Wither, the primary care physician.

The spiraling dynamics of medical care:

Patient care is transforming daily. It no longer is the “physician” who came via horse and buggy to be greeted at the door of an infirmed patient’s home. Things evolved from that to doctor offices, and hospitals. And as surely the process morphs into another, the doctors became employed by the hospitals for services that only the hospitals could provide and the process moved along.

Just when equilibrium had been restored between the providers of health care, the sting of  change was in the air. The knowledge of medicine increased voluminously, to the point that specialties arose and within them subspecialties blossomed. Times had changed again chaos reigned supreme. The Internist and the Family Medicine practitioner once the gatekeeper of the health of the community was n the crosshairs and found it difficult to make ends meet, since the patients who used to go to him/her for blood pressure now preferred Cardiologist or a Nephrologist and the blood sugar monitoring was being handled by the Endocrinologist. The specialists started to provide additional limited care to the patients by practicing a little bit of internal medical care since patients did not desire to frequent many physicians. The conflict soon arose between the “gatekeeper” internist/family medicine physicians and the specialist. Noting this irony the insurance companies hopped in to reap some rewards keeping more of the premiums as year-end profits and encouraged patient care to be meted out at the primary care level with the additive incentive for the physician receiving bundled payments. They deemed that if the transfer to specialty care were required then there would be some severance or partial payment at the end of the fiscal year. Their (Insurers) cost benefit spreadsheets showed that specialty care was more expensive then primary care for a similar patient. The complex formulae employed forced many primary care physicians to limit the referrals outside their practice. Unfortunately that limitation was associated with the legal side weighing in with their cries of inadequate care.

The floodgates of crying foul and dashed interpersonal relationships between physicians became the hallmark of medical society. Trust became an empty shell that echoed only the words that were yelled into it. The trade organizations were busy collecting dues as the society was witnessing a turmoil with far-reaching consequences.

As happens with change many physicians not willing to lose the war decided to throw in the towel and if they were in they’re 50s decided to retire from medicine. Their knowledge and experience lost to the multitudes of would-be patients. Those that were younger joined the forces of hospitalists where they were bereft of the tumult of daily practice and the 9-5 job or its equivalent was all they cared about. Do your job, get the paycheck and call it a day.

What then? Well as all things have unintended consequences so does this theme. The hospitals under the scrutiny of the third party payers when squeezed for money ruled in favor of solvency over the contracted doctor. And as surely as this ink dries there are hospitals reducing salaries of the hospitalists or outright canceling their services just to keep their doors open.

Another consequence of greater import is that the independent thinking by the private practitioner has become relegated to the “guidelines” created by the hospitals to streamline their revenue stream for “cost-effective” medical care. Invoking the scout’s honor the hospitalists are dutifully saluting to the demands in order to keep their jobs. When you take the nobility out, all that remains is business. The check is still in the mail at the end of the day and that is all that matters.

A once noble profession is being thrashed on the brutal rocks of economics. And if this wasn’t enough, the depleting supply of those tried and true stalwarts of medicine, the primary care physicians, is rapidly dwindling due to cuts in their practice from attrition of patients and in their professional fees.

Meanwhile the boys in the ivory tower, now have another brilliant idea: Lets get the nurses to start practicing medicine! Now if that isn’t the most illogical form of thinking, I don’t know what is? Why not let the nurses who wish to practice medicine go to medical school. Why not encourage the needs of medical education to those busy science and art majors. Why not make medicine attractive and noble again. Why not have the old strange attractor called desire due to societal influence imbued with nobility be the flag that makes for new converts. Why not call the doctors, “doctors” instead of “providers.” Why not?  Why not resurface the pothole-riddled roads of understanding with fresh thoughts from the physicians in the trenches rather then those opining from their lofty environs? Why keep slipping on the slippery slope to mediocrity and oblivion? There are too many whys and why-nots.

We have entered the realm of unintended consequences due to a few professorial types that entered the hierarchy of medicine and its governance a while ago and as “ivory tower intelligentsia” is wont to do, they have ceded to the pressures of their egotism by creating verbiage and an environment that has slowly disintegrated the nobility and care in medicine.

To that I say, “Leave medicine to its rightful trustee: the physician!”

Hypothesis and Evidence

It was a Sunday afternoon or was it evening? Not quite sure of the time element but I do recall the dent on the rear fender of the car. It was a small indentation, something that I thought might have been the outcome of a parking lot minor mishap. But it gnawed at me for a while and so I decided to investigate it. That little journey took me into the realm of “evidence,” as proof began to reveal itself. Slowly in stepladder fashion, I climbed my way to a new understanding. The hypothesis of the mishap was correct but when and where?

So what is evidence really? Is it a thing, an object, a thought or an imagined corollary without permanence of form in material? Interesting wouldn’t you say? It does have that mind-jangling, asymptotic, confusing ring to it.

Philosophy of Evidence:

Evidence, it appears, is a philosophical construct. Now lets not get too far ahead and collapse this argument by closing our minds. Seriously, stay with me on this one. Evidence can be a bloody knife, a set of fingerprints, a historical construct based on previously accepted principles, a color of an object, a sound wave, a mentioned reasoning in a book, the smell of a plant or a golf glove. You see all these so-called evidences can be used in science, law, biology, medicine, engineering and related fields. So “evidence” by definition has no limitations on the type of construct. It is an informational piece of relevance that is reasoned to agree or disagree with a hypothesis.

So it becomes clear that evidence, is a secondary phenomenon, required to prove a hypothesis. Without one of these you cannot prove one of those. But to generate a hypothesis one has to have a thought construct based on some relevant information that allows you to undertake such an enterprise, doesn’t it?

So evidence can be gained prior to the hypothesis being developed but here in lies the poverty in all scientific disciplines. If one finds certain data and develops a hypothesis to fit the data then one has committed the act of “observer bias.” For, there the question remains, was the hypothesis just a ruse based on the data accidentally at hand and thus a conjecture made and arrived at by forcing a square peg in a round hole, or in some cases a round peg into a round hole. Or is it simply like shaking a tree and the apples fall down thus making us declare that it is an apple tree? There hides a lot of intent in these revelations.

Let us test a hypothesis then to clarify the subject; Man can fly. We both know that is impossible. Yet given the evidence that exists today with thousands of aircraft flights man does indeed hurtle through space albeit in an aircraft designed for such purpose. Yet he himself cannot fly. So the evidence seems to prove the hypothesis that man can fly, yet it does not quite prove that. Does it? Another corollary would be if someone postulated that clouds occur as a result of rain. Well here the reverse is true but the premise postulated is obviously in peril since our observations hold that clouds occur without rain all the time.

Similarly in a criminal case a bloody knife found near the victim does not convict the perpetrator of the crime, unless his fingerprints are found on the knife. Even then the evidence is limited since the context of the fingerprints’ presence on the knife has to be taken into account; the real perpetrator may have stolen someone else’s knife. And on and on the lawyers pick through the haystack to get at the needle.

Evidence supporting a hypothesis is usually static in time. It is the governing principle of that day, week, month, year, decade or even sometimes a century. Today’s evidence may not be relevant for tomorrow and the hypothesis from today may not carry weight the next month let alone the next hour given new evidentiary information. Thus a true proof of a hypothesis is the epistemological data from the past and present as it relates to the truths, beliefs and justifications.

In evidentiary proof of a given hypothesis, rational explanations or justifications are not a guarantee of being correct. It may be rational to think that “reason to believe” and “evidence” are synonymous although the former is a mental construct and the latter may reference material substance. Thus “evidence” which justifies belief may be rational but not proof for a given hypothesis. Similarly being mistaken and doggedly representing reasoned rationality does not determine qualified proof. In the book “Proofiness,” Charles Seife mentions, “Hamlet Evaluation System” utilized by the U.S. Military to justify the purported sham victory in Vietnam that later became labeled as the “Five-o’clock Follies” for their misrepresentation of the actual events.

The term used for judicious and careful thinking and scrupulously obtaining evidence is “Cognitive Prosperity” which implies the holding of large number of true beliefs and relatively few false beliefs is used for individuals who use tedious and time-labored endeavors in uncovering the proofs for a given hypotheses.

“I thought we should require physical determinations, and not abstract integrations. As pernicious taste begins to infiltrate, from which real science will suffer far more than it will progress, and it would be often better for the true physics if there were no mathematics in the world.”- Daniel Bernoulli.

Mathematical Hypotheses:

The use of the Probability calculus as the key to all evidence is glazed over by the sweet syrup of statistical nuances whereby manipulation of the numbers can relate proof to some hypothesis. Looking at the Probability of Confidence Intervals in a Gaussian distribution suggests that a 95% probability indicates a defacto proof for any proposed hypothesis, especially in medicine and that the remaining 5% (2.5+2,5) on either side of this normal distribution can be considered outlier and therefore not representative of the factual evidence. Not only this thinking obscures the truth, it also misrepresents the entire evidence. The real truth in mathematical modeling comes from the “law of large numbers” where the “Normal Distribution” will give a 99.7% confidence interval at the 3^rd standard deviation, which one might argue is still not 100% and therefore not the real “truth.” In other words the larger the “x” in N=(x) the better the evidence to convict the hypothesis.

The rampant use of Bayesian rules holds that it is reasonable for one to believe that the evidence to which one is exposed is related to one’s prior probability distribution. So in fact that if one has had previous encounters, the relatedness to those encounters and the probability derived from them can lay the foundation for the future evidentiary proofs for hypotheses. Now any reasonable, thinking and fair-minded person would vociferously object to that line of reasoning. Yet it is in use today and accepted widely.

“What is Creditable… is not the mere belief in this or that, but the having arrived at it by a process which, had the evidence been different, would have carried one with equal readiness to a contrary belief.” – Blanshard, Reason and Belief.

Proving a hypothesis thus must avail of all evidentiary information both pro and con before being labeled as fact. “Evidence thus must become a neutral arbiter of all proposed theoretical commitments including axioms and hypotheses”.

The objectivity of science is secured by the shared relevant evidence conceived, discovered or brought forth in the discovery process prior to rendering a hypothesis as a fact.

Astronomical Hypotheses:

The Geocentric theory espoused by the Greek Astronomers for centuries and explained by Claudius Ptolemy (c90-148AD) was rendered moot by Galileo Galilei (1564-1642AD), who proposed the Heliocentric theory, championing the Copernicunism of the day, that still survives today, based on a telescopic evidence of the movement of the    planets and the stationary status      of the sun. The Ptolemaic arguments were based on a complex mathematical modeling derived from visual evidence only. Of course the heliocentrism is now in slumber mode since the knowledge that the solar system revolves around the galactic center and the galaxies roar by at light speed to the far edges of space in an ever-expanding universe ever increasing in distance from their neighbors. This expansion has been in progress since the Big Bang.

                 Cosmic Microwave Background Radiation from the Big Bang

The serendipitous discovery of the (CMB) Cosmic Microwave Background Radiation by Arno Penzias and Robert Wilson in 1964 at Princeton, NJ was the first evidentiary proof of the Big Bang. 

              Arno Penzias and Robert Wilson in front of Radiotelescope Princeton, NJ

When all possible reasons for the cosmic microwave chatter received via the radio telescope including “bird-droppings” had been considered and rejected, only then the hypothesis was generated and this information rendered as proof since the CMB was universal in its presence. So the Big Bang did happen based on the CMB.

Medical Hypotheses:

Ignaz Philipp Semmelweis (1818-1865) a Hungarian physician described as the “savior of mothers” imposed strict hand-washing disinfection with chlorinated lime in obstetrical clinics to prevent “puerperal fevers.” He did not have proof of the germs but intuitively knew that “something” was causing the fever that could be prevented with this simple solution. Preventing maternal death, it did!

Edward Anthony Jenner (1749-1823) inoculated an 8 year-old child named James Phipps in 1796 with Cowpox blister material to successfully vaccinate him against Smallpox. There are sketchy references that other non-physicians had utilized this vaccinating procedure before him. The hypothesis therefore existed and Edward Jenner was the first to lay the scientific proof as the foundation of vaccination against smallpox and earning the endearing term, “father of vaccination.”

                                           Edward Jenner

Barry James Marshall (September 1951-) from University of Western Australia proved that Helicobacter Pylori was the causative agent for peptic ulcers. Hitherto the reasoning had been that stress, spicy foods and excess acidity were the leading causes. However he proved his premise after a monumental struggle against the established rigidity of embedded medical reasoning, by drinking water teeming with H.Pylori followed by an endoscopic evaluation that showed the development of ulceration in his stomach and then treated it with an antibiotic to cure the illness without repercussions all without the aid of antacids. Dr. Marshall received a Nobel Prize in Medicine for his efforts.

                          Barry James Marshall

Marie Sklodowska Curie (1867-1934) the first recipient of two Nobel Prizes in Physics and Chemistry discovered radioactivity from Radon. She, based on her inspiration established the use of radiation therapy for cancers. The premise of radioactivity and its potential use to benefit humans was her hypothesis and when the therapeutic use was undertaken, it showed success in patients, proving the hypothesis with proof.

Germ Theory:

In spite of greats like Girolamo Fracastoro, Agostino Bassi, Anton van-Leeuwenhoek and Ignaz Semmelweis, the first individual to formulate that germs were the cause of illness was John Snow. He discovered that Cholera outbreak in Soho London in 1854. Filtering and boiling it to prevent further spread of the illness proved the hypothesis of dirty water, but it did not get proven until Koch’s Postulate was established that Vibrio Cholerae, the organism was the proximate cause of the illness.

The incredible diligence in the yesteryears towards the etiology of disease has slowly disintegrated into mathematical probability events. Where once absolute proof was a requirement now probability suffices. Cases in point are the various “Epidemiological proofs” that are arrived at with incongruous data. For instance there were initial studies that maintained that carbohydrate diets were heart healthy, finding that a high carbohydrate diet leads to high triglycerides led to mathematical modeling to suggest increased protein was better, except if one’s kidneys cannot process the nitrogen from the proteins, and now we find ourselves with the old commonsensical grandma’s tenet that less is better and fruits and vegetables are extremely important for health. There are further proofs that ingestion and retention of excess fat (obesity), smoking and alcohol usage are deleterious to human health. The changeable thinking shows the gravitas placed on cigarettes, when in 1893, smoking was actually promoted as a treatment for bronchitis. Now we know that it is a curse of/on civilization. We laugh at that original therapeutic premise, yet it was a practical suggestion based on faulty reasoning then. Smoking temporarily suppressed the coughing induced by bronchitis, therefore it was hailed as a panacea.

Genetics:

It was once postulated not to distant in the past when the human genome project was completed that disease especially cancer would be cured since discovery of the 25,000 active genes allowed us to peer into the machinations of what makes humans tick. The one-gene-one-disease concept, since has been discarded as information regarding epi-genetics and inter-genetic workings of the DNA helix has come to light. Genes work through varying degrees of modulation under the governing of other molecules like the interference RNA (miRNA). 

These agents can over-express, or suppress a gene’s function. Not only does the human DNA play musical chairs to Barbara McClintock’s “Jumping Genes” or "Transposons"

                            Transposons (jumping genes) that cause the striped colored corn

 it also can through the various SNPs (Single Nucleotide Polymorphisms) that occur randomly allow the process of evolution for survival through making us “fitter.” 

These changes have unintended consequences. Sure we have the DNA mismatch repair mechanisms to protect ourselves, but if inundated with errors, some can pass through and wreak havoc on the body. This relative change on the gene makeup can shut off the protein production that gene produces  conversely it can allow production in excess amounts. The varying degrees of function thus changes the growth potential of the cell in which this corrupted influences is being waged. A wayward cell with a renegade genetic mechanism is the hallmark of cancer. The hypothesis that knowing the genetic makeup will yield cure for cancer remains unfulfilled. More evidentiary information is needed. And more is to come.

Unintended Consequences:

The rampant use of antibiotics is creating a dangerous scenario that finds the pharmaceutical industry on its heels to find newer and newer generations of medicines. This ambitious project is governed by both the desire to have saleable product and also because the organisms are evolutionally quite expedient in their mutational edict to escape the death threat imposed by such agents. This broad and generous use of antibiotics has caused the emergence of newer strains of bacteria eg. MRSA (Methicillin Resistant Staphylococcus Aureus), VRE (Vancomycin Resistant Enterococcus), Resistant strains of TB (Tuberculosis) and AZT resistant strains of HIV. Additionally the constantly mutating and evolving Hepatitis B virus ten years ago had 4 sub genotypes now the HBV has evolved into eight, due to selection pressures imposed upon it by vaccination. More importantly a new mutant Poliovirus was recently discovered in Africa that has caused over 450 deaths in children.

Our understanding of the germ theory has taken on a whole different premise. Having fought the battle against the germs with products that allow humanity to survive has brought consequences of a new emergence of evolutionally mutated agents with newer tools to fight against us. The population of the viruses is in the trillions and humanity is in the billions. Victory in any battle belongs to the agile, constantly evolving and deceptive force.

Evidence based Medicine:

“Evidence based Medicine” is a terminology that has found a haven in medical circles. The intent in the statement is to provide proof for all the guidelines and dicta invoked in the premise of “how-to and what-to” in practicing the art of medicine. Those guides and dicta become concrete with the use of the term “evidence based medicine” and when used in that manner, no questions may be asked. It is a method by some to stifle scientific thought and therefore progress. Medicine is constantly changing because the environment changes too. To place a burden on the practice of medicine with past tense information is deliberately preventing the use of newer methodologies for the betterment of human health. The failure of this logic is in evidence throughout history. Agility and changeable thinking with newer hypotheses and newer proofs will lead to a better outcome. Today is in flux due to the understanding of the past and the unknowns of a hypothetical future.

… Oh, and not forgetting the minor mishap that started this whole thinking, the evidence of a bluish color present in the dented fender matched with a child’s blue colored metal tricycle. Faced with irrefutable evidence of matched colors between the dent and the bike Junior had nowhere to hide. QED.

References:

1. Kelly, Thomas, "Evidence", The Stanford Encyclopedia of Philosophy (Fall 2008 Edition), Edward N. Zalta (ed.)

2. Blanshard, Brand (1974). Reason and Belief. (London: Allen and Unwin).

3. Carnap, Rudolf (1950). Logical Foundations of Probability (Chicago: University of Chicago Press).

4. Carnap, Rudolf (1966). An Introduction to the Philosophy of Science. Edited by Martin Gardner. (New York: Dover).

5. Fisher, R.A. (1930). ‘Inverse Probability’, Proceedings of the Cambridge Philosophical Society 26(4): 528-535.

6. Goldman, Alvin (1979). ‘What Is Justified Belief?’ in George Pappas (ed.). Justification and Knowledge (Dordrecht: Reidel Publishing Company): 1-23.

7. Horwich, Paul (1982). Probability and Evidence (Cambridge: Cambridge University Press).

8. Silins, Nico (2005). ‘Deception and Evidence’, in Philosophical Perspective, vol.19: Epistemology (Malden, MA: Blackwell Publishers)

9. Williamson, Timothy (2000). Knowledge and Its Limits. (Oxford: Oxford University Press).

10. Seife, Charles Proofiness, The dark art of Mathematical Deception,  pub Viking Press 2010.

Open Access

Medicine lives in the shadows of vulnerability. The granite conformity that exists if peeled would reveal the distortions and countless contrary opinions. Each layer has been imbued with the color of discord.

The medical venue is rich in its diversity in spite of the outward image of uniformity. For so long the shroud that has covered - protected that image, is finally being swept away. The hidden knowledge up until now available to a select few is falling in the hands of all. No longer does one have to find and comb through the journals stored away on shelves of a hard to access medical library. The written word once ensconced in the hallowed halls is at the fingertip of anyone with access to a computer jacked into the Net. This medium not only allows the ability of fast access but also allows those hitherto with dissenting voices to express their rants to merge with the raves.

                            Disciplines and Open Access to Information

The tedium of the glacial paced written word on a journal’s page is now available instantly and open to question. The richness of differing opinions prevents a well-articulated -but minimally reviewed article, to become the hard currency of thought. Previously this currency, could lay its foundation into the minds of many scientists and physicians and become permanently inked. It would become the style of thought and the mode of action. But that is a-changing.

The past although rejoiced for its many advances has also been the historical review of too long entrenched a thought that went unquestioned for too long. The promoters of such thought for whatever reason, either drenched in egotism or delusional perceptions, failed to call their own data into question. Now change is afoot; the thousands of pairs of eyes that review such information are armed with easily available broad spectrum of knowledge that can critique any potential error before it gains semi-permanence.

Open access is ready to revolutionize the science and soon in the near future, the art of medicine. But there are flies in the ointment; if the finder of the research pays for the online publication for open access then one might consider a conflict of interest, or if the peer evaluation process is based on "single blind" analytical review then bias can creep in. Here lies the broadened knowledge base of the reader, who, given this open access can now make a critical and qualified evaluation of the study for all to consider. The process does and will on a rapid basis weed out the charlatans. The written publication which, moves at a glacial pace from completion of the study to information dissemination for consumption, equally hampers the flow of criticisms in letters to the editors taking even larger parcels of time to get through to the authors, makes the old printed publication process archaic.

History has taught us that a published journal article without the applied criticism can become ingrained into the minds of the scientists especially the physicians and thereby can alter patient care and management. Equally this sluggish pace leads others to using the "published article" as a reference in future studies thus contaminating and obfuscating the truth.

                                                    Dr. Anil Potti

A recent case of a Duke University scientist, Dr. Anil Potti grabbed headlines when his study could not be reproduced by others but at time of discovery, Dr. Potti's article had been cited 100 times in the scientific literature- the contamination had gone "viral." The drama has ended with his resignation from the university. Other notables of ill-repute in the recent past include; Maria Carmen Palazzo, a psychiatrist on the payroll of GlaxoSmithKline has been sentenced to 13 months in prison after pleading guilty to committing research fraud in trials of the company’s antidepressant Paxil on children. Dr. Scott Reuben, a Massachusetts anesthesiologist with several hundred papers to his name, 21 of which were found to be pure fiction pleaded guilty to charges of research fraud in 2010.

                                                      Dr. Scott Reuben

The dilemma of fraudulent research is significant; Dr. R. Grant Steen in the Journal of Medical Ethics reported that 788 retracted papers from 2000 to 2010. Steen's research found that U.S. scientists were lead authors on 169 of the papers retracted for serious errors, as well as 84 retracted for outright fraud. This practice, although rare in overall terms (1 in 6109 published paper is retracted or 0-0164 retraction rate) is also prevalent in other countries: China with 89 retractions, Japan with 60 followed by India and the United Kingdom.

Additionally there is monetary cost associated with this fraudulence. Researchers from the Roswell Park Cancer Institute in New York has developed a model that estimates the monetary costs of scientific misconduct cases placing a direct cost of investigation for each case at $525,000.00 or $110 million for 217 cases of alleged misconduct in 2009.

Today's headlines are tomorrow's footnotes and day after tomorrow's retractions. The open access process would, given a wide net of critical thought, clear the cobwebs of improper technique, observer, selection and a whole host of biases with quick dispatch. Although hoped but improbable, it certainly will not weed out all bias or errors and in fact it might add unneeded and questionable comments, but on the whole it will purge the unnecessary, the delusional, the slipshod- intentional or otherwise, the dogmatic and the unexamined axioms of scientific arguments. The discordant clamor and exposed inattention from diverse viewpoints will loosen the grip of firm misconceptions revealing a better reality.

Medicine is at the threshold of a transformative change. Open access will enable a larger number of researchers and would-be researchers to have access to information that might lead to new ideas. Each new idea can generate a new hypothesis and thus a new scientific breakthrough. This arborized venous knowledge base will herald a new era in understanding. A minority opinion based on legitimate scientific research can call to question the stranglehold of the conforming thought. The partitioned cells of knowledge will coalesce into an amalgam of rich diversity easily harvested for use.

Suppose you want information about a specific gene function and related research, it will be a click away. The isolation between scientists will end and even though the desire to compete for the top prize will always linger, as it should- since we are humans, the shared information will give others in the field help with their own research. More importantly it will bring the breakthroughs closer and faster to the practicing clinician who can formulate the best plan for his or her patient.

Where does one go today in search of this scientific grail?

There are easy search engines that provide free information backed by peer-reviewed scholarly information. The list by no means is complete but serves as a starting point.

There is a vast growing library that can be freely accessed today: Directory of Open Access Journals: http://www.doaj.org/doaj?func=findJournals In Health Sciences alone there are 422 journals dedicated to General medicine, of which 252 are  internal medicine related, 78 are surgery specific publications and 70 related solely to oncology.

Among the many other free access areas, included below are a few that can be accessed via computer or through iPad apps:

PubMed. This excellent resource gives abstracts of all available information in its database. There are free full text articles also available. Those that are in abstract form can be purchased through a separate online source. But the diversity of the information available makes the search more productive for a specified query. An app for the iPad is also available.

Medscape: This resource is an excellent collation of recent scientific data well referenced by peer-reviewed scholarly articles. An app for the iPad is also available.

Google Scholar: The references mentioned here are similar with an as yet smaller database than that which is available in Pub Med. But it is growing rapidly.

PLoS (Public Library of Science): This online service has scholarly peer-reviewed new articles unpublished elsewhere open access for all. The references are excellent and an app for the iPad is also available.

PNAS or Proceedings of the National Academy of Sciences is considering online publishing (PNAS Plus) as a major format starting in 2011. Other major leading widely read scientific journals including Science, Nature, JAMA and Cell amongst others are also online bringing abstracts and an occasional full text article to the public for free. Times-are-a-changing when 20% of all peer-reviewed scientific articles are available through open access!

These examples are heralding a future of intellectual properties freely available to all. Some are free and some tease with abstracts only, hoping to sell entire articles for a price, I believe time will dispel such pecuniary limits.

And although open access is the wave of the future, just like any other new paradigm its control has to remain with the users. A worrisome historical record encountered in the book “The Master Switch” by Tim Wu suggests that when a technological breakthrough paradigm sprouts its wings, there is a desire by some elite to control and manipulate it. Vigilance, in a dialogue for openness will always be a prerequisite for open access survival.

Courage!

“I am frightened!” she said, her blue eyes wide with anxiety. Who wouldn’t be frightened when confronted with a diagnosis such as hers’ I thought.  Her face was flushed with mixed emotions. And as she uttered the words, tears welled over her lower eyelids threatening a torrent.

“Don’t be frightened.” I said to the 16 year-old, who lay in the bed like a limp doll.  I could see that fear had manifested itself within her tiny form. The three words might have had a calming effect on her or it might have been the stethoscope dangling around my neck or maybe my white coat might have projected some authority over her malady and then again it was her emotional reset. Whatever it was, it seemed to quiet her senses a bit. Her eyes stopped darting left and right looking for answers from the ghost of the future. Her stilled gaze looked right through me in search for answers. After all I had the knowledge and experience to afford those answers.

“All I said was that I felt tired, to my doctor and before you know it, here I am.” She said with agitation in her voice and visible tremors in her expressive hands, as her thumbnail were busy in a nervous ritual of ridding the demons from beneath her fingernails. “And now they tell me that I might have can…” her voice trailed into gentle sobs, unable to finish the word. All this happened under the scrutiny of the stuffed pink teddy bear that sat next to her bed in stony silence.

“I know that this nightmare will end soon and you can go on to live your dreams. I also know that your dreams will change somewhat as a result of this but it will be for the better for you and everyone else around you.” I said quietly and as calmly as I could manage without exposing my own emotions of “Why?” and “Why her?” It was important for her to feel hope. “You will have some difficult times initially but we will guide and help you through it.” I added giving her some sense of truth and reassurance.

As I turned to leave her bedside, her right hand shot up and gripped mine, her eyes pleading for something to hold on to and as she did so her eyes gazed right into mine, rooting me to the spot, where I stood.

She did not say a word while she held my hand but continued the unblinkingly stare. After what seemed a long minute her grip loosened and then with her eyes lowering she mumbled a “thank you.” I replied with a “you are welcome,” but did not know what I had done to deserve that.

The next morning her case was presented to the “Intake Conference.” Most of the medical staff was there. Some with coffee mugs and others still with bleary eyes that even coffee could not blow the cobwebs of their sleep deprivation.

She had an uncomplicated case of Acute Promyelocytic Leukemia.

 The APML was a garden-variety type with its standard translocation of the t(15;17)(q21;q12) and expression of the RARa gene. 

The only problem was that she was younger then the average patient with that disease. However, after half hour of mind melding, thoughtful criticism from the assembled group a decision was made and her treatment was started the same day.

I remember that day vividly. It was a frosty November morning. It was a kind of a virtual memory milestone, with autumn leaves covering the driveways and the lingering chilled breath of those people walking on the sidewalks. That was the day we embarked on a journey together; her in her darkened world and I with a team of others working to make her world brighter.

Nothing extraordinary happened until the third month of her therapy when she developed a fever. It seemed like an interminable time to diagnose the cause of the fever as each hour her pulse and respiratory rate rose and her blood pressure lowered, finally the clarion call of sepsis sounded through the unit and she was transferred to the ICU. IV-Bags filled with antibiotics, anti-fungals and anti-virals were pumped into her every four hours. After days of fighting the vile element, that was never identified, the slow process of healing began. She had marshaled her youthful reserves to allow her to sail the stormy seas. She had survived.

I remember also the slant bright morning sunlight of the March sun filtering through the windows as she sat in her wheelchair in the lobby waiting for her ride. A swarm of well-wishing nurses by her side joyous in their dialogue and happy in this circumstance all animatedly talking, kissing and hugging her. I stood by the window looking at the proceedings. Even though I was partially hidden, I saw her raise her arm towards the window and wave. I waved back with a smile and then it was all over. Hearing my name announced over the overhead speaker, I was back tending to the sick once again, the sight of her leaving the hospital firmly locked in my memory. It was a triumph of human resilience and courage. And, boy what a fighter she was, the best I had, had the privilege of caring for!

Two years later as I was winding down my fellowship in hematology-oncology, sitting in my cubicle with papers strewn over the table, frustrated in trying to resolve the scientific paper, I was writing. With my head in my hands the problem seemed insurmountable at that moment. A soft knock alerted me to someone’s presence. I turned to look and there stood a young woman. Her face was full of life and her blue eyes caught my attention. The slow spread of recognition in me must have shown on my face for as I stood up I must have broken out into a smile that probably ripped my ears of the edges. She smiled back and held out her right hand that I took and for a moment she did not say a word. Then after what seemed like a while she let go of my hand, “I came to give you back what you gave me two years ago and thank you for all you did.” Speechless and still smiling all I could say to her “thank you,” was “you are welcome.” And before I knew it she was gone. That same evening, I competed the article, I had been working on and sent it for peer-review.

 I have often wondered at the many blessings that come from being a physician and never has there been one that has so filled me with utter joy then the memory of that encounter. I have often wondered at what it truly was and now maybe, I think I know. It was the touch of a concerned human for another to lift her out of her despair and give her the strength to fight the fight and win. Sometimes a simple act of a smile or a touch means more than a thousand words.

also published (without images) in Oncology Times:

Voices 

Opinion articles 

Sunday, January 23, 2011Author 

Paradigm Shift

Today I thought of asking the question. What is a paradigm and how do they happen? First you have to agree that a paradigm is a mental construct. It is not really a feel-able, touchable smell-able entity. It is viable only in the brain. It is a kind of a mental note.

For instance if a person were to state, “This is a new paradigm!” What does that person mean? Is he referring to a product or the meaning of the product as it relates to social interaction between us, Homo sapiens? Is paradigm-shift therefore a referential construct?

On a very small-scale, there is an understanding between humans; for instance between me and you, the reader, unless you disagree, in which case you are entitled to your voice as always and carry your own paradigms in your head, but just in case you do agree, then wouldn’t you accept that individual concepts in my brain are personal and therefore differ from the concepts in your mind. So, then we have small-scale paradigms within each one of us. Large scale ones are those where several people agree to agree and small scales ones are within the confines of the invisible castles of our existences where others may agree to disagree.

The next question arguably would be what makes a large-scale paradigm happen? How do large groups of people agree to agree and therefore tenably create this phenomenon that all viewers of that phenomenon consent to force a frame shift in the concepts of belief. Let me give you an example so that we can go from the abstract to the real.

Imagine the building of the wheel. According to archaeologists, it was probably invented in around 8,000 B.C. in Asia. The oldest wheel known was discovered in Mesopotamia and probably dates back to 3,500 B.C. The wheelbarrow was first invented in ancient Greece. Two building material inventories for 408/407 and 407/406 B.C. from the temple of  Eleusis list suggest such timelines. This circular object made of troglodytic material used by our ancient ancestors changed the game of mobility. They were able to traverse distances in search of food and water and a better life through migration on land, move material and foodstuff and engage in trade. The spread of civilization may have been on the primitive wheels made of wood. That, you would agree would be considered a paradigm shift since it made large scale changes in human migration which then added diversity within communities as different groups with varied cultures met and got assimilated into the whole. It made for progress; there were more hands on the till as more people were involved with hunter-gatherer operations as communities to keep their home fires burning and better fed families began to emerge with more robust children.

                                            Antique Spinning Wheel

The thrust for survival in other species made the primitive man invent weapons to protect himself and his creed from invading forces of these predatory animals. In doing so he was also able to lord over the animals for his own survival. The use of the flint for an arrowhead, spearheaded the beginnings of hunting and gathering. This ancient tool dates back to 7000 BC and might also be considered a paradigm shift on an evolutionary scale.

                                                  Flint Arrowheads (circa 7000BC) 

As certainly as the growth of the human population began to excel, in its climb the ladder of the evolutionary tree, to conquer the mantle of the “intellectual-knowing species” so too did the dynamics of the littlest of creatures change. Every species wants to survive, thrive and procreate. It is within the DNA of every living organism that it must procreate and replenish. Darwin spoke about the “Survival of the fittest” and he was right as we find that 3 species go extinct every hour and the planet has been in that mode for the known history of life cycles of species as evidenced by the fossil data. Those that survive, well they have the wherewithal to counter all attacks from predatory forces and those that don’t, perish into the pages of the fossil data. The survivalist attributes must continue even to the littlest of all creatures including viruses and bacteria.

Man and his intelligence came to understand that disease at least in the earlier phases of humanity was linked to unseen critters that would invade the body and cause illness and death to the humans. The recognition of these little “critters” and then how to deal with them was, you would agree a paradigm shift. Martinus Beijerinck discovered viruses as “infectious agents” in a bacteria free culture medium in 1898 and not until 1935 did the first electron microscopic picture of the TMV (Tobacco Mosaic Virus) was seen by human eyes.

                                          TMV (Tobacco Mosaic Virus)

So as humanity would, do as it does best, instigate scientific curiosity and in doing so demand a means of circumventing the “raids” of these “little critters” on the human body. The fever previously treated with “blood-letting” had morphed into poultices and ingestible materials from the apothecaries. Given the new tools of the trade another paradigm shift was to occur shortly.

And it did. Along came the likes of Louis Pasteur who discovered the germ theory of transmission followed by Edward Jenner who discovered cowpox vaccination abolished smallpox, followed by Alexander Fleming who discovered Penicillin from a fungus for treating bacteria. These great men were pioneers for they raised the bar on human intellect and helped increase human longevity.

As insight into the chemical structure of penicillin was discovered another shift was to become a reality. Companies starting with one or two individual members/workers grew into pharmaceutical behemoths creating the next greatest antibiotic and antiviral agent that they could devise in their labs. This was and is all for the good and preservation of humanity. And this is as it should be. But there lurks, somewhere another shift in the making that might be seismic in might and catastrophic in casualties, just beyond the horizon. We don’t see it but it is there. It might be in the form of a mutational change in the very structure of the virus or bacterium that may render us helpless, due to the promiscuous and profligate use of antibiotics, antiviral agents or, it may be another zoonotic illness that might transgress the limit of one species and jump to the humans as HIV did, or it might be a virus cultured in a laboratory mutating in a tiny Petri dish that finds its way from the sealed airtight confines and travel outside to make the human its host. We just don’t know when this might occur, but occur it will. Remember the movie “The Andromeda Strain!”

The 1918 Influenza epidemic is a perfect example of large-scale human life loss from a virulent and mutant virus that wiped out millions of its victims. We already have seen the emergence of MRSA (Methicillin Resistant Staphylococcus Aureus) and VRE (Vancomycin Resistant Enterococcus), resistant TB and a killer Poliomyelitis in an Indonesian city of Cidadep. The list goes on. The shores are inviting and the uninvited guests are arriving.

Speaking of viruses they are the self-starters and very smart in their survival since they constitute the largest population on this planet. If you saw the movie “War of the Worlds” the concept of exposing an alien population to the lethal attacks of this tiny entity (flu virus) can bring down aliens and their space ships.

 It can do the same with the human race if it arrives in a different form with different “clothing” that human immune defenses cannot identify. The virus and bacteria mutate to survive just like we create newer “anti-agents” against them for our own survival. And the battle goes on. The one with the better abilities will win.

Another surreptitious and incipient paradigm shift that has occurred over the millennia is the cohabitation by the viruses within the humans. The bacteria do it in the human GI flora, skin and elsewhere where they provide beneficial effects for their hosts and survival for themselves. The viruses have inserted their DNA within the humans and that resides in our chromosomes as “junk-DNA” or Introns. Thus embedded within the human genome they have modulated the human history.

                                                  DNA Double Helix

                                                         RSV transfection

Viral oncogenes were first defined in RSV, (Rous Sarcoma Virus) which transforms chicken embryo fibroblasts in culture and induces large sarcomas within 1 to 2 weeks after inoculation into chickens. In 1976 Harold Varmus, J. Michael Bishop, and their colleagues,  showed that a cDNA probe for the src oncogene of RSV hybridized to closely related sequences in the DNA of normal chicken cells as the culprit for the sarcoma induction. 

Direct evidence however for the involvement of cellular oncogenes in human tumors was first obtained by gene transfer experiments in Robert Weinberg’s laboratories in 1981. 

The genomic revolution had begun. A paradigm shift in how we view disease was taking shape and treatment of disease would never be the same.

The human history details shifts in human thinking and behavior. Paradigm shifts occur either at a slow steady state or as a veritable “bolt from the blue.” This bolt is placed at the doorstep of humanity by an outside-the-box-thinker. Galileo’s heliocentric view in agreement with Copernicus was one giant step. Newton’s Laws of Motion inspired physics, Edison’s electricity, Alexander Bell’s telephone, Einstein’s theory of relativity are all seismic upheavals in the understanding by us of ourselves and the planet we inhabit. These would be called in today’s lingo; “Game changers.”

It would not be correct if I did not mention two individuals who have transformed the recent landscape of how we interact and communicate and how we all view and relate to each other. These two have the distinction of spawning an industry that helped initiate the DARPA project precursor to the Internet boom; Steve Jobs, CEO of Apple and Bill Gates, the former CEO of Microsoft Corporation. They wrote on their blank slates and transformed us from writing on paper to clicking keyboards and sending mail via postal service to instant gratification with written communication, to video conferencing and cloud computing.

The massive shifts that are in the making through technology will change culture, humanity and our view of the world in very short order due to the availability and thrust of the computing power. We are reaching the massive 100 trillion megabyte storage-and-use capacity (Hans Moravec) of the human brain. Moore’s Law that governs the transistor density on the silicon chip has proven to be correct with a doubling in the power of the chip over a eighteen month period. The increase in capacity also helps when multiples of the processors are placed in parallel, the computer ability to evaluate large scale data increases by distributing the processing load over several processors simultaneously and the added Artificial Intelligence software based on logic gates helps computers in assisting humans in the decision making process. Von Nuemann’s envisioned his robots would create tinier replicates of the machine-self and that is how our DNA is envisioned to ride across galaxies via anthropomorphic adaptation.

Anthropomorphic changes is another intermediate scale shift that lurks closer around the corner. It is the incorporation of the “non-self” machine with the “self”-human. 

This integration has been in place for a few decades now and continues to get more sophisticated. Besides bionic limbs, choclear implants for hearing and insertion of electrodes in the occipital part of the brain where visual references are interpreted, there are bilateral sub-thalamic part of the brain implants for the treatment of Parkinson’s Disease and artificial patch boosters to support the heart in the patients waiting for a heart transplant. Meanwhile the military is using exo-skeletal supports for humans to make them jump higher, run longer and crush materials without the use of human muscle strain.  Brings to mind the movie “Avatar.” Soon smaller contraptions will be added to achieve similar abilities. The human and machine merger is destined to reshape humanity sooner than later.

Recorded human history is adorned with the “peaks and valleys” of human thinking. Such is the way of life. Such is the destiny of the human organism. If we don’t destroy ourselves, we will populate other celestial bodies. These are the large-scale paradigm shifts in the affairs of human beings yet to unfold.