CC: I am talking to Dr. Malcolm Holliday in the series of the Oral History of Nephrology. I first came to this University, the University of California, San Francisco 30 years ago, almost to the day. I had decided that I wanted work on kidney disease in children and I was interested in why children with kidney failure didn't grow and it was the accepted wisdom at that time, not only would they not grow normally, but they wouldn't mature. The one person in the world who was interested in this and was making significant contributions in this field was Mac Holliday. So I was very fortunate to come here as a Medical Research Council Visiting Fellow to work with Mac and that started a friendship which continues to this day.
So Mac, we are going to talk about the history of pediatric nephrology and your part in it. I happen to know that you qualified as a doctor at the ridiculous early age of 22, so we might start as to why you became a doctor in the first place.
MH: I'm afraid my reasons for going into medicine were somewhat uninspired, judged by conventional standards. I had a lot of medical procedures when I was 3 and I blurted out that I wanted to become a doctor and get even! The idea of being a doctor was sufficiently attractive that I never changed my mind. So from that inauspicious beginning, I went to medical school.
CC: You did have a kidney removed didn't you?
MH: I had a kidney removed when I was 3.
CC: And you say you are living proof of the fact that one kidney's enough.
MH: It's been that for me!
CC: You went to college when you were 16, to medical school when you were 19 and qualified as a doctor when you were 22. Why a pediatrician?
MH: I found in-patient practice of pediatrics, which is what students really see, to be very exciting at that time. Children were coming in sick, often, in that period, with severe diarrheal dehydration and, with IV fluid therapy, they rapidly recovered. Children seemed much more flexible and recovery more likely. As often is the case the faculty in pediatrics (and there were only 2 of them) were pleasanter than the faculty in internal medicine which was the other option I considered.
CC: During your time as a medical student you were interested in physiology in general and electrolyte balance.
MH: Yes. In the first year of medical school (1943) the professor of biochemistry introduced us to the then relatively new idea of body fluids and the fact that the composition of extracellular fluid was remakarbly stable. He used the syllabus written by James Gamble, then at Children's Hospital in Boston. The idea, not all that common then, to define sodium and chloride concentrations as milliequivalents per liter as opposed to milligrams percent appealed to me; most of my classmate didn't agree. Rushing through college, none of us had been exposed to physical chemistry. When I got to Children's as an intern, Dr. Gamble, was near retirement but still cast a large shadow. Later I applied for and received a fellowship in his lab.
CC: So you went as a fellow into Gamble's laboratory in 1948, two years after you had graduated, and worked with other fellows under the guidance of Bill Wallace?
MH: Yes, Bill Wallace, after graduating and interning, was awarded a coveted fellowship to work in the laboratory of A. Baird Hastings, Professor of Biochemistry at Harvard. He made basic observations on intracellular pH. Following a residency at Children’s Hospital, Boston, he volunteered for service when the US entered World War II. He served four years as a battalion surgeon in George Patton’s tank corps in North Africa, Sicily, France and Germany- culminating in the Battle of the Bulge. He came back and, along with other veterans, was senior resident to the “fresh out of medical school” interns. He was a compelling figure, surprisingly kind given his wartime experiences, but appropriately skeptical, both as resident and, later, as my mentor.
CC: He was Chief at Gamble's laboratory.
MH: That's right. At that time he was developing a new method for measuring sodium and potassium using flame photometry. The flame photometer was fashioned from modified lab glassware, photocells from the Radio Shack, and a string galvanometer assembled in a plain plywood box. When it worked we could do an astounding 15-20 sodiums and potassiums in one day, each requiring but 0.2 ml serum. This contrasts with gravimetric analysis taking 4 days to analyze 4 samples. Having the flame photometer gave the lab a head start in clinical research on the factors controlling extracellular fluid (ECF) sodium and potassium.
CC: Did you get out of bed at night to measure sodium and potassium?
MH: I had to get out of bed at night to measure a lot of things during my student days. I had a lab externship - it was called - which meant you did emergency work at night in return for room and board.
CC: Using the flame photometer?
MH: No, serum sodium measurements on patients weren’t available then.
CC: So what would you say Dr. Gamble's main contribution was?
MH: Dr. Gamble's contribution was quite singular. In 1923 he published an article which described the urinary losses of electrolytes and other compounds of four children who had fasted as treatment for epilepsy. He followed the changes in ECF fluid volume and concentration showing how little it changed in spite of urinary losses from fasting. The real impact of this article was to introduce into clinical medicine the concept of ECF, its physical chemistry attributes, and the value of adaptations that minimized changes in its composition when subjected to various stresses. This work led to research that dramatically improved clinical practice. The work was noted by those in medicine and surgery as well as pediatrics. Subsequently he was honored by all three of these specialties. The syllabus, which had attracted me as a student, summarized the renal responses to fasting and other stresses and how these processes minimized changes in ECF. The concept came from Walter Cannon, one of the founding fathers of physiology in the early 1900s, who developed the general concept of physiological processes maintaining stability in the face of challenge- processes he termed homeostasis. Gamble’s work illustrated powerful examples of homeostasis. His work was the cornerstone of teaching and clinical practice for using fluid therapy in patients with dehydration due to gastroenteritis, diabetes and intestinal obstruction.
CC: But I suppose that it is not in any way surprising in classes of pediatricians that the understanding of the importance of the stability of body composition should have come from a pediatric-based laboratory because children are in much greater threat than adults.
MH: That's true. Gamble did this landmark work in 1914-16 before going to France in WW I. He worked in John Howland’s laboratory in Baltimore, devoted to clinical research in children. Johns Hopkins, had started the first full-time departments of medicine, pediatrics and surgery. Gamble was one of the stars of Howland’s original group; The resources of that laboratory allowed them to landmark research at that time. With laborious analyses completed and wartime service over, Gamble’s 62 page article was published in the Journal of Biochemistry 1923.
CC: So Gamble was one of the first to show the importance of the kidney in the maintenance of the ECF volume and content?
MH: That's true. In the original and subsequent studies he not only measured the changes in composition of plasma as a stress was imposed but what was excreted in urine; he drew the relationship between the changes in urine composition that “came to the defense of ECF” as he put it. He described these findings in teleological terms more readily grasped by clinicians but somewhat out of step with evolutionary concepts then being introduced in basic sciences. Homer Smith was the person who described the evolution of the kidney basic to the evolutionary process.
CC: Tell me about the Salt and Water Club.
MH: The Salt and Water Club was a group of less than twenty of investigators in Boston, New Haven and New York. It had a rather distinguished membership. It included some of the later big names in medicine - Lou Welt, Don Seldin, Alex Leaf, Bob Schwartz, Bill Schwartz and John Merrill. We'd meet and talk for a half a day, have supper and go home. Members became emeritus when they we moved elsewhere. I became an emeritus at the age of 25 when I went to Indiana!
CC: What about Peters and van Slyke?
MH: Peters and van Slyke were senior investigators who published a textbook, "Quantitative Clinical Chemistry" in 1931 that summarized what we knew about body fluid physiology and metabolism at that time. It was an extraordinary book that summarized in one volume clinically relevant physiology at that time. An important note was that Gamble’s work provided major portions of the chapters on acid base, sodium, potassium, chloride. At that time new terminology for acid base balance was being used, which Gamble neglected to adopt. That neglect affected Gamble's later reputation. But it didn't diminish his contribution of bringing the clinical physician's attention to ECF.
CC: After your time in Boston, and you were there for two years, you went as a research fellow to Yale to work with Dr. Darrow. What are your memories of that?
MH: Darrow was a good friend of Gamble's. He was a bit younger, quite different. Gamble was the quintessential New England well-to-do scholar of medicine. Darrow was a mid-westerner from North Dakota whose suffragette mother fostered independence. He was lively, had strong opinions but was very generous and kind. But not afraid to take on the establishment. Darrow was the first person to introduce IV potassium administration into clinical practice. That certainly was his most signal contribution although he also described for clinicians the consequences of both hypo- and hypernatremia in terms of shifts of water. Now these are well understood but at that time they weren't.
CC: But they are still responsible for significant and morbidity in children.
MH: Yes they are. Darrow was in some ways a committed physiologist during his career. His idea of teaching medical students was to explain basic physiology and the rest would follow. Sadly, I don't think that idea has as much substance as we all wish it had.
CC: Certainly that was the way I was brought up. What did you do when you were working with Dr. Darrow? What was your purpose?
MH: I developed an interest in lesions in the kidney that resulted from potassium deficiency. He'd had reported on lesions in the heart and kidney. I should also note that I came to know John Peters (see above) and Lou Welt (see below) in the Dept of Medicine at Yale. I subsequently went to Indiana University and continued those studies.
Later, when I was drafted into the Army from Indiana and was stationed at Fort Bragg, near the University of North Carolina. I did a project with Lou Welt (now at UNC), Bob Winters, Walt Hollander and, most importantly, Jean Oliver the renal pathologist who used nephron microdissection to define the precise site of tubular injury. We correlated the renal lesion with the concentrating defect; a series of reports followed. The microdissections demonstrated that the distal nephron was the affected site responsible for the concentrating defect. Jean Oliver was a memorable figure-a fearless curmudgeon- sufficiently productive to be funded by the NIH into his eighties.
CC: You've told me about him many times but repeat if for a larger audience.
MH: Jean Oliver used the technique of microdissection to define the architecture of the kidney during its development and as it is affected by disease. He collaborated with the first micropuncturists who analyzed the composition of tubular fluid; he showed that it did come from the proximal tubule (1941). He later collaborated with Carl Gottschalk; they took micropuncture-microdissection to new levels in the 1960s coordinating anatomical-physiological results extending to the distal nephron. He published (1968) an oversized classic (16 x 12 in) “Nephrons and Kidneys: A quantitative study of developmental and evolutionary mammalian renal architectonics.”
CC: So we established that you became a pediatrician because pediatricians are nice people which I agree with and you got interested in the kidney because the main function of the kidney is the maintenance of body composition within limits compatible with health and your interest was in body composition. So what then took you into nephrology? Your fascination with the nephrotic syndrome, for example?
MH: No it was not my fascination with the nephrotic syndrome! Part of my job as a fellow in Gamble's lab was to help Jack Metcoff measure GFR in nephrotic patients; work I did not find interesting. Nonetheless, the nephrotic syndrome was to prove interesting for me in a specific instance. Relapses causing edema from massive proteinuria as plasma volume contracted. Shock sometimes followed, requiring IV saline.
CC: I do remember that because there was a moment in my life when I thought I'd discovered the fact that these young children sometimes became profoundly hypovolemic. And that when I was at the Hospital for Sick Children in London. We had a child whose hemoglobin was 21! I went to the library and found that you'd already written on the subject many years earlier in the American Journal of Diseases of Children.
MH: That was my only “nephrosis” contribution; steroid treatment held no interest.
CC: So it's not nephrotic syndrome...
MH: No. Given the lesions we saw in potassium deficiency and the interest I'd acquired from my experience with Jean Oliver, I began noting that children with renal tubular disorders, notably obstructive uropathy and inheritable disorders, developed renal tubular acidosis, salt wasting, or nephrogenic diabetes insipidus. So it became part of the clinician's job to find out what that child needed to sustain ECF once the tubular defect was documented. I remember a child in Pittsburgh who had the extraordinary requirement of 30 grams of salt a day to sustain his ECF volume. He had a GFR less than 15, only twice his urine volume. If he missed a couple of doses he would come into the hospital in shock. That was a dramatic example of a renal tubular function gone wrong. At the same time we were beginning to see children with renal failure. Around 1960 Belding Scribner was beginning a chronic dialysis program for adults in Seattle and John Merrill a transplant program for adults in Boston. But nothing for children. I felt these treatments should be available to children with renal failure as well.
CC: So we're now in the mid 1960s. You've survived the U.S. Army. You've been to Pittsburgh. You've worked as a career investigator supported by the United States Public Health Service and in 1963 you came to California. After a brief period at Children's Hospital in Oakland, you came to the University of California San Francisco in 1966, where we are now sitting. That's when you became interested in growth failure and the endocrine, renal and metabolic changes that are the consequences of renal insufficiency.
MH: Yes, I think one of the things that had struck me, even much earlier, was that some of the children with kidney disease were remarkably growth retarded - cystinosis is the extreme example - and the reason for that was not clear. Salt wasting appeared to be one of the causes, renal acidosis another. Nephrogenic diabetes insipidus was another when water requirement was so high it interfered with calorie intake. Then we focused on growth retardation in renal failure itself. That's when you came to the laboratory and we began to look at the problem of calorie deficiency as a factor that impaired growth.
CC: Yes, I suppose that in the wonderful year I had I learned quite a lot about renal physiology, more than I ever expected to learn about American history and the University of Virginia but I left with a very clear view in my own mind that there wasn't a single cause of growth failure but it was the consequence of the many changes in body composition that are the consequence of renal insufficiency and the adaptations that have to take place in order for children to maintain life in the face of renal failure.
MH: I took from Homer Smith the idea that the kidney let primitive man and other animals survive on the food they could get, when they could get it, and that they could survive extended periods of fasting, as Gamble showed in children with normal kidney function. The kidney was the key to that adaptive response. As we got more affluent and people had food all the time, we could eat whatever we wanted, whenever we wanted it. But with the loss of kidney function, that tolerance narrowed. In extreme cases patients with clearances <5% normal, with strict diets, could survive. Careful dietary control- high calorie, low protein, sodium and phosphorus diets allowed survival for months. An early example was provided by Thomas Addis of Stanford who described the management of a young man with progressive renal failure and how important it was to limit dietary protein while giving adequate calories. And social support. This problem is even more difficult in children whose needs/kg are greater because of a higher calorie need per kg and a need for growth.
CC: Of course another difference that the pediatrician has in managing young children with renal failure is that it is not possible to directly control intake. You can say to some adults, and in the 60s before dialysis they did: “If you don't eat this diet you will die and that's an egg a day providing 20 grams of protein plus adequate protein free calories.But if you say that to a child, the child will say, "Well so all right, I'll die" and so what we had to do was to develop the notion that you had to maintain energy intake and then start modifying intake of other nutrients in a way which was acceptable for the child.
MH: You mention another element that I should cite, because I am forever indebted, to social workers who understood the impact of disease on children and their families, and the difficulties special diets, as Addis had noted earlier posed for them. You may remember a particular social worker, Carol Levine, who worked with us. She made the point, that we should understand the burden a special diet placed on the family. She showed how social workers make important contributions to child care, in helping physicians understand the consequences to the family of sickness in children and the difficulties our treatments incur.
CC: And it's also the role of other members of what's now an overused word, the "clinical team" but I think anybody who's worked with children with renal failure knows that it is not possible to do a good job unless you are working with a strong team of social workers and nutritionists because if you are to persuade a child to modify their intake in a way which doesn't destroy the family, then you need their input.
MH: That's certainly proved to be the case. Carol made a tape of one child who talked of dreaming of water melons and steaks raining down on him, both of which he was not supposed to eat. Another child admitted "Oh well, we all cheated a little." We got insight into the difficulties these “average” children faced with our special treatments. In 1967, when we started, there was no Medicare to provide funds for this. We had a very small program which could train two children at a time for home dialysis. The same program could train ten adults. That was the sole dialysis capacity in Northern California. At the same time the kidney transplant program, restricted to live related donors, got started at UCSF; we referred children. A memorable experience was one grandmother giving a kidney to one grandchild and the other doing the same when the second grandchild turned up. Four people sharing four kidneys!! The transplant surgeons, after initial resistence, were enthusiastic. One child said he wanted to know what doctors said on rounds- “if it’s good”. A generous state program for disabled children sustained the progam until Medicare took over in 1972.
CC: I don't know whether you'll agree with me that dialysis whilst wonderful because it saved children's lives, was always a completely unsatisfactory way of living your life and that transplantation had to be the only sensible long term solution.
MH: I think that initially I had hoped that dialysis, being a physiological treatment, would make care more challenging,. Shades of Dr Darrow. How naïve! I remember one of the kids who was learning home dialysis and was quite afraid. He was a smart kid whose mother was not adept. He hid under the covers until his mother was about to do something wrong and then he stuck his head out and said, "No mama that ain't the way"; that patient become a veterinarian and did well for a long time. As far as I know he's still doing well. But, to confirm your point, he did well after he got a kidney transplant.
CC: But dialysis is more complicated in children than in adults because of the different relationship between metabolic rate and therefore the necessity for food intake and circulation and therefore the capacity to dialyze and I learned about that relationship from your work on size so perhaps you could talk about that.
MH: My interest began in Gamble’s lab when I read an article showing metabolic rate/kg declined as size increased. An early project (1949) was measuring body water in infants and children. We noted that in the first year of life body water was linearly correlated with both surface area and body weight. Weight, surface area and energy metabolism all increased at the same rate in the first year of life, but after that metabolic rate/kg and calorie need/kg decreased at a progressive rate. Later Bill Segar and I devised a rather simple formula for calculating metabolic rate from body weight in 100 kcal increments as it decreased with growth. It was and still is used to estimate maintenance water needs.
Later (1966) we found out why: the decrease during human growth after the first year of life is fully explained because organs (brain, liver and kidney), with very high metabolic rates, grow slower and muscle mass, with a low daily metabolic rate, grows faster after the first year. In the first year rapid brain growth accounts for the sustained high metabolic rate.
The important clinical consequence for children with renal failure is that the higher calorie need/kg requires a higher calorie intake, hence more protein, phosphorus and salt/kg- or a very modified diet. To get needed calories in, you get more protein and need more dialysis. That is one reason dialysis proves less successful in children.
CC: Mind you, even for adults, what is still a serious problem in long-term dialysis is calorie deficit and bone disease. Many adults die of malnutrition or disabling bone disease, even now.
MH: You took the bone problem further and showed that lowering phosphorus intake improved growth. Your evidence is quite convincing. Some still think that massive doses of vitamin D is an adequate alternative. I guess there's a tension between those who want to restrict intake within the limits that are tolerable and those who say "Go ahead and then find a pharmacologic means to get around it." Realistically I say there is something to be said for both but you and I favor trying to keep the intake more appropriate.
CC: Yes, as long as the price the child pays for it is not unacceptable but this notion that you can just dialyze children harder and not manage their energy or food intake never strikes me as sensible because you are always working at the limit of dialysis surface area and circulatory volume.
MH: Dialysis in its various forms produces a kidney function, measured in simple clearance, that is around 5% normal. That's not much tolerance.
CC: I suppose the same argument applies to the use of growth hormone. That whilst large doses of growth hormone will improve growth, that shouldn't be taken as a simplistic solution to not bothering with any other things that you need to manage like intake because certainly I think you can manage many children with chronic renal failure without using growth hormone.
MH: Yes, I think part of this gets down to both in the case of the child, the parent, the doctor, how much they are willing to participate in some restrictive regimen to enjoy better health as opposed to do what you please and find a pharmacological way around it. Sometimes that works but sometimes it doesn't and there are those of us, , who think there is some virtue in the discipline of restraint.
CC: Can we go to talking to services because I came to work with you in 1971 by which time there was a strong dialysis emphasis to this transplant program here and you were very concerned about how that service - the same sort of access to the service might be organized across the whole of the United States - and I remember you making many trips to Washington at the time.
MH: That's true. I was chair of the Committee of the National Kidney Foundation on Dialysis and Transplant in 1971 and influenced by my experience in children. The government was implementing the Medicare Amendment to pay for dialysis and transplantation. It hadn't happened yet and the very social worker I mentioned to you, the psychologist who worked with her and the nutritionist who had all indoctrinated us in the importance of providing far broader services than simple visits for dialysis would provide. As the programs for dialysis- transplant began to be funded by government, we tried to build those services as part of a national program and, coincidently, maintain a registry with good data. As you know, we were not successful. You were. The Dialysis Transplant Registry of adults and, later, children that you supported was an invaluable source of information. I'm afraid we were laggards!
CC: Well I'm afraid it's not turned out quite like that because in fact the European Registry which did do wonderful work for the first maybe 30 years then collapsed and is now having to be reinvented, as you have invented and carried through a very good registry for children. Why do you think that the sort of network of centers that you were hoping to develop was not a way forward that the United States was able to take?
MH: The United States represents a very different problem from the UK and Europe in general. It's a large country with long distances between centers for a large number of patients. And US psychology is different- more entrepreneurial, less equitable. Every medical school wanted to have its program. At the time you're talking about, our calculation was one pediatric program in 20 medical schools would provide the needed services and also assure the needed experience to develop a good rational approach. I think the truth is that with every medical school trying to do it, we wound up having pediatric nephrologists working to find enough patients to sustain the program. That is an exhausting and debilitating effect of lack of organization. The individualism in medicine that is characteristic in our country is a serious flaw in the way it promotes equity in medical services generally and specifically the way the medical services developed here. The argument that has been made to me particularly as applied to adults is that making dialysis generally available and funded serves more adults than my plan would. That's true, but somehow I think the dialysis program and the funding consequences for adults was part of the process of medicine as it changed from a service organization to a business organization. I personally lament that change although most people disagree.
CC: As you say, I certainly watched what you were planning to do and we talked a lot about it and when I got back to England Martin Barratt, Dick White and I wrote a program based on the same ideas to the United Kingdom. It took awhile but eventually the government decided that renal failure services for children would be provided and they did so on the basis of a limited number of centers that had the proper backup which had to include a close association with the adult services which I think is a very necessary relationship.
MH: Yes, I think there is an interdependency in the case of pediatrics, between nephrology and pediatric nephrology which got lost in this country because of this compulsion to be independent and on your own. I still think internists could learn a lot from watching pediatricians manage families, and we could learn a lot about efficiency.
CC: I think a lot of nephrologists, we'd call adult nephrologists, have been interested in services for children and they have been immensely beneficial. Certainly I've had that experience in London. But what about pediatric nephrologists because I guess we don't know when pediatric nephrology started but it certainly wasn't around when you were born or when I was born and I don't think it was around when I became one but it certainly around now with training programs but you've seen pediatric nephrology develop and in fact you've played some part in developing training programs for systematizing nationally if not internationally.
MH: In 1966 when nephrology was just getting started, pediatric nephrology was needed, because, as noted already, pediatricians better understood children who need nephrology services than do internists. Many felt that pediatricians could learn from internists to manage endstage renal disease better; internist could learn how to cope with patients better. A lot of people disagreed but a Board was formed, exams were given and pediatric nephrology came to be.
CC: You were in the first group to take the exams weren't you?
MH: I helped write the first exams. We exam writers first had to pass the exam for Nephrology Boards which we all did. We wrote the exams for pediatricians. I think children are better off for our having our own Boards. You can speak for the U.K. and Europe better than I. One of the peculiar things about our country is that we start these things but don't give a lot of thought to long term consequences; other people observe and do them better. That happened in Europe and the U.K.
CC: I don't know. I think the grass looks greener on the other side of the ocean! But pediatric nephrology now is a worldwide enterprise but still small enough for us to know what each is doing and to develop and maintain friendships like you and I have done.
MH: That's certainly true. I was struck at an international meeting I attended in 1989 that we could all get in one room- Europe, UK, US, Japan, China, India, Australia, South America and Africa. I give the IPNA great credit for bringing in people from what was then behind the Iron Curtain to those meetings and now from Africa. I remember dramatic moments in the 80s when people from Czechoslovakia or Russia would come to meetings; it was an eye-opening experience for them and helped them get started with their programs. Now, how we in the West deal with chronic disease in children influences pediatric care world wide. It strains countries with limited resources.
CC: I suppose it is the unresolved question that as technology develops, and becomes widely available the questions become not what can be done but what should be done and those are questions that have to be examined at the extremes of life in particular.
MH: True. It's very hard, however, because treatments evolve, so that dialysis becomes more efficient and easier, so that it is extended to more people; it worked despite my predictions. If you believe in equity at home then do you believe in equity where these same services demand resources that that create inequity in poor countries. In "Pediatric Nephrology", we had a section called "From Around the World" that identified unique problems in different cultures. I’m glad to see its also in the Fourth Edition. Getting people from other countries to tell us what their problems are reminds us that western medicine is not the only medicine. Many more children live in the world beyond ours.
CC: And the medicine has to be efficient, effective and economic so that as many people as possible benefit from it. Did you enjoy editing the textbook? For the sake of posterity I should point out there is one major textbook on pediatric nephrology!
MH: I did. It gave me a chance to recruit people from around the world to write the chapters. I learned a great deal from chapters I edited for both editions. Yes, I enjoyed it.
CC: There is one thing worse than having a chapter rewritten for you and that's being asked to rewrite it yourself! The book itself seems to me to, during your time as the editor, to reflect both your approach and your career and that all the conditions, particularly those relating to renal insufficiency were approached from, first of all, understand the physiology, then understand how that is affected by the disease, then you move into the management. Would you say that?
MH: That's certainly true, and I think the thing we emphasized was renal function in relation to the whole body.
CC: Now is there anything we haven't covered that you'd like.
MH: No I don't think so. I very much appreciate being asked to do this and I appreciate you for being a thoughtful interrogator.
CC: Dr. Holliday, thank you very much.