Monday, April 25, 2016

Uncertain Health in an Insecure World – 82

“Dearly Beloved”

"We are gathered here today
To get through this thing called life"

When a mourning dove dutifully cares for its mate's lifeless body, it cries out in loneliness.

 Knowing the cause of a single death is less important than what our reactions say about the meaning of that life.

Today, there's no mysterious missing airplane, no sub-equatorial viral threat, and no refugees fleeing from the sound of gunfire. There is just a 57 year-old previously healthy Black male who died suddenly at home in an elevator.

Dumbstruck fans and the 24/7 global media demand to know, “Why? Under these unique conditions, a full autopsy and toxicology are undertaken to answer the world’s question. Eventually, medical investigators deliver an answer, but this does nothing to resolve the finality of such a loss for friends and family.

We are a curious tribe, with limited tolerance for ambiguity. It makes us go crazy...

But pending the outcome of the definitive studies into Prince Rogers Nelson’s death, we can develop a differential diagnosis that applies to 99% of his health risk profile. This probability analysis can be fit to the likeliest causes of sudden death in his cohort.

There’s an old saw among doctors and pathologists that “common things are common.” The most common cause of sudden death in previously healthy middle-aged men is coronary heart disease. A clot unexpectedly forms in a major coronary artery (above), without any previously known plaque blocking the vessel. This acutely reduces the downstream blood flow to heart muscle, creating an electrical instability in the heart rhythm. The heart muscle chokes, begins to die, and develops “bag of worms” dysrhythmia called ventricular fibrillation (above). Cardiac arrest is often followed by a full cardiac standstill (i.e., asystole).

If the above events are “witnessed”, a potentially lethal catastrophe can be salvaged in the field by effective CPR (above), and in medical facilities by clot-busting lytic drugs. If these are unavailable, the outcome is almost universally fatal (below) – yet another sudden cardiac death. For this reason, Prince’s post-mortem will include a careful examination of the heart for coronary artery blockages, blood clots and heart muscle damage (i.e., myocardial necrosis).

A person who dies suddenly is not available for doctors to obtain a medical history. Just as the police were called into Paisley Park rule out trauma and foul play (apparently, not the case with Prince), forensic investigations of previous life circumstances and habits, including recent medical conditions or related health events, can be highly revealing for contributing factors.

In Prince’s case, the press has revealed the following clues. First, he had been suffering from “flu-like” symptoms for several weeks, forcing him to cancel some appearances. Certain non-flu viruses (i.e., Coxsackie) can spread to infect the heart muscle, producing lethal viral cardiomyopathy, predisposing to a sudden cardiac death. Second, it is reported that Prince received naloxone (Narcan™) to reverse the effects of a narcotic (oxycodone?) when his airplane emergency landed in Moline Illinois. While he was not known to being suffering from drug addiction, a narcotic overdose could cause an acute respiratory collapse. However, stimulant drugs like cocaine are more likely to produce a lethal heart rhythm disturbance and/or coronary artery spasm. Third, if Prince had been physically inactive from long airplane flights or suffering from undiagnosed cancer, this might have caused a deep vein thrombus (DVT) in the legs or pelvis that could throw off a blood clot to the lungs. A resulting pulmonary embolism (PE), if massive, could have caused sudden death; the full autopsy included a careful look at the lungs.

Although Prince had access to the best medical care during his life, it is conceivable that he had an unknown medical illness. He could have been born with a congenital coronary blood vessel abnormality, or a genetic heart muscle condition called hypertrophic obstructive cardiomyopathy (HOCM) that is more common in Black males. But these conditions usually restrict physical activity early in life, causing warning symptoms like chest pain, shortness of breath, dizziness and/or fainting.

Prince had not recently traveled abroad (other than to Canada in March), so it’s unlikely that his sudden death was from a common South American heart muscle inflammation caused by T. Cruzi infection, called Chaga’s Disease. Another immune-mediated heart muscle inflammation (sarcoidosis) that is more common among Blacks could have created the flu-like symptoms and weight loss that some had observed in Prince.
The causal list is long… the possibilities are almost endless.

But “common things are common”, even among uncommonly talented people.

In the end, understanding things after death (i.e., through post-mortem examination) does not assure that death could have been prevented. A 2003 British Heart Foundation study showed that among 3,500 apparently healthy U.K. adults who die suddenly each year, in 4% no cause for death can be found despite a full autopsy. Like Sudden Infant Death Syndrome (SIDS), British experts coined the term “Sudden Adult Death Syndrome” (SADS) to characterize these mysterious, presumably electrical heart rhythm sudden deaths. Like SIDS parents, surviving SADS family members crave answers and deserve explanations.

Unfortunately, medical science is imperfect, without answers for every life & death circumstance. 


Prince was an exceptional artist, and an imperfect human organism.

Regardless of his musical greatness and personal legacy, he was just a man, and subject to the physical frailties of all middle-aged men.

We all rail against the unruly suddenness of The Artist’s unexpected passing.

And while his fans cry, they will eventually get past this natural death, whatever the cause. 

We in the Square do not have a favorite Prince song; his was a body of work from a soul that lives on.

Thursday, April 21, 2016

Uncertain Health in an Insecure World – 81

“Fog of War”

In the aftermath of the Battle of Waterloo in 1815, Prussian military theorist General Carl Von Clausewitz coined the term “fog of war.” Napoleon's defeat required several lucky (or unlucky) turns of timing and twists of fate, and hung in the balance from hour to hour for three days.

A less famous but more prescient Von Clausewitz observation was that, “Politics is the continuation of war by other means.” Let's explore how the potent forces of science and politics do battle now. 

The capacity of age- or disease-damaged tissues to self-repopulate with stem cells, traced to the blastocyte layer of embryos (above), is part science and part magic. As an embryo matures, these stem cells are responsible for transforming themselves (i.e., differentiating) into heart, brain, lung, skin, etc. tissues.

In 1981, Dr. Gail Martin at University of California San Francisco derived stem cells from early phase mouse embryos (below), and sub-cultured these embryonic stem (ES) cells to differentiate into teratocarcinoma cells (Proc. Natl. Acad. Sci., USA 78, 7634-7638, 1981). The capacity to culture pluripotential ES cells was confirmed by Evans and Kaufman (Nature 292, 154-156, 1981).

Over the following decade, scientists understood that turning genes on and off was critical to making undifferentiated stem cells differentiate.

Stem cells can be manipulated to differentiate, and be transplanted and engrafted onto other organ tissues. Matsui et al (Cell 70, 841-847, 1992) used epigenetic reprogramming to derive pluripotential ES cells from primordial embryonic germ (EG) cells. In the early blastocyst (below), EG cell precursors are specified by signaling molecules – gene-directed proteins that tell the EG cells to reach their so-called ‘somatic fate’. EG cells multiply and migrate within the growing embryo, usually with a unipotential fate (bone, muscle, or kidney, etc.). However, when explanted and cultured, they can be returned to pluripotent EG cells.

Stem cell research advanced steadily until Dr. James Thompson used a similar method to derive stem cells from human embryos obtained from failed in vitro fertilization (IVF, below); human ES cells could be grown in the laboratory (Science 282, 1145-1147, 1998). Dr. John Gearhart also identified and cultured embryonic germ (EG) cells from the gonadal ridge of fetal tissue obtained through elective abortions (PNAS, USA 95, 13726-13731, 1998).

But using failed IVF and abortion-derived stem cells was a political trip-wire.

Speaking to Americans from his Crawford, Texas ranch in August 2001, just one month before 9/11, President George W. Bush presented a mixed pro & con policy position on federal funding of ES cell research. He also announced the creation of a ‘special council’ to oversee stem cell research, and focused much of his speech on the ethics of ES cells derived from IVF procedures. “At its core, this issue forces us to confront fundamental questions about the beginnings of life and the ends of science.” By the time of his 2004 re-election campaign, President Bush had strictly limited federal funding and ES cell lines available for research.

In the private sector, a 2006 research breakthrough occurred at Advanced Cell Technology (Worcester, MA, above) where scientists genetically reprogrammed specialized adult cells into a stem cell like state – so-called induced pluripotent stem cells, or iPSC’s. In 2007, researchers in Japan and the U.S. developed a virus transfection method to reprogram somatic skin cells to function like stem cells (below), and then converted them to blood and other non-skin tissues.

In 2009, President Barack Obama lifted the 8-year federal restriction on IVF-derived ES cell research.

The tissue regenerative capacity of ES cells has created the discipline of cell-based therapy, also known as regenerative or reparative medicine. Diseases that might respond well to this approach include retinal macular degeneration [my mother], Parkinson’s disease [Michael J. Fox], spinal cord injury [Christopher Reeve], stroke, burns, heart attack, type-1 diabetes, osteoarthritis and rheumatoid arthritis.

But results of stem cell therapy clinical trials have been mixed, and disappointing in many cases.

For clinical uses, the stem cells must also be shown to function normally (i.e., heart muscle cells must contract), while also avoiding harm to recipient tissues from triggering immune rejection, or DNA damage that increases future cancer risks. These hurdles remain a real challenge to basic and clinical research towards the use of stem cells in human disease sufferers. 

Use of pluripotential stem cells – of embryonic or somatic origin – in biomedical research has significant ethical repercussions.

Related societal and cultural concerns have creative divisive politics and aggressive advocacy on both sides of the stem cell research issue. In response to this, related governmental policies have evolved, or twisted, in the white-hot crucible of public opinion. Whether or not embryos are going to be discarded by IVF clinics, pro-life groups strongly assert the “sanctity of life” beginning at the moment a sperm fertilizes an egg. Human cord blood and amniotic fluid derived stem cells are less controversial for research purposes, in that they do not require the direct manipulation of embryos. However, these stem cells are not inherently pluripotent.

Anti-abortion politicians tend to vote against the use of ES cells for research purposes.
In the current U.S. Presidential Campaign, there has been political push back against fetal tissue research. Republican candidate Carly Fiorina’s (above) anti-abortion position in the early debates was awkwardly counter-posed with her highly paid 1999-2000 service on the Merck & Co. board of directors, when the big Pharma company was making vaccines using fetal ES cell lines derived from aborted tissues.

The Republican-controlled U.S. House Select Investigative Panel on Infant Lives is now behaving as if fetal tissue research is a national security matter. Representative Marsha Blackburn (R-Tennessee, above), who chairs the Panel but opposes most fetal tissue research, favors subpoenaing researchers, saying “We are going to review the business practices of these (fetal tissue) procurement organizations and do some investigating of how they have constructed a for-profit business model from selling baby body parts.

The panel is now compelling fetal tissue scientists and their institutions to release identities and other personal information. Their disclosure demands apply to researchers, graduate students, healthcare providers and staff with ANY involvement – scientifically significant or not – in fetal tissue research. University of California San Diego, for one, has complied with the committee’s demands, but redacted the names of individual researchers. Given the heated emotional debate and a history of targeted violence, including a November 2015 attack on a Planned Parenthood clinic in Colorado that killed three, there are grave concerns about the safety of individuals and institutions identified in such activities.

Only 0.25% of the National Institutes of Health budget funds fetal tissue experiments. But the effect of such subpoenas on stem cell and fetal tissue research could still be chilling.

Medical school and research university advocacy organizations have strenuously objected, on the basis of a lack of compelling cause, and the lack of assurance that such information would be adequately safeguarded.  The Association of American Medical Colleges, a Washington D.C.-based academic healthcare and medical school advocacy organization, warned of such restrictions causing “serious downstream effects,” including “limiting research on vaccines not yet developed, for treatments not yet discovered, for causes of diseases not yet understood.

Not surprisingly, U.S. Democratic Party politicians have called this a “witch hunt.”

Republican political outrage over videos of alleged Planned Parenthood fetal tissue sales ground the 2015 U.S. budget process to a halt, costing then House Speaker John Boehner his job.

A 2015 report from the Union of Concerned Scientists titled “Freedom to Bully: How Laws Intended to Free Information Are Used to Harass Researchers” that predated the Congressional panel subpoenas, pointed out other widely shared concerns. Public universities and publicly funded research grants & contracts are subject to freedom of information act (FOIA) and open records requests. While using the public purse is a good reason to publish federally funded research in peer-reviewed scientific journals, these researchers should not be subjected to fishing expeditions by those with a narrow anti-science agenda.

Scientists usually carry out ethical research to advance human health.

But Superman died a mere mortal, without a medical miracle to regain the use of his legs.

Post-revolutionary politicians promote societal advancement in the guise of war.

But Napoleon died a prisoner, isolated from a fearful society on a deserted island.

We in the Square see through this fog of war. We are mindful of the march of science on human disease, and fearful of the confluence of political extremism.

Tuesday, April 12, 2016

Uncertain Health in an Insecure World – 80

“The Big Short”

A meltdown begins with a house of cards.

Wall Street traders short a security (stock or bond) when they become convinced that the price will go down in the future. Usually, they have come to recognize a fundamental flaw in the market sector in which the security is traded. The shorting transaction is to borrow a stock from a so-called counterparty, sell the borrowed stock on the open market (for $100), return the stock to the counterparty at a future date specified for less than the selling price ($75), and walk away with the difference ($25).

In The Big Short movie (above left), the house of cards was illustrated by a tower of Jenga blocks with various credit rating symbols stamped on their sides (Aaa = immune from default, to D = default, above right). In the mid-2000’s, tranches of mortgage loans at varying risk of default made up mortgage-backed securities (MBS). MBS’s underpinned a larger investment target made up of diverse assets called a collateralized debt obligation (CDO). In The Big Short, many such CDO’s were simply a collection of poorly rated MBS’s on steroids. Shorters bought derivative contracts called credit default swaps (CDS) on the cheap, as insurance against a highly unlikely CDO collapse. Their insurance policies paid out big-time when the MBS-infected CDO’s collapsed.

Big Shorters take out theft insurance on someone else’s home in a low crime neighborhood, knowing for certain that a theft is about to take place.


Pharmaceutical company research is another major market in flux.

A decade of flat U.S. public bio-medical research funding, despite the political party in power, has combined with a shift in R&D investment from Big Pharma to smaller start-up firms. These smaller firms are often the target of merger & acquisition (M&A) and/or corporate VC activities. The pharma market’s volatility since 2011 is reflected by the fact that there were more company exits than entries. The explosion of biotechnology firms over the last two-plus decades has been truly remarkable, at both the scientific and business levels. Either working on their own or through licensing deals with Big Pharma companies, these emerging research powerhouses have created new drugs and diagnostics that frame the basis for precision medicine.

A recent paper in Drug Discovery Today by Sarah Kinch and Denton Hoyer reviewing the FDA’s approval of new molecular entities (NME’s, above in purple) through 2013, revealed a peak of 55 NME’s in 1997. More than 150 drugs have been brought to market as a small company’s sole NME. But there has been a recent decrease in the number of unique companies with approved NME’s due to the large number of M&A’s, repositionings and market exits.

Big Pharma companies like Celgene, Biogen and Amgen continued their strong new drug development and market introduction. Regeneron (NASDAQ:REGN, above) biotech stocks have paralleled this megatrend, buoyed by the success of two new small-market drugs: one for wet macular degeneration (aflibercept, Eylea®) and another for moderate-severe eczema (dupilumab). Despite recent intellectual property woes with its new lipid-lowering drug (alirocumab, Praluent®), REGN has produced five FDA-approved new drug assets in the past few years, more than the rest of this sector combined. Yet its share price (below) falls, like all the rest!

There are numerous Aaa assets in the biotech portfolio. But investing involves risk.

As evidenced by early 2016 being the worst NASDAQ Biotechnology Index quarter since 2002, with this sector’s market cap falling by -23%, a once broad advance is experiencing a real reversal. The entire biotech sector has been dragged down because of the bad acts of price-gouging specialty pharma player Valeant Pharmaceuticals International (although it is not part of the NASDAQ index). Other specialty pharma powerhouses like Endo International and Horizon Pharma (both traded on NASDAQ) were down 25-50% in the last quarter, as a result of a broad sell-off in this sector, due to fundamental concerns about the business model, resulting it its characterization as a “bubble” marketplace.

Today, the troubled tranche of specialty pharma assets taints the entire biotech sector.


Technology proffers the benefit of broadly-based human advancement.

Use of personal health information (PHI) technology is helping advance healthcare. But limited access to PHI data is reducing access to important health advances.

Patient privacy protections were passed into U.S. law in 1996 (HIPAA), primarily to prevent insurance company denials for pre-existing medical conditions. Electronic medical records (EMR’s) originally put into place for fee-for-service (FFS) billing and provider reimbursement purposes, are now the technological basis for healthcare system conversion to capitated risk contracts under Obamacare. The marketplace access benefits of this 2010 law are now positioning healthcare systems to convert into payers and accountable care organizations (ACO’s). Under Obamacare, ACO’s are multiplying and emerging as too not dissimilar from the access-limiting managed care insurers of the 1990’s.

Healthcare futurists like Dr. Eric Topol (above) consider PHI ownership to be a civil right. “It is important for individuals to seize ownership of their data in order for the real benefits of a new data-driven high-definition era of medicine to be actualized." Efforts are underway to connect highly diverse EMR systems and data repositories into a single platform, and make to made myriad systems more interoperable.

In this way, there is movement afoot towards “unknotting” the problems of PHI access, increasing the likelihood of precision medicine being put into action, according to Farzad Mostashari (above), former U.S. National Coordinator for Health Information Technology (HIT). Dr. Mostashari is now the CEO of Aledada (est. 2014), a VC-funded ACO network creation startup. Mostashari says Aledada will be “almost a turnkey solution” for those establishing new ACO’s to comply with new Obamacare payment regs.

These days, it’s not about patients seeing their doctor as much as who owns the patient’s data.

Growing concerns exist that the 21st Century Cures bill passed in 2015 by the U.S. Congress propagates “the same old measures to increase the spread and use” of PHI by private interests (i.e., insurers, Pharma, big data Cloud repositories), while taking control out of patients’ hands.  The associated patient-provider disintermediation trend has also resulted in frightening increases in physician burnout, depression, and suicide!

Healthcare information privacy advocates like Deborah Peel (above) note that the HIT infrastructure is “designed to produce problems forever.” It's a paradigm of programmed obsolescence – a system not scale-able for handling massive data sets, while putting the PHI of millions of patients at risk from accidental breaches and malicious cyberattacks. Washington D.C.-based MedStar Health (March 28, 2016) and other major U.S. healthcare systems are the latest victims of cyberattacks. A March 28, 2016 attack targeted emails and healthcare data. MedStar clinical units were denied access to patient data for days.  The practice of stealing data subject to return (ransomware) has emerged as a (likely) offshore strategy to extort money, before access to healthcare system operations and data are restored.

Deborah Peel has signaled another alarm, noting that “The promise of electronic health information was supposed to be to help with treatment, not to create massive, hidden business models where people are using your data for purposes we don’t even know about.” The entire U.S. healthcare system is highly leveraged on promises of security, policies for propriety and expectations of meaningful use for health improvement.

But none of these are in evidence.


Biotech firms have taken business risks to introduce important novel therapies into the market.

But troubled specialty pharmacy assets has imploded this investment portfolio. 

An unanticipated populist movement exists among patients demanding their PHI civil rights.

But the PHI market is consolidating to the benefit of a few private special interests.

In the Square, we are long on these two market sectors. But a meltdown is on… a theft is coming… and the house of cards is real.

Friday, April 1, 2016

Uncertain Health in an Insecure World – 79

“Dark Chambers”

Vaporization of human tissues is hard to imagine, even for combat-hardened veterans and emergency first responders.

After centuries of reliance on low-grade black powder for musketry and firecrackers, the era of high-grade explosives began with the invention of dynamite by Alfred Nobel in 1867 (below, based on nitroglycerine). Nobel bequeathed his fortune to an eponymous prize, after reading a premature obituary condemning him as an arms dealer.

Other deadly innovations followed.

When a solid or liquid is rapidly converted to a gas, the sudden release of energy is either a flash (deflagration) or a bang (explosion), or both. Detonation of a high-grade explosive produces a supersonic ignition and blast wave – the resulting noise is a localized sonic boom.

The pressure released by a blast creates shock waves (below) that instantaneously exceed atmospheric pressure (over-pressure).  The shear force between propagating wave peaks is highly destructive, as is the subsequent spalling which sheds small fragments internally from the impact surface, even without physical penetration.

The most common cause of American military casualties treated at Walter Reed Army Medical Center since 2006 was blast injuries from improvised explosive devices (IED’s) in Iraq and Afghanistan. In the modern terrorism era, high-grade explosives have frequently been used in domestic attacks on non-combatants. 

The sad long list grows every year:
·  1995 Alfred Murrah Building bombing in Oklahoma City (ammonium nitrate),
·  7/7/2005 London Underground attack (tri-acetone tri-peroxide, TATP),
·  Patriot’s Day 2013 Boston Marathon finish line IED’s (below, made from a pressure cooker with a blasting cap).

Miraculously, nineteen year-old Mormon missionary Mason Wells (below) escaped unscathed from the Boston Marathon bombing and the ISIS-inspired Nov. 13, 2015 Paris attack, only to fall victim to the March 22, 2016 bombing at the Brussels airport. A terrorist detonated his TATP device less than 50 feet away from Wells, who recounted, “My body got really hot and then really cold... I was covered in a lot of fluids, a lot of blood – not necessarily mine.” 

Casualties of such bombs are characterized by three concentric blast zones: the epicenter (kill zone), the secondary perimeter (critical casualty zone) and the periphery (walking wounded zone). The human destruction associated with the addition of nails, screws (below) and ball bearings to the explosive device causes carnage beyond belief, by intent.

The capacity to launch a shell at an enemy position miles away, to dig an IED into a roadside and detonate it, or even to drop a bomb from an airplane into a civilian neighborhood pales in comparison to the up-close and personal nature of a suicide bomber attack on a public gathering place – a so-called soft target.

Like many of you, I have ridden on a double-decker bus through the streets of London (above) and strolled the streets of Paris. Like some of you, I have run across the finish line of the Boston Marathon. Like a very few of you, I flew into Oklahoma City the day the Murrah building (below) was destroyed, seeing dense black smoke rise from downtown as we landed.

Terrorists are not warriors. They inflict fear among the peaceful masses, by murdering an unlucky few.

In the words of veteran Iraq war correspondence, Michael Ware (above), “Certain dark chambers of the heart, once opened, can never be closed again.

A merciful God will grant Mason Wells amnesia regarding the cool liquid that drenched his burned skin – body fluids from an ISIS-inspired suicide bomber.
 “Allahu Akbar”… Really?

We in the Square continue to live with, and some of us will die from, this sad reality.

The main casualty of such brutality is humanity.