Tuesday, May 29, 2012


Consider the wording “graveyard spiral”. It is a concept so scary that your mind wants you to look elsewhere, maybe the ads on the next page. We will see how it starts but lets first see how it would terminate. Given the right circumstance (discussed below) the g-forces accumulate in a fury and exceed the structural integrity of the airframe causing disintegration or as NASA would call it a “system anomaly”. A 1954 study by the Air Safety Foundation revealed 19 of the 20 pilots who inadvertently entered the graveyard spiral in IMC lost control of aircraft and life. The average time of entering IMC and entry into spiral was 178 seconds. Chilling! And to boot 5-10% of GA accidents are attributed to loss of control due to spatial disorientation and 90% are associated with loss of life.

Space is certainly a frontier that has all to do with visual control. As long as the VFR mind can see the blue above and the green/brown below it is happy. Void the visual cues and the mind’s reliance falls on unreliable senses. So the eyes have it and they control 90% or greater sensitivity in orienting to space. This is by virtue of visual cues. Consider flying VFR on top on a sloping cloud deck and before you know it you would have banked the aircraft to align with the slope. The perceived rate of error can build at the rate of 0.2-0.3 degrees per second. The accumulation of these errors creates the spiral. The pilot thinks he /she is flying straight and level all the time never once considering the instruments crying for his/her attention. By that time the ears and the seat of your sweat-drenched trousers are crying foul and damn-it there is utter confusion and chaos because you have never felt this before. You tug, pull and push and complicate a situation already maximally torqued out of form and there you have a full-blown spiral looking at a graveyard.

Lets look at the psychophysics of this event: The pilot is stationary and restrained in his seat with seat belts. The space around him is spinning and out of control. In these circumstances susceptibility to imbalance is unrelated. The inputs placed by the pilot are relational to experience and performance. The susceptibility to spatial disorientation is inane to human. It is the belief placed on the virtual environment enclosed in a grayed space of clouds where the instrument represent and depict the space around us that we have to learn, believe and then react to, that influences our navigation behavior and thus helps keep us from a system anomaly.

The Human ADHRS and its microcomponents 

Driving a car is a 2 dimensional space  requires “Wayfinding” and motion to achieve the desired result of arriving at a destination. Driving a car on a banked highway prevents the centrifugal force to uproot the tires off the road. Trying to straighten the car on that banked road will lead to unpleasant results. Flying a plane is similar only in 3 dimensions. The banked highway in the sky is an interpolation of aeronautical facts, spatial orientation and a balance of the four forces of flight. Nowadays the mental maps of airspace are virtually depicted on the computer screens in the cockpit hence the positional loss is a remote error at best, unless the computer gives up the ghost and we have a spine chilling lack of situational awareness euphemistically called RAIM loss. That RAIM loss is nothing but satellite chatter providing pseudo-vectors due to downtime as there are not enough of them to provide guidance. With the GPS functional and given that we know where we are the next step is to make sure we are right side up all the time. That is a dependence on the attitude indicator along with a democratic concert with the other five standard equipments. Most of the depiction of the attitude indicator now is represented on the glass screen, but the information is the same.

The Human ADHRS

Assume you have lost it in the maze of clouds. It is getting dark and a tingle down your spine tells you something is wrong but you can’t figure it out. Look at the primary instrument cluster. Is the attitude indicator showing a straight and level? Is the Turn coordinator showing straight and level? Is the DG/HSI not spinning? And Is the Airspeed indicator constant? And the altimeter is rooted to the altitude of your designated choice? Well the democracy has it – you are straight and level and eventually if you hold your brain cells together you will fly out of it – descend, climb or straight through.  It is not a good measure if you are a VFR pilot in the throes of the cottony smooth cloud to attempt a turn unless ATC tells you that there is an endless sea of clouds in front of you- but then why on earth were you venturing there in the first place? No preflight weather? unh!. Keep it straight and ask the ATC for VFR ahead of you. If there is a discrepancy in, say, the attitude indicator, which is banked, and the turn-coordinator is straight and level, look at the DG/HSI. If it is not spinning then the turn-coordinator is correct and the attitude indicator has lost the vacuum. Therefore democracy amongst instrument determines the right course to follow. Navigation through the clouds is an aggregate of Way-finding, motoric (motion) and a relational event that requires a democracy from the instrument cluster. The discomfort of disorientation is unsettling feeling in an unfamiliar surrounding. Ground yourselves in the basics of flight.

Lets look at perception through the eyes of a pilot. The visual reference that determine our place in space is based on distance, speed and depth of objects. The comparative size of similar objects determines distance. The change in the texture and contrast between two objects also define distance. Relative velocity of objects at different distances are different, thereby determining speed. Looking through the window of a moving train the closer trees whoosh by while the trees at a distance move slowly across the landscape. The clarity and blurriness of objects gives us the depth perception. All these perceived differences reside with the eyes and the brain interprets accordingly. Loss of the surrounding landscape can limit that focus and so trouble begins.

Night flights in VFR conditions can be disconcerting to a pilot too. It is important to use peripheral vision for gathering information from the landscape. Focusing on an object directly will limit information since the cones (structured for bright light and acuity) are centered and the rods (designed for lower ambient light and greater recruitment for stimulation) are aggregated around the center. The rods react to low intensity light and their function is wiped out for 30-40minutes after exposure to bright light at night while the cones function well during the day and their recovery time is 3-5 minutes after exposure. So when the sun is spanning the other side of midnight, focusing on objects is not a good practice. For one, it can create a jumbled sense of understanding. It can create false movement. This is called Autokinesis, an event that can occur in the dark when a lighted object is focused upon on a dark moonless night – the object appears to move on its own volition. It is therefore important to scan the environment in sectors periodically for total landscape visualization and orientation. My personal belief is to fly instruments at night all the time no matter what the meteorological condition. Oh and by the way if someone ahead of you on the taxiway has his/her strobes on use your deepest airline voice and tell him, “Kill those strobes”. That goes for everyone.

What then operates when the eyes don’t have it. There are two other senses that help/hinder. The two systems that give us some back up are the vestibular system and the kinesthetic sensorium. The former is a resident in the middle ear and resides in a space a lot smaller then the ADHRS in the black boxes in the airplane. The vestibular system comprises of a contained space collocated as three semicircular canals mated together to the same cavity- the Utricle. These canals are natural gyroscopes located in three orthogonal planes depicted on (figure 1) and they align us for pitch, yaw and roll motion. Within the Utricle and the canals is a fluid called endolymph and mixed into this fluid are little sand-like particles called otoconia. Resident in the walls of the Utricle are hair-like projections. As we move the fluid moves within the canal and the otoconia rest on the hair cells, which bends and defines positional awareness, (Figure 2). The minimal detection rate by the vestibular system is 1.5 degrees per second. Once the movement continues in the same direction for a period of time  The fluid movement stabilizes, the hair straighten and the sensation of movement ceases. It is the deformation of the hair cell imposed upon it by the angular force vector of movement that determines the velocity. Once the force is continuous in the same plane the hair cells relax and the perception of movement is lost. Thus the rate of change defines the position rather than the change itself. This is called the “washback motion” effect where magnitude of motion falls below the threshold of perception. That is the problem in flight. If you close your eyes and the CFI in the right seat puts the plane in a coordinated 10-20 bank doing a 360 degrees turn, the turning sensation will cease and you will feel that you are straight and level. Or if he/she changes the bank angle from 45 degrees to 30 degrees the student pilot will sense straight and level again. This very sensation then causes faulty inputs in times of distress to a VFR and a non-proficient IFR rated pilot.

The Kinesthetic sensorium is located in the skin and the joints. The baro-receptors in the joints give us the tale of the tape related to g-forces, hence the “flying by the seat of the pants”. A CFI does not have to see the attitude indicator nor the VSI to see the student is doing poorly on 45 degrees banked 360 degrees turn. He “feels” it!

Conclusions drawn from above lead anyone including pilots with one and only one determination:
1.                     If you are a VFR only pilot get an IFR rating and fly in actual conditions with an instructor to get comfortable.
2.                     If you are IFR rated then fly in the actual condition with an instructor till you have achieved comfort level.
3.                     Flight at night should be considered an instrument flight. Reliance on the eyes in the cockpit on reliable instruments is a gateway to safe flight.

Let me change hats and discuss the rationale for cerebral (brain) safety. By that I mean the cognitive efforts of understanding the information gathered is interpreted by the brain. If the brain is under duress from any sets of circumstances then the interpretive imaging by the brain will falter and alter the perceived data. Studies done by using the BOLD method (Blood oxygen level dependent) fMRI (functional Magnetic Resonance Imaging) revealed that there is a definite reduction in the functional cortical mass given a depressive influence. These influences include: Fatigue or lack of Rest, Alcohol, Sedatives, and Tranquilizers, Some Over The Counter medications and Emotions. It is therefore imperative to have fully functional vault of tricks up your cortex prior to a flight. There are many things that will make you go bump in the night. Limit them to zero and live to fly another day.

Here are a few rules to live long by:

1.     Don’t drink and fly
2.     Don’t take medications and fly – unless you are past three times the dosing of the medication. If the medication is to be given every six hours then delay flight 18 hours after the last dose
3.     Get plenty of Rest
4.     Get plenty of daily exercise and don’t smoke – nicotine is a drug!
5.     Drink fluids – dehydration makes for sluggish blood flow and contraction of the blood supply.
6.     Check you emotions at the cockpit door – if you cant wait till the cause of that emotion is past.
7.     Don’t fly with a cold – blocks the Eustachian tubes to the middle ear, makes one susceptible to false sensory input and ear aches – as babies in the commercial flight will attest to.
8.     Always have a plan A and a plan B – and execute them in sequence as needed.
9.     Get an IFR rating if you don’t have it and even if you don’t intend to fly IFR.
10.  Verify and Trust your instruments.

Friday, May 25, 2012

Future in Healthcare

You wont need a degree in the future. No PhDs or MDs not even a Batchelor degree in Art for that matter. The future will be about Self-Discovery. You will have finally come around to the stage of Nirvana, where information will unfold before you and you will be the wiser. However, you will have to reach out and take personal responsibility to achieve this vaunted elevation.

It will be all about the educated mind. Educated? But didn’t I just say that there will be no need for degrees? I did and for a reason. Education is not about degrees anymore. Knowledge is disseminating and expanding at the rate predicted by the Moore’s Law. More transistors on the chip leads to more information to cull, akin to more functioning brain cell connections leads to a large fund of knowledge. Those with the curious bent will have their health at their fingertips. They will understand and hopefully educate others. These will be the doctors of the future. Trained to understand and dispense the knowledge. Trained to realize the potential of eliminating disease. Trained to advise a positive change in life-style with close observation. Trained to obviate circumstantiality. Trained to be the physicians of the future.

Internet and the CHIP:
There will be websites to wade through and take quick self-tests for symptoms that will point one to a particular ailment or a differential of ailments. A refined multi-server IBM Watson or its progeny will be main-lined for all. One would then find the appropriate test on the internet-market and perform the test at home. If the quiz determined a 30% probability of say, a certain cancer, then you would buy a multiple gene array chip, drop a drop of your blood/saliva/urine on it and send it back for the answer. Chips exist at this time, but they will need to be marketed for each specific malignancy as well as “many in one.” This however is predicated on the present information and soon to be had future knowledge.
Affymetrix Chips

Microarray chips

Further down the road, did I mention that there will nano-wires and nano-discs floating around in the blood stream for high risk individuals for cancer that will determine the first wayward cell and send alert for where and what based on fluorescent conjugate scanning technology.

Infused nano-wired and scaffolding for stem cells

 Thereafter other nano-devices will be able to send anti-cancer molecules to disrupt the genesis.

Nano-wires interacting with cells

Nano-disks gobbling up cancer cells

Please also read Future of Medicine if so inclined.

Speaking of Diabetes. In the first instance if it is Type 2 Diabetes, and obesity is a factor, you owe life to yourself to quit the high caloric diet and ration yourself along with a healthy dose of exercise. 
Pancreatic Islets of Langerhans

Those with the Juvenile type will have stem cells/epigenetic drivers of certain sugar control genes infused to regenerate the pancreatic Langeran Islets, so that Insulin can force the sugar molecules into the muscles and brain around where its needed.

Heart Disease:
Chronic Heart disease for those who love Twinkies/Brownies will be countered with a pill that regulates the pluri-potent cells to repopulate any damaged cardiomyocytes (heart cells) due to a “heart attack.” 

It will be “transplant in a syringe”. And speaking of atherosclerotic plaques, an oral additive will prevent that just by suppressing the gene that harasses humans currently. It will shut down the inflammatory sequence that invites the cholesterol and creates the artery luminal damage and disruption of the laminar flow of blood. 
CECs (Circulating Endothelial Cells)

A pre-heart attack warning will be notified via the circulating endothelial cells (CEC) in the blood stream or their secretory products detected by the nano-wires. The nano-discs will take over and send signals to reduce inflammation, counter the sticky platelets in the blood stream for appropriate preventative measure. Any coronary artery constriction due to atherogenesis will be dissolved rapidly.

Chronic inflammation will be resolved by reducing obesity, tempering various molecules like NFkB in the blood stream. The nano-wires will detect if the inflammasomes are increasing and give appropriate warnings on the smartphones to increase the inhibiting supplements, available freely in diet.

Prevention will be the name of the game. Will we live longer? Quite possibly yes. But we better make sure the Star trek "Replicators" are invented to put food on the table for all. Funny that the therapy of the future in the form of nanodisks looks so much like Wimpy's Sandwich. "What goes around comes around."

Wimpy and his sandwich

I do pity the educated hypochondriac of the future though.

The uneducated or  “other side of the coin” will unfortunately filter through the jungle of “take this” for “that hurts.”

So if you want the future, educate yourself in ways that will benefit you and your family.

Live Long and Prosper!

Tuesday, May 22, 2012


“I heard the news today…Oh boy…” ~ Lennon-McCartney

The litany of words, “bad, rogue, fraudsters, dishonest, heartless, money-hungry” and such abound in the media today when they describe doctors. Why? And you should ask this question as the number of times the sun comes up for you. Why? A one-person anomaly is brought to bear on the whole profession. A single bad apple and the entire orchard is condemned. Using these logical fallacies through transitive relationship to promote a viewpoint drips of bias. No one ever said that all physicians are saints, although the small miracles that some perform should automatically enter them in the Vatican roster of potential Saints. But with the vitriol that exists today, sainthood is doubtful, let alone livelihood. Something is amiss and the whole equation falls apart on one side of the equal sign.

When you ask an individual about his or her doctor, he or she will use glowing adjectival descriptors. But ask the same question a different way, like what do you think about doctors? And they will reverse course and begin a diatribe of curses. What gives? How can on the one hand, one doctor be good and the rest bad and in today’s illogical world, the one to the many come back to rest on the one.

I think that a 24/7 media, the determined few, and the mindless many, carry most of the blame and I will not shy away into a politically correct cabinet of silence, here. Imagine this, as a corollary, if a small airplane crashes, there is a media blitz for 24 hours and politicians beneath their well-oiled hairdo are behind podiums, pointing fingers, hurling invectives and trying to enact new regulations to control personal freedoms. This back and forth sells news and makes the newsmakers happy to the detriment of the many, until some other tragedy in some far away land beckons their attention. 

Similarly when the actual news is slow, you know, like no airplane crashes, murders, killings, house fires or earthquakes and tsunamis anywhere, where do you think their attention seems to self-direct? You got it, healthcare! So what to do, they can pick up on a story that “broccoli can cause flatulence” ah but that wouldn’t get any attention. Or “smoking causes lung cancer” no that wouldn’t do it either, its old news. There, then starts the wheels and gears of the media machinery, churning away, creating news from the ethereal vapors of conjecture and axioms destroying as they go, faith in the most noble of all profession and those that have sworn to uphold it.

Seriously, think about why we as doctors suddenly became “healthcare providers” or HCPs? If you think about it, its quite simple. The reduced numbers of trained physicians (projected at 45,000 by 2020 

and close to 125,000 by 2025, by the latest estimates, to handle the burgeoning ranks of baby-boomers within the next decade is going to create NON-MDs/DOs to handle medical care. And they are all too happy at the circumstance to step into shoes that they cannot fill. Did you know that a bill in the UK parliament to allow Operating Room Nurses to do major abdominal surgery was defeated by ONE vote recently? Adding further insult to injury, now the powers that be are attempting to reduce the training time for the physicians, which is nothing more then increasing the mindless herd with the same unified mentality. "Apply within, No critical thinking required." There is a large cache of NPs. RNFAs, PAs that are ready to take on the duties and they are making no bones about it. Yes, they have a significant part to play in medicine but to play the doctor theme (and its not TV anymore) just does not fit. The learning curve is not the same. The knowledge base has a flatter curve based on the curriculum and the experiential reference is limited. The pay schedule will be reduced for all (Its all about money anyway) and everyone will be addressed the same way so that no one feels terminologically abused in this politically correct universe. Surprised? You shouldn’t be. After all that is what the politicians and their prospectors want. Depending on the lobbying efforts, the regulators control the show. If you can take care of a toe than the whole foot is a part of the toe and the ankle and then the knee and then the hip and then the whole body. Why not? Meanwhile doctors compartmentalize themselves into organ specialties of limited view and grand expertise, while the Primary Care physician gets crunched. What happened to the black bag and the stethoscope?

Oh and don’t forget the fact that the sudden policies that are streaming out of the special forces of policy-makers is attempting through a mish-mash of selective data crunching, restraints on certain diagnostic screenings and required/needed therapeutic interventions of diseased patients. Try as they may, they cannot seem to win the battle of lesser screening for prostate cancer, colon cancer or breast cancer is better for you, because someone comes up with a methodologically well defined study to flip the fried egg on their faces. And so they bundle their argument with buzz-words, "This policy will cut costs and improve care." Bull-manure, I am sure.

Travesty? You think? No! Immodest Collusion!

So there we have it. The slow demonization of the noblest of all professions at the altar of a devilish fiscal, perverted science and authoritative control that has accelerated by the applied energized fuel from those that game the system for their own benefits. 

Grand schemes unmoored of logic are stuff of chaos. 

As humans, truth is what we are, without it we become implicit axioms to illicit convictions, like "the earth is flat," for the eye can see no further.

Wither, I dare say, the once noble society of thinking physicians into the robotic multitudes of "healthcare providers" guided by the mandates of illogical thought, untested guidelines, unmoored and mechanical answers, all, with a wink and a smile.

"The King is dead. Long Live the King!"

Saturday, May 19, 2012

The Game's Afoot

The Game's afoot ~ Shakespeare

There is a fervent hope in patients to find trust in their physician and as a consequence of that, faith in their management. The results of therapy are partly the human “thing” and partly the created salve. If you have doubts figure the 20% benefits that arise from placebos. Or in psychiatry over 40-50% of benefits can be derived from placebos added to a good verbal session. So medical care is not all in the machines, pills and injections. There is a strong component of the psyche involved. A good bedside physician is able to cure a lot more maladies within the limitations of his knowledge and available tools as compared to a “super-duper expert.” That is why the need for the primary physician remains paramount to patient care.

After all why do we go to the physician? We seek help from him or her for a malady that afflicts us. We don’t go to him to socialize, nor do we go to shoot the breeze, although during the process of evaluation personal discussions occur and they help immensely in differentiating the etiologies and finding the human connection.

I came across a letter the other day. It was written the old fashion way, in a hand-written cursive, single-lined ink. The handwriting leaned this way and that but was clear. The words scratched off here and there but they had meaning. The sentences ran into each other but they held emotions. The paragraphs were riddled with hanging participles but they had clarity. It was a letter from the mother of a patient. It was sad. It was emotional but it was also factual. The letter described the last days of her son. She had unburdened herself of the weight of a million invisible tons. It created tears that had to be held in check. It made for the bubble of emotion that can easily ride its own wave of despair, that had to be managed. It was very sad. He, the son, had died after a short battle with an undisclosed illness. He had previously had a malignant Lymphoma that was cured through treatment and then this ugly virus had stepped in and churned the immune defenses until nothing was left. He was forty years old at the time of his death. I must have held that letter in my hands for a long time. His face came flooding back into my mind’s eye. His easy smile and the colorful blush of his twenty-something gift of wonder flashed before me. We had talked of baseball. We had talked about cars, about his work, about his future, about his life. We had talked about his mother and his family often, I knew them all well. And yet here it was, the end. The sum total of a once beautiful life that had touched so many hearts and minds, snuffed –relegated to the forests of memory.

She wrote how he had always talked about our conversations and how he found the courage to do what he had done in his life. The goals he had achieved. The progress he had made as a person. In the end the last sentence struck me, “he attributed his optimism to you.” Nicer words then that could not have been written on paper by a grieving mother to her son and daughters’ physician. There was a relationship of trust and an element of faith with which he had fought and won the earlier battle but died in the course of the long war.

I remember walking into a patient’s room and saw the resident with his face buried in the computer tablet asking questions and inputting information, never once connecting through an eye contact. The resident seemed completely at peace with his fingers flying over the tablet crossing the boxes and using short-cuts for the verbose glossary that made the electronic record. There were too many digital words with little meaning and none to satisfy the need of the patient.

The world of medicine is in turmoil. We know not what we do nowadays. We promulgate to promulgate, we strategize to strategize, we plan to plan, but we never actually do. We hide behind the comforts of technology so we may not expose our fragile senses of self. The human connection of “how are you?” is changed to “and what are you here for?” Instead of holding a hand or placing a comforting one on the shoulder, we write, “patient is emotional.” What have we become? Is this the evolutionary face of an intellectual society, or the decline of an aging dinosaur?

And so, from hour to hour, we ripe and ripe,

And then, from hour to hour, we rot and rot;

And thereby hangs a tale.' ~ Shakespeare

And so I thought, what if we were to connect C3P0’s wires to IBM Watson’s brain and give “it” the “provider” hat all the technology experts and some in the ivory towers are proposing, that will definitely satisfy the pundits. What will be the outcome? Will C3P0/Watson ask so “how was the game last night?” or “did you see that homer off the right field wall?” or “how are sales of the new 2012 model car?” No I don’t think C3P0 would be able to connect at that level. Maybe “it” will answer with “the game was good Mr. Jones.”

Now supposing C3P0 makes a wrong diagnosis from its list of differentials, it might address the mistake like HAL 9000 did in 2001 Odyssey, “It can only be attributable to human error.” And if the programmers at IBM or those for C3P0 decide to take it offline, it may answer like HAL 9000, “This mission is too important for me to allow you to jeopardize it.” And its assertion of its importance to the Healthcare issue of providing the ultimate best care to patient, here is what it might mimic HAL9000 again, “Let me put it this way, Mr. Amor. The 9000 series is the most reliable computer ever made. No 9000 computer has ever made a mistake or distorted information. We are all, by any practical definition of the words, foolproof and incapable of error.”

So we are head long into this love affair for the higher artificially intellectual endowed technology with, as usual, our eyes closed. And placing more and more reliance may ultimately lead to a certain self sufficiency that it (the computing device) might give a retort back, but the damage would already have been done to countless by then and the need for unplugging and reprogramming so vital to the future health of humans, would invite a similar remark in HAL 9000’s firm and decisive one, “I'm sorry, Dave. I'm afraid I can't do that.”

The human connection that is being undermined steadily today for fiscal and other reasons will and already to a certain extent, has unintended consequences. We may choose to keep the blinders on firmly over our eyes, but the inescapable future sits defiantly planted before us. Who will “feel” the empathy? Who will ask about baseball? Who will… but I digress, for that is not in the outline of our current or near future system where everyone is ogling over the latest and greatest invention and freest of freebies. They are more concerned with what is the written word, however inaccurate or untrue, then to the reality of the existing facts. Today, the elitist use of the word “sympathy” that supercedes the down-to-earth expression of an act of  “empathy” by a commoner. While the decision makers “stand like greyhounds in the slips, straining upon the start,” they are oblivious or unconcerned about the forced course of history their actions will enable, for they have “Disguise(d)  fair nature with hard-favour'd rage.”

When in the why and the wherefore is neither rhyme nor reason? ~ Shakespeare

Monday, May 14, 2012


Once upon a time there were daffodils that grew in the wild. There were fewer cars and fewer accidents, but not from what you might expect, but from common courtesy. The cars were not made with a preplanned obsolescence. You got what you paid for. There were skilled people whose skills were honored with loyalty. That was a time of innocence.

Once upon a time there were physicians who spoke of life and health with their patients. They communicated as friends in soft tones. Oh there were harsh words, there always were but much subdued in pitch and loudness. The physician healed through a sense of human dignity, loyalty to life and the personal desire for the best outcome for his or her patient. The physician knowledge was more holistic. There was a basic fabric of intelligence imbued within the basic human science and the art was practiced with reasoned parallel to human dignity. The nobility of the profession was cherished. Physicians spent their life in seeking benefit for the sick. They were scientists ruled by their own conscience to win the battle against disease. They had an open mind and freedom of thought. Money was not made the root of their being. They were free to express their knowledge and undermine the pathology of disease. That was the time of invention.

Once upon a time a picket fence was the desire. You worked until you could afford it and then you made it your castle, pristine and beautiful. And you were the king and the queen of that domain. The tax collector still knocked on the door and you gave him what was owed without prejudice of thought. The roads had to be made, streetlights had to be lit and safety of an individual guaranteed. So you paid. You walked the street with the knowledge of freedom. You strolled down the paths and watched the streetlights come on. There was a personal freedom. There was intent by all to keep it that way, for it was beneficial to all. You never locked your house with alarm systems blaring accidentally into the night. The car doors were left unlocked and the windows opened to air the cars on hot summer days, never once fearing theft. You never heard the chirp of a remote keyless alarm system being activated or an inadvertent alarm being set off with no one paying attention. That was the time of freedom.

Once upon a time there were few television stations and one television per household. The broadcast from the stations was the same news in the evening. You watched and listened and made up your mind about what was in store. The news was not outright propaganda based on an ideology but information. It was information to be gathered and each mind was to see fit to its own interpretation based on its knowledge. No pundits told you of what you should do or not do. No pundits told you where to go or where not to step, or suggest that this was a result of that when they had little or no knowledge of the facts themselves. No the information was delivered clean for consumption, not a predicate to change, cajole, modify thinking, mollify a differing mindset, nor to destroy enterprises of wealth for the simple sport of seeing it being done. That was the time of honesty.

Once upon a time, you looked into someone’s eyes rather than on a screen and communicated. Once upon a time the sport was “stick-ball” and not a flashing screen. Children ran and played hide-go-seek and laughter in the yards was the norm. The children demurred to their parents for their wisdom and age. They had respect in their eyes and their demeanors. Once upon a time snacks were for hunger not for convenience and boredom. That was the time of health and togetherness.

Once upon a time money had a hard asset behind it, called gold. The value was based on an asset. There were no printing presses that manufactured money on paper. There was no push to usher in a method to prevent deflation or inflation by infusing more money (with less value) in the system and thus artificially keeping the availability of capital to balance the spreadsheets and eventually lowering the value of buying power of that paper money. The stability of the economy was predicated on the yin and yang of the enterprises. The rise and fall based on supply and demand and all things always regressed to the mean eventually and were allowed to do so. Failures were a natural byproduct of decision-making and risk-taking. If you won, you made it and if you did not, you could lose it all. That was the time of reason.

Ah but we have come a long way from there. That was then and this is now. We have legislated and regulated to intervene into personal freedoms. We have deemed, deferred and isolated our instincts from our better angels. We have gained little for a lot that has been lost. Hate has replaced love. Anger has drowned civility while dogma has trumped reason. Times have changed.

And this is the time when we have grown fearful of each other. When neighbor does not speak with neighbor. When anger is the mode of discussion. When loyalty is a relic of the past. When love of money and material goods outshines every other virtue. When pointing fingers against others is a sport for the politicians. When balance sheets are massaged and manipulated for greater gain. When success is an isolated castle in the wilderness. When a 24/7 media generates news rather than report it. When doctors are demeaned and vilified and some use it as a sport for capital gains. When hard work is considered a travesty impinging on rights of others and lack of free flow of capital to the uninitiated is the call to arms. When words hurt. When feelings are all. When speech is stilted and stilled. When harm is considered a harmless sport. When humanity has lost its virtue.

Do I think that humanity is lost? No I don’t, but then I am an optimist. I think we will survive this, for the pendulum that swings, eventually returns to the center of human consciousness and decency. And it will. No matter how much the earth's tilt, to the Foucault’s Pendulum, the center always beckons.

And then again sometime in not too distant a future, the generations to come will write a different tale, “Once upon a time there was anger and greed and jealousy and...”

Wednesday, May 9, 2012


                            One touch of nature makes the whole world kin ~Shakespeare

There was something quite unexpected in the motions of the mother, but they were exquisitely precise and very effective. She would reach and gently lay her index finger on the forehead of her child and lo and behold, the child would in mid-expression of raw emotion be stilled into a cooing baby. And another time a different but equally emotive cry led to a slow deliberative production of a milk bottle, the sight of which, brought peace to the infant. Now to my ears there was no different in the shriek or scream or cry or whatever you want to call it that the baby emitted, the mother had an answer for it. She seemed to know what the baby needed. The baby was talking to her in a language that I was not quite versed in. Amazing, I thought, how wonderful for the mother to know precisely what her infant needs are at all times? And to the mother, each cry had a meaning. There was a rhythm and pulse to this interaction, for whatever the need was, it was expressly met. The mother’s hands were always near the baby’s face and at times, if not the hands her cheek was touching the soft young skin.

Humans have a longing for togetherness, mostly. Those nurtured with an attentive mother certainly have the security and knowledge to find the comforts when in anguish. It is the human desire to be joined in limbic resonance with your parent or child, or spouse or friend. Those lucky enough find this harmony in the form of peace and comfort. Alas those nurtured under the diffident eye of a careless distraction find neither peace nor comfort and live lives of remoteness in an unsocial environment.

If you go back to the days of the thirteenth century, when King Frederick II ruled southern Italy, you would find that given the polyglot nature of his intellect, he was indeed a burgeoning experimentalist, a cruel one at that. He decreed, at the behest of his intellectual curiosity, one day that all mothers would only feed their children and blanket them for comfort but not spend playing or holding them. In other words, he banished the coddling and comforting of the infants. As recorded by historians there was an alarming increase in the death rate of children. (The information was chronicled in "Chronica" by a Franciscan monk named Salimbene di Adam. Whoa there, what happened, you ask?  Okay we will get to that in a minute, while I bring you another message from the nature-nurture sponsor.

Moving on to the 1940s and beyond, in the days of the “behaviorists” you know those sorts who made a living, touting that children need not be coddled for they would turn into whiners or worse, emotionally dependent souls. Blasphemous as it might seem, it appears these behaviorists,
John Watson

like John Watson, who famously said. “Mother love is a dangerous instrument,” probably were never nurtured in the first place. The drive to alienate the infant and baby’s emotional needs from those of the mother found a resonance within the intellectuals. A plethora of books were written about this unattached nature of rearing the young. “Go ahead let the baby cry. It is good for him or her,” they would say.  Even today there are advocates of that including Richard Ferber, who recommends that parents should never sleep with their children. If the parents divorce later, that the children might blame themselves. How ludicrous. How very loosely dispatched a Freudian statement from a man who understood so little about himself. To consider that a child must be forced away from a parent is an abominable idea. Infants learn to synchronize themselves with their mothers.  The rhythmic heartbeat and the swells of easy breathing is a source of tremendous comfort to the infant. And it is through this comfort that the child finds security. Children deprived of proximity to their parents learn to have insecurity and a deep seeded thirst of wanting. Of mother and children, James McKenna and Colleagues stated that "on a minute to minute basis, throughout the night, much sensory communication is occurring between them." The further proof of this aloofness that blinds the American household is evidenced by the fact that SIDS or Sudden Infant Death Syndrome in the US is 2 deaths for every 1000 live births, which is ten-times higher than Japan and a thousand times higher than Honk Kong. What gives?  In the Asian countries where mother and infants sleep together SIDS is virtually nonexistent, let alone known.

Sigmund Freud

And it all began from a false premise by the once famous Sigmund Freud who felt all angst was derived from the repressed emotional domain of the human mind and that free associative expression through transference of the repressed unconscious mind was the answer to all behavior.

While Anna Freud, his wife publicly voiced her disdain with John Bowlby’s maternal “attachment theory,” which showed a high death rate amongst nurture-deprived children, a fate similar to the unwanted foster children in Romania that were fed and dressed but remained deprived of human touch, speaks volumes against the current vogue of those and these times.

Rene Spitz determined that these children had a 40% mortality rate when contracting measles vs the general population was limited to a 5%.
Rene Spitz

The stalwarts in their field of behaviorist discipline continued to form and shape human destiny for a few generations. The result of course is what we see today, a rising tide of sociopathic behavior. Emotional and human deprivation leads to insecurity, lack of empathy and the “me” syndrome. Reading this, a few will have snarky thoughts right about now, while others will go hmmm and still others will look deep within themselves. And that is the purpose of this discourse, isn’t it?

As history has a way to reach the present, plodding through time and incorporating into its vast tomes, we now arrive at the moment about five years ago. The winter light had abated and the glow of the sun more radiant. The shadows had lengthened and the winds of change had turned brisk outside with a mix of cold and warmth. Funny, how you remember these moments. They are ever so fresh, each entangled moment, a repository of emotions.

Kindness is more than deeds. It is an attitude, an expression, a look, a touch. It is anything that lifts another person ~C. Neil Strait 

I had walked into the intensive care unit to see a patient. He had undergone chemotherapy and had his immunity decimated by the drugs. There were posters outside his private room, claiming that he was an infection risk and that all must take appropriate precautions. The man was in his seventies, still quite robust in his physique, but with all the tubes emanating from him, that was hard to see, but for the discerning eye. I put on the blue terry-cloth skullcap; the large wrap around blue clean paper-gown and put on a set of white paper booties. I looked around and found the nurse behind the desk, hide a smirk. Yeah that has happened so many times before and since. So here I am suited and my mind plays a trick. I found myself imagining that I was hovering inside the patient’s head- looking back at me entering the room. The restriction of the wrist “supports” felt confining, you know the sort that we put on the patients to protect themselves from themselves. I felt the endotracheal tube and the sore throat with the active ventilated air being forced into my chest in rhythmic swells. Oh yes in that mangled moment of fictional reality, I was there and what did I behold was this man dressed in blue paper overalls, comical in looks, scary in intent and detached in being. entering, this technologically littered room of modern machines replete with bells and whistles announcing the slightest inadvertent movement I made. This man was like an alien. All I could see were his eyes yes they were dark. He made some comments about me and then examined my chest with his stethoscope, and with his gloved hands he pressed on my abdomen, all the while peering at responses evoked by me. “Good, so far so good,” he said. I tried to lift my hand but the restraints held my wrists. “You have a question?” he asked. I tried to nod, but my neck would not move. He waited a little and then reiterated, “You are improving” With that, he turned around to walk out of the room.

At that moment, my thoughts and imagery came back to me. I was draped in that blue uniform and he was my patient. I turned around, in a totally discombobulated mental strain and finding the chair, sat down next to him. I could see his eyes brimming with tears. Oh the isolation of it all, he must feel, I thought. I pulled the chair closer to his bed and unrestrained his hand, “Mr. J, I am going to untie your hand, please don’t try to pull the tube out.” He nodded.

With his hand unrestrained, he grasped my gloved hand and then let go. It was sudden and quite alarming. I looked up to him and then his hand, his fingers were scattered in a gesture of “what’s the use.”  And you know how moments beckon you to do things that are involuntary and unpracticed, I got up walked to the sink, washed my hands again and then without wearing any gloves, I sat down and held his hand. Tears came streaming out of his eyes. I pulled the facemask down momentarily and smiled at him. Comfort knows many emotions, they are all instantaneous, unrehearsed and come from the primitive, nurtured emotional treasure chest of time. I must have sat there holding his hands for a long time, it seemed, yet when I exited the room, only fifteen minutes had lapsed.

The next day, I arrived back at the unit to find the room empty. I asked for the patient and the staff nurse said, he had died in his sleep. Oh the horrible images that streamed across my mind’s eye were unrelenting, until the nurse reached back from the desk and produced a notepad and on it in shaky capital letters, the kind you see when a patient with Parkinson disease replete with tremors tries to write, were these words, “Thank you for holding my hand.”

“We all can’t decide what that means, can you?” The nurse asked.

The neural connect to the brain happens through all our senses. None are stronger or longer lasting then the feel of a human touch.

Creation ~ Michaelangelo

Saturday, May 5, 2012

Progression Free Survival (PFS)

The lecture hall was dark and the only faint glow was the low-lit lamp of the podium and the screen behind. Somewhere during the lecture, a hesitant hand went up in the far right corner of the room. It caught my eye and I hesitated in my delivery, then stopped and acknowledged the request.
“I don’t seem to understand the difference between “Time to Progression” and “Progression Free Survival?”
“Well, they are pretty much one and the same.” I remarked then added, “One determines the end point of death from any cause (PFS) and the other only concerns with the disease progression as in (TTP) There are however several scientific publications that muddy the waters by using them interchangeably.”
“But then that would confuse a meta-analysis if those studies were compared?”
“Exactly! Good question.”

Saad and Katz state this definition in their paper:

Progression-free survival (PFS) is defined as the time elapsed between treatment initiation and tumor progression or death from any cause, with censoring of patients who are lost to follow-up. Many recent trials have used PFS or time to tumor progression (TTP) as the primary end points, with TTP theoretically differing from PFS in that the event of interest is only disease progression Both PFS and TTP have traditionally been considered as surrogate end points for OS, as far as the drug approval process is concerned… http://annonc.oxfordjournals.org/content/20/3/460.full

And thus followed a discussion that eclipsed the lecture and brought everyone to the edge of their seat. The questioner was none other than a very bright, very young nursing student. The more the discussion ensued the more her intellect blossomed before everyone’s eyes. Yes she was special. The entire episode ended after the hour had elapsed and the lecture hall lights had been turned on, but the memory lingers. Such intelligence makes for sweet memories.

And while the whole premise of PFS was and remains in doubt because of the arbitrariness of the combined data, the balm of understanding was far from soothing.

To answer the progression free survival or PFS question, one might have to take on at least two issues. One is what is the importance of such a designation, in terms of new drug approvals and two, how does it impact patient care and costs in the longer term.

Lets address the issue of the makeup of the PFS and both the answers will come tumbling down like Alice falling into the rabbit hole to find more and more curious things in the math of medicine.

Dissecting the terminology, it is quite self-expressive, isn’t it? PFS determines the time period between initiation of any treatment and the progression of the disease to death. The concept being: If you get treatment A on Date 1, and disease stays stable for a duration X months, until the patient passes away from any cause, the PFS is X months. This is simple and quite straightforward, or so it seems. The implication is that the disease was kept in abeyance for a certain period of time longer than that it would with the standard therapy.

Now here are some interesting tidbits and the raw meat of the details.

Starting any study one accrues patients. The accrual rate is incremental at first and then reaches a steady state, correct? In other words if you are planning to accrue 100 patients, you are not going to get them all on the same day, are you? No! Certainly not! So there are calculations to allow for the initial accrual state and steady state to determines the PFS for each. So far so good, you say? But here is a minor wrench, the time period allocated to the steady state is not only based on accrual but on the consideration of when the last accrual site was opened and when the public became aware of the study itself. There lies a python in that basket of surprises, if you wish to take time and think through that. What has the public awareness got to do with any of this? I really don’t have a clue. But the movers and shakers do.

Let me inject a minor bit of information in regards to what is considered progression of a disease. The EORTC has determined a fresher guidelines for Response Evaluation Criteria or RECIST 1.2 and here by definition a disease increment of 5 mm or more, gain in size by 20% on 2-3 Dimensions of appearance of a single or multiple new sites of metastasis via tangible diagnostic procedure, such as CT scan, MRI, on occasion X-Ray and clinical examination is required. All valid and true. They also mention that the thickness of the slice of 5-mm cuts as the bare minimum needed for true and verifiable reference. This inclusion is important since a 10-mm slice may miss the lesion completely or cut through it at one end or another and thereby give a false reference to the increment or decrement of the actual size of the lesion. (Akin to cutting an orange at one end vs. the middle the cut circumference differs). Of course, the contrast material used in the determination must remain constant as differing materials or none at all will give different results due to their penetrance. (The image below copied from the article listed below for demonstration purposes only: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435346/)

 For more read the .pdf file below:


Basic mathematics:
Ok so we move on to the next level down the rabbit hole. Say one patient had a progression free disease period of 4.5 months and the second patient had a progression free period of 5.4 months, contrary to your thinking the result is not a mean, average or median. It is based on the time to assess the disease which if it is every two months then the progression free survival will be logged in as, you guessed it, 6 months or if it is every 12-weeks then it would be 7 months. Great! You say, but, isn’t that inflationary in at its basic level? Of course it is. So the question then arises, who is that PFS really serving, the patient or the experimenter? You make the choice.

The following are the real world calculations:

Here Ceil is the minimum integer greater than or equal to this argument.
(4.5/2)*2=3*2=6 (The calendar time of PFS is PFS plus the enrollment time)

Confidence Intervals and Standard Deviations:
No, we are not over yet. After the accrual is complete and such a PFS has been calculated, it is then compared to the standard arm, which may be standard therapy, placebo or whatever has been deemed an appropriate measure of comparison. Those numbers are then grated by the peeler and put into the juicer of statistics and a number is arrived at which is placed on a Normal Distribution Curve and if it lies within 2-Standard deviations or a Confidence Interval of 95% that number is published (The 5% outliers need not apply). If therefore the number (X-Months) is higher than the standard therapy survival number then the treatment is considered to afford some benefit to the patient. YAY! Or just yay. So supposing that the PFS is higher by four months (arbitrary figure) and there is an 85% probability of its validation then, my dear friends as it may be obvious to you, there, the full descriptive disclaimer would go something like this: There is a 80% chance that the PFS is 4-months better than standard therapy and falls within the  Confidence Interval of 95% (CI 95%). You see! (There are two (exactly 2) percentages feeding off each other. Below is an excerpt from the PFS calculation model citing the notorious p-value.

If you really want to dwell into the meat and potatoes all by yourself and leave this corned beef sandwich alone, please read: The FDA Guidance, at various levels of discussion, indicates the issues of bias in this disease assessment format:

But even though you haven’t yet walked into the quicksand of thinking, this will really blow “your ever lovin’ mind. “ So lets say that the Proposed therapy A has shown a better PFS then the standard therapy, here is the kicker, who is to say that this has anything to do with the therapy itself but everything to do with the biology of the disease. In other words if the number of patients are stacked in one arm of the study with a slow growing tumor against a faster growing version of the same tumor with similar stage etc. wouldn’t you get the higher PFS just by virtue of the tumor biology? Sure you would. The slow growing one would grow slowly and therefore manifest progression later and the patient will live longer.

Annals of Internal Medicine March 6. 2012, 156

That question is answered with a, well, the computer designates the patient to the arm independent of the Principal Investigator’s knowledge. That may be so, but the bias is built in absent real information. Hence the need for very large numbers in properly done studies, hence the Law of Large Numbers comes to apply. That is why different studies of small numbers show wide disparities when comparing the same therapy choices and very few institutions or experimenters are willing to redo the study because of cost. If you have what you need, why bother! Additionally, and now this might throw you off the curb completely, different ethnic groups have differing mechanisms to counter disease within their bodies. Yes, you read that correctly, we are after all humans and live in different areas and are exposed to different things and given the traits of the Transposons (those jumping genes) that manipulate the epigenetics of the DNA and suspend or accelerate certain genes, the ability to fight disease varies based on environmental and natural selective influences.

You can read about Transposons here if so inclined: http://jedismedicine.blogspot.com/search?q=transposons

The experimenters, however not willing to give up data, use any such study as a steppingstone to add another layer to the complexity, using the study as the base model. They would rather concur with prejudice then revalidate the original premise.

In worshipping the strength of the Greek mythic Heroes, one must also consider the limits of their tragic flaws. All great is not good and neither is all bad.

Arguments in favor:
There are arguments in favor of PFS though. Huh? You shrug. Why can’t he make up his mind? Ok, in full disclosure there is a bit of importance, in the study of tumor biology, PFS noted as a function of TTP is a good indicator for first progression of disease based on high yield diagnostic procedures (e.g. CT scans, MRI and MRI/PET fusion studies). In other words using sharp diagnostic criteria the time to progression information can be of significance, but not in the sense it is being used. Needless to say, the FDA and the pharmaceutical industry use these criteria for drug approval. And you wonder why they don’t work their magic in the real world. Oh well!

Overall Survival and the Randomized Clinical Trials:
Now why, I ask don’t we just go back to using the time-honored measure of absolute patient survival. obtained through the rigor of Randomized Clinical Trials? Because they are expensive! Although there are some who argue to the contrary and there always are some, like the small gremlin that annoys the hell out of you when it takes a seat and grumbles at everything thought in your brain and finds a contrarian’s point of view to all. The problem is expediency. TTP and to some extant PFS is faster route to show “benefit” and gain approval by the FDA. But is it the right method?

But that can be good, you say. Yes, true, but the OS route is more deliberate and a comparator of apples and apples. The measure of determining this would be as I just mentioned in a Randomized Control Trial or RCT, where the criteria of inclusion/exclusion are clearly spelled out and there are no lurkers in the mix. The speed of approval is not necessarily a function of OS but the regulatory maze that the drug –maker has to work through. Using OS as the final arbiter may weed out some “would be” contenders early, but maybe you wouldn’t want that when bazillion$ are at stake. This, then makes for a speedy review, but at what cost? And that is the thought. 

I mean even If there is a bias of tumor biology, the over all survival or OS gives a pretty good indicator of the value of therapy in a well-constructed time-honored validated methodology of a Controlled Trial, don't you think? If patients live longer and not by a few days or a couple of weeks but by a “significant” number of months or years, the “Evidence” becomes a tad bit stronger about the efficacy of the therapy, medicine can then base its decision on that, rather than the "EBM" they continue to mouth without a shred of understanding.  And then there is the Lead Time Bias issue of early diagnosis will by its own nature give you a false sense of increased survival. True. Therein lies the dilemma of why investigational studies fail in the real world. They just do. Expensive studies with large accrued numbers of patients "weed" out some of this dilemma and to some extent honor the old system of good science.
Annals of Internal Medicine March 6. 2012, 156

For further investigative thought: http://jama.ama-assn.org/content/307/17/1838.short

Have I been too harsh?

Have I been too unkind?

I must be cruel only to be kind;
Thus bad begins, and worse remains behind ~ Shakespeare