most cases the embryo will be immunogenetically distinct from the host. If a bacterium or a virus enters your body, the immune system attacks it because it’s different. But when the embryo gets into the uterine environment, it attaches to the endometrium, and it doesn’t get attacked. It doesn’t get attacked largely because of a uterine immune[GS1] cell compensatory mechanisms. This paradox is often referred to as “the immunologic riddle of pregnancy”.
The fact that most people differ with regard to their DQ alpha/HLA genotypes explains why so few male-female partnerships involve alloimmune matching. In addition (as referred to earlier), even if there is a match, it takes repeated exposures to DQ alpha/HLA matching embryos for uterine NK cells to become activated. AND, as stated, no Match….. no problem!
If the embryo is too similar and shares DQ alpha/HLA genes, then what happens is that the embryo is regarded by the host-uterus as being an “invading” foreign body and is attacked. But it takes repeated exposures to an embryo before that happens. That is why in many such cases, the woman ends up having a baby, and thereupon can’t get pregnant or repeatedly miscarries. In fact one of the commonest causes of secondary infertility, a woman has had a full term pregnancy and then can’t get pregnant, is this alloimmune variety where it is due to the immunologic similarities.
If you get a woman who has had repeated miscarriages, especially if she has had a baby initially and then keeps miscarrying, or develops secondary infertility, it is often due to alloimmune, IID, even though this type of IID only occurs in about 15% of women with NKa.
Dr. Aimee: I think what you’re describing so well is parental compatibility. Right? Is that the kind of evaluation that you also do for patients who reach out to you for this kind of workup?
Dr. Geoffrey Sher: My practice is rather unique because I commonly see patients that have been given up on or who are on the verge of giving up themselves. older and they’ve been through the mill. so, there is often a great deal of anxiety added on.
Unfortunately, some Physicians (present company excluded) are often insensitive to the emotional needs of struggling patients. I believe that while doctors in training can and are” taught to give care, they are often not able to care”. To do what we do as physicians, caring about the human condition is central. You must care about your patients. You have to nurture them as if they are the center of your universe, and if you do so…. they’re going to feel it.
Truthfully, people come to me because of unexplained IVF failures with good embryos. Those are the ones that I hone in on most. I don’t do immunologic evaluations on most of my patients. Only when there is a background personal; or family history of autoimmune diseases; endometriosis, unexplained IVF failure, RPL or unexplained infertility do I test for IID.
Dr. Aimee: If a patient out there is listening to us and they’re saying, “Now that I’m hearing this, I’m suspicious that this might be happening with me,” how do they communicate with their doctor so that they get this testing done? If not, how can they engage with you?
Dr. Geoffrey Sher: The last thing I want to do here or anywhere else is get between a patient and their doctor. Unfortunately, I’m at the stage of my professional life where I’m no longer career building. I’m trying to do less than I did by a major factor, but I still want to make the third act of this play called life, meaningful. For me, it is only meaningful if I can help people who have problems that others aren’t ready to address.
I’m not here to interfere with a doctor. If people want to work with their own doctor, I invite those doctors through them to call me and I will walk them through things. It doesn’t cost anything. It doesn’t cost the patient anything. Patients who consult with me are invited to share the consultation report with their primary doctors.
But be prepared, because many doctors will say, “I don’t buy that……. I don’t believe in immunology for IVF”. When you then ask them what exactly it is that they do not buy into this, the response is often incoherent, or you are confronted by a blank stare. The truth is that most, just do not wish to take the time to understand the very complex issues involved. But that is their problem.
Anyone who is interested in getting my input should visit my website, www.Sherivf.com or to call my assistant, Patti Converse at 702-533-2691.She will arrange for us to have an online one-hour consultation after the patient fills in a detailed questionnaire. I spend an hour before each consultation preparing and then another hour in consulting . This is followed by a detailed report which I send to the patient(s). After that, it is up to the patient (s) whether they need my services or whether they want to go back to their original doctors for treatment..
Dr. Aimee: I also want to talk about your book and where patients can find it. I know you’ve written more than one, but specifically Unexplained IVF Failure and Recurrent Pregnancy Loss: The Immunologic Link. Can you just let us know a little bit about that book and where patients can find it?
Dr. Geoffrey Sher: It’s a 45-page eBook which I wrote free of charge. Anybody who goes to my website can access the book free of charge. Once they become a patient of mine (have had a consultation), they can down-load the entire book from my website. Alternatively, a phone call to Patti at 702-533-2691 for the URL link through which the book can be downloaded free of charge, gives anyone access to this book which will explain everything we’ve spoken about in far more detail than we have time to do now. It also offers case reports that support all of this.
Dr. Aimee: That’s great. What kind of trends do you see in the future for our field, future trends?
Dr. Geoffrey Sher: I see more and more telemedicine. I can consult with a patient for an hour on the internet just as personably as I can do face-to-face. It’s more convenient, and my patients travel from all over the USA and from more than 50 different countries for treatment by me at SFS in New York city. It’s not necessary for anyone to fly in to see me in-person for the initial consultation and work-up. It is a waste of both money and time. We can talk, I can lay out a plan of action. Almost everything I would need can be obtained and can be done in their own home city. As I said earlier, I’m also more than happy to consult with the patient’s local Physician if he/she is open to this. I think telemedicine is going to be the way of the future to a large extent.
I think there’s also going to be a move towards larger (Mega) IVF centers over time because it’s much more cost effective. I will give you an example, if I may. We introduced PGT for IVF into the field in 2004. Obviously, it would not be cost effective to set up a PGT testing Laboratory in every IVF center. However, when this all started, we had our own lab. Very quickly it became ridiculous, so I decided to hand testing over to one of the most prestigious genetics labs in the country. Their team came to Las Vegas to see and learn the process. They went back and developed /improved on the methodology and then rolled it out all over. We didn’t try first to cash in by patenting it. Maybe we should have, but we didn’t. I could not justify withholding the technology for personal gain.
With these kinds of advances, the whole field is becoming technologically advanced. We also introduced PGT performed on human eggs. In fact, published a paper which showed that if you actually performed PGT on the polar bodies removed from eggs, and determined which eggs were chromosomally normal, it is possible to improve the baby rate per frozen egg by a factor of 4-6 times. But the technology was very costly and this, sadly never went anywhere,
But again, I think we’re moving more and more into a direction where genetics is going to play a greater role. Larger centers are needed to be able to offer all of these things. If smaller centers get together and form coalitions where they can cost contain, it may be just as effective.
Dr. Aimee: Before we end our interview, is there anything else that you want to share with our listeners today?
Dr. Geoffrey Sher: I only want to say this, and this is important. If you have a complex problem and you’re not getting pregnant with IVF and/or you are repeatedly miscarrying, we may not always be able to identify the reason but be assured that there is always a reason. It could be as simple as that the doctor doing the embryo transfer doesn’t have optimal technical prowess. I’ve seen that. I’ve worked with numerous REs in my career. Or it could be as complex as some of the issues we spoke about in this podcast.
I can only say this. When someone tells you “Well, IVF didn’t work last time…. it was bad luck, let’s try again. Realize that this might well be the case, but usually, it is not. Remember, there’s no such thing as truly “unexplained” infertility or Reproductive Failure. This just means that we can’t explain it now or we’re not looking deep enough to find out why things are happening. It’s only when we do find out why they’re happening that we can fix it.
If women are miscarrying repeatedly, don’t give up on yourself and just say, “I’m miscarrying. The doctor says eventually I’ll be lucky.” The likelihood is that you’re not going to be lucky. You have to find a cause for the problem, even if in the end it means that you need to use someone else to carry your baby, or you need someone else’s eggs to make embryos to put in you. Your doctor must be open with you, direct and transparent so that you can make informed choices. It’s never the role of the doctor to tell a patient what to do. It’s our role to give information so they can make their own informed decisions.
Dr. Aimee: I feel like you should have several courses for young physicians just coming out of training. I love your quote; I’m going to make sure to share that and give you credit.
“You can teach people to give care, but you can’t teach people to care.” That’s very true.
I’m just so glad that you care as much as you do, because you’re a great example for all of us with how you continue to inspire us, and you continue to move the field forward. I hope by sharing this interview on the podcast that other people will be inspired by what you say, and they’ll stand up for themselves and they’ll ask questions of their doctors.
Dr. Geoffrey Sher: Thank you Aimee! That is the bottom line. When I look at young people like you coming up in the field, obviously knowledgeable, obviously caring, obviously trying to take a step in the right direction, I feel very optimistic about the future.
When we started doing IVF in the early 80’s there was a 5-10% chance of pregnancy. Later, when we reported 20% birth rates, no one believed us. The bottom line is today we have reached the stage where if you do two or three embryo transfers of well-chosen embryos in a younger woman (because the older you get the poorer the quality of your eggs and the poorer your ovarian reserve), the chance of having a baby can be upwards of 75% if you avail yourself of all options. It is a huge change.
But it’s not about getting a woman pregnant or even getting her to have a baby. Ultimately, it’s about focusing on the quality of life after birth. It’s our role to optimize the quality of life so that the offspring can have the same opportunities that we have had, to aspire to greater things. I think that’s the direction we must and will go.
Dr. Aimee: Brilliant. Thank you again for your time today.
Dr. Geoffrey Sher: Thank you so much. I appreciate it.