New York Biotechnology Association (NYBA) Annual Meeting
Target Health is pleased to announce that Dr. Jules T. Mitchel will be moderating a panel entitled: “FDA Innovations to Enhance Drug Development” at the annual meeting of NYBA in NYC, on May 2, 2012. The panel will address and assess FDA’s recent Innovation Initiative which promises to redouble the agency’s efforts to encourage innovations that will promote public health as well as strengthen the American economy. In addition to Dr. Mitchel, the esteemed panelists include:
Afia K. Asamoah, JD, Covington & Burling LLP
Chris Szustkiewicz, PhD, CK Regulatory & Compliance Associates, Inc.
Glen Park, PharmD, Target Health Inc.
Please let us know if you will be attending so we can plan to meet.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com
If you were thinking of emulating William Shakespeare and/or Rem Koolhaas, consider all of the following scientific discoveries regarding creativity, including meditation. USC researchers are working to pin down the exact source of creativity in the 1) ___ and have found that the left hemisphere of your brain, thought to be the logic and math portion, actually plays a critical role in creative thinking. Even though it mainly was handled by the right hemisphere, the creative task actually lit up the 2) ___ hemisphere more than the noncreative task. The results indicated that the left brain potentially is a crucial supporter of creativity in the brain and that it takes two hemispheres of your brain to solve a creative problem
Most people view 3) ___ as an asset — until they come across a creative idea. That’s because creativity not only reveals new perspectives; it promotes a sense of uncertainty. In a 2012 upcoming issue of the journal Psychological Science a paper reports on two 2010 experiments at the University of Pennsylvania involving more than 200 people. The studies’ findings include:
- Creative ideas are by definition novel, and novelty can trigger feelings of 4) ___ that make most people uncomfortable.
- People dismiss creative ideas in favor of ideas that are purely practical — tried and true.
- Objective evidence shoring up the validity of a creative proposal does not motivate people to accept it.
- Anti-creativity bias is so subtle that people are unaware of it, which can interfere with their ability to recognize a creative idea.
To uncover bias against creativity, the researchers used a subtle technique to measure unconscious bias — the kind to which people may not want to admit, such as racism. Results revealed that while people explicitly claimed to desire creative ideas, they actually associated creative 5) ___ with negative words such as “vomit,” “poison” and “agony.” The researchers said that this bias caused subjects to reject ideas that were novel and high quality.
“Our findings imply a deep irony,” wrote the authors, who also include Jennifer Mueller of the University of Pennsylvania and Shimul Melwani of the University of North Carolina, Chapel Hill. “Revealing the existence and nature of a 6) ___ against creativity can help explain why people might reject creative ideas and stifle scientific advancements, even in the face of strong intentions to the contrary.” Uncertainty drives the search for and generation of creative ideas, but “uncertainty also makes us less able to recognize creativity, perhaps when we need it most,” the researchers wrote. “Revealing the existence and nature of a bias against creativity can help explain why people might reject creative ideas and stifle 7) ___ advancements, even in the face of strong intentions to the contrary. The field of creativity may need to shift its current focus from identifying how to generate more creative ideas to identify how to help innovative institutions to recognize and accept creativity.”
The outcome of a study by cognitive psychologist Lorenza Colzato and her fellow researchers at Leiden University, published 19 April in Frontiers in Cognition, show that certain meditation techniques can promote creative thinking. This study is a clear indication that the advantages of particular types of meditation extend much further than simply relaxation. The findings support the belief that 8) ___ can have a long-lasting influence on human cognition, including how we think and how we experience events. The study investigates the influences of different types of meditative techniques on the two main ingredients of creativity: divergent and convergent styles of thinking.
Divergent thinking: Divergent thinking allows many new ideas to be generated. It is measured using the so-called Alternate Uses Task method where participants are required to think up as many uses as possible for a particular object, such as a pen.
Convergent thinking: Convergent thinking, on the other hand, is a process whereby one possible solution for a particular problem is generated. This method is measured using the Remote Associates Task method, where three unrelated words are presented to the participants, words such as ‘time’, ‘hair’ and ‘stretch’. The participants are then asked to identify the common link: in this case, 9) ___.
Analysis of meditation techniques
Colzato used creativity tasks that measure convergent and divergent thinking to assess which meditation techniques most influence creative activities. The meditation techniques analyzed are Open Monitoring and Focused Attention meditation.
In Open Monitoring meditation the individual is receptive to all the thoughts and sensations experienced without focusing attention on any particular concept or object.
In Focused Attention meditation the individual focuses on a particular thought or object.
Different types of meditation have different effects
These findings demonstrate that not all forms of meditation have the same effect on creativity. After an Open Monitoring meditation the participants performed better in divergent thinking, and generated more 10) ___ ideas than previously, but Focused Attention (FA) meditation produced a different result. FA meditation also had no significant effect on convergent thinking leading to resolving a problem.
ANSWERS: 1) brain; 2) left; 3) creativity; 4) uncertainty; 5) ideas; 6) bias; 7) scientific; 8) meditation; 9) ‘long’; 10) new
Architect Rem Koolhaas: Seattle Central Library Seattle, USA
Architect Rem Koolhaas: The CCTV building in the new financial center of Beijing
Shakespeare and Medicine
(April 23, 1564 to April 23, 1616)
The Chandos portrait, one of several thought to depict William Shakespeare and to have been painted during his lifetime.
By medicine life may be prolonged, yet death Will seize the doctor too. Cymbeline: V.5.29-30
William Shakespeare’s ability to fathom the dysfunctions of the human mind has astounded theatergoers for more than four hundred years. His portraits of Hamlet, King Lear, Othello, and Macbeth all attest to his genius for reaching into the depths of the soul and pulling out its pith for all to examine. But Shakespeare also excelled at identifying and describing afflictions of the body, such as scurvy, gout, epilepsy, rheumatism, and venereal disease. Each of these afflictions – and scores more – sicken the kings and commoners of his plays; they are the Furies of old come to torment Medieval and Renaissance England.
Shakespeare’s knowledge of both physical and mental illness enabled him to enlighten audiences about the soma and psyche of a character and their failure to work in harmony. Not infrequently, Shakespeare exhibits surprising insights into medicine. For example, in Henry IV Part II, Northumberland – down with a fever – describes the principles behind immunization when he receives bad news from the battlefield.
In poison there is physic; and these news,
Having been well, that would have made me sick,
Being sick, have in some measure made me well
In The Winter’s Tale, Camillo presents a revolutionary concept: that a person can carry and spread illness even though he or she remains disease free:
There is a sickness
Which puts some of us in distemper, but
I cannot name the disease; and it is caught
Of you that yet are well.
In Richard III, after Hastings informs Richard that the king languishes with a fatal illness, Shakespeare calls attention to the importance of nutrition in the following lines spoken by Richard:
“O, he [the king] hath kept an evil diet long, / And overmuch consumed his royal person”.
In Pericles, Prince of Athens, Shakespeare demonstrates an awareness of altered states of consciousness that mimic death. In the key passage, Cerimon opens Thaisa’s coffin, observes “how fresh” she looks, and remarks,
Death may usurp on nature many hours,
And yet the fire of life kindle again
The o’erpress’d spirits. I heard of an Egyptian
That had nine hours lien dead,
Who was by good appliance recovered.
Cerimon then revives Thaisa, noting, “She hath not been entranced above five hours”.
Scholars often conjecture that Shakespeare’s knowledge of medicine was mainly the product of his relationship with John Hall, a physician and herbalist who earned a master’s degree at Cambridge University in 1597 and, after further studies on the European continent, settled in Stratford and married Shakespeare’s oldest daughter, Susanna, in 1607. However, it seems just as likely that Shakespeare gained most of his medical knowledge on his own. Supporting this view is the fact that he had already written many of his plays – including dramas with medical references – before Hall left Cambridge. More important, though, Shakespeare had lived in London in the early 1590’s. The city at that time was a prolific breeding ground of disease because of crowded, unsanitary conditions. Garbage littered streets. Residents emptied chamber pots out windows. Brothels incubated syphilis. Dung clogged gutters and waterways. Flies and rodents carried bacteria and viruses from one section of the city to another. Hygiene was almost nonexistent. Even the queen bathed only once a month. Consequently, the London of Shakespeare was dirty, raw, and noxious. When plague ravaged the city between 1592 and 1603, Shakespeare witnessed human suffering on a vast scale. The infected burned with fever of 104 degrees Fahrenheit or more, shivered incessantly, and suffered bouts of vomiting, insomnia, and delirium.
Spread from rats to humans by fleas, plague could manifest itself in three forms: bubonic plague, which caused painful swellings (buboes) in the lymph nodes of the armpits and groin; pneumonic plague, which filled the lungs with fluid; and septicemic plague, which poisoned the bloodstream. Sometimes one form of the disease killed by itself; at other times, it progressed into another of the forms before claiming a victim. Together, these three manifestations of plague were known as the Black Death because of the livid hue of corpses caused by subcutaneous hemorrhaging. As the bodies accumulated – and the rats and fleas multiplied outbreaks exponentially – Shakespeare saw it all. At his writing table, death sat at his elbow. On his walks through streets and byways, it saluted him with the flopping arms of wagon-borne corpses. Physicians were powerless against the disease. In fact, one of the most distinguished physicians of the age – William Gilbert, physician to Queen Elizabeth I and, after her death, to King James I – died of plague in 1603.
In The Medical Mind of Shakespeare, Aubrey C. Kail describes efforts to contain plague: “Special officials called ‘searchers’ were appointed, whose duty it was to go into houses and search out plague victims. They were paid a higher rate if the victims were found dead.” Kail says the practice of using searchers, along with the imposition of quarantines, provided Shakespeare a plausible explanation for a significant development in one of his most popular plays.
The use of the word ‘searcher’ in this sense appeared in 1592 in Romeo and Juliet. Friar John, suspected of being in an infected house, was shut in by the ‘searchers,’ and was thus prevented from carrying the all-important message from Friar Lawrence to Romeo. No messenger could be found to return the letter to Friar Lawrence, so afraid were the citizens of Verona of the infection. The communications breakdown precipitated events leading to the tragic ending of the play. Another common affliction in Shakespeare’s time was venereal disease – in particular, syphilis. Although the crew of Christopher Columbus is sometimes blamed for carrying syphilis from the New World to Europe, the disease probably existed in Europe long before Columbus set sail for the first time. However, it was apparently mistaken for leprosy. Giovanni Fracastro, an Italian poet and physician, coined the word syphilis in a poem in 1530. Shakespeare refers to the illness as pox in ten of his plays. Of special interest is Measure for Measure, in which three citizens of Vienna openly discuss venereal disease. One of them, Lucio, upon seeing a brothel madam approaching, says, “I have purchased many diseases under her roof”. Shakespeare first staged the play in 1604, the year after the government closed the brothels of London.
Besides plague, venereal disease, and other afflictions of the body, mental illness and its symptoms – including depression, obsessive-compulsive disorder, and recitations of gibberish – were commonplace in Shakespearean London. In fact, because treatment was virtually nonexistent for the mentally disabled and because most of the mentally disturbed roamed freely for lack of institutional care, London and other European cities teemed with the eccentric, the paranoid, the schizophrenic. When Shakespeare ventured forth on the streets of London, he entered an alfresco asylum. All he had to do was etch images in his memory and he had raw material for his plays.
.In his dramas, both mental and physical illness sometimes inhabit the same character at the same time. For example, in Richard III, Richard exhibits the symptoms of kyphosis (hunched back) and psychopathy (asocial and amoral behavior), which shape him into a grotesque killing machine. In the opening lines of the play, Richard soliloquizes on his appearance and his mindset:
But I, that am not shaped for sportive tricks,
Nor made to court an amorous looking-glass;
I, that am rudely stamp’d, and want love’s majesty
To strut before a wanton ambling nymph;
I, that am curtail’d of this fair proportion,
Cheated of feature by dissembling nature,
Deformed, unfinish’d, sent before my time
Into this breathing world, scarce half made up,
And that so lamely and unfashionable
That dogs bark at me as I halt by them;
Why, I, in this weak piping time of peace,
Have no delight to pass away the time,
Unless to spy my shadow in the sun
And descant on mine own deformity:
And therefore, since I cannot prove a lover,
To entertain these fair well-spoken days,
I am determined to prove a villain
And hate the idle pleasures of these days.
Plots have I laid, inductions dangerous,
By drunken prophecies, libels and dreams.
.For modern audiences, Shakespeare is a window on human affliction and its treatments in the late 1500’s and early 1600’s, an age when medical science was an oxymoron and gleeful germs had the run of both the king’s household and the peasant’s hovel. Some people of Shakespeare’s time believed disease was a punishment for sinful behavior. Others thought it resulted from the movement of the stars and the planets. Whatever the cause, virtually everyone agreed that it triggered illness by creating an intolerable imbalance in four vital fluids in the body: blood, phlegm, black bile, and yellow bile. Called “humors” (from a Latin word for liquids), these fluids controlled health and human behavior.
Persons in whom blood was the dominant humor were kind, loving, merry, enthusiastic, and passionate. Those ruled by phlegm were sluggish, apathetic, cowardly, and dull-witted. Persons dominated by yellow bile were stubborn, impatient, vengeful, and easy to anger, and those dominated by black bile were melancholic, depressed, irritable, brooding, and cynical.
When the body produced too much or too little of a humor – or if the humor altered its consistency or ventured beyond its normal location in the body – illness resulted. Diagnosis consisted in one or more of the following: observing symptoms such as fever and headache, evaluating urine for discoloration and frothing, plotting astrological charts, and checking the pulse for the rate and strength of the heartbeat and for rhythm abnormalities. In Hamlet, Prince of Denmark, Hamlet underscores the importance of the heartbeat as a measure of well-being when he tells Gertrude “My pulse, as yours, doth temperately keep time, And makes as healthful music”. Treatments to restore the proper balance of humors consisted mainly in ridding the body of humoral excess by blood-letting (phlebotomy), vomiting (emesis), and cleansing the bowels (purging). Blood-letting, a frequent practice, required opening a vein or applying leeches. The other treatments required administration of concoctions to induce vomiting spells or bowel movements. In the latter case, a patient could choose from oral laxatives or enemas. Medical practitioners also used a variety of preparations – with ingredients ranging from animal dung and ground gemstones (including emeralds, sapphires, garnets, and topaz) to licorice, mint, rosemary, and basil – to heal the sick. Some preparations, such as herbal remedies, occasionally worked. Patients themselves often prayed for a miraculous cure, touched their bodies with the relics of saints, or went on pilgrimages. A few turned to religious rites to rid the body of a demon. Persons offering preventive, diagnostic, and therapeutic services included well educated physicians, minimally educated surgeons, barbers, herbalists, apothecaries, exorcists, astrologers, sorcerers, soothsayers, and do-it yourself healers. At barber shops, patrons could get a haircut, then have a tooth extracted. They could also undergo blood-letting, a service advertised by a spiral red stripe on the barber pole outside the typical barber shop. The striped barber pole survives to the present day as a symbol of the tonsorial profession.
A 17th century copy of the First Folio edition of William Shakespeare’s plays. (Matt Dunham / Associated Press / April 23, 2012)
Agent Reduces Autism-Like Behaviors in Mice Boosts Sociability, Quells Repetitiveness
National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD) using an experimental compound, called GRN-529. GRN-529 increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors. GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for the chemical messenger glutamate, which are being tested in patients with an autism-related syndrome. Although mouse brain findings often don’t translate to humans, the fact that these compounds are already in clinical trials for an overlapping condition strengthens the case for relevance.
The study was reported online in the journal Science Translational Medicine (April 25 2012).
The study followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs. To test their concept, the authors examined effects of GRN-529 in a naturally occurring inbred strain of mice that normally display autism-relevant behaviors. Like children with ASDs, these BTBR mice interact and communicate relatively less with each other and engage in repetitive behaviors – most typically, spending an inordinate amount of time grooming themselves. The authors found that BTBR mice injected with GRN-529 showed reduced levels of repetitive self-grooming and spent more time around — and sniffing nose-to-nose with — a strange mouse. Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice.
Effect of Daily Aspirin on Risk of Cancer Metastasis
It has been shown that daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. As a result, a study published in The Lancet (2012; 379:1591-1601) was performed to establish the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control.
The analysis included all five large randomized trials of daily aspirin (>75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumor histology (adenocarcinoma vs. other) and clinical characteristics.
During a mean in-trial follow-up of 6.5 years of 17,285 trial participants, 987 had a diagnosis of a new solid cancer. Results showed that allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0.64; p=0·001; adenocarcinoma, 0.54; p=0.0007; other solid cancers, 0.82; p=0.39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0.52; p=0.0006).
Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (0.69; p=0.02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (0.45; p=0.0009), particularly in patients with colorectal cancer (0.26; p=0.0008) and in patients who remained on trial treatment up to or after diagnosis (0.31; p=0.0009).
Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (0.50; p=0.0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (0.65; p=0.0002), but not the risk of other fatal cancers.
Effects were independent of age and gender, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses.
According to the authors, the findings suggest that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis.
Higher Prevalence of Obesity Among Children With Asthma
According to an article published in Obesity (2012;20:1041-1047), a study was performed to investigate the association between childhood obesity and asthma, and whether this relationship varies by race and/or ethnicity.
For this population-based, cross-sectional study, measured weight and height, and asthma diagnoses were extracted from electronic medical records of 681,122 patients aged 6-19 years who were enrolled in an integrated health plan 2007-2009. Weight class was assigned based on BMI-for-age.
Results showed that overall, 18.4% of youth had a history of asthma and 10.9% had current asthma. Adjusted odds of current asthma for overweight, moderately obese, and extremely obese youth relative to those of normal weight were 1.22, 1.37 and 1.68, respectively (P trend < 0.001). Black youth are nearly twice as likely (1.93), and Hispanic youth are 25% less likely (0.75), to have current asthma than to non-Hispanic white youth. However, the relationship between BMI and asthma was strongest in Hispanic and weakest in black youth. Among youth with asthma, increasing body mass was associated with more frequent ambulatory and emergency department visits, as well as increased inhaled and oral corticosteroid use.
According to the authors, overweight, moderate, and extreme obesity are associated with higher odds of asthma in children and adolescents, although the association varies widely with race/ethnicity, and that increasing BMI among youth with asthma is associated with higher consumption of corticosteroids and emergency department visits.
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FDA Approves Imaging Agent to Estimate Cognitive Decline
The FDA has approved Amyvid (Florbetapir F 18 Injection) a drug for Positron Emission Tomography (PET) imaging of the brain in adults who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline. Cognitive decline refers to a condition where the ability to think and form clear, rational thoughts and decisions has decreased. It can cause an individual to lose touch with reality, oneself, other people, and external events and surroundings.
Amyvid is used to produce PET scans that estimate the brain beta-amyloid neuritic plaque density in patients with cognitive impairment. beta-amyloid protein is a type of protein that forms in patients with AD and some other cognitive disorders. Neuritic plaques, also called amyloid plaques, are abnormal clumps of brain cells mixed with beta-amyloid protein. A negative Amyvid scan indicates few to no neuritic plaques and reduces the likelihood that any cognitive impairment is due to AD. A positive scan indicates moderate to frequent plaques. This amount of beta-amyloid plaque can be found in patients with AD, in patients with other types of cognitive impairment, and in older people with normal cognition.
Following intravenous injection, Amyvid (a radioactive drug) binds to brain beta-amyloid. A radioactive signal is detected with a PET scanner to produce images of the plaque in the brain. A positive Amyvid scan indicates moderate to frequent plaques. However, a positive Amyvid scan does not establish a diagnosis of AD because, although patients with AD always have an increased brain content of plaque, the test also may be positive in patients with other types of neurologic conditions, as well as in older people with normal cognition.
Amyvid is not a test for predicting the development of AD-associated dementia and is not for monitoring patient responses to AD therapy. Amyvid does not replace other diagnostic tests used in the evaluation of cognitive impairment. This is a new type of nuclear medicine test and images should be interpreted only by healthcare professionals who successfully complete a special training program developed by the manufacturer. The Amyvid label includes information on interpretation of Amyvid PET images.
Common adverse reactions include headache, musculoskeletal pain, fatigue, and nausea. Safety risks include radiation risk and risks associated with image misinterpretation.
Amyvid is manufactured for Avid Radiopharmaceuticals in Philadelphia.
From Other Pages
By Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.
Regular readers of On-Target will recognize that, customarily, medical publications serve as sources for this Policy Section. This week we shall deviate and instead look for inspiration to the May issue of Commentary Magazine a (self- described) “independent journal of thought and opinion” published by the American Jewish Committee.
Novelist Jesse Kellerman provides this inspiration with a tale of his efforts to purchase health insurance in the individual market, a tale which will resonate with many and terrify most. As a self-employed author, Kellerman relied on his more traditionally employed wife for health coverage; when she left her job the couple needed to obtain insurance on the ‘individual’ market, and Mr. Kellerman began his journey through insurance purgatory. Skipping many of the gory details (and I highly recommend reading Kellerman’s piece in Commentary; consistent with its provenance, it is well written and highly entertaining), in essence Mr. Kellerman was denied coverage due to a pre-existing condition, a condition which made him a (potential) surgical candidate. The fact that conservative therapy had eliminated his symptoms and he did not need or want surgery proved irrelevant. To secure coverage, he was ultimately forced to endure an unwanted operation with its attendant complications.
The ‘physician’ in me found this narrative so outrageous that for a brief time I thought it must be a fictional account (the author, after all, writes novels), a bit of ‘medical gallows humor’. Sadly, I’ve concluded this saga is real, fitting comfortably into the category of ‘you can’t make this stuff up’.
Closing the health care policy circle, the sad irony is that the situation described here is one which I suspect virtually all Americans would agree needs to be fixed. Yet, guaranteed issue insurance at reasonable rates is precisely that component of the Affordable Care Act most at risk. Even the Administration agrees that this specific element of the Act must go if the Supreme Court rules the individual insurance mandate unconstitutional. Therefore, there is risk that, after all the effort, rhetoric, and obloquy, we may be left with hundreds of pages of costly rules and regulations broadly impacting health care delivery without a fix for a (perhaps THE) key problem plaguing Americans around which consensus may have been achievable, the inability to obtain reasonably priced insurance for those with pre-existing conditions.
How did this happen?
Was it Congressional overreach, political intransigence, a hopelessly divided polity, excessive influence of ‘experts’ with agendas inconsistent with the broad public interest? It’s impossible to know; all (or something else entirely) may have played a role, but the reality is unsettling. We had a chance to fix an insurance system which, based upon Mr. Kellerman’s experience (likely not at all atypical), is highly dysfunctional. If that opportunity is lost, it is by no means certain that there exists the ability, or political will, to reconnoiter and try again. Sadly, we are all losers in this.