Evidence-Based Medicine: the Holy Grail of Value in Health Care. Reflection of GDD, chronic disease, Immune System Dysregulation, and Everything Else

THe Holy Grail

It is not accidental to use the concept of the Holy Grail, as it is considered a symbol of some form of perfection, and yet it is elusive, and probably does not exist. But has been used repeatedly and successfully in stories from King Arthur, to Tom Hanks DaVinci Code to Indiana Jones and the Last Crusade.

So Evidence-based is the current most popular concept for truth, perfection, fact, reality, etc, in Medicine. this could be termed the Medical Truth. It is elusory though and often used as justification for procedures, but may not align with actual truth.

So there are no absolute truths, no absolute facts, not in anything, and certainly not in Medicine. What we hope for is close approximation to 'truth' by the theories we develop.

Many readers, maybe the overwhelming majority, in the modern age have a level of distrust of formal modern medicine, and somehow then cling on to various forms of 'health care influencers'. Many of these seem to be repeating already stated opinions by well informed scientists/ physicians, which is very good. But a good number stary out into their own gut- opinion, or more accurately wallet-driven opinions of things.

There are though in general in health care theories that very closely approach truth: the triad of

a healthy balanced diet, some moderate amount of exercise and keeping your stress level down, are critical central observations of health and well being, probably recognized for millenia, and certainly by ancient Greek philosophers, so for 25oo years. So hundreds of influencers over the centuries have come up with theories to attempt to match those objectives, often with some component of self-gain.

So theories can more defensibly closely match reality when they show properties that have some underlying science associated with it, metrics associated with it, are reproducible with extensive experience, and are described by a rational, wise, fair, experienced

reporter. Gut-instincts alone are not among the properties.

Randomized controlled trials (RCT) are considered the gold standard for close approximation to medical truth. The problem with RCTs to achieve significance (meaning importance) it generally requires thousands of subjects. So the bottom line they general cost millions to tens of millions of dollars and take years to perform. As a result, most of these studies are funded by companies that make the agent or device under investigation. Hence it is clear that there is always some level of bias to them. Also bias introduced by how randomized are these studies, and if based on a agent with a targeted effect, how randomized to populations that would benefit/ or not to the intervention. One of the most interesting terms for bias that has recently been developed for medical research is 'immortality bias' for the purpose of this bog its definition is irrelevant - I like it because it conjures the image of the ancient Greco-Roman gods. Nonetheless RCTs, which major journals like NEJM, JAMA, Lancet strive for are imperfect (as RFKJr focuses on) but by and large as good as it gets in a human drive world.,I take with this the same effort that many universities engaged in when several years back they decided to disband using SAT scores for university entrance of students, but instead focused on their gestalt of the applicant as a total human. That movement away from grades was ofcourse a pompous self-conceit of pseudo-enlightment/ Wokeness. Grades may be imperfect, but they are as good as it gets.

Let us put Gadolinium Deposition Disease (GDD) to that scrutiny.

1. does GDD exist. Patients describe consistent symptoms that arise shortly after the GBCA given. Gd is a heavy metal, like all other heavy metals, lead, Cadmium, mercury, etc. If they all can cause obviously so can Gd. In fact if anything Gd is the most clearly shown to be toxic based on the very close time frame between documented exposure and symptoms. Most of these others the exposure is protracted over many years, and symptom onset therefore not clearly definable.

   So it is pure folly to think the heavy metal Gd does not cause a toxicity. GDD is the more precise term and should be used for all heavy metals, primarily to distinguish from Storage Condition (SC).

2. A GBCA is a chelate which is a form of molecular bonding that is unique to metals. This is part of Coordination Chemistry, which Werner received a Nobel Prize in 1913 for. All the interactions between GBCAs, salts, acids, proteins and other chelators are all founded on the basis of Coordination Chemistry. So to deny that chelation with a strong chelator works, is to deny science well established for 100 years by credible scientists. In fact in my own account, although in retrospect it should have been self-evident to me with the years I spent as the most published authority on the use of GBCAs in humans, that GBCAs are a chelate, and are subject to the chemical principles of Coordination Chemistry. The obvious principle was introduced to me over a decade ago by the Chair of Molecular Pharmacy, at UNC Chapel Hill. Michael Jay, PhD. His particular expertise was in Coordination chemistry, and he had developed a prodrug form of a DTPA-type chemical to chelate heavy metals. I turned his attention to Gd. So denying the concept of chelation is folly.

3. Objective metrics. Gd can be measured both in blood and in urine at any time after a GBCA injection. I employ 24 hr urine measurements within a few days before chelation, and immediately after iv DTPA chelation ( 1 g Ca- the standard). Prechelation, urine Gd is low, to unobserved (years post GBCA) and is elevated post chelation. So DTPA removes Gd by objective metrics. There is also cytokine release following chelation with DTPA. The accurate detailing would take thousands of subjects due to the complexity of the data.

4. Clinical response. The lab findings for response using cytokines would require thousands of subjects. In the mean-time we employ the approach used always with mental health drugs, and most often with other drugs: symptom response. In patients with GDD there is a clear triphasic response: early heavy metal removal Flare, intermediate clinical improvement, late re-equilibration Flare. Over time, the Flares get shorten and less severe, and the central period of improvement expands. All of this based on Science, importantly le Chatelier's principle. In fact chelation provides the most elusive and most important step of the Bradford Hill for causation of toxicity by a drug. That is: if you give the drug again it creates the symptoms again. CHelation, effectively by the nature of its action, drawing Gd back into circulation, emulates a repeat exposure by generating the Gd removal Flare.

5. All of the above reflects the 10 year clinical experience of a highly accomplished (most published author on the value of GBCAs) scholar and researcher. Perhaps most importantly whose original work was in sharp contrast to these observations So having the wisdom to challenge his own strongly held beliefs, when clear new contrasted science-based information came available. So a wise, experienced, rational, fair reporter. What is a critical aspect of wisdom is I am prepared to consider any idea that I may put forth as subject to change. Dogmatism is a child of ignorance.

There are some malinformed individuals who feel that GDD, chelation, etc require an RCT to be considered valid. This is an uninformed knee-jerk malice directed assault, reflecting their lack of knowledge, wisdom and experience. There probably is no existing RCT for any disease entity with the rarity oif GDD (approximately 1 in 10,000). So all the efforts with pretreatment for GBCA or Iodine based reactions, none of them have true RCT basis. It would cost in the tens of millions of dollars and thousands of subjects to do such a study. At the same time it would contain the same or more bias then what has been done with GDD/ chelation/ future directions.

There may be few treatments in medicine that have matched the proximity to truth as the criteria for GDD and chelation. In fact this should serve as the model for management of all other Immune Mediated Inflammatory Diseases (IMIDs), Immune System Dysregulations (ISD), and chronic disease in general. The work is best described as Expert-Observer Led Extended Longitudinal Case Series. So that also means I pay attention to everything and adapt accordingly, which no RCT can do.

My current focus of attention is genetics/ epigenetics. biochemistry, of GDD. I will discuss this in an upcoming blog, and will talk about Functional Genomics Analysis. This is in addition to the current work with the interplay of GDD with other IMIDs and ISDs.

Finally everything I have described for GDD also applies to all other heavy metals, and I am advanced in the process of bringing new insights and rethinking to all of them.

In an imperfect world, there are no facts, one strives for close proximity to truth with one's theories.

Richard Semelka, MD