Latest Review of Evidence for Vitamin D & Calcium Supplements

I have reviewed the complex and inconsistent evidence concerning the potential risks and benefits of vitamin supplements here, and concluded that most of the common claims for health benefits are unjustified. I recently discussed an example of this sort of unjustified claims, a veterinarian promoting screening tests for blood levels of Vitamin D and recommending supplements for nearly all patients. Fortuitously, a new comprehensive review of the evidence regarding Vitamin D and Calcium supplementation has just been published, which illustrates the lack of real evidence for many of these sorts of claims.

Agency for Healthcare research & Quality, U.S. Department of Health & Human Services. Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update). Evidence Report/Technology Assessment 217. AHRQ Publication No. 14-E004-EF. September 2014

Not surprisingly, the review concludes that the evidence is insufficient to support most of the claims made for supplements of these substances.

In solid agreement with the findings of the original report, the majority of the findings concerning vitamin D, alone or in combination with calcium, on the health outcomes of interest were inconsistent. Associations observed in prospective cohort and nested case-control studies were inconsistent, or when consistent, were rarely supported by the results of randomized controlled trials. Clear dose-response relationships between intakes of vitamin D and health outcomes were rarely observed. Although a large number of new studies (and longer followups to older studies) were identified, particularly for cardiovascular outcomes, all-cause mortality, several types of cancer, and intermediate outcomes for bone health, no firm conclusions can be drawn…it is difficult to make any substantive statements on the basis of the available evidence concerning the association of either serum 25(OH)D concentration, vitamin D supplementation, calcium intake, or the combination of both nutrients, with the various health outcomes because most of the findings were inconsistent.

It is particularly important to note that the evidence is often inconsistent, and that uncontrolled study designs often lead to conclusions that don’t turn out to be true when examined in controlled trials. The value of any single study is low, and the balance of the evidence must be evaluated to draw meaningful conclusions.

Regarding cancer specifically, the review did not find consistent evidence that low Vitamin D levels predispose to cancer nor that supplementation is protective.

Synopsis

No qualified systematic reviews have evaluated relationships between vitamin D and total cancer incidence or mortality. No new RCTs were identified for the current report that addressed the effect of vitamin D or vitamin D combined with calcium on the risk for total cancer or cancer mortality. One cohort study found no association between total (all-cause) cancer and 25(OH)D concentrations (rated A), whereas a second cohort study observed an association in men but not in women (rated B). Ten cohort studies and one nested case control study addressed the association of serum 25(OH)D concentrations and cancer mortality. Five of the cohort studies (1 rated A, 4 rated B) observed no association of serum 25(OH)D concentration with total cancer mortality. Three cohort studies and the nested case control study observed a trend toward increased risk with decreased serum 25(OH)D (all rated B). One analysis using updated NHANES III data (rated B) observed a trend toward increasing risk for death with increasing serum 25(OH)D among men at higher latitudes whose blood was drawn in summer but the reverse in women. One cohort study observed a U-shaped association of increasing mortality with both low and high serum 25(OH)D.

One RCT in the original report showed no effect of combined vitamin D3 (1000 IU/d) and calcium (~1500 mg/d) supplementation versus calcium supplementation (~1500 mg/d) alone on the risk of total cancer in healthy postmenopausal women (>55 years old) living in Nebraska (latitude 41°N). Another RCT also found no difference in total cancer mortality or incidence between supplemental vitamin D3 (100,000 IU every 4 months) and placebo in elderly (71+ years old) men and women living in the United Kingdom (latitude 52° N). Both RCTs were rated B quality.

Analyses using NHANES III data (general adult populations living in the United States) showed no significant association between baseline 25(OH)D concentrations and total cancer mortality.

As always, this review doesn’t preclude the possibility that Vitamin D and Calcium may be associated with the risk for some cancers in some populations. But it does expose the lack of real support for the often-heard claims about these vitamins and cancer.

 

Posted in Herbs and Supplements | 3 Comments

Choosing Wisely-The Video

Here is some good advice about overdiagnosis and overtreatment–with a beat!! :-)

Posted in Humor | 6 Comments

Is There a Blood Test for Cancer in Dogs & Cats?

I am often asked by clients if there is a blood test that can tell if their apparently healthy pet has cancer. Obviously, “cancer” is a scary word, and many of the various diseases given that label are difficult to diagnose and treat. Many people have had personal experiences of a family member, human or non-human, developing cancer, and they are understandably looking for a way to identify such disease as early as possible, with the hope this will make it easy to control or even cure. Unfortunately, like most things in medicine, the reality is far more complex and uncertain than a simple blood test that will identify a hidden cancer in time to treat it.

Cancers differ in their basic biology and behavior, so each requires a different approach to diagnosis. Leukemia may show up as an abnormal number of white blood cells in a complete blood test, but breast cancer will not. High calcium levels have been associated with several cancers, but these range from lymphoma, a common white blood cell cancer spread throughout the body, to anal gland carcinoma, an uncommon tumor that shows up in that particular location only. The variety among cancers make any single test for most or all types very unlikely.

A Bit About Screening Tests

It is also important to understand a bit about the difference between testing for a disease when there is some symptom or other reason to suspect it is present (diagnosis) and testing for the presence of disease in apparently healthy patients (screening). The chances of getting the right answer from a specific test for a particular cancer are much higher when the patient has typical symptoms or other test results that suggest the presence of that cancer. All tests are imperfect, and all give false positive or negative results sometimes. If large numbers of healthy patients are tested, most of whom don’t have the disease, then a lot of the positive tests will turn out to be wrong, but most of the negatives will be true. This is the case even for very, very good tests.

The best way to illustrate this is—brace yourself—with a little math.

Say you have 10,000 people to test, none of whom have any symptoms or problems to suggest they have cancer. However, 200 of them have the cancer you are testing for (2%), while 9,800 do not. You have a test that is about as close to perfect as you can get–98% sensitive and 98% specific. That means that if you have 100 patients with the disease, 98 will test positive and 2 will test negative even though they have it (sensitivity). It also means that if you test 100 patients who don’t have the disease, 98 will test negative and 2 will test positive even though they don’t have it (specificity).

So we test all 10,000. Here are the results we will get:

True positive (test positive and have cancer)- 196

True negative (test negative and don’t have cancer)-9,604

False positive (test positive but don’t have cancer)-196

False negative (test negative but actually have cancer)-4

So we found most of the cases of cancer and we re-assured most of the healthy people. BUT, we also told 4 people with cancer that they were fine. And we told 196 healthy people they had a terrible disease. Did we do more good than harm?

Well, it depends on lots of other things. If early detection leads to more effective treatment and better survival, then at least the true positive patients will benefit. However, those we missed will think all is well and may ignore future symptoms or test results that might actually help them get treatment.

On the other hand, if early detection with this test doesn’t lead to better treatments and outcomes, then all we’ve done is give people bad news which they can’t do anything about even if it’s true. Screening doesn’t help anybody if there is nothing we can do about the disease at the point at which we detect it.

It is also likely that those who got a positive test will have to undergo uncomfortable and expensive testing and maybe even cancer treatment even if they don’t actually have cancer (which, remember, is almost 200 of our patients). We have actively harmed these folks with our test.

There has been a lot of controversy in human medicine recently about screening tests for cancer that were once widely recommended. PSA testing for prostate cancer, for example, turns out to cause a lot of harm. Positive test results often result in expensive and uncomfortable treatment with some serious side effects, and yet it appears not to reliably improve long-term outcomes. In other words, men who get tested will often suffer more harm from treatment without actually living any longer than men who did not get early detection with this test. While the test still has some appropriate uses, widespread screening of men with no symptoms of disease turns out not to be a very good idea. Similar concerns have led to changes in screening for breast cancer and to a growing recognition in human medicine that screening tests of apparently healthy people lead to significant overdiagnosis and harm in many cases.

The situation is a bit different in veterinary medicine. For one thing, there are few blood tests that have been tested at all for the ability to detect cancer before symptoms develop. And for most cancers, there is no research evidence that such early detection would allow us to better treat or even cure such cancers if we could find them. While it is often assumed that the earlier we detect cancer the more we can do about it, this has not been proven in dogs and cats and has actually turned out not to be surprisingly often in humans.

But My Vet Said There Was a Good Screening Test for Cancer

Unfortunately, there are still some veterinarians who will recommend, and sell you, cancer screening blood tests for your pets with a good deal more confidence in their benefits than is justified. A recent article, written by an alternative medicine practitioner I’ve written about before, makes strong claims for his ability to use a couple of blood tests, C-reactive protein, thymidine kinase, and Vitamin D3 levels, to detect cancer or precancerous conditions before your pet is sick and then treat them effectively.

A series of simple, new, inexpensive blood tests bundled into a diagnostic panel now allows doctors to detect cancer and other serious problems before they develop in your dog or cat…These new blood tests can determine your companion’s risk of developing this dreaded disease, and even detect it in its earliest stages.

While these new cancer tests are very helpful for determining the status of your animal’s health before he becomes ill, they are also helpful for monitoring dogs and cats that already have cancer. For those already diagnosed with the disease, monitoring [these] levels helps veterinarians make decisions about changing treatment and to predict when/if the cancer may return and when the animal may come out of remission.

This cancer testing is very cost effective. In our office, we charge under $200 for the entire three-test profile, making it very inexpensive considering the wealth of information we receive from it. Additionally, this profile is the easiest and least expensive way to screen dogs and cats for cancer and other serious inflammatory diseases. There are really no disadvantages to having this testing done.

These claims raise a number of important questions: 1. Can these tests really detect cancer before your pet has symptoms? 2. What should we do if we have a positive test result? 3. Does testing, and whatever we do next, help prevent illness or prolong health and life? 4. Can this testing do any harm?

Can these Tests Really Detect Cancer Before My Pet Gets Sick?

The short answer is, we don’t know. It is important to remember that none of these tests is routinely used or recommended for cancer screening of healthy people or animals by doctors or organizations specializing in cancer detection and treatment. This kind of screening is not a widely accepted practice. Nevertheless, there is research evidence looking at the possible value of these tests for cancer screening. I will offer a brief summary of the evidence and try to answer our four questions.

Thymidine kinase (TK1)- This is a substance which is produced by dividing cells. Since cancer cells typically divide more rapidly than healthy cells, it tends to be produced in greater amounts when there are cancer cells present. This is particularly true for cancers of blood cells, such as lymphoma and leukemia. TK1 it is less consistently elevated in patients with other kinds of tumors. To a lesser extent, elevated TK1 levels have also been associated with viral infections and inflammatory conditions as well as cancer.

There is a lot of evidence to suggest that TK1 levels are higher in dogs with known cancer than in healthy dogs, especially when the cancer is lymphoma or leukemia. Most studies compare health animals with those already diagnosed with cancer by other methods, and they usually find higher TK1 levels in the cancer group. These are not, however, animals with occult cancer, that is cancer that hasn’t caused any symptoms or been diagnosed yet. Whether TK1 levels are consistently higher in dogs who have cancer but not symptoms hasn’t been clearly demonstrated. The TK1 levels of healthy dogs, dogs with cancer, and dogs with other diseases overlap quite a bit. There are even some studies in which as many as half of the dogs with known lymphoma had normal TK1 levels. So there are certainly not clear absolute differences to distinguish these groups.

While it has some potential, TK1 testing is not clearly a useful diagnostic or monitoring tool for dogs with most cancers, much less a screening tool for dogs who might or might not have cancer. As usual, there is even less data related to cats, though there are some suggesting TK1 might behave similarly in this species.

C-Reactive Protein (CRP)-

CRP is a protein associated with inflammation. Inflammation can be caused by many different things, such as infection, autoimmune disease, and of course cancer. CRP is quite sensitive to inflammation, but it does nothing to help distinguish the cause. In dogs, CRP is elevated in at least some kinds of cancer, and the values are generally higher than in dogs without cancer. However, there is significant overlap between these groups, so some dogs with cancer will have normal CRP and some without will have elevated CRP. Interestingly, dogs with lymphoma who are in remission (no illness or detectable tumor but microscopic cancer still present somewhere) generally have lower CRP than dogs with active lymphoma. This means CRP could possibly be used to test for relapse of this cancer. However, dogs in remission are just like dogs without symptoms of cancer who we would be using a test like this to screen, so these data suggest we wouldn’t be able to find lymphomas with this test if there were no symptoms or obvious tumors.

Vitamin D-

Vitamin D, like all vitamins, has a number of essential functions in the body. It has been well known for decades how much vitamin D people (and dogs and cats) require to prevent symptoms of Vitamin D deficiency disease. However, it has been a bit of a fad for a while now to claim that even higher levels would have protective effects against a variety of diseases, including cancer.

This is based largely on a few studies which found that people with certain disease, including some kinds of cancer, tend to have lower Vitamin D levels than healthy people. However, additional research has failed to demonstrate that low levels cause these diseases or that supplements prevent them. People who are sick may have low Vitamin D levels as a symptom of their illness rather than as part of its cause. For the most part, testing for Vitamin D and supplementing to prevent cancer is not recommended in humans unless there are specific reasons to believe an individual patient is at risk for low Vitamin D levels (in other words, routine screening is not recommended).

There is not good evidence to suggest that subclinical Vitamin D deficiency is a real problem in dogs or cats either, or that supplementation beyond the levels currently used in commercial diets is of any benefit.

Veterinary Diagnosic Institute Cancer Tests-

Despite the fact that these tests are not used as general cancer screening aids in humans, and the lack of strong evidence to show they can reliably predict cancer in dogs and cats, there is a company selling these tests as a tool for cancer screening, as well as for cancer diagnosis and monitoring response to therapy. Apart from the general information for each test I’ve already discussed, the company has produced one clinical study to evaluate its screening test.

Selting KA, Sharp CR, Ringold R, Knouse J. Serum thymidine kinase 1 and C-reactive protein as biomarkers for screening clinically healthy dogs for occult disease. Vet Comp Oncol. 2013 Jul 16. doi: 10.1111/vco.12052. [Epub ahead of print]

This study involved collecting blood from about 360 dogs (German shepherds and golden retrievers) to test for CRP and TK1 and then following them for 6 months or more to see which developed cancer or died of some other disease. The dogs were not evaluated by a veterinarian as part of the study, and most health information was obtained from questionnaires completed by owners. This raises the possibility that some dogs may not have been properly classified or diagnosed, which might change the results and conclusions significantly.

As expected, over the short course of the study the incidence of cancer was pretty low, about 3%. This means 11 dogs developed some kind of cancer. Because CRP is not very specific for cancer but simply detects any inflammation, it was not used by itself to predict cancer development. However, the TK1 test tends to be more specific for cancer but not as sensitive as the CRP, so the authors looked at both the TK1 by itself and the combination of the two tests (called the neoplasia index or NI) to predict cancer development.

Sensitivity and specificity of a diagnostic test are always in opposition to one another. The more sensitive a test is (that is, the more actual cases of disease it finds), the less specific it is (that is, the more healthy patients will test positive for a disease they don’t have). This is true for any test, and the balance between the two numbers is related to what value of the test one uses as a cutoff. In this study, the authors followed the common practice of  analyzing their data with a variety of cutoffs to try and find the best balance between sensitivity and specificity for the test.

In the case of cancer screening for apparently healthy patients, there are dangers to both a low sensitivity and a low specificity. If the test is very sensitive but not very specific, then it will indicate a lot of healthy animals have cancer when they don’t. Apart from the worry this creates for their owners, there will be a lot of expensive, and sometimes uncomfortable or even dangerous, follow-up testing and possibly even unnecessary treatment for a disease that isn’t there. This is the danger of overdiagnosis.

On the other hand, if a test is very specific but not very sensitive, a lot of animals with cancer will show up as healthy on the test. This is a problem if early detection and treatment could lead to a better outcome, though as I mentioned earlier this has not generally been demonstrated for dogs and cats with cancer.

For TK1 alone, the best sensitivity achieved was 100%, meaning all dogs that developed cancer later had an abnormal test at that particular cutoff. However, when that level was used, the specificity was 0, meaning that everybody would test positive whether they had cancer or not. At the other end, the best specificity achieved was 98%, but at this level sensitivity was only 27%. Between these extremes, it was possible to get one or the other value around 80% with the opposite value about 70%. This is not a very good compromise for a test intended to be used in a population with a very low rate of cancer because there will be a lot of patients misclassified with regard to a very serious disease.

The authors expected, of course, the TK1 to be pretty specific (good at ruling out cases that don’t have cancer) but not very sensitive. This is why they combined it with the more sensitive CRP to try and improve the overall sensitivity without losing too much specificity. This combined neoplasia index had an optimal balance of sensitivity and specificity at 82% sensitivity and 91% specificity. In the case of a cancer screening test, it is probably better to favor specificity so you don’t do unnecessary tests and treatments on healthy animals. A lower sensitivity will miss some true cases of disease, but it isn’t clear yet that finding these cases earlier improves their outcome, and of course they will eventually develop symptoms that will lead to a diagnosis.

In the case of a screening test, which is intended to be used on a population which is mostly healthy and disease is rare (about 3% in this study, for example), there are a couple of numbers more useful than specificity and sensitivity. These are the positive predictive value (PPV) and the negative predictive value (NPV). The PPV is, essentially, the percentage of positive tests that are correct, that is the patient actually has the cancer the test says they have. The PPV for this test in this study was 22.5%. That means that when a patient has a positive test, only about 22% of the time is there actually a cancer there. That leads us to  the second question….

What Should I Do if my Pet Has a Positive Test?

The veterinarian promoting this test offers some hint of how he responds to positive results.

In my practice, animals with increased TK levels are supplemented with specific herbal remedies (Healthy Qi, CA Support, etc.) to support their immune systems. The blood is retested one month later. If TK levels are back to normal, no further testing is needed for four months. If TK levels continue to increase, then we must search further for the reason why it’s increasing. A persistent elevation of TK levels predicts the likelihood of cancer developing over the next six months.

So this doctor recommends responding to a positive test with the use of unproven, and untested, herbal products from the pre-scientific system of myths and metaphors known as Traditional Chinese Veterinary Medicine (TCVM). Given the implausible and unvalidated methods used in this system, the risks of untested and unregulated herbal supplements, and the fact that the concept of “boosting the immune system” is itself nonsense, this is certainly not a useful response. Of course, the plan proposed here also ignores the fact that values such as these vary with time for many reasons, and the fact that they might decrease when such remedies are used does not, of course actually mean the remedies are responsible, though that is undoubtedly the implication here.

I would like to be able to say that this approach is only that of this individual “holistic” veterinarian, and it does not necessarily imply that VDI has a similarly dubious and evidence-poor approach to the use of their products. However, among the informational materials VDI offers vets to help understand how to use this test is an article, entitled The Holistic View, by this same doctor. Clearly, the company is willing to endorse such dubious practices in the interest of marketing its products.

Simply following TK1 levels over time, if one chooses to measure them, may be a more reasonable strategy. Persistent elevations or increases over time are more likely to be meaningful than individual values. But instituting dubious treatment in response to an elevation is not rational. Neither is an extensive diagnostic workup looking for cancer. While the risks of diagnostic imaging, such as chest x-rays and abdominal ultrasounds, are low, these tests do have costs, they can find irrelevant abnormalities which would lead to unnecessary further testing and treatment, and they can generate false reassurance when they fail to find an abnormality. Effective use of such tests requires establishing a reasonable clinical index of suspicion which can help guide interpretation of the results and further actions.

This author makes similar recommendations for responding to elevated CRP levels, including the use of supplements of unproven or questionable value without a specific diagnosis or clear clinical purpose for making use of them.

In animals with elevated CRP or Hpt levels, specific nutritional supplements (antioxidants, fatty acids, etc.) are administered to reduce harmful inflammatory proteins. Diseases know to be associated with inflammation, such as dental disease, arthritis, and allergies, are diagnosed and treated appropriately to reduce inflammation in the body. The blood is retested in one month and CRP/Hpt levels should have returned to normal. If they haven’t, further investigation is undertaken.

And finally, the author makes a number of strong claims about the prevalence of Vitamin D deficiency and the need for supplementation that are not supported by real evidence or accepted by veterinary nutrition specialists.

While pet food is formulated with enough vitamin D3 to prevent deficiency disease (rickets), the levels are too low for maximum health. Testing shows most dogs have blood levels considered insufficient for optimal health, and would benefit from supplementation. Once the vitamin D3 test results are available, supplementation is given with the goal of shooting for a blood level of 100 mg/ml (in studies, animals with cancers tended to have vitamin D3 blood levels lower than 100.) Additional testing is done to confirm if the prescribed amount of vitamin D3, typically given once daily with food, is enough to reach the recommended blood level.

While there is certainly evidence that dogs with cancers, and other diseases, often have lower levels of Vitamin D than healthy dogs, as in humans it has not yet been clearly shown that the low levels increase the risk of developing disease or that supplementation prevents it. The specific number this author recommends as a target comes from a single study of dogs with a particular kind of cancer. And Vitamin D supplementation has risks as well, so recommending it based on inadequate data is not appropriate or helpful.

When screening tests of unproven value is recommended, and all abnormal results are taken as an indication to prescribe (i.e. sell) supplements that also have unclear value, it is difficult not to see profit as a significant motive in the marketing of this test. And while I don’t doubt this individual believes he is finding, and then treating or preventing cancer with this approach, this does not eliminate the potential influence of the obvious profit potential in this approach, nor excuse the lack of concern for the very weak evidence behind the practice.

A more evidence-based answer to the question of how to respond to a positive test result simply isn’t available, which is one of the major reasons why this sort of testing is not widely recommended. Until it is clear that the test consistently identifies real disease at a stage where it is both otherwise undetectable and can be more effectively treated, the testing and the diagnostic or therapeutic followup is based on little more than speculation or intuition, not sound, science-based medicine. This is also the answer to our third question….

Will Testing & the Followup Prevent Illness or Prolong Life?

The answer, unfortunately, is no one knows. The current evidence suggests some of these tests could lead to more effective detection and treatment of some cancers. However, as I mentioned earlier, this has not yet been proven to actually be true for humans or veterinary patients. The majority of promising ideas in medicine fail to fulfil their promise, which is why thorough scientific research is vital. Leaping on the bandwagon too early might occasionally work out well, but the odds are far better that it will lead to taking useless or even harmful actions that later evidence clearly shows we would be better off not having taken. If this particular testing strategy does turn out to work well for at least some patients, the folks promoting it will naturally look like prescient geniuses. If, as is more likely, it turns out to be less useful than hoped or even worthless or harmful, most people will probably not notice as we will likely move right on to the next promising idea. But a careful review of medical history suggests that we could make much better decisions, for ourselves and our pets, if we waited until the evidence was a lot stronger. After all, we are talking about testing healthy animals with no signs of disease! How much should we really put them through in an effort to prevent diseases they may not get using a test and therapies we don’t know actually work? Let’s not forget our last question…

Can These Tests Do Any Harm?

As I’ve already mentioned, overdiagnosis is a real, and serious, risk. The data shows that the PPV for this test, the proportion of positive results that are actually true, is quite low. So we are going to identify a lot of animals as having a disease they don’t have. If we put these animals through a lot of expensive diagnostic tests or, even worse, subject them to untested treatments as suggested by some proponents of this screening test, then we will generate a great deal of unnecessary stress for pets and their owners and unnecessary expense for some clients, and we may even harm some of the pets we are trying to help.

Of course, we will certainly detect at least some animals who actually do have cancer. Isn’t this a good thing, and doesn’t this balance the possible expense and harm we might do? Unfortunately, we don’t really know the answer to this either. Since we can’t be sure that detecting these cases earlier actually helps them, there is no way to balance that against the costs and risks of the testing.

Bottom Line

Screening tests, which try to identify hidden disease in apparently healthy animals, can sometimes be beneficial. If these tests are sufficiently accurate, and if we have truly useful treatments to offer the cases we find, then we can use such screening to reduce disease and suffering. However, at the moment there is no such screening blood test for cancer in dogs and cats.

The specific tests suggested here, thymidine kinase, C-reactive protein, and Vitamin D, do have some potential value in testing for cancer and monitoring cancer treatment. The evidence, however, is very preliminary and does not clearly tell us that these tests, alone or in combination, are sufficiently accurate to find most hidden cancers and not misidentify too many healthy animals as having cancer. Much more research needs to be done before these tests can be recommended as part of soundly scientific and evidence-based medicine.

And there is little evidence that if we had such a test we could actually help the pets with cancer we identified live longer or healthier lives. In addition to working on developing good screening tests for cancer in dogs and cats, we will need to find out which treatments, if any, can help these pets to live longer and stay healthier once we find them. Given unproven herbal remedies and supplements to these animals, even if the tests showing they have hidden disease are correct, does not benefit them and may do harm.

It is natural to want a clear, simply way to reassure ourselves our pets are healthy, and to want effective treatments to give them if we find they have cancer even though they appear healthy. However, taking the best care possible of our animal companions does not mean subjecting them to testing which is unreliable and therapies which aren’t proven to be safe and effective. Good preventative health care means scientific, evidence-based healthcare, not chasing after comforting promises without real evidence.

The best strategy for preventing disease in our pets is to feed them nutritionally complete diets, maintain them at a healthy, lean body condition, keep up with appropriate preventative care for infectious diseases and parasites, and provide them with appropriate socialization and training, physical and mental exercise, and love. While less dramatic in some ways that blood tests, supplements, and other kinds of constant tinkering with their physiology, this is still the best preventative health care we can give our pets.

 Bibliography

There are many basic science articles investigating TK!, CRP, and Vitamin D in dogs and cats (mostly dogs). This is intended as a sample of the literature to illustrate the state of the existing evidence. There have not yet been systematic reviews of these tests and compounds for companion animals, but plenty of other studies are indexed on PubMed.

1. Vet J. 2013 Sep;197(3):854-60. doi: 10.1016/j.tvjl.2013.05.036. Epub 2013 Jul 4.

High levels of inactive thymidine kinase 1 polypeptide detected in sera from dogs
with solid tumours by immunoaffinity methods: implications for in vitro
diagnostics.

Kiran Kumar J(1), Sharif H, Westberg S, von Euler H, Eriksson S.

Determination of serum thymidine kinase 1 (STK1) activity has been used as a
proliferation marker for neoplastic diseases in both human and veterinary
medicine. The purpose of this study was to determine STK1 activity and enzyme
levels in different dog tumours. Serum samples from three dogs with leukaemia,
five with lymphoma, 21 with solid tumours and 18 healthy dogs were analyzed for
STK1 activity, using an optimized [(3)H]-deoxythymidine (dThd) phosphorylation
assay, and for STK1 protein levels using an immunoaffinity/western blot assay.
STK1 activity in dogs with haematological tumours was significantly higher than
in the solid tumour and healthy dog groups (mean ± standard deviation [SD] = 65 ±
79, 1.1 ± 0.5, and 1.0 ± 0.4 pmol/min/mL, respectively). Serum samples were
analyzed after immunoaffinity isolation by western blot and the TK1 26 kDa band
intensities quantified revealing that concentrations were significantly higher in
dogs with haematological tumours and solid tumours compared to healthy dogs (mean
± SD=33 ± 12, 30 ± 13, and 10 ± 5 ng/mL, respectively). Pre-incubation with the
reducing agent dithioerythritol (DTE) showed a decrease in STK1 activity and
protein levels in most samples, but an increase of about 20% in sera from healthy
dogs and from those with haematological malignancies. Compared to animals with
solid tumours, the specific STK1 activity (nmol [(3)H]-deoxythymidine
monophosphate (dTMP)/min/mg of TK1 protein of 26 kDa) was 30-fold higher in
haematological malignancies and 2.5-fold higher in healthy dogs, respectively.
The results demonstrate that there is a large fraction of inactive TK1 protein,
particularly in sera from dogs with solid tumours. The findings are important in
the use of STK1 as a biomarker.
2. Vet Comp Oncol. 2013 Jul 16. doi: 10.1111/vco.12052. [Epub ahead of print]

Serum thymidine kinase 1 and C-reactive protein as biomarkers for screening
clinically healthy dogs for occult disease.

Selting KA(1), Sharp CR, Ringold R, Knouse J.

Thymidine kinase (TK1) is a biomarker that correlates well with diagnosis and
prognosis in certain canine cancers. Canine C-reactive protein (cCRP) is a widely
accepted marker of inflammation correlated with increased risk and severity of
various diseases. We evaluated serum TK1 and cCRP concentrations in apparently
healthy dogs (n?=?360). All dogs were followed up for a minimum of 6?months by
health questionnaire. All dogs with cancer were identified using a proprietary
dual-biomarker algorithm [termed Neoplasia Index (NI)]. Specificity of positive
NI is 0.91 and high positive is 0.98. All-cause mortality was 20% in dogs with
elevated cCRP and 3% in dogs with low cCRP. The performance of serum TK1 and cCRP
as tools for screening for occult cancer is improved when evaluated together.
Serum TK1 and cCRP (unified in the NI) are useful in the screening of occult
canine cancer. cCRP is useful in screening for other serious diseases.

3. Vet Comp Oncol. 2013 Mar;11(1):1-13. doi: 10.1111/j.1476-5829.2011.00296.x. Epub
2011 Dec 8.

Thymidine kinase assay in canine lymphoma.

Elliott JW(1), Cripps P, Blackwood L.

The aim of the study was to evaluate if thymidine kinase (TK) correlated with
duration of first remission (DFR) or survival in dogs with lymphoma and if
initial TK levels correlated with stage and substage; and also to assess if TK
level at diagnosis correlated with immunophenotype. TK was assayed in 73 dogs
with treatment naïve lymphoma, then again after treatment; 47% had an initial TK
above the reference interval. Dogs with B-cell lymphoma had higher initial TK
activities than dogs with T-cell lymphoma. TK levels were not higher in dogs with
higher stage disease and TK activity prior to treatment was not associated with
DFR or survival. Where TK was elevated at diagnosis, it fell into the reference
range during remission. TK was normal in 53% dogs at diagnosis, which is higher
than previously reported. Further studies are warranted to assess the utility of
TK in dogs with lymphoma.

4. J Feline Med Surg. 2013 Feb;15(2):142-7. doi: 10.1177/1098612X12463928. Epub 2012
Oct 17.

Serum thymidine kinase activity in clinically healthy and diseased cats: a
potential biomarker for lymphoma.

Taylor SS(1), Dodkin S, Papasouliotis K, Evans H, Graham PA, Belshaw Z, Westberg
S, von Euler HP.

The thymidine kinases are enzymes that convert deoxythymidine to deoxythymidine
monophosphate and have a function in DNA synthesis. Rapidly proliferating cells
will have higher levels of thymidine kinase. Serum thymidine kinase activity
(sTK) is a useful tumour marker in humans and dogs, with utility as a prognostic
indicator in lymphoma. In the current study serum samples were collected from 49
clinically healthy cats, 33 with lymphoma, 55 with inflammatory disease and 34
with non-haematopoietic neoplasia (NHPN). sTK was measured using a radioenzyme
assay and a reference interval (1.96 × SD) was established from the clinically
healthy cats (<5.5 U/l). Mean sTK activity for healthy cats was 2.2 U/l (range
0.8-8.4, ± SD 1.7). Mean sTK activity for cats with lymphoma was 17.5 U/l (range
1.0-100.0 SD ± 27.4). Mean sTK activity for cats with NHPN was 4.2 U/l (range
1.0-45.0, SD ± 8.6). Mean sTK activity for the inflammatory group was 3.4 U/l
(range 1.0-19.6, SD 3.9). Cats with lymphoma had significantly higher sTK
activity than healthy cats or cats with inflammatory disease (P <0.0001) and cats
with NHPN (P <0.0002). sTK activity is a potentially useful biomarker for feline
lymphoma and further study is required to assess its utility as a prognostic
indicator.

5. Vet Comp Oncol. 2012 Dec;10(4):292-302. doi: 10.1111/j.1476-5829.2011.00298.x.
Epub 2011 Oct 20.

Elevated serum thymidine kinase activity in canine splenic hemangiosarcoma*.

Thamm DH(1), Kamstock DA, Sharp CR, Johnson SI, Mazzaferro E, Herold LV, Barnes
SM, Winkler K, Selting KA.

Thymidine kinase 1 (TK1) is a soluble biomarker associated with DNA synthesis.
This prospective study evaluated serum TK1 activity in dogs presenting with
hemoabdomen and a splenic mass. An ELISA using azidothymidine as a substrate was
used to evaluate TK1 activity. Sixty-two dogs with hemoabdomen and 15 normal
controls were studied. Serum TK1 activity was significantly higher in dogs with
hemangiosarcoma (HSA) than in normal dogs (mean ± SEM = 17.0 ± 5.0 and 2.01 ±
0.6, respectively), but not dogs with benign disease (mean ± SEM = 10.0 ± 3.3).
Using a cut-off of 6.55 U/L, TK activity demonstrated a sensitivity of 0.52,
specificity of 0.93, positive predictive value of 0.94 and negative predictive
value of 0.48 for distinguishing HSA versus normal. When interval thresholds of
<1.55 and >7.95 U/L were used together, diagnostic utility was increased. Serum
TK1 evaluation may help to discriminate between benign disease and HSA in dogs
with hemoabdomen and a splenic mass.
6. Int J Oncol. 2009 Feb;34(2):505-10.

Monitoring therapy in canine malignant lymphoma and leukemia with serum thymidine
kinase 1 activity–evaluation of a new, fully automated non-radiometric assay.

Von Euler HP(1), Rivera P, Aronsson AC, Bengtsson C, Hansson LO, Eriksson SK.
Thymidine kinase 1 (TK), which is involved in the synthesis of DNA precursors, is
only expressed in S-G2 cells. Serum TK levels correlate to the proliferative
activity of tumor disease. Determinations of TK levels have so far relied on
radio enzyme assay (REA) and experimental ELISA methods, which have limited the
clinical use of this biomarker, although recent studies in dogs with malignant
lymphoma (ML) demonstrate its wide potential. A non-radiometric method based on a
competitive immunoassay with specific anti-3′-azido-deoxythymidine monophosphate
(AZTMP) antibodies has been further developed into the fully automated Liaison TK
assay (DiaSorin). Sera from healthy dogs (n=30), and dogs with leukemia (LEUK)
(n=35), ML (n=84), non-hematological tumors (n=50), and inflammatory disease
(n=14) were tested using both methods. Lymphoma and LEUK samples were available
before and during chemotherapy. The coefficients of variation for the Liaison TK
assay in this study were 6.3 and 3.4% (low/high TK, respectively), and the
correlation between TK REA (X) and the Liaison TK assay (Y) was y=0.9203x+1.3854
(R2=0.9501). The TK1 levels measured during chemotherapy gave very clear
differences between dogs in complete remission and dogs out of remission. A
Tukey-Kramer analysis showed that all LEUKs and MLs out of remission differed
significantly from the other groups. The Liaison TK assay showed high precision,
high sensitivity and a good correlation to the TK REA. The Liaison TK assay
provides valuable clinical information in the treatment and management of canine
LEUK and ML, with a potential to be further validated in human trials.

7. J Vet Intern Med. 2004 Sep-Oct;18(5):696-702.

Serum thymidine kinase activity in dogs with malignant lymphoma: a potent marker
for prognosis and monitoring the disease.

von Euler H(1), Einarsson R, Olsson U, Lagerstedt AS, Eriksson S.

Serum thymidine kinase (sTK) activity was evaluated as a tumor marker for canine
malignant lymphoma (ML). The objective was to investigate if sTK, as in humans,
could be used as a prognostic marker for survival time in dogs with ML and if sTK
could identify early signs of progression of disease in treated dogs. Serum
samples from 52 dogs with ML were tested for initial TK activity. Samples from 21
normal dogs and 25 dogs with nonhematologic neoplasms were used for comparison.
Forty-four dogs with ML were treated. Serum TK activity was measured in treated
dogs before each treatment and every 4 weeks thereafter until relapse. Dogs with
ML had 2-180 times higher TK activity (TK 5-900 U/L) than normal dogs (TK <7 U/L)
based on the mean + 2 standard deviations. In the group of other neoplasms, only
2 dogs had a moderate increase (6.4 and 7.5 U/L) compared with the controls. Mean
sTK activities in the dogs with ML that had gone into complete remission (CR)
were not significantly different from activities in healthy controls (P = .68).
Mean sTK at least 3 weeks before and at the time of relapse was significantly
higher than activity measured at CR (P < .0001). Dogs with ML that initially had
sTK >30 U/L had significantly shorter survival times (P < .0001). Furthermore,
sTK activity reflected the clinical staging of ML. Measuring sTK can be used as a
powerful objective tumor marker for prognosis and for predicting relapse before
recurrence of clinically detectable disease in dogs with ML undergoing
chemotherapy.

8. J Vet Intern Med. 2004 Sep-Oct;18(5):595-6.

Serum thymidine kinase activity: an alternative to histologic markers of cellular
proliferation in canine lymphoma.

Madewell BR.

Thymidine kinase (TK) is a cellular enzyme which is involved in a ‘salvage
pathway’ of DNA synthesis. It is activated in the G1/S phase of the cell cycle,
and its activity has been shown to correlate with the proliferative activity of
tumor cells…. Clinical studies have reported high serum TK concentrations in a
variety of neoplasias. The majority of these studies concerned hematological
malignancies. TK seems to be a useful marker in non-Hodgkin’s lymphoma, where it
correlates with clinical staging and provides marked prognostic information on
(progression-free) survival.

PMID: 15515571  [PubMed - indexed for MEDLINE]
9. J Vet Med Sci. 1997 Oct;59(10):957-60.

Plasma thymidine kinase activity in dogs with lymphoma and leukemia.

Nakamura N(1), Momoi Y, Watari T, Yoshino T, Tsujimoto H, Hasegawa A.

Plasma thymidine kinase (TK) activity was evaluated as a plasma marker for canine
lymphoma and leukemia. A tentative “cut-off” value was set at 6.0 U/l as the
upper level of plasma TK based on the mean + 2SD of plasma TK activity in 13
clinically healthy dogs. The levels of plasma TK activity in all of the 20 dogs
with lymphoma and leukemia were higher than the cut-off value, whereas those in
dogs with lymphoma decreased in parallel with the reduction of the tumor mass
after chemotherapy. These findings suggested that estimation of plasma TK
activity can be used as a plasma marker for lymphoma and leukemia in the dog.

10. Vet Comp Oncol. 2014 Jul 8. doi: 10.1111/vco.12101. [Epub ahead of print]

Serum 25-hydroxyvitamin D concentrations in dogs – correlation with health and
cancer risk.

Selting KA(1), Sharp CR, Ringold R, Thamm DH, Backus R.

25-hydroxyvitamin D (25(OH)D) is important in bone health as well as many
diseases including cancer. Supplementation may increase responsiveness of cancer
cells to chemotherapy. Serum 25(OH)D, intact parathyroid hormone (iPTH) and
canine C-reactive protein (c-CRP) were measured in healthy dogs and dogs with
haemoabdomen. Regression analysis determined optimal 25(OH)D concentrations. In
healthy dogs (n = 282), mean iPTH concentrations correlated inversely (r(2) =
0.88, P < 0.001) to 25(OH)D concentrations. Variation in both iPTH and c-CRP
plateaued at 25(OH)D concentrations of 100-120 ng mL(-1) . Haemoabdomen dogs (n =
63, 43 malignant and 20 benign) had 25(OH)D concentrations ranging from 19.4 to
>150 ng mL(-1) . Relative risk of cancer increased with decreasing 25(OH)D
concentrations [RR = 3.9 for 25(OH)D below 40 ng mL(-1) (P = 0.0001)]. Serum
25(OH)D concentrations in dogs vary widely, and are influenced by dietary VitD
content. Serum vitD measurement can identify dogs for which supplementation may
improve health and response to cancer therapy.

11. Vet Parasitol. 2014 Jun 16;203(1-2):153-9. doi: 10.1016/j.vetpar.2014.02.001.
Epub 2014 Feb 25.

Serum acute phase protein concentrations in dogs with spirocercosis and their
association with esophageal neoplasia – a prospective cohort study.

Nivy R(1), Caldin M(2), Lavy E(1), Shaabon K(1), Segev G(1), Aroch I(3).

Spirocerca lupi, the dog esophageal worm, typically induces formation of
esophageal nodules, which may transform to sarcoma. Ante mortem discrimination
between benign and malignant esophageal masses is challenging. Serum acute phase
proteins (APPs) are utilized in diagnosis and prognosis of various canine
diseases as markers of inflammation. This study characterized serum APPs
concentrations in dogs with benign and malignant esophageal spirocercosis and
evaluated their accuracy in differentiating benign from malignant lesions.
Seventy-eight client-owned dogs with esophageal spirocercosis were included.
Serum C-reactive protein (CRP), haptoglobin, serum-amyloid A (SAA) and albumin
concentrations were measured upon diagnosis and follow-up visits, and compared
with healthy dogs, and between malignant and benign cases. Haptoglobin, CRP and
SAA concentrations were higher, and albumin concentration was lower (P<0.001 for
all) in infected dogs compared to healthy controls. Dogs with suspected neoplasia
had significantly higher CRP (P=0.011), haptoglobin (P=0.008) and SAA (P=0.05),
and lower albumin (P=0.012) concentrations compared to dogs with benign
esophageal nodules. APPs moderately discriminated between suspected malignant and
benign esophageal disease. None of the dogs with suspected neoplasia had
concurrent normal concentrations of all APPs. The present results indicate that
canine spirocercosis is characterized by an acute phase reaction, both at
presentation and during treatment. When concentrations of all four APPs are
within reference range, esophageal malignancy is highly unlikely. Although
concentrations of all positive APPs were significantly higher in suspected
neoplastic cases compared to benign ones, moderate discriminatory power limits
their clinical use. Neither APP was useful to monitor response to treatment.
12. Vet Rec. 2012 Jun 23;170(25):648. doi: 10.1136/vr.100401. Epub 2012 Jun 1.

Acute phase protein levels in dogs with mast cell tumours and sarcomas.

Chase D(1), McLauchlan G, Eckersall PD, Pratschke J, Parkin T, Pratschke K.

The acute phase proteins (APP) form part of a non-specific host response to
inflammation. They may be induced by a range of different causes, including
infection, inflammation, cancer and trauma. As they form part of the earliest
response to such insults, they have potential for early identification of
disease. In people, APP levels have been shown to correlate both with the extent
of disease and also the prognosis in several forms of neoplasia, including
prostate, oesophageal and colorectal cancer. As such, they can be used as
prognostic and monitoring tools. To date, similar studies in veterinary patients
have been limited, largely retrospective in nature and many are non-specific for
tumour type. The purpose of this study was to evaluate a panel of four APPs in
dogs with naturally occurring mast cell tumours (MCTs) and sarcomas to identify
in the first instance whether increased levels of individual APPs, or
identifiable combinations of APPs, was linked with the presence of disease. In
the patients with MCTs, C-reactive protein (CRP) and a-1 acid glycoprotein levels
increased, with a concurrent drop in serum amyloid A levels. In the sarcoma
patients, CRP, a-1 acid glycoprotein and haptoglobin were increased. These
findings suggest that specific solid tumour types in dogs may be associated with
specific changes in APP profiles.
13. Vet Clin Pathol. 2009 Sep;38(3):348-52. doi: 10.1111/j.1939-165X.2009.00139.x.
Epub 2009 Apr 16.

Evaluation of serum haptoglobin and C-reactive protein in dogs with mammary
tumors.

Planellas M(1), Bassols A, Siracusa C, Saco Y, Giménez M, Pato R, Pastor J.

Author information:
(1)Department of Animal Medicine and Surgery, Universitat Autonoma de Barcelona,
Barcelona, Spain. marta.planellas@uab.cat

BACKGROUND: In veterinary medicine, there is increasing interest in measuring
acute phase proteins as a tool in the diagnosis and monitoring of neoplastic
diseases. Although mammary neoplasms are the most common type of cancer in dogs,
acute phase proteins have not been extensively evaluated in dogs with mammary
tumors.
OBJECTIVES: The aim of this study was to evaluate serum haptoglobin (Hp) and
C-reactive protein (CRP) concentrations in the dogs with mammary tumors and
assess their potential association with malignancy.
METHODS: A retrospective study of dogs with mammary tumors was performed. Serum
concentrations of CRP and Hp were determined in healthy control dogs (n=20) and
dogs with mammary tumors before surgery (n=41). Mammary tumors were grouped as
carcinomas (n=24), fibrosarcoma (n=1), malignant mixed tumors (n=7), benign mixed
tumors (n=6), and adenomas (n=3). CRP and Hp concentrations were compared in dogs
with different tumor types and were also compared based on tumor size, lymph node
infiltration, skin ulceration, fixation to underlying tissue, and time between
tumor identification and removal.
RESULTS: Hp concentration was significantly (P<.043) higher in dogs with mammary
tumors (median 2.03 g/L, range 0.09-2.94 g/L) compared with controls (1.38 g/L,
range 0.08-3.00 g/L), but the range of values overlapped considerably. CRP
concentration was higher in dogs with carcinomas (4.70 mg/L, range 0.63-128.96
mg/L) vs controls (2.11 mg/L, range 0.25-6.57 mg/L) (P=.0008) and in dogs with
ulcerated skin (14.8 mg/L, range 5.7-128.9 mg/L, n=3) compared with those without
ulceration (2.4 mg/L, range 0.11-30.3 mg/L, n=38) (P=.048).
CONCLUSIONS: Serum Hp and CRP do not appear to have value in diagnosing or
predicting malignancy of mammary tumors in dogs. Higher CRP concentrations in
dogs with mammary carcinoma suggest a role for inflammation in this tumor type.

PMID: 19392756  [PubMed - indexed for MEDLINE]
14. J Vet Intern Med. 2007 Nov-Dec;21(6):1231-6.

Serum C-reactive protein concentration as an indicator of remission status in
dogs with multicentric lymphoma.

Nielsen L(1), Toft N, Eckersall PD, Mellor DJ, Morris JS.

BACKGROUND: The acute-phase protein C-reactive protein (CRP) is used as a
diagnostic and prognostic marker in humans with various neoplasias, including
non-Hodgkin’s lymphoma.
OBJECTIVE: To evaluate if CRP could be used to detect different remission states
in dogs with lymphoma.
ANIMALS: Twenty-two dogs with untreated multicentric lymphoma.
METHODS: Prospective observational study. Blood samples were collected at the
time of diagnosis, before each chemotherapy session, and at follow-up visits,
resulting in 287 serum samples.
RESULTS: Before therapy, a statistically significant majority of the dogs (P =
.0019) had CRP concentrations above the reference range (68%, 15/22). After
achieving complete remission 90% (18/20) of the dogs had CRP concentrations
within the reference range, and the difference in values before and after
treatment was statistically significant (P < .001). CRP concentrations of dogs in
complete remission (median, 1.91; range, 0.2-103) were significantly different (P
= .031) from those of dogs with partial remission (median, 2.48; range, 0-89),
stable disease (median, 1.77; range, 1.03-42.65), or progressive disease (median,
8.7; range, 0-82.5). There was profound variation of CRP measurements within each
dog.
CONCLUSIONS: CRP is useful in determining complete remission status after
treatment with cytotoxic drugs. However, the individual variation between dogs
means CRP concentration is not sufficiently different in other remission states
to permit its use in monitoring progression of the disease. Greater reliability
in determining remission status might be achieved by combining CRP concentration
with other serum markers.

15. Vet J. 2007 Jul;174(1):188-92. Epub 2006 Aug 9.

Changes in C-reactive protein and haptoglobin in dogs with lymphatic neoplasia.

Mischke R(1), Waterston M, Eckersall PD.

Acute phase proteins (APP) are regarded as a useful diagnostic tool in humans
with lymphomas, leukaemias and multiple myeloma. C-reactive protein (CRP) and
haptoglobin concentrations were measured in dogs with malignant multicentric
(high grade) lymphoma (n=16), acute lymphoblastic leukaemia (ALL) (n=11), chronic
lymphocytic leukaemia (CLL) (n=7) and multiple myeloma (n=8). Twenty-five healthy
dogs served as controls. Measurements of the CRP plasma concentration were
performed using a commercial ELISA and haptoglobin was measured with an assay
based on its haemoglobin binding capacity. Global group comparisons using
Kruskal-Wallis-test revealed significant group differences for both APPs
(P<0.0001). Median CRP concentrations were increased in all groups with
neoplastic lymphatic disorders (lymphoma: 37.2mg/L, ALL: 47.8mg/L, CLL: 35.5mg/L,
myeloma: 17.6mg/L) compared to controls (1.67mg/L; P<0.001). Compared to the
healthy controls (median=0.59g/L), haptoglobin was especially increased in dogs
with ALL (6.8g/L, P<0.0001) followed by dogs with malignant lymphoma (3.8g/L,
P<0.0001), CLL (3.2g/L, P=0.0008), and multiple myeloma (3.0g/L, P=0.0163). For
both APPs, a wide range of values was found in all patient groups. The results
indicate that particularly severe and acute lymphatic neoplasia, such as high
grade lymphoma and ALL, cause significant acute phase reactions in dogs and must
be included in the differential diagnoses of increased blood levels of these
APPs.

16. J Am Vet Med Assoc. 2007 Feb 15;230(4):522-6.

Serum C-reactive protein concentrations in dogs with multicentric lymphoma
undergoing chemotherapy.

Merlo A(1), Rezende BC, Franchini ML, Simões DM, Lucas SR.

OBJECTIVE: To determine whether serum C-reactive protein (CRP) concentration is
high in dogs with multicentric lymphoma, whether CRP concentration changes in
response to chemotherapy, and whether CRP concentration can be used as a marker
for relapse in dogs with multicentric lymphoma.
DESIGN: Cohort study.
ANIMALS: 20 dogs with multicentric lymphoma and 8 healthy control dogs undergoing
chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or with
vincristine, cyclophosphamide, methotrexate, and L-asparaginase (VCMA) and 20
other healthy dogs.
PROCEDURES: Serum CRP concentration was measured weekly during the first month of
chemotherapy and then at 3-week intervals until relapse in dogs with multicentric
lymphoma, weekly for 16 weeks in healthy dogs undergoing chemotherapy, and once
in the healthy dogs not undergoing chemotherapy.
RESULTS: For both groups of dogs with lymphoma, mean serum CRP concentration
during week 1 (prior to treatment) was significantly higher than mean
concentrations following induction of chemotherapy and at the time of relapse.
Mean serum CRP concentration in the healthy dogs undergoing chemotherapy was not
significantly different at any time from mean concentration for the healthy dogs
not undergoing chemotherapy. No significant differences were observed between
dogs treated with CVP and dogs treated with VCMA.
CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that serum CRP concentration
is high in dogs with multicentric lymphoma but that serum CRP concentration is
not a useful marker for relapse and that chemotherapy itself does not affect
serum CRP concentration.

19. J Vet Intern Med. 2005 Nov-Dec;19(6):865-70.

Preliminary studies of serum acute-phase protein concentrations in hematologic
and neoplastic diseases of the dog.

Tecles F(1), Spiranelli E, Bonfanti U, Cerón JJ, Paltrinieri S.

Serum concentrations of acute-phase proteins (APPs): haptoglobin (Hp),
ceruloplasmin (Cp), serum amyloid A (SAA), and C-reactive protein (CRP) were
determined in healthy dogs (n = 15) and dogs with different diseases grouped as
acute inflammation (I, n = 12), hematologic neoplasias (HT, including leukemia
and lymphoma, n = 16), nonhematologic neoplasias (NHT, including epithelial,
mesenchymal, and mixed, n = 20), and autoimmune hemolytic anemia (AIHA, n = 8).
SAA and CRP were analyzed using commercially available enzyme-linked
immunosorbent assay (ELISA) kits, and Hp and Cp were measured using colorimetric
methods, all previously validated for use in dogs. Increased concentrations of
all APPs were observed in all groups of diseased dogs, but statistical
significance only was observed with Hp (I, P < .001; HT, P < .05), Cp (I, P <
.05; AIHA, P < .01), and CRP (I, P < .001; HT, P < .001; AIHA, CRP P < .05). High
variability in individual APPs within each group of diseases was found with no
significant differences between leukemia and lymphoma as well as among different
types of neoplasia. The AIHA group had smaller increases in Hp, SAA, and CRP but
higher concentrations of Cp. When follow-up of individual cases was possible, a
decrease in APPs generally was found in cases with favorable outcome. The results
of this study suggest that neoplasia and hematologic diseases such as AIHA should
be considered as possible causes of mild increases in APPs in dogs. Measurement
of APPs may be helpful to assess clinical evolution and monitor treatment of
these processes.

20. Biochem Biophys Res Commun. 2003 Jan 31;301(1):212-7.

The canine mast cell activation via CRP.

Fujimoto T(1), Sato Y, Sasaki N, Teshima R, Hanaoka K, Kitani S.

We report here canine mastocytoma-derived cell (CMMC) activation via two
pentraxin, limulus- and human-CRP. Mast cell chemotaxis was measured by Boyden’s
blindwell chamber. To confirm that the cell migration was chemotactic,
“checkerboard” analysis was performed. We used Fura-2 to investigate CRP-mediated
cytosolic calcium elevation. To examine whether CRP-induced stimulation is
mediated through G-proteins, CMMC were incubated with pertussis toxin (PTx)
before use in chemotaxis assay and Ca(2+) mobilization. CMMC migration in
response to CRP was both chemokinetic and chemotactic. Limulus-CRP induced a
transient Ca(2+)-mobilization dose-dependently. Preincubation of the cells with
PTx inhibited CRP chemotaxis and Ca(2+)-mobilization, suggesting that G-proteins
of the Gi-class are involved in the chemotaxis. We suggest that CRP may
participate in the migration of mast cells to inflamed tissues during an
acute-phase response. CRP-mediated recruitment of mast cells might play an
important role in hypersensitivity and inflammatory processes.

 

 

Posted in General | 24 Comments

FDA Might Regulate Stem-Cell Therapies for Dogs & Cats: But Probably Not

I’ve written extensively, though not lately, about veterinary stem-cell therapies (1, 2, 3, 4, 5). These are treatments in which stem cells are injected into an animal to treat some disease. The most common current use is to inject stem cells extracted from a patient’s own fat in order to treat arthritis or other orthopedic problems.

The basic science research so far suggests these might turn out to be useful therapies for some conditions. There is, however, very little real-world clinical research to support using them. In humans, these therapies are not legal outside of special circumstances, typically research studies, because even most proponents of these therapies do not believe they have yet been adequately studied to justify widespread routine use. The evidence in dogs in cats is extremely sparse. So while I consider this a promising therapy worth studying, it is essentially experimental and unproven and so should be reserved for situations in which all better-understood options have been exhausted.

Veterinarians are frequently able to make use of therapies not permitted for human use for a variety of political and legal reasons. Technically, most therapies for pets are regulated in the same way as therapies for humans, and most should be subject to appropriate scientific testing and licensing before clinical use. However, the regulatory agencies (primarily the FDA and the USDA) recognize that evidence will always lag behind in veterinary medicine compared to human medicine, due to the lower priority and fewer available resources for studying potential therapies. Uncompromising, strict adherence to all regulations would leave few therapies available to vets. There is also little political will to support stricter enforcement given the general waning of confidence in government regulation in recent decades. So veterinarians are often able to provide therapies that are technically illegal with an understanding that these agencies will not enforce the rules in most cases.

While there are some good pragmatic reasons for this situation, it is often forgotten that the regulations exist for a purpose. Prior to the age of vigorous government oversight of medicine, people were routinely harmed and even killed by unsafe and ineffective medical and cosmetic products. This is why the FDA was created in the first place. Without enforceable requirements for appropriate scientific testing, such products tend to be marketed and used well beyond anything justified by available evidence. Not having been rigorously tested, they may well be ineffective or even harmful. This may be a chance worth taking under the circumstances, but we shouldn’t kid ourselves that this risk isn’t present.

The FDA is continuing this tradition with a recent draft statement on the regulation of stem-cell therapies in veterinary medicine. The statement does a number of useful things, including asserting the agency’s authority to regulate these products and establishing legal definitions related to the various kinds of therapies involved. However, the agency also inserts a little statement which suggests that since therapies applied strictly to pets rarely have a direct impact on human health or food safety, they don’t really intend to enforce any regulation of these products:

Autologous Type II (ATII) ASCPs for Non-Food Producing Animals

Although ATII ASCPs require an approved NADA, conditional approval or index listing to be legally marketed, FDA recognizes that these products pose a lower risk to human and animal safety than other categories of ASCPs when used in non-food producing animals and are, therefore, a lower enforcement priority.

While I recognize that rigid enforcement of regulations to the standard of human medicine would restrict the availability of therapies for companion animal use, there ought to be a middle ground between full enforcement and essentially no enforcement at all. Several companies currently profit from stem cell therapies aggressively marketed to vets and the public without much evidence of safety and efficacy. There is a reason such therapies cannot be legally marketed for human use. The uncertainty in the lack of data represents some real risks.

To their credit, some of these companies have conducted some clinical research on their products, though this is likely as much for the value of such studies in marketing to veterinarians as for the protection of patients. And as I’ve often said, there is definitely good reason to be hopeful some of these therapies will turn out to be truly beneficial. But nothing is without a downside, and so far the data isn’t there for us to confidently determine the risks and benefits of these products. It is encouraging that the FDA is recognizing a need to assert some regulatory oversight in this area, it will not help to protect the public or our pets from potentially ineffective or harmful therapies if no actual oversight is implemented.

Public comment on this statement will be accepted until September 30, 2014 at: regulations.gov (search for the docket number FDA-2014-D-0634). I have posted the following comment, and I encourage anyone interested in this subject to comment as well:

As a veterinarian concerned about the safety and efficacy of the treatments I employ, I support the FDA asserting regulatory authority in this area and establishing appropriate guidelines and definitions. However, despite the lack of direct risk to human health and food safety in the use of stem-cell therapies in non-food animals, a failure to enforce the requirements for pre-market testing and approval for these products leaves the public and their animals vulnerable to unproven claims of safety and efficacy as well as unforeseen health risks. These therapies are not permitted in humans without appropriate regulatory approval because it is understood that the absence of such evidence of safety and efficacy places patients at risk. The same is true for non-human animal patients.

In addition to protecting public health, premarket testing regulations are an important form of protection for the consumer of medical products. The marketing of stem-cell therapies in veterinary medicine frequently implies or directly makes claims of safety and efficacy not yet proven by appropriate research evidence.

While strict enforcement of pre-market testing to the standard for human medical products is not feasible and would restrict too severely access to potentially beneficial veterinary therapies, I believe some level of oversight is still called for. I encourage the FDA to amend this statement to allow for some flexibility in format and timeframe but to still require some form of NDA trials and licensing for these products.

 

Posted in Law, Regulation, and Politics | 5 Comments

What is “Integrative Veterinary Oncology” & can it be Evidence-Based?

An interesting article appeared recently in a widely-read veterinary journal that discusses so-called “integrative medicine” in veterinary cancer care in terms of evidence-based medicine (EBM). This article raises a number of interesting questions and concerns.

Raditic, DM. Bartges, JW. Evidence-based integrative medicine in clinical veterinary oncology. Vet Clin Small Animal 2014;44:831-853.

I’ve written about the notion of “integrative veterinary medicine” (IVM) before, and it is a highly problematic concept. These authors define it as “the use of complementary and alternative medicine (CAM) with conventional Western medicine systems.” This already contains some fallacies in that it labels science-based or “conventional” medicine as “Western,” which ignores the fact that the scientific approach to health and disease that underlies modern medicine has been developed and very successfully employed in all cultures around the world. While much of the development of modern science initially took place in Europe and North America, critical contributions to scientific medicine have come from many other places. And there is nothing intrinsically “Western” about scientific medicine. It has come to dominate medical practice around the world because of its demonstrable success, crossing cultural barriers rapidly and continuously.

This label also implies that the alternatives to conventional scientific medicine are fundamentally culturally distinct in origin and character. This may be true for some, such as Traditional Chinese Medicine (itself somewhat misleadingly named), but it is certainly not true for chiropractic, homeopathy, and many herbal and nutritional therapies which are include under the CAM umbrella and yet which were invented and practiced predominantly in Europe and North America.

In any case, defining IVM and the use of CAM along with conventional medicine begs the question of what CAM itself really is. As I’ve discussed before, it is largely an ideological category with little scientific meaning. It exists in part because of fundamental philosophical differences between CAM practitioners and proponents of science-based medicine, and partly to protect specific therapies in which proponents have personal faith from criticism and rejection regardless of the state of the scientific evidence concerning them. To call something CAM is not to define it, since many of the therapies included under the label are mutually incompatible in fundamental ways and have very different evidentiary profiles. The label signifies a particular kind of attitude and belief, not a real difference from the perspective of how or if one can demonstrate these therapies to be safe and effective using scientific means.

The authors further expand on their definition of IVM by defining CAM in terms of specific therapies they would include in the category and, tellingly, as anything “that are rational and supported by evidence to alleviate physical and emotional symptoms, improve quality of life (QOL), and possibly improve adherence to oncology treatment regimens.” This definition contains within it the assumption that these therapies are rational and supported by evidence. However, this often turns out not to be true for many of the practices included in the CAM fold, so this cannot be justly blithely assumed.

The authors then go on to justify the importance of knowledge about CAM therapies by pointing out some CAM therapies are widely employed. I agree, and I think it is vital that clinicians understand what the category itself is about and what the evidence says about specific therapies, though I suspect my conclusions would be quite different from those of the authors. They also acknowledge that the major drive for use of these therapies is psychological rather than based on any objective reason to expect they are safe and effective:

…human oncology patients use natural products to empower themselves, attempt to take control of their health… logically pet owners would apply these same emotions.

Once again, I agree, and I think it is important that veterinarians understand the roots of CAM use among our clients. This doesn’t mean, as the authors appear to imply, that we must support or encourage these practices, only that we must be knowledgeable about them and effective in understanding and communicating with our clients about their use. Often, if we are practicing truly evidence-based medicine, this communication is likely to involve discouraging the use of therapies for which there is no good reason to expect they are safe and effective.

 

The authors go on to acknowledge that the research evidence, particularly the most useful types of research, clinical trials, is scarce for most CAM practices. However, they imply that the reason for this is not the lack of a belief on the part of CAM practitioners that their therapies need scientific evaluation but simply a lack of funding for therapies that are not likely to be profitable:

Evidence-based research on CAM in an IM plan in veterinary clinical oncology is scarce, which is expected because large-scale research funding is typically provided for projects with potential for profits, such as with new, patented drugs.

This would seem to be contradicted by their own admission that, “In 2010, US herbal supplement sales exceeded $5.2 billion.” The reality is that CAM therapies are often very profitable. The reason herb and supplement manufacturers invest far less in scientifically evaluating the safety and efficacy of their products than to pharmaceutical companies is not because there is no profit to be made in these products but simply because the government does not require them to. Pharmaceutical products must demonstrate safety and efficacy to a certain, albeit imperfect, standard set by the FDA. Politics and ideology has led, however, to a different and far more lax standard for herbs and supplements, which are often assumed to be safe despite the abundant evidence that they can cause as much harm as conventional medicines.

In the absence of much clinical trial evidence, the authors place greater emphasis on less reliable kinds of evidence, such as in vitro and animal model studies and extrapolation across species. They hold out particular hope that metabolomics, the study of how the compounds and chemicals involved in metabolism are affected by particular diseases and interventions, such as herbs and supplements. While a great deal of useful knowledge can be gained by this kind of research, the study of such proxy markers for clinically relevant outcomes cannot substitute for clinical trials. The response of cancer cells in a petri dish or in a mouse to a purported cancer therapy have never proven to be very reliable indicators of the actual clinical response of cancer patients to the same therapy.

The rest of the article is largely a review of selected clinical and pre-clinical research on a few herbs, dietary supplements, and acupuncture. This is fine as far as it goes, but like any narrative review the only studies mentioned are the ones the authors, who are avowed proponents of such therapies, choose to discuss, so one has to bear in mind they may not be representative of the real state of the scientific evidence. In any case, what strikes me about this part of the paper is that the authors are describing the process of scientific evaluation of potential medical therapies from in vitro and animal model studies up through clinical trials. How, exactly, is there anything complementary or alternative about this?

What they describe is essentially the process of scientific, “Western” medicine, which routinely investigates the therapeutic and preventative value of such interventions. The only reason to call any of this alternative or distinguish it from conventional scientific medicine is to suggest that the use of these therapies should be somehow viewed differently from other medicines such as pharmaceuticals. The usual next step, which the authors never make explicit here, is to claim that these therapies should be open to use regardless of the state of the scientific evidence. They do, however, suggest that rather than evaluating the science for themselves as they would ordinarily do, veterinary oncologists should rely on the expertise and personal experience of veterinarians already using such therapies and already convinced of their value despite the lack of scientific evidence.

Collaboration between conventional oncologists and practitioners of IM, who have knowledge, experience, and training to use HDS and acupuncture, is needed to explore the possibilities of integrative veterinary…Although individual herbs are discussed here, integrative practitioners more often use herbal formulas and have identified safe, reliable sources of HDS products with known content; they also know possible interactions and understand dosing to prevent adverse effects. Veterinarians with this special training, education, and experience can be found through the organizations in Box 1.

The suggestion here is that these remedies can be viewed as “safe and reliable” and that adverse effects can be predicted and avoided despite the lack of scientific research simply because these veterinarians have personal experience in their use. This illustrates the underlying theme that occurs again and again in apologia for CAM. Proponents use language like “evidence-based” and promote supportive scientific research because these things have marketing value; they generate acceptance and the appearance of scientific validity. Yet in their hearts, the lack of scientific evidence for safety and efficacy does not diminish a confident belief in the safety and efficacy of these therapies. Science is a nice extra, something to convince the skeptics, but it isn’t seen as fundamentally necessary to the evaluation and safe use of these therapies. This attitude is incompatible with evidence-based medicine despite the appropriation of EBM terminology.

I appreciate the authors’ acknowledgement of the lack of convincing evidence to support the use of most CAM therapies in veterinary cancer care. And I agree that despite this, there is interest in such therapies on the part of clients. Veterinarians absolutely should be knowledgeable about these practices so they can guide and advise their clients. However, the appropriate response to the lack of good evidence for these practices is not to suggest that it cannot be obtained or that we can comfortably rely on individual experience and expertise instead.

Ultimately, for potential therapies with reasonable plausibility, the usual practice of science should be followed. Pre-clinical testing followed, if the evidence warrants, by clinical trials. Any use prior to the development of strong scientific evidence should be viewed as experimental, as likely to harm and to help the patient, and this should be clearly disclosed to clients. There is no reason to treat these therapies differently from any others or to give them special exemption from the usual standards of evidence.

 

 

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Testimonials Lie: More Evidence for Why You Can’t Trust Anecdotes or Personal Internet Reviews of Medical Treatments

By far the most common response to those posts I write questioning the claims for medical therapies advertised on the internet is a flood of testimonials from people who believe the scientific evidence is wrong or irrelevant because the product seemed to work for them and because so many people report it works. There are many reasons why anecdotes aren’t trustworthy, and I’ve written about this at length before. As psychologically compelling as our own experience are, and as hard-wired as we are to appreciate and believe stories more than data, the truth is that our uncontrolled observations are deeply unreliable.

Cognitive biases are a particularly significant part of the problem. These are little mental quirks and shortcuts that lead us to the wrong conclusions and to bad decisions. I’ve written about the effect of these biases on veterinary clinical decision making, and many, many books have been written about the specific details of these biases, how they work, and what effects they have on our reasoning**

A recent study has produced some specific and compelling evidence for the degree to which internet reviews of medical products grossly overestimate the actual value of the treatments being reviewed. The bottom line is that people who have positive experiences are far more likely to write testimonials than people who don’t, which creates a false impression of how well a therapy works, if it does at all.

Mícheál de Barra; Kimmo Eriksson; Pontus Strimling. How Feedback Biases Give Ineffective Medical Treatments a Good Reputation. J Med Internet Res 2014;16(8):e193)

The study first compared reviews of a diet plan on Amazon with results of clinical research on the same diet.

After 6 months on the diet, 93% (64/69) of online reviewers reported a weight loss of 10 kg or more while just 27% (19/71) of clinical trial participants experienced this level of weight change.

This figure shows the results of three clinical studies compared with those reported on Amazon. Clearly, the studies found consist results far less dramatic than those indicated by the online testimonials.

feedbakc bias and weight loss graph

The same phenomenon was found when evaluating a dietary supplement/herbal product supposed to improve fertility.

feedbakc bias and fertility graph

And when the investigators evaluated the influence of reviews on decision-making, they found that positive reviews did affect people’s choice of a weight loss plan.

feedbakc bias and choice graph

The author’s conclusions were:

We found that the reputed benefit of weight loss diets and fertility treatments is larger than the real benefit, apparently because people with typical or poorer outcomes are less inclined to tell others about their experiences. Thus, the real-world reputation of medical treatments seems to be subject to a reporting bias akin to the publication bias toward positive results that is seen in scientific research. Moreover, we found the resultant reputation distortion to be large enough to influence people’s decisions about which diet to begin…

Researchers have pointed out that several processes make it very difficult to identify benefits and harms of medical treatments when data are not systematically collected. In particular, treatments with no direct effect will sometimes appear effective because of the statistical phenomenon known as regression to the mean and the physiological phenomenon known as the placebo effect. It has also been suggested that treatments that prolong illness may, perversely, spread better because they are “demonstrated” for a longer period than effective treatments. Here, we have explored an additional mechanism, reporting bias, and its logical consequence: when people with poor outcomes remain silent, the reputed benefit of a treatment will exceed its real effect.

Though there are already more than enough nails in the coffin of the idea that anecdotes and testimonials can be trusted when making decisions about medical therapies, this study provides yet another solid reason not to rely on this kind of evidence. That will not, of course, stop people from responding to substantive, evidence-based critiques of specific products with pointless testimonials, but it will help remind all of us why these shouldn’t be taken very seriously.

 

**Brief Bibliography

Burton, R. (2008). On Being Certain: Believing You’re Right Even When You’re Not. New York: St. Martin’s Press

Carroll, RT. (2000) Becoming a Critical Thinker – A Guide for the New Millennium. Boston: Pearson Custom Publishing.

Gilovich, T. (1993). How We Know What Isn’t’ So: The Fallibility of Human Reason in Everyday Life. New York: The Free Press.

Kahneman, D. (2011). Thinking, Fast and Slow. New York: Farrar, Straus and Giroux.

Kida, T. (2006). Don’t Believe Everything You Think: The 6 Basic Mistakes We Make in Thinking. New York: Prometheus Books.

McKenzie, BA. Veterinary clinical decision-making: cognitive biases, external constraints,and strategies for improvement. Journal Amer Vet Med Assoc. 2014;244(3):271-276.

Park, RL. (2001) Voodoo Science: The Road from Foolishness to Fraud. Boston: Oxford University Press.

Sagan, C. (1995). The Demon-Haunted World: Science as a Candle in the Dark. New York: Random House.

Shermer, M. (1997). Why People Believe Weird Things: Pseudoscience, Superstition, and Other Confusions of Our Time. New York: Holt, Holt & Company.

Tavris C. Aronson, E. (2008) Mistakes Were Made (But Not by Me):Why we Justify Foolish Beliefs, Bad Decisions, and Hurtful Acts. Boston: Mariner Books.

Burch, D. (2009). Taking the Medicine: A Short History of Medicine’s Beautiful Idea and our Difficulty Swallowing It. London: Chatto & Windus

The Skeptic’s Dictionary

Veterinary Medicine and the Philosophy of Science

 

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Is Enough Ever Enough? Wasting Resources on Clinical Trials for Magic and Pseudoscience

A recent editorial from Trends in Molecular Medicine does an excellent job explaining why clinical trials testing the effects of highly implausible therapies, like homeopathy and energy medicine, are not an example of evidence-based medicine but of science tricked into serving as advertising.

Gorski DH. Novella SP. Clinical trials if integrative medicine: testing whether magic works?
Trends in Molecular Medicine 2014; In Press

Clinical trials are the last in a series of steps to evaluate potential therapies, and those that fail at earlier levels, or that have not been subjected to appropriate pre-clinical testing, should not be inflicted on patients. It is unethical and dangerously misleading to conduct such clinical trials.

When poorly designed and conducted, such trials generate spurious positive findings that mislead. When properly designed and conducted, they most often generate negative findings (read Snake Oil Science for numerous examples). However these negative studies do nothing to discourage the use of these therapies among proponents. Conducting such studies in hopes of finding a rare exception in which they prove effective and long-standing scientific principles are overturned is not an efficient use of limited resources for testing novel therapies. We should focus our energy on therapies that don’t conflict with well-established principles of basic science and which are promising on the basis of pre-clinical research. Most of these will fail at the clinical trial level as well, of course, but at least the odds are somewhat better than for trials on what amounts to magic.

This is relevant to veterinary medicine as well as human medicine, though as usual the scope of the problem is smaller. For example, conducting trials of homeopathic remedies for cancer (Banerji Protocol as Adjunct Nanotherapy for Treating Canine Appendicular Osteosarcoma: A Double Blind, Randomized Study Design), despite the overwhelming evidence that homeopathy is inconsistent with fundamental and well-established laws of physics and chemistry and has consistently failed pre-clinical and clinical testing (1, 2), is simply unjustifiable ethically and scientifically. It is an irrational use of limited resources for investigation of novel treatments.

Here is part of Dr. Gorski and Dr. Novella’s conclusion from the editorial:


In RCTs [randomized controlled clinical trials] testing modalities with low pre-test probability (i.e., low plausibility), confounding effects are vastly magnified, easily producing false-positives. In these days of extreme scarcity of research funding, it is difficult to justify spending precious research dollars carrying out RCTs of treatments where the likelihood of producing a true positive trial is so low and that have real risks that can lead to outcomes like the TACT or pancreatic cancer trials. All clinical trials, not just RCTs, should be based on scientifically well-supported preclinical observations that justify them, preferably with biomarkers to guide patient selection and follow-up. Until specific CAM and IM modalities achieve that level of preclinical evidence, RCTs testing them cannot be scientifically or ethically justified. That is science-based, rather than evidence-based, medicine.

Sadly, many of the vets I talk to, even those who are sincerely committed to science and evidence-based medicine, appear to still believe that conducting clinical trials on even the most egregiously pseudoscientific therapies is appropriate and will make a difference in whether these therapies are chosen by clinicians. There was a time when I believed this. Unfortunately, this view doesn’t reflect the reality of alternative medicine research.

The problem is that the clinical trial literature, which is often questionable in mainstream human medicine and frequently poor quality in veterinary medicine overall, is consistently abysmal when it comes to alternative medicine research. I have previously reviewed the positive literature presented by the Academy of Veterinary Homeopathy last year in defense of homeopathy, for example. It took many hours of locating and reading dozens of papers in detail to determine that this evidence was thoroughly unconvincing. And yet these poor quality studies are constantly put forward as supportive of continued clinical use for these modalities, and the majority of clinicians simply don’t have the time or interest to go beyond the abstracts and appraise them critically.

Such studies create the appearance of legitimacy, which is used to make such modalities more widely acceptable even when the literature doesn’t actually support efficacy. In some cases, for example in China, negative trials of alternative therapies are virtually never published, which illustrates the uniquely unreliable nature of this literature. It is effectively marketing rather than science.

So in light of this, clinical trials of highly implausible treatments don’t accomplish their ostensible purpose. They don’t accurately evaluate safety and efficacy, and they don’t discourage the use of modalities that are pretty clearly ineffective. The work of the National Center for Complementary and Alternative Medicine (NCCAM) is another great example. This agency has spent billions of dollars testing therapies that have not met basic preclinical plausibility criteria. The vast majority of these trials have found no evidence of efficacy. And these results have had little effect on the popularity or use of the modalities studied. (3, 4, 5).

Now of course by saying “alternative medicine,” I am lumping together many very different approaches, most of which are mutually incompatible theoretically as well as sometimes inconsistent with the mainstream scientific understandings of health and disease. But I am not suggesting none of these deserve to be evaluated in clinical trials. Many herbal remedies, manual therapies, dietary manipulations, nutraceuticals, etc. are quite plausible and can and should be evaluated scientifically like any other novel therapy.

But when talking about methods which could only work if fundamental scientific principles upon which much of our technology and medicine is based is wrong (e.g. energy medicine, homeopathy, the theoretical structures of TCM, etc.), or which have effectively been disproven already (e.g. homeopathy, magnet therapy) I can see nothing to gain from clinical trials. They will almost certainly be of low quality and evidentiary value, and even if negative they will not discourage the use of such therapies.

And yes, there are plenty of different evidentiary problems with conventional medicine. Pharmaceutical companies often shamelessly manipulate data, treatments like hyperbaric oxygen and stem cell therapy are rushed into use well before sufficient evidence is available to justify this, and so on. But clinical trials examining therapies which either can’t work, unless much of established science is wrong, or which have already been extensively tested and failed to show evidence of efficacy, are simply wasteful and misleading.

And from an ethical perspective, it is truly disturbing to see veterinary cancer patients treated with homeopathy, especially when otherwise respected individuals and institutions are involved.. I think this is unfair to the patients even in the context of a clinical trial when there is so much evidence in human medicine that there have been systematic reviews of the systematic reviews of research on homeopathy (which, as I have discussed previously, have shown that the positive results come only from inadequately controlled studies).

It seems fundamentally unethical to do work such as this in the name of science when it is clear that nothing short of a miraculous overturning of established science could allow for a positive result, and it is equally clear that no one who believes in homeopathy is going to give it regardless of a negative outcome in such a trial. Such research wastes resources, creates no clarity, does not allow for real falsification, and exposes patients to therapies for which there is really no reasonable expectation of a benefit.

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Thimerosal–Should I worry about mercury in vaccines for my dog or cat?

Many health concerns among pet owners reflect concerns regarding human health that have been extrapolated to the health of our pets. It is natural to assume, or at least suspect, that factors which influence human health also influence the health of our animal companions. This doesn’t always turn out to be true, but it often does. Given there is much more information and scientific evidence about health risk factors available in the human health field than in veterinary medicine, sometimes it makes sense to apply this information to health issues in our pets, though

We must always bear in mind the dangers of extrapolation between species with significant biological differences.

 

Concerns about the safety of vaccinations for children have been partly responsible for stimulating increased concern about the safety of veterinary vaccines. I have addressed this subject several times (e.g. 1, 2), but recently I was asked by another practitioner about a very specific vaccine safety issue—the risks, if any, of thimerosal.

 

Thimerosal is a preservative used in vaccines since the 1930s. Such preservatives which added to vaccines following several terrible incidents of children acquiring deadly infections from contaminated vaccines. It has been widely used since, and few health concerns have been raised until quite recently.

 

Following some of the first allegations that vaccines, in particular the MMR vaccine, might be associated with an increased risk of autism or other developmental disorders, the hypothesis was put forward that thimerosal might be responsible because it is a mercury compound, and other types of mercury compounds are known to have toxic effects on the nervous system.

 

Because of public concern about this, thimerosal was removed from most vaccines for children in the U.S. in 1999 pending additional research, a recommendation endorsed by the American Academy of Pediatrics. Subsequently, additional research and epidemiologic evidence following the removal of thimerosal from vaccines concluded quite definitively that there was no evidence of any increase in risk associated with this compound. The AAP withdrew their statement on removing thimerosal from vaccines in 2002 based on new evidence.

 

It is now established that vaccines are not the cause of autism in children, and there is no evidence that thimerosal is responsible for any significant health effects when used as a preservative in vaccines for humans (see also 3, 4, 5).

 

Thimerosal is present in some veterinary vaccines. I have not found any specific published research on the issue of whether this preservative has harmful effects when used as a preservative in vaccines for dogs or cats, apart from one study suggesting it can cause local irritation that might confuse the results of one kind of allergy test. The only study regarding thimerosal in vaccines looked at whether the thimerosal in vaccines influenced the mercury content of hair in dogs. This study found that thimerosal in vaccines did not increase the amount of mercury detected in the dogs’ hair, and that this mercury was primarily associated with eating foods containing fish.

 

I am not aware of any scientific evidence showing any significant health risks associated with thimerosal in veterinary vaccines. According to one toxicologist I contacted, there are no clinical studies in veterinary patients, but studies in laboratory animal research suggests no risks at the levels used in vaccines. This is consistent with the robust evidence in humans that thimerosal used in vaccines is not a health risk.

 

This has not stopped the more extreme voices in the anti-vaccine community from insinuating that thimerosal is a health risk for our pets despite the lack of evidence for this. There is at least one veterinary vaccine marketed as “thimerosal free,” and there is no harm in using such a vaccine. But there is also no reason to think this vaccine is any safer than those which do contain thimerosal, and there is no reason to expect your veterinarian to prefer it over other brands.

 

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Artemisinin-Is It a Useful Drug for Cancer Treatment in Dogs?

A couple of readers have asked about a purported cancer therapy agent called artemisinin. This is a compound derived from a plant and used for a variety of purposes in the system known as Traditional Chinese Medicine. It is sometimes recommended outside of this system as an herbal therapy for cancer, with the usual claims of dramatic benefits and virtually no risk of side effects. As we’ll see, the truth is more complex and more interesting than such simplistic claims.

What Is It?
A number of compounds have been identified in the plan known most commonly as Sweet Wormwood. Artemisinin is the most widely studied of these and the one most often claimed to have medicinal benefits. The usual forms in which the drug is given is as a dried herb or infusion (steeping the plant in water like tea).

It has been claimed to have benefits in treating cancer and fungal or parasitic infections in pets. It is also widely used, in conjunction with other drugs, in treatment of malaria in humans.

Does It Work?
There is no question that artemisinin has been useful in the treatment of malaria. Like any effective medicine, of course, it has been shown to have side effects (relatively low rates of nausea and vomiting, rare allergic reactions and possibly liver damage), and there is now evidence that malaria is developing resistance to artemisinin-based therapy.

The evidence for use in cancer therapy is not nearly as convincing (see also this review). There are a number of in vitro and lab animal studies showing potentially useful effects on cancer cells. However, this has been true for most cancer therapies that have gone on to be failures in actual clinical trials, so all it establishes is the possibility the drug might be useful, not that it actually is.

The next level of evidence is the case report, which is simply a formalized, published version of the anecdote. There are some case reports showing improvement in human cancer patients with use of artemisinin and related compounds (e.g. 1, 2). However, as with all anecdotes, these reports are subject to enormous risk of bias and confounding, and it is not appropriate to draw conclusions about the safety and efficacy of artemisinin from them. At most, they suggest the possibility that further, controlled testing is appropriate.

There isn’t much in the way of such evidence in humans. One clinical trial combining the compound with chemotherapy for lung cancer patients found no difference in terms of short, medium, or long-term survival. Some difference was seen in the rate of disease progression, but the reality and clinical relevance of this is doubtful, and the source is pretty questionable since it is a Chinese alternative medicine journal, and such journals appear to never publish negative results.

There is, similarly, virtually no clinical trial literature in veterinary species evaluating artemisinin as a cancer therapy. A clinical trial investigating the related compound artesunate as a therapy for lymphoma in dogs has recently been published:

J.N. Bryan, D. Tate, S.M. Bechtel, K. Choy, L. Donnelly, K. Fitzpatrick, B.K. Flesner, B. Fowler, B. Gallis, C.J. Henry, C. Herrera, M. Jabbes, K.A. Selting, T. Sasaki. Randomized, blinded, placebo-controlled trial of artesunate with doxorubicin for B-cell lymphoma of dogs. J Vet Int Med. 2014;28(4):1362.

Artemisinin has described anti-cancer properties. Artemisinin can down-regulate VEGF, HIF-1alpha, and survivin in cancer cells, causing apoptotic death. Artesunate, a water-soluble derivative, has better oral absorption in dogs than artemisinin. The hypothesis was that oral artesunate is tolerable with doxorubicin and results in longer disease-free interval (DFI) than doxorubicin and placebo in dogs with stage 3a or 4a B-cell lymphoma.

Twenty-one qualifying dogs were randomized (blinded) to receive artesunate 20 mg/kg or equivalent placebo. Dogs received study drug alone for 72 hours, then received 30 mg/kg doxorubicin q.3 weeks for three doses with study drug. Thereafter, lymph node measurement, CBC, chemistry profile, and urinalysis were monitored monthly until disease progression. Differences and DFI were compared by Mann-Whitney and Kaplan-Meier logrank tests. Significance was set at P ? 0.05.

Artesunate alone did not cause clinical remission (P = 0.1347). Artesunate induced no biochemical toxicosis. One dog experienced progressive disease following doxorubicin; all others experienced a complete response. Artesunate caused no greater neutropenia or thrombocytopenia following doxorubicin (P = 0.6234 and P = 0.2311). DFI was not different between groups (70d for placebo and 122d for artesunate, P = 0.967). Dogs receiving artesunate had higher nucleated red blood cell counts (median 272nRBC/100WBC artesunate and 9nRBC/ 100WBC placebo, P = 0.0142). Red cells displayed poikilocytosis and basophilic stippling in artesunate-treated dogs.

Artesunate did not cause remission as a single agent, nor improved DFI in dogs treated with doxorubicin. 20 mg/kg artesunate caused evidence of heme stress in treated dogs. Artesunate was otherwise well tolerated with doxorubicin. Artesunate cannotbe recommended as a therapy for B-cell lymphoma in dogs.

This trial, like that reported in humans, found no evidence that artesunate improved survival used in conjunction with chemotherapy, and it did not appear to have any beneficial effects used alone.

Another uncontrolled clinical trial in dogs was identified some possible toxicity as well as some possible benefits, but was the heterogeneity of patients and treatments make any firm conclusions impossible.

So far, the clinical trial evidence does not strongly support the preliminary in vitro and lab animal studies or case reports that suggested these compounds might have benefits in cancer patients. This is not unusual, since the vast majority of drugs fail to become useful treatments in actual patients even when they initially look promising in pre-clinical studies. More research may help clarify the value, if any, of artemisinin in cancer therapy.

Is It Safe?
A number of potential risks to artemisinin have been reported in humans and other species. Generally, side effects have been mild and rare in humans, with low rates of vomiting and other GI symptoms reported. There have been concerns about neurologic toxicity, including hearing damage, but it is not yet clear how significant this risk really is. In the context of malaria treatment, where there are clear benefits, the risks appear to be small enough in most cases (other than pregnant women and, possibly, young children) to justify use. However, the risks in cancer patients have not been established.

In dogs, there have not been safety studies in cancer patients either, however there is stronger evidence of risk with artemisinin use. One study of various forms and routes of administration found anemia, neurotoxicity, and changes in mitochondria. Other studies have also found significant toxicity at high doses (see also this study). However, other studies using different forms and dosages have not reported adverse effects.

Bottom Line
There is clear clinical trial evidence that artemisinin is useful in the management of malaria in humans, though there are some concerns about it losing its efficacy. Side effects are reported, but they are usually mild and uncommon.

There is some pre-clinical evidence (in vitro studies and lab animal studies) suggesting artemisinin and related compounds might have some benefit in cancer treatment. This is supported by a few uncontrolled case reports in humans. However, the limited clinical trial evidence does not generally support any real benefit for actual patients, human or canine. More research is needed to clarify whether there are circumstances in which the drug might be helpful, but it is by no means a reliable, proven cancer therapy.

Pre-clinical trials in dogs have found some potentially significant risks, which seem to be greater than those seen in humans. Some of these, such as changes in red blood cell production, have also been seen in the limited clinical trials done in dogs, but others have not.

Overall, there is enough evidence to support further controlled clinical research but not to use the treatment in patients outside the context of appropriate clinical trials designed to assess safety and efficacy.

Posted in Herbs and Supplements | 2 Comments

Routine Vaccinations for Dogs & Cats: Trying to Make Evidence-based Decisions

Introduction
As part of my effort to practice medicine based solidly in scientific evidence, I regularly review my own practices and recommendations and make adjustments as seems indicated by new evidence. The quantity and quality of scientific research in veterinary medicine is often less than ideal, so absolute right or wrong answers are seldom clear. But over time changes in the available evidence sometimes justify changes in practice. One area in which this has been particularly true in the more than 15 years since I started in vet school is the subject of vaccinations for dogs and cats.

Unfortunately, the vaccination issue is all too often taken out of the realm of rational, science-based discussion and made part of ideological battles over different approaches to medicine that have little to do with a sound assessment of the risks and benefits of vaccines. This is unfortunate and unnecessary, but given the politicized nature of this topic, I will begin by stating my basic perspective before getting into the details.

I believe vaccines are one of the most successful and beneficial healthcare interventions ever developed. Like any real medicine, vaccines have risks as well as benefits, but history is unequivocal that vaccines have saved and improved the lives of humans and animals to a degree that dramatically overshadows any harm they have done. Most of the opposition to vaccination in the last decade, for children as well as for pets, has been irrational, unscientific, and pretty thoroughly baseless. The kinds of dangerously misguided and misinformed anti-vaccine positions of all too many proponents of alternative medicine are not based in science and represent a serious threat to the health of our pets.

With all of that said, the mainstream veterinary approach to vaccination has often not been soundly based in science either. Habit, inertia, and economic considerations have led some vets to ignore growing scientific evidence and continue giving some vaccines more frequently than necessary. The latest data I have been able to find, which is from 2006, suggests up to a third of small animal vets give certain core vaccines more often than is recommended (I’ll get into the details in a bit). This is far fewer than the majority sometimes claimed by critics of science-based medicine, but it is still an illustration of the resistance to change in routine practices even when good evidence supports the change.

So what does the evidence say about vaccinations for dogs and cats? What should they be vaccinated for? With which vaccines? How often? Not surprisingly, these are complicated questions with complicated, nuanced answers. Simple, one-size-fits-all rules may be convenient, but they don’t reflect the complex nature of biology. The best review so far of vaccination research concerning dogs is the 2011 American Animal Hospital Association Guidelines on Canine Vaccinations. For cats, the 2013 American Association of Feline Practitioners Vaccination Advisory Panel Report is a useful document. Both of these are consensus statements issued by a limited group of experts, and they don’t meet the standards of a fully transparent, systematic review of the evidence. But they do provide a good summary of existing research and a reasonable interpretation of the how the research might translate in vaccination practices.

Vaccination, like any medical therapy, needs to address the specific needs of the individual patient. One cannot make a decision about which diseases to vaccinate against until one has some understanding of which diseases a patient is at risk of getting. This involves considerations such as age, exposure to other animals, general health, and so on. Unfortunately, the specific risk of a particular disease in a given setting is not always known since there are no regular, systematic or comprehensive surveys of how common most cat and dog diseases are everywhere in the country. However, some general guidelines and the experience of practitioners in a given area can help give a crude idea of whether a particular patient is likely to be at risk for a particular disease and to benefit from vaccination for it.

Dogs
The AAHA guidelines for dogs categorizes vaccines as core, those that are most likely to be widely beneficial, because the diseases they protect against are common, and non-core, those which are only appropriate for dogs with specific know risk factors for a particular disease. The guidelines also assess the general efficacy and safety of particular vaccines and the available information on duration of protection, which helps us decide how often to repeat particular vaccines.

Based on this information, most puppies should have a series of vaccinations for canine distemper and parvovirus every 3-4 weeks from about 6 weeks of age to 16-18 weeks of age, one rabies vaccination after 12 weeks of age and boosters for these one year after the last in the puppy series.

Duration of protection is at least 3 years for most licensed canine rabies vaccines, and they are legally required in most places every three years for life. From a medical point of view, a reasonable argument can be made for less frequent rabies vaccination or for alternatives, such as monitoring antibody titers. But in most cases these alternatives are not legally permitted. This is a function of the fact that rabies is widely present in wildlife and nearly 100% fatal for humans (and all other mammals) who catch it, so the public health authorities choose to err on the side of caution when using vaccines to prevent transmission from dogs to humans.

Some research efforts are under way to try and support changes in these laws, so these rules may be altered at some point. However, it is important to remember that while the evidence suggests less frequent vaccination for rabies might be effective in protecting dogs (and humans), it also suggests that the current guidelines of revaccination every three years is safe and very, very unlikely to harm most dogs. While I would welcome an evidence-based change in the rules regarding rabies vaccination intervals, I do not think there are risks that justify defying the rules in the meantime.

For distemper and parvovirus, the other core vaccines, there is strong evidence that protection for most dogs lasts at least 5 years, and pretty good evidence for longer duration of immunity. The guidelines recommend repeating vaccination no more than every 3 years, and 3 years is the interval most commonly used today. However, longer intervals are probably justified. There is certainly no need for annual boosters, and this is a practice that really isn’t defensible scientifically.

Antibody titers can be useful in some cases, since a high titer does indicate a dog is protected and does not require additional vaccination. However, a low titer does not necessarily mean a dog is susceptible, so it is less useful in trying to decide when to revaccinate.

Given the length of protection, and some evidence that susceptibility to parvovirus is low in older dogs, most probably do not need to be vaccinated after about 8-10 years of age. There is clear evidence that older dogs do respond appropriately to vaccinations, and there is not evidence that they are more likely to be harmed by vaccines than younger dogs, so continuing to vaccinate after this age is not likely to be harmful, but it is probably unnecessary. In humans, there is evidence that older people may be more susceptible to some diseases than younger adults, and thus may be more in need of vaccination, but this hasn’t yet been demonstrated in dogs.

Given the degree of safety for most of these vaccines, if there is significant uncertainty about whether a given dog is protected or has had appropriate vaccination for these diseases, giving the vaccine is safer than not giving it.

The AAHA guidelines cover in detail many of the other available vaccines. Most are not regularly recommended, usually because the diseases they protect against are mild or uncommon or because the vaccines are of poor or uncertain effectiveness. Some are quite controversial, such as that for Lyme Disease. Most are only appropriate for dogs with particular risk factors, not for routine use on all dogs.

Cats
The AAFP guidelines for cats are similar to the AAHA canine recommendations, identifying core and non-core vaccines and providing general guidelines for use of these as well as suggestions for how to develop individualized vaccination recommendations. Most cats should have a series of vaccines for feline herpes virus (FHV) and calicivirus (FCV) and panleukopenia (FPV) between 6 and 20 weeks of age and boosters for this one year later. Thereafter, 3-year intervals are recommended for life, though there are a variety of factors that may alter this plan.

Feline leukemia vaccination is also recommended for most cats. While many indoor only cats may not be exposed to this disease, the recommendation is for all cats to have an initial vaccine and one year booster because it is not always possible to predict future lifestyle or exposure status for kittens. Boosters are recommended every 1-2 years depending on risk of exposure. Recommendations for other vaccines depend on the needs of individual cats. Other vaccines are assessed on a case-by-case basis.

In general, I recommend following these guidelines for the initial vaccine series and the one year booster. I often cease vaccination for strictly indoor cats after that, however this involves a thorough discussion of the possible risks. If a cat escapes every once in a while, for example, they should certainly be kept current on rabies vaccination. And, of course, if there are legal requirements for rabies vaccination, these should be followed. Cats that visit other cats or have visitors or new cats come into the household, cats who attend shows or are boarded, and cats with owners who interact with cats outside the household may benefit from vaccination even if they are strictly indoors.

The risks of vaccination are generally similar in cats as in dogs, and very small, with one significant exception. The evidence is stronger for the development of a very serious kind of cancer, called a sarcoma, associated with some vaccines in some cats. The risk of this is still very low (reported to occur following as few as 1/10,000 doses of vaccine to as high as 36/10,000 doses), but it is a very dangerous and often fatal disease. Changes have been made in the vaccine used in cats to try and reduce this risk, but it isn’t absolutely clear if these changes have lowered the risk. This disease needs to be considered when making vaccination decisions for individual cats, and certainly we need to make a serious effort to avoid unnecessary vaccination. However, irrational fear of this disease is not a good reason to subject cats to unnecessary risk from equally serious infectious diseases by avoiding appropriate vaccinations.

Conclusions
Because the scientific evidence is never perfect or complete, it is not unusual for different individuals to have different interpretations of it, and more than one of these may well be reasonable and appropriate. For example, I tend to recommend distemper and parvo boosters every five years, but there is nothing wrong with recommending these every three years.

On the other hand, the evidence is often sufficient to make some interpretation unreasonable. Annual boosters for these vaccines are almost never justified, and complete avoidance of them, or refusal to vaccinate adult dogs is not sound medical practice. The evidence may not always provide a single right answer, but it can help establish a range of reasonable options from which to choose.

My own vaccination practices have changed significantly during my career as a result of both changes in the evidence and new assessments of existing studies. The practice of evidence-based medicine requires regular re-assessment of the interventions we offer. Unlike in some domains, such as politics, changing one’s mind in science is understood to be a good sign, and indication that a good clinician is committed to providing the best science-based care possible. I always emphasize in this blog that our patients and clients deserve the best care, and that care is going to be treatments for which we have as much scientific evidence as possible to understand the real risks and benefits.

This applies to all veterinary interventions, conventional as well as alternative. I tend to focus on alternative therapies here partly because there is so little skeptical, critical information about them available to help pet owners make informed decisions and also because, frankly, they are quite often far less founded in science-based theory and evidence than conventional approaches. However, the same scientific standards of evidence should apply to all treatments regardless of their provenance. Accepted conventional practices need to be scrutinized as closely as alternative therapies. When there is some uncertainty about the evidence, I endeavor to apply this scrutiny just as I do for unconventional treatments. My articles concerning neutering, cruciate ligament disease, and stem cell therapy, in addition to this and previous discussions of vaccination, are examples of this.

Since my position on vaccines tends to be very similar to that of many proponents of alternative therapies, I thought it would be useful to discuss it explicitly here. There is a tendency to caricature and demonize those with whom we disagree on issues we feel strongly about. It is often assumed, for example, that I blindly give all dogs annual vaccinations because this is a stereotype image of veterinarians who are critical of alternative therapies. But of course a science-based evaluation of an intervention like vaccination can and should be every bit as thoughtful and focused on the needs of the individual and the risks and benefits of the intervention as alternative practitioners claim they are. I believe the science does not support annual boosters for core canine vaccines, so I no longer recommend them.

Similarly, it is tempting to assume all proponents of alternative therapies hold the most extreme anti-vaccine views espoused by members of their community, but that is likely inaccurate and unfair also. I see no reason to shy away from points of agreement with folks on some issues even when one has serious disagreement with them on others. Hopefully, such points of agreement might even act as bridges to allow more realistic and respectful communication and disagreement, though my experiences in this area haven’t led me to be very optimistic about that.

In any case, it happens that I often agree with the criticism of vaccination practices put forward by proponents of alternative medicine, if not always on the basis of the same reasoning or evidence. This will likely neither tarnish my credibility with skeptics nor improve it with proponents of alternative medicine, but hopefully it will illustrate that I am committed to following the evidence over ideology as best I can.

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