Book Review- Age Later by Dr. Nir Barzilai

Dr. Nir Barzilai is a well-known researcher and advocate for longevity studies. He is an MD and the founder or driving force behind many geroscience institutes and initiatives. In 2020, he also became one of a growing number of scientific figures in the aging biology field who have written popular books on the subject for the general public.

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Among the aging science books I have reviewed so far, this one is the most casual and conversational. It conveys the impression that the reader is sitting in a living room as a relaxed but enthusiastic Dr. Barzilai shares anecdotes, recollections, and opinions over a few glasses of wine. This approach has both advantages and disadvantages. 

The material is easy to read and not overly technical or full of scientific jargon. It is also very loosely organized, even a bit rambling at times, and it is heavy on anecdotes and opinions and light on evidence and critical assessment. One could easily come away with the impression that every idea, every hypothesis about aging is exceptionally promising and that radical transformation of human lifespan and healthspan is just around the corner. Unfortunately, that is probably not the most accurate picture of the field, and it glosses over the complexity of aging biology and the scientific challenges of significant lifespan extension. 

Dr. Barzilai does talk quite a bit about the political and financial challenges, going so far as to say “the only thing standing between [a world of healthy, productive elderly people] and the one we have is money.” Much of the book is about commercial ventures he has been involved in that hope to turn promising scientific hypotheses into readily available therapies and products at warp speed; much faster than the painstaking, laborious processes of non-profit scientific investigation and regulatory approval. Again, the reader gets a very clear impression (accurate or not) of Dr. Barzilai’s personality and views on the best way to move forward with geroscience. Though he is a well-respected scientist who has made significant contributions to aging biology, he seems a bit impatient with the speed of progress and inclined to suggest the market could do a better, or at least faster, job of capitalizing on the scientific possibilities with sufficient funding and less conservative regulatory constraints.

The book shares many anecdotes about the human experience of aging, and this fits well with one of the central stories, which is Dr. Barzilai’s work with centenarians attempting to uncover the secrets to their exceptional longevity and health. The predominant message coming from this work appears to be the importance of genetic factors in protecting some individuals against aging and age-related disease. This may disappoint some readers looking for tips to improve their own health and lifespan, but Dr. Barzilai also provides plenty of these. Despite the appropriate caveats about not blindly following his example, he shares with his friend Dr. David Sinclair a willingness to try out new treatments on himself long before the scientific evidence and the drug approval system endorse doing so, and he shares many of these in this book.

In several of these reviews, I have talked about the tricky balance of skeptical optimism. As researchers in a relatively new and rapidly changing field, we must be sufficiently hopeful and open-minded to take up and test new ideas, even with relatively little to go on at first. However, such enthusiasm can easily carry us beyond the boundaries of rigorous science and good sense if we don’t balance it with appropriate skepticism. Particularly when writing for a non-science audience, it is easy to convey the false impression that big problems are easy or on the verge of being solved or that we already have good reason to put treatments into use that, in reality, we have not yet proven are effective or safe. Striking the perfect balance, to sustain excitement and energy without giving in to wishful thinking, is a difficult and ongoing challenge in the field.

Dr. Barzilai leans a bit too far to the side of enthusiasm over skepticism for my taste. He lists many approaches as “promising” even when the evidence or scientific rationale for these is pretty weak. Reasonable advice about exercise and diet are mixed in with questionable ideas about supplements and fasting, and even some pretty fanciful stuff about the benefits of pseudoscience like reflexology or the claim that prayer can lengthen telomeres. In the long list of ideas put forward in the book, little meaningful distinction is made between science, speculation, and fantasy, and that has significant potential to create a misleading picture for many readers.

Overall, Dr. Barzilai’s book is an engaging, relaxed, and relatively personal look at the aging biology field. It skims the surface broadly with limited scientific depth and it leaves a positive, rosy picture of the state of the field. While Age Later may not be the most scientifically detailed or critical assessment of the field, it is easy to see why Dr. Barzilai has been so successful at organizing and leading geroscience research efforts and finding funding for his endeavors. These activities require the kind of exuberance and optimism that comes across quite clearly in his book. 

Posted in Aging Science, Book Reviews | 1 Comment

Managing Sepsis: A Rational Approach & the Vitamin C Controversy

Introduction
Sepsis is currently defined as a life-threatening organ dysfunction secondary to a dysregulated physiologic response to infection. There are widely used, evidence-based guidelines for diagnosis and management of sepsis in human medicine,1but there is no single guideline or consensus statement on sepsis management in veterinary medicine. The guidelines most veterinarians follow, and those which we use at my hospital, are derived from expert opinion and the adaptation of human sepsis protocols employed at several academic veterinary institutions

Management of sepsis is a great example of the challenge of practicing evidence-based medicine in an evidence-poor environment. Extrapolation from evidence in humans and reasoning from physiologic first principles are rational and necessary strategies, but of course they sometimes lead to practices which turn out to be ineffective or even counterproductive in veterinary patients. Such approaches should always be viewed as a starting point, a provisional strategy pending the development of better evidence in clinical studies of the target patient population.

Human medicine, though often blessed with much higher quality evidence that we can typically expect, still finds itself mired in controversies over questionable practices that become widespread despite limited or poor-quality evidence and which later turn out to have been ineffective. A condition such as sepsis, which is acutely life-threatening and for which no universal, highly-effective therapy is yet available, is fertile ground for such disputed approaches. These often spill over into veterinary medicine when we adopt new practices in human patient care, and it is important for us to keep an eye on the evolution of ideas and evidence regarding such practices. In the case of sepsis, for example, the use of Vitamin C, alone or in combination with steroids and other vitamins, is an example of a controversial practice that has been ported into our patient care protocols to some extent based on limited, and controversial, early evidence and which we may now want to rethink.

Diagnosis of Sepsis
Confirming sepsis and identifying a source of infection can be challenging. However, the emphasis in sepsis management is now on early initiation of therapy since this has been associated with lower mortality in human patients, so diagnostic criteria have been developed to favor rapid diagnosis and therapy. Based on the definition of sepsis given above, a tentative diagnosis of sepsis should be made whenever there is a known or suspected infection and evidence of organ dysfunction or a systemic inflammatory response. Suspicion of infection should be based on history and physical examination findings. Suggested criteria for identifying organ dysfunction and an inflammatory response in dogs and cats, adapted from those used in humans, include:

Therapy
The emphasis on early intervention for sepsis has led to the development of treatment and monitoring “bundles,” that is sets of tests and treatments to be implemented universally when sepsis is suspected. There are no validated guidelines or consensus statements to define sepsis bundles in veterinary patients, however many institutions use treatment protocols adapted from those recommended for humans. The priorities for sepsis treatment are:

  1. Early institution of antibiotic therapy2
  2. Hemodynamic stabilization
  3. Identification and control of the source of infection
  4. Supportive care and recovery

Immediate Therapy for Sepsis

Following a tentative diagnosis of sepsis, recommended immediate care should include:

  1. Culture samples- Samples for culture should be obtained before antibiotic administration if this does not delay the use of antibiotics more than 45 minutes. Samples should be specific to the site of infection if this has been identified and can be accessed. If the site is unknown or inaccessible, blood cultures and urine cultures can be taken. Both aerobic and anaerobic cultures should be run.
  2. Antibiotics- A de-escalation approach is currently favored in the treatment of human sepsis patients. This involves early initiation of broad-spectrum antibiotic therapy and then a reduction in antibiotic coverage as soon as possible as indicated by culture results. Recommended duration of antibiotic therapy for humans is 7-10 days unless the source of infection cannot be definitively controlled

    There are no evidence-based guidelines for antibiotic use in veterinary sepsis patients. Ideally, antibiotic selection should be based on culture results, local population susceptibility patterns, and the history and condition of the individual patient. Common empiric protocols used in veterinary sepsis patients include:
  • Ampicillin/Unasyn + Amikacin
  • Ampicillin/Unasyn + Enrofloxacin
  • Cefazolin + Cefotaxime
  • Cefoxitin 
  • Clindamycin + Enrofloxacin 
  • Lactate Measurement- Lactate is an important biomarker for sepsis management. Values > 2.5 mmol/L should be interpreted as an indicator of inadequate perfusion.
  1. Fluid therapy- Crystalloids are the initial fluid of choice, and aggressive fluid therapy (e.g. boluses of 20-30mL/kg over 15 minutes) should be initiated for patients with evidence of hypotension (e.g. MAP< 65mmHg) or poor perfusion (e.g. lactate > 4.0 mmol/L or consistent physical exam findings) unless there is a clear contraindication (e.g. primary cardiac disease, evidence of overhydration). Fluid therapy should be titrated to endpoints, including:
  2. Normalization of heart rate
  3. Normalization of respiratory rate
  4. Normalization of blood pressure (MAP> 65mmHg, systolic > 100mmHg)
  5. Normalization of lactate (< 2.0mmol/L)
  6. Normalization of mentation
  7. Normalization of urine output (UOP> 1mL/kg/hr)

Hetastarch is not recommended in human sepsis patients due to some evidence of increased mortality and risk for acute kidney injury. It is unclear the extent to which this applies to veterinary patients,3 however many experts recommend avoiding synthetic colloids if possible. Canine albumin is preferred as a colloid, though it is often unavailable or unaffordable. 

Additional Therapy

  1. Continued hemodynamic stabilization- If the targets for fluid therapy (blood pressure, lactate, etc.) are not met with initial crystalloid treatment, vasopressors should be started early because hypotension in sepsis is often due to decreased peripheral vasomotor tone. Based on guidelines for humans and limited evidence in veterinary patients, the following are common recommendations for use of vasopressors in sepsis patients:

Warning! Some vasopressors can cause ischemic necrosis due to extreme vasoconstriction. They should ideally be given through a central line, and clients should be advised of this possible complication.

  • Norepinephrine- 0.1-0.5mcg/kg/min Start low and titrate upwards in 0.1mcg/kg/min increments every 5-10 min until BP targets are reached (e.g. MAP>65mmHg) or 2-3mcg/kg/min is reached.
  • Vasopressin is often recommended as a second-line pressor or to reduce the dose of norepinephrine in humans, but it is often unavailable to veterinary patients due to cost.
    • Epinephrine-  0.05- 1mcg/kg/min. This can be added to norepinephrine if needed and titrated upwards every 5-10 min until BP targets are reached.
    • Dopamine- This drug has historically been the pressor of choice in veterinary patients, but recent practice has shifted to norepinephrine based largely on extrapolation from research in human sepsis patients. 
    • Dobutamine- This is primarily an inotrope and is only recommended if there is evidence of poor contractility because it decreases vascular tone and can decrease BP

It is important to identify all physiologic abnormalities that can be treated in patients with sepsis and septic shock. These may include:

  1. Electrolytes
  2. Blood Glucose
  3. Lactate
  4. PCV/TP/albumin
  5. Coagulation- PT/PTT/platelet counts 
  6. Blood Pressure
  7. Vital signs- HR, RR, body temperature, pulse quality, mm color, CRT
  8. SPO2
  9. ECG
  10. Pain Score and mental status- Analgesia should be provided if there is  evidence of pain. NSAIDs should be avoided if there is hemodynamic instability or evidence of GI or renal impairments.
  11. Urine output and renal values
  12. Body weight- this is a key measure for assessing fluid balance

    Other Therapies
  • Gastroprotectants- (e.g. pantoprazole) 
    These can be considered if there is evidence of gastrointestinal lesions or symptoms
  • Anti-emetics- (e.g. maropitant, ondansetron) 
    These can be considered if there is evidence of nausea or vomiting.
  • Promotility drugs- (e.g. metoclopramide, low-dose erythromycin) These can be considered if there is evidence of GI hypomotility or ileus.
  • Blood products- 
    There is significant controversy and uncertainty regarding the use of blood products in septic patients. Strict arbitrary cutoff values for use of blood products are now discouraged in human patients due to growing evidence of harm related to transfusion. There are no clear guidelines for veterinary patients.
  • Treatment of Anemia- 
    Most critical patients become anemic at some point. Anemia should be treated when associated with significant clinical symptoms (e.g. hypoxia, tachypnea/tachycardia), ongoing losses of red blood cells, or anticipated losses associated with surgical source control procedures.. Though strict cutoffs are discouraged, a Hb of 7.0g/dL is often used as a guideline for when to transfuse in human sepsis patients.
  • Treatment of Thrombocytopenia- 
    Platelet-rich plasma is given to humans when there is clinical evidence of bleeding (e.g. petechiae, ecchymoses, epistaxis), when a surgical procedure is planned and platelet count is < 50k/mm3, or prophylactically when platelet count is <10k/mm3.
  • Treatmwnt of Coagulopathy- It is not recommended to give fresh-frozen plasma (FFP) to correct clotting times in the absence of active bleeding. If PT/PTT are elevated and there is bleeding or a surgical procedure is planned, FFP may be beneficial.

Vitamin C
Though this is, at best, an ancillary therapy to consider in patients with sepsis, without the acknowledged critical importance of many others and not necessarily widely used in veterinary patients, I want to focus a bit on it because it illustrates the challenges of an evidence-based approach to a complex medical problem. 

In human medicine, as in the veterinary field, practices may be adopted based on early evidence that is both encouraging and extremely limited. Unlike veterinary medicine, however, follow-up studies are much more common and robust, and better evidence that shows the true state of affairs is often available within a few years. Unfortunately, in our profession we are more likely to adopt a practice based on a single small study and then employ it widely for a long time before subsequent studies either confirm the benefits or show them to be illusory. Vitamin C for sepsis is a cautionary tale that should encourage us to try harder to confirm our initial assessment of new therapies.

In 2017, a study of 94 human patients with sepsis was published comparing patient given standard treatment and those also given Vitamin C, thiamine, and low-dose hydrocortisone (called HAT therapy).4 This was a small by the standards of human medicine, though larger than many equally influential veterinary trials, but it appeared to show dramatic benefits. Mortality was 8.5% in the experimental group and 40.4% in the control group, and there were apparent benefits in terms of other standardized measures of disease severity.

This study had a dramatic impact in the human critical care field, with reverberations in veterinary medicine. Debate and additional research began immediately in human medicine. In the veterinary profession, there was buzz about this new treatment at conferences5 and online, and some veterinarians began adding it to their management of sepsis cases.6 It is unclear how widespread this practice became in veterinary circles, but the published research on Vitamin C in critically ill veterinary patients is pretty sparse, and there are not prospective randomized clinical trials specifically comparing HAT to standard care in veterinary sepsis cases.5–7

In contrast, the five years since the publication of the original HAT study has seen a flurry of research in humans, and there are now more than a dozen systematic reviews and meta-analyses evaluating studies in thousands of sepsis patients.4,8–17 Unfortunately, the majority of these have failed to confirm the dramatic results from the original study. Most have found no reduction in mortality from adding HAT to standard care. Some have shown modest improvement in some assessments of disease severity, but many have found no statistically significant nor clinically meaningful effect at all. 

This is about as clear an example of the Decline Effect as one could ask for. Dramatic effects seen in initial studies of a new therapy get smaller and smaller as subsequent studies attempt to replicate the results until the literature settles on a far less dramatic reality, which surprisingly often turns out to be no effect at all. The explanations for this involve both intentional and, most of the time, unconscious bias on the part of enthusiastic researchers studying a new idea, as well as the limitations of small, often poorly controlled research studies in unrepresentative patient populations. This phenomenon is the main reason we should avoid enthusiastically embracing new therapies before appropriate replication of such initial studies has been done.

In the case of HAT, the controversy has grown more dramatic than usual. The primary author of the original study, Dr. Paul Marik, vehemently stands by his results despite all the failed attempts to replicate them. A recent letter to the editorof the journal in which this study was published has alleged that analysis of the results and statistics reported in the original paper is not only suggestive of data fabrication but clear proof of misconduct. An investigation by the journal is likely, especially in light of a very similar controversy involving the same investigator.

Dr. Marik has also published a study purportedly showing a different novel approach with equally dramatic benefits in COVID-19 patients. This paper has recently been retracted due to evidence of data manipulation. The author has also been reprimanded by the Virginia Medical Board for misconduct, resigned his academic position, and become involved in a lawsuit with his hospital over the use of ivermectin as a COVID-19 therapy. Like HAT, the approach Dr. Marik advocates for COVID-19 appeared promising in his early studies, but the elements of it have so far failed to show benefits in subsequent research.18,19 Dr. Marik illustrates starkly how hard the habit of excessive enthusiasm for new therapies based on preliminary evidence is to break.

Bottom Line
Sepsis is a serious and complex problem with numerous possible treatment approaches and mixed, often disappointing results. An evidence-based approach involves attention to the limited and weak evidence available in veterinary patients and judicious extrapolation from the more robust, but still imperfect, evidence available in humans. 

The use of Vitamin C, alone or in combination, in sepsis patients has evolved from an exciting and promising new idea to an example of failed promise, and of the dangers of unconscious bias, if not outright scientific fraud. The lesson we should draw from this is not merely that use of Vitamin C in veterinary sepsis patients is probably not warranted, but that we should proportion our acceptance of and confidence in new therapies to the strength of the evidence for them. For veterinarians, this often means a perpetual state of using treatments in which we can have very little confidence, but this is still preferable to enthusiastic commitment to practices which later prove ineffective or even dangerous for our patients.

References

1.        Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337

2.        Abelson AL, Buckley GJ, Rozanski EA. Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis. J Vet Emerg Crit Care. 2013;23(5):n/a-n/a. doi:10.1111/vec.12092

3.        Glover PA, Rudloff E, Kirby R. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use. J Vet Emerg Crit Care (San Antonio). 2014;24(6):642-661. doi:10.1111/vec.12208

4.        Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036

5.        Silverstein D. Treating Sepsis with Vitamins? The Risks, Benefits, and Evidence. In: International Veterinary Emergency and Critical Care Symposium. Washington, D.C.; 2019.

6.        Taylor SD. Oranges for Horses? Exploring Vitamin C in the Fight against Equine Sepsis. Purdue Equine Heal Updat. 2019;21(2):5.

7.        Gordon DS, Rudinsky AJ, Guillaumin J, Parker VJ, Creighton KJ. Vitamin C in Health and Disease: A Companion Animal Focus. Top Companion Anim Med. 2020;39:100432. doi:10.1016/j.tcam.2020.100432

8.        Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock. JAMA. 2020;323(5):423. doi:10.1001/jama.2019.22176

9.        Anderson MJ, Ibrahim AS, Cooper BR, Woolcock AD, Moore GE, Taylor SD. Effects of administration of ascorbic acid and low-dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses. J Vet Intern Med. 2020;34(6):2710-2718. doi:10.1111/jvim.15896

10.      Lee YR, Vo K, Varughese JT. Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review. Nutr Health. 2022;28(1):77-93. doi:10.1177/02601060211018371

11.      Wu T, Hu C, Huang W, Xu Q, Hu B, Li J. Effect of Combined Hydrocortisone, Ascorbic Acid and Thiamine for Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Shock. 2021;56(6):880-889. doi:10.1097/SHK.0000000000001781

12.      Assouline B, Faivre A, Verissimo T, et al. Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis. Crit Care Med. 2021;49(12):2112-2120. doi:10.1097/CCM.0000000000005262

13.      Patel JJ, Ortiz-Reyes A, Dhaliwal R, et al. IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2022;50(3):e304-e312. doi:10.1097/CCM.0000000000005320

14.      Fujii T, Salanti G, Belletti A, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16. doi:10.1007/S00134-021-06558-0

15.      Ge Z, Huang J, Liu Y, et al. Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis. Eur J Emerg Med. 2021;28(3):189-195. doi:10.1097/MEJ.0000000000000812

16.      Scholz SS, Borgstedt R, Ebeling N, Menzel LC, Jansen G, Rehberg S. Mortality in septic patients treated with vitamin C: a systematic meta-analysis. Crit Care. 2021;25(1):17. doi:10.1186/s13054-020-03438-9

17.      Somagutta MKR, Pormento MKL, Khan MA, et al. The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis. Acute Crit care. 2021;36(3):185-200. doi:10.4266/acc.2021.00108

18.      Popp M, Stegemann M, Metzendorf M-I, et al. Ivermectin for preventing and treating COVID?19. Cochrane Database Syst Rev. 2021;(7). doi:10.1002/14651858.CD015017.PUB2

19.      Lim SCL, Hor CP, Tay KH, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities. JAMA Intern Med. 2022;182(4):426. doi:10.1001/jamainternmed.2022.0189

Posted in Science-Based Veterinary Medicine | 2 Comments

Recent Canine Aging Science Articles

If my posts have seemed few and far between lately, one of many reasons is I have been busily typing away producing some scientific publications in my new focus area- canine aging science. My collaborators and I have produced several recent papers which I hope will be of some interest to some of you. Since not all are readily available outside of academia, I will post them here. Enjoy!

McKenzie, BA. Chen, FL. Gruen, ME. Olby, NJ. Canine Geriatric Syndrome: A Framework for Advancing Research in Veterinary Geroscience . Front Vet Sci. 9:853743. April, 2022.

Abstract
Biological aging is the single most important risk factor for disease, disability, and ultimately death in geriatric dogs. The effects of aging in companion dogs also impose significant financial and psychological burdens on their human caregivers. The underlying physiologic processes of canine aging may be occult, or early signs of aging may be ignored because of the misconception that biological aging is natural and therefore inevitable. The ability to detect, quantify, and mitigate the deleterious processes of canine aging would greatly enhance veterinary preventative medicine and animal welfare. In this paper we propose a new conceptual framework for aging in dogs, the Canine Geriatric Syndrome (CGS). CGS consists of the multiple, interrelated physical, functional, behavioral, and metabolic changes that characterize canine aging as well as the resulting clinical manifestations, including frailty, diminished quality of life, and age-associated disease. We also identify potential key components of a CGS assessment tool, a clinical instrument that would enable veterinarians to diagnose CGS and would facilitate the development and testing of interventions to prolong healthspan and lifespan in dogs by directly targeting the biological mechanisms of aging. There are many gaps in our knowledge of the mechanisms and phenotype of aging in dogs that must be bridged before a CGS assessment tool can be deployed. The conceptual framework of CGS should facilitate identifying these gaps and should stimulate research to better characterize the processes and effects of aging in dogs and to identify themost promising preventative strategies to target these.

McKenzie, BA. Comparative Veterinary Geroscience: Mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats. Amer J Vet Res. 2022;83(6:). https://doi.org/10.2460/ajvr.22.02.0027. 

Abstract
Aging is the single most important cause of disease, disability, and death in companion animal species. Contrary to the common view of aging as mysterious and inevitable, it is more usefully understood as a set of complex but comprehensible and modifiable biological processes that are highly conserved across species. The purpose of this Currents in One Health manuscript is to describe key mechanisms of aging at the cellular and molecular level and the manifestations of these in the tissues of the musculoskeletal system, adipose, and the brain. The characteristics of these processes as identified in common laboratory animal models and in humans will be described and compared with the much more limited information available concerning aging in dogs and cats. This will highlight important targets for future research in these species. The consistent patterns across species in the hallmarks of aging and their manifestations at the level of tissues, organ systems, and individual animals signify potential targets for interventions to mitigate the negative health impacts of aging and extend both life span and health span (the period of life free of significant disease or disability). Further research to elucidate aging mechanisms in companion dogs and cats will eventually support development, testing, and implementation of clinical therapies to prevent and ameliorate age-related dysfunction, disease, and death.

McKenzie, BA. Lacroix-Fralish, ML. Chen, F. The phenotype of aging in the dog: How aging impacts the health and wellbeing of dogs and their caregivers. J Amer Vet Med Assoc. 2022;260(9):963-970. 

Abstract
Aging is the single most important cause of disease, disability, and death in adult dogs. Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the phenotypic expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this feature is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. Important gaps in our knowledge of the canine aging phenotype will be identified, and current research efforts to better characterize aging in the dog will be discussed. This will help set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.

Posted in Aging Science | 4 Comments

Are Vegan Diets Healthier for Dogs & Cats?

Introduction
Given the media frenzy the article has kicked off, it is unlikely very many people are unaware of a recent study reported in the journal PLOS One that claims to show vegan diets are healthier for dogs and cats than diets containing meat. 

Knight A, Huang E, Rai N, Brown H. Vegan versus meat-based dog food: Guardian-reported indicators of health. PLoS One. 2022 Apr 13;17(4):e0265662.

Dramatic headlines have appeared in many major news sources proclaiming that vegan diets are “linked to better health” or “are healthier and safer” than conventional diets. Getting beyond the headlines, one may even read that this study demonstrates raw diets to be healthier than conventional foods, though that is less emphasized in both the original article and the media coverage.

I’ve written about vegan diets for dogs before, and indeed this article cites my column on the subject, though only to dismiss my claim that vegan diets “should not be recommended” as “without evidence.” This is not entirely accurate, since my article did cite the limited evidence available, and I did not actually recommend against vegan diets for dogs, though I did conclude they were a bad choice for cats. My actual claims were:

There is no evidence vegetarian diets have health benefits for dogs and cats, and no real reason to believe they should, based on the physiology and nutritional requirements of these species.

Dogs are omnivores that are able to eat both plant and animal foods, and in theory, they should be able to thrive on vegetarian or vegan diets. However, these diets must be carefully formulated, and many commercial vegetarian dog foods do not appear to be nutritionally adequate. There is also little reliable research evidence showing dogs can remain healthy when fed only a vegan diet. Given the unexpected health problems seen with theoretically adequate grain-free diets, we should be cautious about the potential risks of vegetarian formulations for dogs until there is better and more evidence showing their long-term health effects.

Cats are clearly obligate carnivores with nutritional requirements that are unlikely to be effectively met by vegan diets. Such diets offer only risks and no benefits for cats and should be avoided.

In any case, I am sympathetic to many of the potential environmental and health benefits of plant-based diets, and I have been a vegetarian, though not a vegan, for almost 20 years  (technically, an ovo/lacto/pescatarian, though realistically I don’t like fish and so eat very little of it). However, the evidence for benefits of plant-based diets for dogs and cats is far weaker than that for humans, which is itself often nuanced and not always conclusive. And I believe in following the evidence wherever it leads, even when it doesn’t support my personal beliefs or practices.

So, does this paper change the game in terms of showing real health benefits to raw and/or vegan diets? Spoiler, but not really! Let’s look at the actual findings a bit closer.

The Study- Results
The study reported the following statistically significant differences between “conventional,” raw, and vegan diets (leaving aside the fuzzy definitions of these, the ubiquitous feeding of unidentified treats to all pets, and the lack of clarity about how strictly feeding practices corresponded to each category).

  • Dogs fed raw and vegan diets were less likely to have had multiple veterinary visits in the year observed.
  • Dogs fed raw and vegan diets were less likely to have been given medications
  • Dogs fed raw and vegan diets were less likely to have been transitioned onto a therapeutic diet
  • Dogs fed raw and vegan diets were less likely to have an owner-reported veterinary assessment of poor health status
  • Dogs fed raw and vegan diets were less likely to have an owner reported assessment of poor health
  • Dogs fed raw and vegan diets were less likely to be reported to be “unwell,” and when unwell dogs on raw diets had fewer reported disorders than dogs on conventional diets.
  • There were differences in the occurrence of specific health conditions between diet groups as illustrated in this figure and table:
  • Dogs fed raw and vegan diets were less likely to have had multiple veterinary visits in the year observed.
  • Dogs fed raw and vegan diets were less likely to have been given medications
  • Dogs fed raw and vegan diets were less likely to have been transitioned onto a therapeutic diet
  • Dogs fed raw and vegan diets were less likely to have an owner-reported veterinary assessment of poor health status
  • Dogs fed raw and vegan diets were less likely to have an owner reported assessment of poor health
  • Dogs fed raw and vegan diets were less likely to be reported to be “unwell,” and when unwell dogs on raw diets had fewer reported disorders than dogs on conventional diets.
  • There were differences in the occurrence of specific health conditions between diet groups as illustrated in this figure and table:

All-in-all, these results would seem to be pretty bad news for conventional diets (whatever that means) and pretty good news for feeders of raw and vegan diets. Anyone reading this, however, can probably sense the “but” coming, so let’s get into the caveats.

The Study-Limitations
The biggest limitation (and boy is it a big one!) is that all the data were collected from online surveys of pet owners. Everything from the diet fed to the health status and even the reported veterinary assessment of health all relied entirely on the responses of pet owners who found the survey online and took the trouble to complete it. None of the facts, not the feeding practices nor the health of the pets, were verified objectively in any way. Right from the start, then, that makes this a study of what some small subset of pet owners believe about their pets’ diet and health, not about the actual feeding and health of these animals.

It is not difficult to find reasons to be concerned that these responses may not reflect reality, or even the opinions of other groups of pet owners. The respondents were overwhelmingly female (92%) and European (86%), which is a pretty narrow population to survey. They were, of course, also in a socioeconomic class inclined to participate in online pet health surveys, which is also not representative of many other pet owners.

More concerning, 22% of the population of owners were themselves vegan. This is a group likely to have strong beliefs and biases about plant-based vs meat-based nutrition and health, so it would be, frankly, shocking if they did not report that plant-based diets were healthier than other diets. 13% of these owners fed their pets vegan diets and 33% fed raw meat, indicating nearly half fed unconventional diets not usually recommended by veterinarians or veterinary nutrition specialists. Such a group is clearly a population biased in favor of the kind of outcomes reported in this study, and given the study only shows us the opinions of owners, not actual objective data about health and diet, the outcomes are simply a fancy way of reporting what people in this group think. 

Other studies in other populations have reported lower rates of veganism (5.8%) and of feeding vegan diets to pets (1-3%), which emphasizes that this study surveys a very specific, narrow group of owners. A review of previous owner surveys also shows more nuanced and variable feeding practices reported in these studies, again suggesting this paper may not be applicable outside of the specific population included in the survey.

In terms of potential sources of bias beyond the survey population, it is worth pointing out that the lead author is a consistent advocate for plant-based diets, for humans and pets, on environmental and ethical grounds. The study was also funded by a plant-based diet advocacy group. As I have discussed in detail in previous articles on conflict of interest, these facts do not indicate the research is fraudulent or inaccurate, nor are they a justification for ignoring the claims, arguments, and evidence provided in this paper. They are, however, a reason to consider carefully the potential for uncontrolled unconscious bias in the design, conduct, analysis, and reporting of the study. Given that the study itself was essentially a survey of subjective opinions, methods to control such bias are minimal, so the results have to be viewed in that context.

The authors, to their credit, do acknowledge some of these limitations. They call out the fact that, for example, fewer reported veterinary visits in dogs fed raw diets may be due to the fact that feeders of raw diets are often skeptical of conventional veterinary medicine and less likely to seek care rather than to any actual difference in health status. The same logic, of course, applies to the frequency of vet visits for dogs fed vegan diets, and to the reported use of medicine and therapeutic diets by owners who have a clear preference for unconventional health practices to begin with.

Conclusions
So what does this study mean? Overall, it means that the particular population of pet owners surveyed believes that feeding raw and plant-based diets are associated with better health in their pets. They also believe that their veterinarians think their pets are healthier (though whether these vets actually believe this is unknown). And these owners report less use of veterinary medical services, though whether this means their pets are healthier or simply that they try harder to avoid taking their pets to the vet is also unknown.

Like previous studies relying on owner surveys and both conducted and funded by folks with strong a priori opinions about diet and health, this is a useful insight into such beliefs. It is not compelling or probative evidence for actual health effects of different feeding strategies. Sadly, the media coverage of the paper rarely recognizes or emphasizes this.

As the authors themselves suggest, though with little evident enthusiasm, controlled studies with objective measures of outcome and more defined and verified feeding practices are required to draw any meaningful, actionable conclusions about the healthiest feeding strategy for our pets. I am neither for nor against vegan diets for dogs, and I am even open to reversing my objection to feeding vegan to cats or raw diets to cats or dogs if strong evidence is generated that these are safe or beneficial practices. However, regardless of the difficulties in funding and conducting the necessary research, we are not justified in making confident claims about the health impact of raw, vegan, or conventional diets without it.

Posted in Nutrition | 8 Comments

Do Dogs Like Music? (Evidence Update)

Over the roughly 13 years I have been writing this blog, I have covered quite a few different topics, though with all I have maintained the central theme of evaluating claims about pet health from a science-based perspective. Part of this perspective is keeping track of the changing evidence as new research results become available. This can be tough as the number of topics, and the volume of evidence, grows over such a long period. 

Today, I am returning briefly to a topic I previously covered in 2015 and twice in 2017 (A and B). As often proves to be the case, my conclusions have remained relatively unchanged, though this is one area in which I began with, and have maintained, some cautious optimism.

2015
While it is very likely some kinds of music can be beneficial to our pets and veterinary patients under some circumstances, the devil is, as usual, in the details, and we don’t know much about the details yet. It is reasonable to experiment with music in veterinary environments, especially with more quiet, instrumental genres, but we must try to develop objective measures of the effect to be sure we are not imply wasting our effort or, even worse, actually adding stress for our patients.

2017- January
On balance, then, I think it is possible that music might have some benefits for dogs in stressful circumstances, such as boarding kennels, hospitals, and shelters, but this is by no means clearly proven. The risk is also likely quite low, so there is probably little harm in using quiet music for this purpose so long as it is not substituted for other, more comprehensive approaches to reducing stress and anxiety.

2017- July
The existing evidence is weak and inconsistent, so no clear conclusion can be drawn. In this study, there was no sign of any effect of classical music or the same music digitally altered with the goal of reducing stress in dogs. The question remains open, and definitive claims for or against the potential effects of music in this situation are not justified.

My reason for revisiting the topic now is that I have run across a systematic review looking at al the available evidence up through 2019.

Lindig AM, McGreevy PD, Crean AJ. Musical Dogs: A Review of the Influence of Auditory Enrichment on Canine Health and BehaviorAnimals. 2020; 10(1):127. 

Systematic reviews are incredibly useful as they provide a comprehensive evaluation of the available scientific literature with an explicit focus on evaluating the strengths and weaknesses of the available evidence. They are never, of course, completely without bias, and they can often be frustrating since they rarely allow definitive conclusions or a high level of confidence in a particular interpretation of the evidence. But having such a review gives us a reasonable chance of getting a good overview of the subject and the evidence.

The conclusions of this review track pretty well with my own assessments in the past:

Interest in the use of music therapy as a behavioral enrichment tool in veterinary medicine is growing. Indeed, an industry has formed around the development of ‘dog music’, which has been purposely designed to relax dogs. Despite enthusiastic uptake of the idea, there is little empirical evidence supporting the design of such tools… As a general observation, animals appear less stressed or anxious when exposed to classical music than to control conditions. [This review] also acknowledges that this field is relatively under-researched, and more rigorous studies must be conducted before species-specific recommendations can be made. Such studies must reflect individuals’ and species’ preferences for different genres and songs, taking care to avoid habituation.

The best we can say about the value of music for dogs is that a few studies have shown short-term changes in behavior and some physiologic measurements that suggest quiet genres of music, such as classical, may have a calming effect on some dogs in some circumstances. Sounds specifically designed for dogs don’t’ seem to have any more effect than classical music. These short-term effects may wane with repeated exposure to the same music. And there is virtually no research on the long-term effects of music exposure, the potential health effects, and the importance of breed and individual differences or preferences.

Posted in General | 4 Comments

Does eating a Raw Diet as a Puppy Reduce later Allergy Risk?

I have written many times about the controversial subject of raw diets for dogs. The bottom line, based on existing evidence, is there are no proven health benefits to these diets and several well-documented risks, including infectious disease and nutritional inadequacy.1

Proponents of these diets offer varied theoretical arguments for why they should be healthier than commercial cooked foods. Many are simply fallacious claims about what is “natural” or “ancestral.” However, there are some plausible, but unproven hypotheses, about the potential negative health impacts of conventional diets or the possible health benefits of feeding uncooked meat.

Concerns about Maillard reaction products (MRPs) in cooked foods, for example, are reasonable given the potential carcinogenicity of some of these compounds at some amounts in some species. However, it is far from evident these compounds actually do cause harm in the form and amount found in cooked dog foods, and research has identified potential benefits as well as risks to their consumption, so the assumption that cooked foods must be unhealthy because they contain MRPs is unreasonable.2

Similarly, the hypothesis that exposure to microorganisms during development can reduce the subsequent risk of allergies and other immune-system diseases is plausible, and there is some supportive evidence, though there is also evidence against this “hygiene hypothesis.”3-6 However, this does not justify the assertion that exposure to such organisms through eating raw meat, dirt, or other substances, has more benefits than risks.

A recent paper published in the Journal of Veterinary Internal Medicine (JVIM) purports to support claims for health benefits from raw diets.7 

Hemida MBM, Salin S, Vuori KA, et al. Puppyhood diet as a factor in the development of owner?reported allergy/atopy skin signs in adult dogs in Finland. J Vet Intern Med. 2021;35(5):2374-2383.

The authors suggest exposure to raw diets in puppies may reduce the risk of later development of canine atopic dermatitis (CAD), and exposure to conventional commercial diets may increase CAD occurrence in adulthood. There are, however, numerous limitations and red flags associated with this study, and it is not strong evidence.

The authors of the paper have a long history of promoting raw diets and various alternative therapies, and they have a clear bias on the subject.8-16 Of course, researchers often have confident beliefs, rather than tentative hypotheses, when they design and conduct scientific studies. It is well-established that “researcher degrees of freedom,” the amount of leeway investigators have in designing studies and in collecting and analyzing data, is associated with the likelihood of false-positive results.17

Given researchers with clear a priori beliefs about raw diets designed the survey, defined the variables of interest, and had total freedom to create and conduct the regression analysis, the results likely reflect the beliefs of the researchers more than the underlying reality of nature.

One example of the clear bias behind this study is in the terminology chosen for different diet categories. They divide foods into “non-processed meats/ingredients” and “ultra-processed carbohydrate-rich foods.” These are artificial categories reflecting the ideological bias of the researchers, not the reality of the kinds of foods dogs are actually fed.

“Non-processed” is meaningless unless the dogs are eating whole prey and plants they find for themselves. Likewise, the term “ultra-processed” is also an inappropriate extrapolation of terms used to describe human snack foods, which are not meaningfully similar to commercial pet foods. The label is a value judgment that implies a negative health impact not actually proven to exist.

Commercial canned and dry foods are also not accurately described as “carbohydrate-rich.” The carbohydrate content of commercial dry diets varies dramatically, as does the type of carbohydrate (from simple sugars to complex fibers). The nutritional value and potential health effects of commercial diets will vary greatly based on these differences, and lumping them all together in this artificial category is not a sound scientific approach.

Another potential influence on this study is funding bias. It is, again, well-established that funding sources can influence the outcomes of research, which is why disclosure of funding sources is required by scientific journals.18 In a web documentary called The Dog Cancer Series, one of the authors of this study herself cites funding bias as a factor in the literature concerning raw diets:

“[Raw food is] not really researched in universities. Most universities get sponsored by these big billion-dollar companies, and you don’t really want to step on their toes, I guess. But, I think that’s not really ethical,” says Dr. Anna Hielm-Bjorkman.19

It is relevant, then, to point out this study received financial support from raw diet manufacturers, as well as Dr. Joseph Mercola, an infamous proponent of alternative medicine and anti-vaccine activist repeatedly warned by the Food and Drug Administration (FDA) for promoting COVID-19 misinformation and selling unproven treatments.20,21 Given the potential for ideological and funding bias in this research project, the lack of rigorous controls for possible bias in this study is concerning.

The main source of data is an online survey available only in Finnish. This is a very narrow sample population, and it is unlikely to be representative of the views or practices of dog owners generally.

More importantly, the responses are simply expressions of the perceptions and beliefs of the owners who participated, not necessarily the nutritional and environmental exposures nor health outcomes actually experienced by the dogs. Self-reporting of diet and health information has been shown to be unreliable in humans, and it is unlikely to be more reliable among dog owners.22,23

Previous reports evaluating this source of data do not inspire confidence.2,15 The researchers validated responses by emailing respondents and looking for consistency in their answers to selected questions. In a previous study, only about 30 percent of the respondents replied to these emails, and almost 13 percent of responses to this survey tool were discarded as “robot” answers. Also, 26 percent of respondents provided inconsistent or discordant answers regarding diet and CAD symptoms.15

The current study reports 4.2 percent of answers were discarded as duplicates or robot responses, but provides no information on discordant responses. The report does indicate, however, 31 percent of the responses were discarded because an analysis of the foods reported indicated significant underfeeding.7

It seems more likely owners were misremembering their feeding practices rather than 30 percent of owners were dramatically underfeeding their dogs.

Asking owners to remember in great detail what they fed their puppy between two to eight months of age, and then trying to associate this with health outcomes years later, is a questionable strategy. With no direct or objective verification, it seems very likely the dietary and health information reported in this survey is unreliable.

The associations discovered during statistical analysis support this interpretation because they are often inconsistent and make no obvious sense in terms of the authors’ hypothesis that raw foods are protective against CAD. For example, why would raw tripe and organ meats be protective, but raw red meat, eggs, and poultry would not be?

If cooking is the main risk factor, why would cooked vegetables be protective and raw vegetables would not? Why would both cooked and raw eggs be protective while neither cooked nor raw poultry is associated with the likelihood of CAD? If exposure to bacteria is the main variable, why is eating dirt, sticks, or carcasses protective, but eating clay and grass is not, and drinking from puddles is actually associated with increased risk?

If excessive processing is the issue, why was there no association with eating processed meats or canned foods, and only a marginal association with dry food when it was the only food offered?

Additionally, the paper reports associations between the proportion of various foods fed and adult CAD risk that are hard to explain.

Dogs with CAD were more likely to be eating no raw food at all than controls, and dogs without CAD were more likely to be fed 20 percent or 90 percent raw, but there were no differences at any other ratio of the two foods. Similarly, allergic dogs were more likely to be fed 80 percent dry than controls, but there was no significant difference if they were fed more than 80 percent dry.

Control dogs were more likely to be fed 50 percent or less than 10 percent dry, but there was no difference at intermediate ratios. It is easier to see cherry picking and researcher degrees of freedom than a consistent dose-response in these results.

Identifying causal associations between nutrition and health outcomes is inherently difficult. Available feeding strategies involve many differences in nutrient form and content other than the narrow aspects we may choose to focus on, such as cooked versus raw.

It is worth conducting research to investigate such relationships, but strong evidence will always be scarce and difficult to produce. However, productive research efforts must involve meaningful attempts to control for bias and to obtain fundamentally reliable data, even when conclusions may always have to be tentative.

The authors of this study continue to publish papers suggesting health benefits to raw diets and risks to conventional diets based on a single online survey tool and a convenience sample of Finnish-speaking dog owners. This is never going to be a solid data set upon which useful conclusions can be based, and the research produced from it are more likely to be an expression of the beliefs and perceptions of the respondents and the researchers, rather than a sound representation of the complex relationships between nutrition and health.

Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.

References

  1. McKenzie B. Debating Raw Diets. Vet Pract News. January 2019:30-31. https://www.veterinarypracticenews.com/debating-raw-diets-january-2019/.
  2. Roine J, Uusitalo L, Hielm-Björkman A. Validating and reliability testing the descriptive data and three different disease diagnoses of the internet-based DOGRISK questionnaire. BMC Vet Res. 2016;12(1):30. doi:10.1186/s12917-016-0658-z
  3. Brooks C, Pearce N, Douwes J. The hygiene hypothesis in allergy and asthma. Curr Opin Allergy Clin Immunol. 2013;13(1):70-77. doi:10.1097/ACI.0b013e32835ad0d2
  4. Kemp A, Björkstén B. Immune deviation and the hygiene hypothesis: A review of the epidemiological evidence. Pediatr Allergy Immunol. 2003;14(2):74-80. doi:10.1034/j.1399-3038.2003.00017.x
  5. Tizard IR, Jones SW. The Microbiota Regulates Immunity and Immunologic Diseases in Dogs and Cats. Vet Clin North Am Small Anim Pract. 2018;48(2):307-322. doi:10.1016/j.cvsm.2017.10.008
  6. Lynch S V, Wood RA, Boushey H, et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J Allergy Clin Immunol. 2014;134(3):593-601.e12. doi:10.1016/j.jaci.2014.04.018
  7. Hemida MBM, Salin S, Vuori KA, et al. Puppyhood diet as a factor in the development of owner?reported allergy/atopy skin signs in adult dogs in Finland. J Vet Intern Med. 2021;35(5):2374-2383. doi:10.1111/jvim.16211
  8. Hielm-Björkman A, Reunanen V, Meri P, Tulamo R-M. Panax Ginseng in combination with brewers’ yeast (Gerivet) as a stimulant for geriatric dogs: a controlled-randomized blinded study. J Vet Pharmacol Ther. 2007;30(4):295-304. doi:10.1111/j.1365-2885.2007.00876.x
  9. Teixeira LR, Luna SPL, Matsubara LM, et al. Owner assessment of chronic pain intensity and results of gait analysis of dogs with hip dysplasia treated with acupuncture. J Am Vet Med Assoc. 2016;249(9):1031-1039. doi:10.2460/javma.249.9.1031
  10. Hielm-Björkman A, Tulamo R-M, Salonen H, Raekallio M. Evaluating complementary therapies for canine osteoarthritis–Part II: a homeopathic combination preparation (Zeel). Evid Based Complement Alternat Med. 2009;6(4):465-471. doi:10.1093/ecam/nem143
  11. Rosendahl S, Anturaniemi J, Vuori KA, Moore R, Hemida M, Hielm-Björkman A. Diet and dog characteristics affect major and trace elements in hair and blood of healthy dogs. Vet Res Commun. November 2021. doi:10.1007/s11259-021-09854-8
  12. Hakanen E, Lehtimäki J, Salmela E, et al. Urban environment predisposes dogs and their owners to allergic symptoms. Sci Rep. 2018;8(1):1585. doi:10.1038/s41598-018-19953-3
  13. Anturaniemi J, Barrouin-Melo SM, Zaldivar-López S, Sinkko H, Hielm-Björkman A. Owners’ perception of acquiring infections through raw pet food: a comprehensive internet-based survey. Vet Rec. 2019;185(21):658. doi:10.1136/vr.105122
  14. Fredriksson-Ahomaa M, Heikkilä T, Pernu N, Kovanen S, Hielm-Björkman A, Kivistö R. Raw Meat-Based Diets in Dogs and Cats. Vet Sci. 2017;4(3). doi:10.3390/vetsci4030033
  15. Hemida M, Vuori KA, Salin S, Moore R, Anturaniemi J, Hielm-Björkman A. Identification of modifiable pre- and postnatal dietary and environmental exposures associated with owner-reported canine atopic dermatitis in Finland using a web-based questionnaire. PLoS One. 2020;15(5):e0225675. doi:10.1371/journal.pone.0225675
  16. Hemida MBM, Salin S, Vuori KA, et al. Puppyhood diet as a factor in the development of owner?reported allergy/atopy skin signs in adult dogs in Finland. J Vet Intern Med. 2021;35(5):2374-2383. doi:10.1111/jvim.16211
  17. Simmons JP, Nelson LD, Simonsohn U. False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychol Sci. 2011;22(11):1359-1366. doi:10.1177/0956797611417632
  18. Resnik DB, Elliott KC. Taking financial relationships into account when assessing research. Account Res. 2013;20(3):184-205. doi:10.1080/08989621.2013.788383
  19. Habib R, Becker K. The Dog Cancer Series: Rethinking the Cancer Epidemic Vol. 1- Chapter 4 (Transcript).; 2018:73.
  20. Satija N, Sun L. A major funder of the anti-vaccine movement has made millions selling natural health products. Washington Post. December 20, 2019.
  21. Science A for. FDA warns Mercola: Stop selling fake COVID remedies and cures.
  22. Fadnes LT, Taube A, Tylleskär T. How to identify information bias due to self-reporting in epidemiological research. Internet J Epidemiol. 2009;70(2). http://www.ispub.com/journal/the_internet_journal_of_epidemiology/volume_7_number_2_25/article_printable/how-to-identify-information-bias-due-to-self-reporting-in-epidemiological-research.html. Accessed December 23, 2021.
  23.  Ravelli MN, Schoeller DA. Traditional Self-Reported Dietary Instruments Are Prone to Inaccuracies and New Approaches Are Needed. Front Nutr. 2020;7:90. doi:10.3389/fnut.2020.00090
Posted in Nutrition | 3 Comments

PEMF (Assisi Loop) for Separation Anxiety in Dogs- A new Study

A recurring topic here over the years has been pulsed electromagnet field therapies. I have reviewed evidence concerning these in 2009 and 2020 (twice), and my conclusions have always been-

  • The therapy is biologically plausible
  • The evidence is weak
  • The claims for these devices routinely go well beyond the available evidence

A reader recently drew my attention to a new study that is a follow-up of a previous pilot trial

Pankratz K, Korman J, Emke C, Johnson B, Griffith EH, Gruen ME. Randomized, Placebo-Controlled Prospective Clinical Trial Evaluating the Efficacy of the Assisi Anti-anxiety Device (Calmer Canine) for the Treatment of Canine Separation Anxiety. Front Vet Sci. 2021 Dec 20;8:775092. 

The good news is that the study is very well designed, with appropriate controls for many important sources of bias and error. The subjects were selected and randomized appropriately, and everyone was properly blinded. Both a subjective owner measure of effect and objective blinded analysis of video were used to assess effects. There were also active and matched sham devices employed.

As always, there were some limitations to the study. Dogs with behavioral problems other than separation anxiety (SA), such as noise phobia, were excluded. While this makes sense to simplify the study, such problems are common in dogs with SA, so the subjects may not represent the population of SA dogs likely to be treated in the real world. 

Dogs were also on varied medications, and none were given a behavior modification program, as would normally be done for this condition, so again how treatment tested might interact with these factors is unclear. The authors also pointed out that some of the study took place during the COVID-19 pandemic, and the activities of owners was likely affected by this event. Finally, there was some missing video due to technical issues, and it is unclear if this might have affected treatment or control dogs differently or otherwise influenced the results.

The authors also mention in the paper that, “after the first 40 dogs completed the study, the devices were sent to the manufacturer for testing; devices that were no longer active were removed from the study and replaced.” They never discuss, however, how many devices malfunctioned and needed replacement, which raises the question of how many dogs may have been “treated” with devices that were not actually operating properly. Presumably, this wasn’t mentioned since it was not a common occurrence, but it would have been useful to include this information.

The less good news is that the results were mixed and inconsistent, yet as is usually the case, they were reported as positive. It is common for research studies that measure multiple outcomes for some to show an effect and others not to. It is often recommended to designate one outcome measure as most important in advance and to use only that to decide if the test treatment works. This avoids the problem of having both successful and unsuccessful outcomes and simply having authors emphasize the positive and de-emphasize the negative.

In this study, the subjective owner assessment showed improvement for all dogs and no difference between treatment and placebo. This is a great illustration of the importance of control groups and placebo treatments in veterinary studies. In this case, the owners were as likely to see improvement with no treatment as with the PEMF device. This was probably due to a combination of caregiver placebo effects and the nonspecific impact of being in a clinical study, where patients get more monitoring and treatment than when they are not in a research trial.

The failure to find any difference in this outcome does not necessarily mean the treatment was not effective, but it does indicate that any benefit it may have had was indistinguishable from placebo to the owners. This is critical since it is mostly the owner perception that determines whether a treatment is thought to be working, and whether treatment is changed or a pet is rehomed or euthanized, in the real world of clinical management of SA.

The more objective analysis of video recordings showed mixed results. In terms of negative behaviors, there was no significant effect of treatment overall, and the comparison between the treatment and sham group was not significantly different at 4 weeks but was different at 6 weeks. The difference from baseline was significant for both groups at week 4 and for only the treatment group at week 6. 

In terms of successful treatment, defined as at least a 100% increase in desirable behavior in the video recordings, the treatment group was significantly higher at 4 weeks but not at 6 weeks, and the difference was borderline overall (a p-value of 0.05 is considered statistically significant, and this difference showed a p-value of 0.047). 

These results illustrate the problem with multiple outcomes measures and no clear statement before the study of which is primary or what the expectations are. Based on the questionnaire, one could conclude the treatment didn’t work. This is probably not justified since this is a weak measure of effect, but as I mentioned it does signify that the treatment may be no different from placebo in the perception of owners, which is important for how dogs with SA are ultimately managed.

The more objective video assessment showed no overall difference in negative behaviors, which again is consistent with no meaningful treatment effect. There was a difference at 6 weeks, however, and this could be cited to argue that the treatment took time to have a measurable benefit. Unfortunately, this is inconsistent with the results for positive behaviors, which were better for the treatment group at 4 weeks than at 6 weeks, and which again showed a borderline level of statistical significance that could be interpreted as either a real effect or no real difference from chance.

Finally, the importance of consistency across studies and replication cannot be overemphasized. It has become apparent in the last ten years or so that there is a huge problem in biomedical science generally, and in human behavioral science in particular, with replication. Decisions about the causes and treatment of disease are made on a few studies, or even a single study, and then it turns out those results cannot be reproduced, which strongly suggests they were not accurate in the first place. 

Veterinary medicine has always suffered from a lack of efforts to replicate research studies, as well as from a lack of good studies in the first place, and this makes it very likely that many of our treatments don’t actually work. All studies should be reproducible before widespread adoption of treatments based on their results occurs, and the mixed results of this particular study make it especially important to show that the findings are repeatable.

Bottom Line
This is a well-designed and well-conducted study that shows a mixture of positive and negative results. The most appropriate conclusion would be that the results suggest PEMF might be useful to separation anxiety, but whether or not it is, and how effective it might be, remain to be determined. Given the minimal risks, use of PEMF for this condition is not unreasonable so long as it is not substituted for therapies with better supporting evidence and owners are made aware that the evidence for PEMF is weak and inconclusive. 

Posted in General | Leave a comment

The Bell Tolls for Resveratrol

Only the most dedicated followers of this blog are likely to remember this (are there any?), but way back in 2009, I first wrote about resveratrol in an article about supplements for cognitive dysfunction and brain aging in dogs. My conclusion at that time was:

Resveratrol, in short, stands at the juncture of hope, profit and scientific promise — a social phenomenon galloping ahead of research that is undeniably intriguing but very incomplete.

That was followed by several updates on the status of resveratrol, which still didn’t find scientific justification for the hype.

2012-

it is a fine example of both the dangers of excessive and premature commitment to a hypothesis and promotion of products based on it as well as of the ultimately self-correcting nature of the scientific process.

2013-

supplementation is probably not justified for most people or for our pets

2014-

The bottom line here is that we don’t know for certain, but the compound is looking less promising the more we study it.

Since then, I haven’t spent much time checking the evidence base for this compound, but I suspect it is still quite popular, at least based on the fact that it keeps showing up in products, including my wife’s shampoo!

Once I started working in the aging biology field, I found that the story of resveratrol is even more byzantine and disappointing than I had realized. Dr. Brad Stanfield has recently released this video tracing the history of this molecule in the aging field, and it is an excellent example of one of my signature soapbox issues- the dangers of rushing to commercialize a promising but unproven therapy. Sadly, this is still the norm in veterinary medicine, and I am not optimistic we will learn from this example.

Posted in Herbs and Supplements | 2 Comments

What is a Conflict of Interest?

One of the most common objections I see to my promotion of science-based treatments is that the scientific evidence supporting them is invalid because it is tainted by some association with Big Pharma, Big Kibble, or some other industry bogeyman. This is a convenient objection to any kind of evidence for science-based medicine or against alternative medicine because it uses elements of truth to make an ultimately invalid argument.

Financial bias is a real thing, and it does impact how we should evaluate scientific research. However, conflicts of interest are a lot more complicated than this, and our understanding and interpretation of them needs to be a lot more sophisticated than “industry funded=bulls$#t” Here is my attempt, from my VPN+ column, to take a more nuanced look at this subject.

Introduction

A key component of evidence-based medicine (EBM), and of modern life, for that matter, is critical appraisal. This means critically evaluating information before accepting or acting on it. In this time of “alternative facts” and widespread harm caused by acceptance of false or misleading information, the core EBM skill of critical appraisal is more important than ever.

In the context of evidence-based veterinary medicine (EBVM), critical appraisal refers specifically to “a formal, unbiased, systematic approach to assessing the quality and relevance of evidence presented in a paper and its applicability to decision making for our patients.”1

As a clinician, before I decide whether to believe the results or conclusions of a published research study, or utilize them in caring for my patients, I have a responsibility to decide for myself how reliable the results are, how likely they are to represent the truth, and whether they are applicable to my patients.

All too often, vets skim the abstract or discussion section of a paper, find the main conclusion, and then take that on faith and use it to guide their practice. Unfortunately, much of what is published in the scientific literature turns out to be more complicated than it first appears, irrelevant to many patients in the world of primary care, or simply wrong. Critical appraisal is the last line of defense between our patients and unsafe or ineffective treatment based on bad information.

There are many aspects of research publications that must be evaluated in the course of a thorough critical reading. The focus of this column is conflict of interest (COI). This is an issue frequently mentioned in guides to critical appraisal, and often used to dismiss the results of published research, but it is an element of critical appraisal that is especially problematic and for which clear guidelines are not available.

What is a conflict of interest?

Even the definition of a COI is challenging and subject to debate.2–4 I find it useful to define a COI broadly as any personal, institutional, or financial relationship that might influence the beliefs, judgements, or actions of an investigator during the design, conduct, analysis, and reporting of scientific research. This helps to distinguish a COI from mere personal belief, but it goes beyond the common and excessively narrow view of COIs as exclusively about financial interests.

A COI is simply one category of bias that can influence the outcome of scientific research. In ordinary use, the term “bias” has negative connotations as it mostly refers to various forms of prejudice or discrimination against groups of people. However, in the parlance of EBM, “bias” simply means any factor that systematically distorts the results of scientific research away from the truth.

If I flip a coin that is unevenly weighted 100 times and get heads 80 percent of the time that is a type of bias. If a researcher chooses only male dogs to study the effects of a drug, that is a type of bias that can lead to a result consistently different from the true effects of the drug on dogs in general. If a researcher has a particular belief that affects how they choose their hypothesis, design their study, analyze the data, and decide whether or not to publish, that is a type of bias, as well.

It should be clear from this definition and examples that bias is ubiquitous in all research. It is not a sign of bad intentions or incompetence; it is an unavoidable consequence of the operation of the human brain and the imperfection of scientific methods. None of us is without bias if we have any beliefs or distinctive individuality at all. The methods of science exist to help compensate for some of the most common and troublesome sources of bias that arise from the operation of the human brain. This is a pretty uncontroversial view in the fields of EBM and the philosophy of science.

I will also make the potentially more controversial claim, however, that none of us is truly free of any conflict of interest either. Science is a community process, rarely conducted in isolation from other people or institutions, and our relationships inevitably affect our beliefs and practices as scientists. Despite the implications of the word “conflict” in conflict of interest, I believe it is useful to think of a COI as simply a type of bias, and as such, morally neutral in most cases. Just as the term bias lacks pejorative connotations in EBM, the term COI should not be seen as implying malfeasance or bad faith.

Of course, deliberate actions to alter or even fabricate scientific data motivated by financial interests, career considerations, or other types of COI relationships are clearly unethical. However, most COI, like other types of bias that trouble scientific research, involves unconscious and unintentional skewing of research results in a direction influenced by our relationships and beliefs. A researcher can be perfectly honest and genuine in attempting to produce objective, reliable data and still have a COI that influences the results of their research.

What constitutes a COI?

The majority of research into COI and how it influences medical research outcomes focuses on financial COI.2,4 If a researcher stands to benefit financially in some way from a certain study outcome, they are considered to have a COI. This may involve financial gain from the success of a product or service being tested, or the effect of research outcomes on the fortunes of a commercial entity, or other institution the researcher is affiliated with.

The classic example of financial COI is research funded by pharmaceutical companies. It has been pretty consistently demonstrated in human biomedical research industry funding of clinical studies is associated with more favorable study outcomes than is funding by government or nonprofit organizations.3,4 There is limited evidence in veterinary medicine, but it seems likely a similar industry funding bias exists in veterinary clinical trials.5

This relationship is often used to dismiss industry-funded research as hopelessly biased, and to suggest there is deliberate manipulation of all such research for financial gain. Such dismissals, not surprisingly, often come from individuals critical of conventional medical treatments and interested in promoting alternatives. However, it is no more accurate or useful to suggest funding bias is simply fraud or it invalidates all research connected with pharmaceutical or other commercial entities than it is to deny such bias exists at all.

Funding bias is a serious problem, especially given the paucity of noncommercial funding sources for veterinary research. However, it is very rarely the case that it manifests as deliberate fabrication or manipulation of data on the part of iindividuals hoping to improve their financial fortunes. Such deliberate cheating would, perversely, be easier to detect and prevent than the real problem, which is unconscious bias embedded in the perspective of researchers, which influences the questions asked, the design and conduct of studies, and the analysis and reporting of results.

Researchers are typically affiliated with institutions; mostly universities or commercial companies. People tend to gravitate toward institutions populated by like-minded individuals with similar views, and we tend to incorporate the views of our close colleagues or mentors into our own perspectives on scientific questions. Similarly, commercial organizations tend to hire researchers and fund research that aligns with their commercial goals.

For example, a scientist interested in the possibility the anti-inflammatory effects of non-steroidal anti-inflammatory drugs (NSAIDs) might suppress the development of cancer is likely to seek work or funding from companies developing such drugs, not from an herbal medicine company that promotes natural remedies as safer than NSAIDs.

Additionally, a nutritionist concerned about the negative health effects of extruded commercial diets isn’t likely to seek or find support for research seeking to identify such harms from a company selling such diets, and they will likely end up working with like-minded researchers and seeking funding from sources with aligned interests.

Finally, a doctoral student in need of mentoring, funding, and help starting a career is very likely to share many of the views of their academic advisors, at the end of their training at least, even if not at the beginning.

These are all examples of the natural alignment of views that tends to occur when people join together in institutions to participate in scientific research. Funding bias, like other forms of COI, is more likely to be an expression of the shared perspectives of individuals grouped in institutions than simple fraud. This does not, of course, mean it is not a serious problem that skews research results away from the truth. The fact commercial organizations choose what research to conduct or support, and influence the way that research is designed, conducted, and reported, can lead to a body of evidence significantly mistaken or misleading even without any fraudulent intentions or actions.

However, it is worth noting the same type of alignment of views, leading to systematically biased research results, can occur when the alignment is fostered by ideological, political, cultural, and other nonfinancial factors. Research supported by pharmaceutical companies is more likely to be favorable to their products than independently funded studies, but research on homeopathy conducted by homeopaths and published in alternative medicine journals is also much more likely than not to be positive.6,7 Studies of acupuncture conducted in China, where the practice is widely embraced by the populace and the government, are much less likely to report negative results than acupuncture studies from countries where the practice is not part of the shared cultural and political history.8–10

While financial incentives and commercial relationships form an important type of COI, we must recognize the problem of COI is seldom simplistically reducible to deliberate skewing of results in the interest of making money. The ways in which we identify and mitigate COI and incorporate it into our critical appraisal will be different, and more effective, if we take the broader view of COI as involving the influence of personal and institutional relationships on belief and judgement rather than simply following the money.

How does a COI bias research?

When viewed in this larger frame, conflicts of interest can be identified as the potential influences of institutional and personal relationships on research results at every stage of the scientific process. Which questions we choose to ask as scientists and how we go about answering them are related to our context and relationships.

As a general practitioner, for example, I have investigated factors influencing the risk of complications from routine neutering surgeries at my practice because this was a relevant subject for me and my colleagues in a way it likely would not be for an academic surgeon. My study was conducted as a clinical audit, not a randomized controlled trial, because it was part of an in-house quality improvement process at my hospital, not an academic research project. The data collection tools (simple questionnaires) reflected the practical realities and interests of the doctors participating in the study. The examination of how various types of suture material might influence complication rates included only those types of suture we use at our practice, and the neutering techniques compared were those our doctors used, even though there are other materials and techniques we could have considered. These and 100 other choices made during the research project reflected bias associated with my personal and institutional relationships.

One might be tempted to argue this isn’t truly an example of a COI. Given the emphasis on financial incentives in discussions of conflict of interest, one could claim there is not a COI for me to disclose if I publish the results of my study because I don’t have an obvious financial stake in the outcome.

Of course, one could imagine a possible financial or personal incentive. Perhaps clients would stop choosing to have their pets neutered at my practice if we reported a high rate of complications? Perhaps my boss would penalize doctors with higher complication rates, and I might be tempted to adjust my findings depending on my relationship with my colleagues?

However, my point is such narrow personal motives are only a limited subset of the ways in which our personal and professional affiliations influence our scientific research efforts, and excessive focus on these types of influences leads us to overlook other important and relevant factors.

I suspect the types of COI-related bias found in research conducted at commercial and academic institutions resembles this example more than the cliché of shadowy figures in industry deliberately manipulating or hiding data to make their companies’ products look good. I have no doubt that happens, of course, but it is far less common than a subtle, creeping bias introduced by a thousand small choices made in an environment where most people have the same perspective and beliefs.

Regular readers will know, of course, in the last year I have begun working in a biotechnology company developing drugs to extend lifespan and healthspan in dogs. Is this a conflict of interest in terms of writing about COI? Sure! Of course, I work for a company with an exemplary ethical and scientific culture, and I wouldn’t have taken the job if I didn’t believe this to be true. And part of my job there is to be the nagging voice of our collective conscience and push for the best possible science within the constraints of regulations, funding, and the ultimate goal of developing successful clinical therapies. However, my perspective is absolutely influenced by the context in which I work and the ethos of my work community.

I have seen how the regulatory and economic framework of a biotech startup differ from the clinical and academic research contexts. The questions we ask, how we frame them, the studies we design to answer them, and how we handle data collection and analysis are all influenced by this context, just as my research in private practice and the research of any university veterinarian is influenced by those environments and relationships. That is why I rush to disclose this relationship any time I talk or write about any scientific subject.

The interesting and important question, then, is not whether a COI exists for a given research project, since it almost inevitably does, but what do we do about it?

How should COI be considered in critical appraisal?

In the past, a potential COI was largely ignored, with the lofty assumption that because scientists had integrity, their work would not be influenced by such relationships. As I’ve already argued, I believe we are all influenced by our relationships in subtle ways against which good intentions are not an effective defense. This has become difficult enough to deny that it is now more common for a COI to be handled through disclosure. Journals, funding bodies, regulators, and others with some authority over scientific work typically require scientists to disclose any potential COI relationships (e.gJAVMA,JVIMJVECCJAAHA). Such disclosure is voluntary and typically limited to financial COIs, which is problematic, but at least it is easier now to know when such relationships exist.

Sometimes journals take failure to disclose potential COI seriously. The Journal of Veterinary Internal Medicine recently retracted a paperbecause the authors failed to disclose an obvious financial COI. On the other hand, I wrote last Octoberabout an undisclosed COI that could have potentially significant relevance for interpretation of a narrative review, and in that case the journal chose to largely ignore the omission when it was pointed out by readers.

The difficult question for the critical consumer of science, however, is what to do with information about COIs when it is disclosed. The sad reality is most often disclosed COIs are ignored entirely (if we agree with the conclusions of the research or share the general perspective of the authors, or simply because we don’t believe “good scientists” can be biased11), or used as a pretext to completely discount the results (if we disagree with the conclusions or have a conflicting perspective on the issues).

To again pick on the extreme case of homeopathy, homeopaths accept the shoddiest and most obviously biased studies as probative when they show efficacy for homeopathy, and they reject any research conducted or conducted by science-based investigators or funded by any kind of entity other than a homeopathy manufacturer.6 (Not surprisingly, of course, I have been accused of exhibiting the same type of bias in reverse, which is fair, though I think the record of my public critical appraisal of research studies of all kinds over the years doesn’t support this claim). Sadly, veterinary students who should know better react in a similar way, discounting their potential susceptibility to bias from associations with the pharmaceutical industry.11

Veterinarians who want to read research studies critically are justly confused about how to incorporate CI into their assessment, and there are few resources available to help them12,13. My perspective is a lot of the problem stems from our view of research evidence as binary. We believe a study either proves or disproves the hypothesis it is testing; a drug either works or doesn’t work; a proposed etiology either does or does not cause a disorder. We think the results must be black or white, and we further believe we can make such judgements for every single study independently. These beliefs are mistaken and inconsistent with how science really functions.

A more useful approach to integrating COI into critical appraisal, and into our overall assessment of what is true and false in medicine, is a philosophically Bayesian manner. Though the mathematic details of Bayesian analysis are complex, the underlying principles are straightforward14,15. They suggest that we should assess the reliability of evidence and conclusions in a research study as follows:

  1. Establish a likelihood of the hypothesis or claim being true or false based on what we already known.
  2. Evaluate the data presented and assess all the usual strengths and weaknesses.
  3. Shift our estimate of the likelihood the hypothesis or claim is true to a degree proportional to the strength of the evidence in the paper.

This is really much simpler than even this stripped down description. It just means COI is only one factor in our overall weighting of the evidence in a given study, and each study is only one bit of evidence in our overall assessment of every claim or hypothesis. There is a continuum of confidence in both the study results and their meaning for our beliefs about whatever subject they address, not a binary state of true or false, pure or biased.

When I read a paper on, for example, a new drug, and I see it was funded by the company making the drug, this reduces my confidence in the conclusions slightly (especially if the conclusions are favorable to the company’s interests). However, if the study was conducted by independent researchers insulated from direct influence by company employees, and if the bias control methods are rigorous, that COI has a pretty small impact on my confidence in the study. In contrast, if the study was conducted in a company facility by company employees using subjective outcome measures and with poor methodological control for bias, the COI will significantly undermine my confidence in any positive results.

The details of how we evaluate the significance of potential COI will vary with the specific research project. The important takeaway here is we shouldn’t use COI as a sole reason to accept or reject evidence. We should consider potential COI in light of both the design and conduct of the specific study, and the potential for researcher bias based on the larger context.

A good example is a recent study of the influence of diet during puppyhood on the risk of canine atopic dermatitis (CAD) developing later in life, which appeared in JVIM. I have written a detailed critical appraisal of this study in my regular Veterinary Practice News column, and contributed to a letter to the editor of JVIM detailing various concerns about the paper.

The paper ultimately concludes, with some caveats, feeding raw diets to puppies may protect them against developing CAD as adults. The authors declared no COI. As required by JVIM, they did declare sources of funding. These included both manufacturers of raw diets and Joseph Mercola, an infamous proponent of raw diets and alternative medicine and an anti-vaccine activist repeatedly warned by the Food and Drug Administration (FDA) for promoting COVID-19 misinformation and selling unproven treatments.16,17

The research group, furthermore, has an established history of publishing research promoting raw diets and claiming detrimental health effects from conventional commercial diets. The senior author, an academic researcher with some minor ties to commercial pet food companies, has specifically identified financial COI as a problem in raw diet research, saying, “[raw food is] not really researched in universities. Most universities get sponsored by these big billion-dollar companies, and you don’t really want to step on their toes, I guess. But, I think that’s not really ethical.”18

This is a great example of what I would consider a COI that does not involve direct financial interests or any intentional malfeasance. The researchers have personal and professional affiliations with individuals and institutions committed to the hypothesis raw diets are beneficial and conventional pet foods are harmful. They are undoubtedly experienced and ethical scientists, and they are unlikely to reap any significant financial gains from promoting this idea. Yet, in the context of their history, and the specific work in this study, their affiliations still amount to a COI that must be considered in weighing the reliability of the evidence they provide.

The bottom line

The more interesting I find a subject, the more I write. Not a great habit in today’s TL;DR culture! (That’s “too long, didn’t read.”)

  1. Conflicts of interest are not just about money! All personal, financial, and institutional relationships influence our perspective in ways that can bias the research we do.
  2. Everyone has some type of conflict of interest. Being smart and ethical doesn’t prevent this from influencing the research we do.
  3. Every possible conflict of interest should be reported when we publish scientific research.
  4. Conflict of interest alone does not justify uncritical rejection of scientific evidence.
  5. We should weigh the significance of possible conflicts of interest in the context of the potential for bias to influence study results and the efficacy of bias control methods employed in the study.
  6. No single study ever proves or disproves anything (OK, maybe once in a while, but not often!).
  7. We should assess individual studies and the overall evidence for or against specific ideas in a Bayesian manner, on a continuum of confidence, not with a binary true or false scheme.

References

  1. Pinchbeck GL, Archer DC. How to critically appraise a paper. Equine Vet Educ. 2020;32(2):104-109.
  2. Johnson C. Conflict of Interest in Scientific Publications: A Historical Review and Update. J Manipulative Physiol Ther. 2010;33(2):81-86.
  3. Mandrioli D, Kearns CE, Bero LA. Relationship between research outcomes and risk of bias, study sponsorship, and author financial conflicts of interest in reviews of the effects of artificially sweetened beverages on weight outcomes: A systematic review of reviews. PLoS One. 2016;11(9).
  4. Institute of Medicine (US) Committee on Conflict of, Interest in Medical Research, Educationand P. Committee on Conflict of Interest in Medical Research, Education, and Practice. Washington, D.C.: National Academies Press (US); 2009. https://www.ncbi.nlm.nih.gov/books/NBK22926/. Accessed January 9, 2022.
  5. Wareham KJ, Hyde RM, Grindlay D, Brennan ML, Dean RS. Sponsorship bias and quality of randomised controlled trials in veterinary medicine. BMC Vet Res. 2017;13(1):234. 9
  6. Cukaci C, Freissmuth M, Mann C, Marti J, Sperl V. Against all odds—the persistent popularity of homeopathy. Wien Klin Wochenschr. 2020;132(9-10):232-242.
  7. Ernst E. A systematic review of systematic reviews of homeopathy. Br J Clin Pharmacol. 2002;54(6):577-582. http://www.ncbi.nlm.nih.gov/pubmed/12492603. Accessed November 12, 2018.
  8. Vickers A, Goyal N, Harland R, Rees R. Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin Trials. 1998;19(2):159-166.
  9. Ma B, Qi G, Lin X, et al. Epidemiology, Quality, and Reporting Characteristics of Systematic Reviews of Acupuncture Interventions Published in Chinese Journals. J Altern Complement Med. 2012;18(9):813-817.
  10. Wang Y, Wang L, Chai Q, Liu J. Positive results in randomized controlled trials on acupuncture published in chinese journals: a systematic literature review. J Altern Complement Med. 2014;20(5):A129. www.liebertpub.com. Accessed November 14, 2018.
  11. Dowers KL, Schoenfeld-Tacher RM, Hellyer PW, Kogan LR. Corporate Influence and Conflicts of Interest: Assessment of Veterinary Medical Curricular Changes and Student Perceptions. J Vet Med Educ. 2015;42(1):1-10.
  12. Lundh A, Boutron I, Stewart L, Hróbjartsson A. What to do with a clinical trial with conflicts of interest. BMJ evidence-based Med. 2020;25(5):157-158.
  13. Resnik DB, Elliott KC. Taking financial relationships into account when assessing research. Account Res. 2013;20(3):184-205.
  14. Homwong N, Hunprasit V, Marthaler D, et al. A Bayesian approach for inductive reasoning to clinical veterinary medicine: The math of experience. J Vet Med Anim Heal. 2015;7(10):308-316.
  15. Gardner IA. The utility of Bayes’ theorem and Bayesian inference in veterinary clinical practice and research. Aust Vet J. 2002;80(12):758-761.
  16. Satija N, Sun L. A major funder of the anti-vaccine movement has made millions selling natural health products. Washington Post. December 20, 2019.
  17. Alliance for Science. FDA warns Mercola: Stop selling fake COVID remedies and cures.
  18. Habib R, Becker K. The Dog Cancer Series: Rethinking the Cancer Epidemic Vol. 1, Chapter 4 (Transcript). 2018:73.
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SkeptVet EBVM Column Makes VPN Top Ten List

My monthly evidence-based medicine column for Veterinary Practice News took the top two spots in this year’s list of top ten feature articles! You can find links to all of my columns right here.

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