Our Personal Lenses (or, My Brain Hurts)

There are certain things that make little to no sense to me.  Earlier in life, I would rather snarkily remark on evidence and how I couldn't BELIEVE people don't GET certain things.  With age comes perspective, or at least a modicum of self-control, and I now remind myself that I see things through the lens of scientific training.  Many people don't, and why should they?  We all see the world through our most relevant lens.  

This post is about vaccine deniers, because another article was recently published that shatters my lens.  The latest study is described here by the Washington Post, and the body of work is described here in "Dartmouth Now".  The original articles were published in the peer-reviewed journals Pediatrics and Vaccine.  The gist of this line of research is that providing evidence of both vaccine efficacy AND lack of harmful effects actually backfires.  In other words, when presented with solid, valid reasons why vaccinating a child against whooping cough will a.) cause her no harm; and b.) protect her from very severe harm (or death), a parent with a preexisting belief is LESS likely to utilize the intervention.  Uh...excuse me?  Scientific training or none, that is absurd.  A parent would rather be right than protect their child?  It makes no sense to me whatsoever.

Part of this stems, of course, from the (mis)perception that the safety and efficacy of vaccines are debatable.  They are not.  Individuals with the appropriate background and training are pretty much in lockstep on this issue.  Are there poorly efficacious vaccines?  Of course.  The BCG/tuberculosis vaccines (not used here in the US) has sub-par at best efficacy.  Are there vaccines with poor side effect profiles?  Yes.  The Y19/yellow fever vaccines is terribly painful, and gifted me with quite the high fever for a day.  Neither of these are standard, because some pretty experienced people have weighed the costs and benefits and decided against it.  Those that ARE standard recommendations for children, though, are so for some very good reasons.  As a parent I often see posts on message boards with questions about vaccines or vaccines schedules by someone genuinely seeking information, and often they give the caveat that they are "not trying to start a debate".  I appreciate the desire for information without wanting to engender hostility, and resent that these parents are forced to think about taking care not to.  I especially resent it because, as mentioned, this is not a debatable issue if one operates in the realm of reality.  Apparently, however, the more reality one tries to interject, the less effective that reality is.  If I'm being polite, this is counterintuitive.  If I'm being kinesthetic, I'm torn between *facepalm* and *headdesk*.    If I'm being realistic... my brain hurts.

 

                                            VS.

An Open Letter to Dr. Nancy Snyderman:

Dear Dr. Snyderman,

It has come to the attention of many (CNN, most recently) that you have been conspicuously absent from the airwaves for longer than "necessary" following your infamous takeout run.  To refresh, this was in violation of your voluntary quarantine following on-site reporting in Liberia with a crew that included cameraman Ashoka Mukpo, who became infected with Ebola.  This is the voluntary quarantine that you imposed in order to "approach this very cautiously, and probably more judiciously than other people, because we want to send the right message".  The trouble is, this wasn't the right message, and you knew that.  You knew that because you didn't abide by the guidelines, knowing they were not necessary.  You never had contact with Mukpo.  In fact, no one had contact with Mukpo once he developed a fever.  None of the crew was at risk, and you knew that.  Yet, you sent the opposite message because it continued the narrative.  You were caught in the inconsistency, and the state of New Jersey promptly imposed a mandatory quarantine in response not to clinical evidence or public health and welfare, but to public outcry.  We all know what happened next.  Your credibility has been called into question; however, I don't question it at all.  Without apology, I question your integrity as a physician. 

Best regards,

Dr. May

The King has Returned

"King Cholera" Rears its Head Again

Since 2010, Haiti has sustained an ongoing cholera epidemic.  In the past few weeks more than 2,000 cases have been reported, and more recently ~100 patients per day are seeking treatment in Port-au-Prince from MSF alone.  This is sadly common this time of year due to increased precipitation.  Cholera treatment centers must be established in a very particular way to avoid reinfecting recovering patients and prevent transmission to staff and surrounding areas, as demonstrated by this nifty animation.  Despite making more than 300 additional beds available, MSF is unable to sustain treatment in the absence of additional funding and human resources.  

Contaminated Waterways Bring Cholera (image: J. Silva/Reuters)

This resurgence serves as a reminder that the crisis continues in Haiti against the backdrop of a pending legal proceeding.  In October, attorneys for the Institute for Democracy and Justice in Haiti argued that a class-action lawsuit filed in US Federal Court against the United Nations should go forward despite the organization's diplomatic immunity.  The basis of the case stems from cholera's accidental introduction by UN peacekeepers from Nepal.  While it is scientifically and epidemiologically indisputable that the UN troops were the source, the allegations that improper sewage disposal allows for contamination of Haitian waterways being due to gross negligence are a little more hazy.  IDJH initially sought redress through official UN channels, but these claims were rejected.  If the suit goes forward in US court, it would be an unprecedented challenge to the UN's legal immunity.  While the legal dispute remains pending, few would argue against the UN's moral obligation to help Haiti eradicate cholera once again...or at the very least, get MSF the beds they need. 
 

5:00 Dose of EIDology: What do Animals Have to do With It?

It starts with a tale called host adaptation.

Pathogens, especially the ones that exclusively rely on their hosts for survival, are not inherently mean-spirited.  Though this may seem counterintuitive at first, parasitic pathogens adapt to, and co-evolve with, their hosts to minimize disease.  If you think about it, if you need to infect a living thing to survive, killing everything in your path doesn't make much sense.  Talk about burning your own house down!  Parasitic pathogens, then, have a vested interest in adapting to a particular host and perfecting that relationship.  


What does this have to do with emerging diseases?  You guessed it.  An emerging disease-causing agent has found its way into an alternative host.  Most of the time nothing happens when a well-adapted pathogen infects the wrong host.  For those rare instances when something happens, however, it tends to be very dramatic.  For humans, the source of our "maladapted" pathogens that cause emerging diseases are animals, be they livestock or wildlife.  They haven't learned how not to kill a human host, for lack of a better way of putting it.  Of course, there is of course a second side of the story on the human front...but I'll leave that to the immunologists to discuss.

4:00 Dose of EIDology: Remembering the Emergence of HIV

The deadliest emerging disease of all time came about in my lifetime.  I have a vivid memory of being in grade school and working on a science fair project about "germs", and my mother told me I should include a disease called "AIDS", because it was going to become very important.  I wrote it on the posterboard, and when asked "what I meant by AIDS", I sternly replied that "it was very important".  Clearly I had no idea what it was or why it was important, but it certainly became so.  That incident happened in 1985, only a year and a half after the causative agent, human immunodeficiency virus, was first isolated, and a year before Ronald Reagan publicly acknowledged the disease after 20,000 American had already died.  It was the same year that Rock Hudson died of it, and Ryan White was banned from attending public school.  Tens of thousands were already infected in the US by then, and many had died.  

The Loss of Queen's Freddie Mercury was a Sobering Reality

The numbers on HIV and AIDS are to this day astounding.  It is estimated that up to 40 million people have died of it since the outbreak began.  An estimated 1 in 20 American adults are HIV positive or in some stage of progression to clinical AIDS [note: HIV is an infectious virus, and AIDS is the disease it causes.  One can be -and often is- HIV infected ("HIV+") prior to developing the disease AIDS].

AIDS has a fascinating history, but biologically speaking where did it come from?  Some things that are clear is that is has entered into the human population more than once, and that it has been around far longer than we have recognized.  The biological ancestor of HIV is simian immunodeficiency virus (SIV), which causes a disease similar to AIDS in other primates.  Humans were infected with SIV almost certainly through hunting/bushmeat slaughter, and then began transmitting it amongst themselves.  As SIV adapted to humans, it became what we now called HIV.  The two major strains of HIV came from two separate introductions and adaptations of SIV.  HIV-1 came from an SIV strain found in chimpanzees, and HIV-2 came from a strain of SIV found in white-collared monkeys.  Rumors abound about where HIV and AIDS came from, many of them vitriolic in nature.  The truth is far less sinister.  The wrong hunters encountered the wrong primates, and the rest, as they say, is history.

3:00 Dose of EIDology: Where the EC did These Things Come From?

EC is the standard clinical abbreviation for Escherichia coli, a bacterial species that is an integral part of intestinal community of many animals.  About 30 years ago, this organism became something of a household name following an outbreak of bloody diarrhea that seems to be associated with having dined at Jack in the Box restaurants.  What was this new "version", and why were people suddenly getting sick from something that has always lived among humans and animals?


This "new version" was E. coli (termed enterohemorrhagic E. coli, or EHEC) was a few extra genes.  These new genes encoded bacterial toxins, or proteins that elicit damage to, and death of, human cells. New genes?  A bacterial cell can just pick up and find new genes???  Yes, they can.  Turns out it's not all that difficult, either.  The toxin genes of EHEC came from a type of virus called a bacteriophage.  The the "parent" E. coli cell was infected, the virus left behind a few genes, and it turns out, those genes allowed this normally harmless organism to become quite virulent.  The more scientists explored this idea, the more it became clear that certain intestinal illnesses could actually be attributed to odd new forms of E. coli, each one producing different toxins.  At this point, we have recognized EHEC (sometimes called STEC), EPEC, ETEC, EAEC, EIEC, and STEC [for EnteroPathogenic EC, EnteroToxigenic EC, EnteroAggregative EC, EnteroInvasive EC and Shiga Toxin-producing EC].  They have been circulating in the population causing periodic outbreaks since then, largely due to consumption of contaminated meat or produced exposed as indicated here:

Image from EcL Lab, Universite du Montreal

The take-home message here is that once infected, even a previously harmless bacterial species can become an agent of emerging infectious disease!

1:00 Dose of EIDology: Coming to America, It's...

...a few possible options!  

In my opinion, the highest probability for loudest and longest-lasting noise comes from Arboviruses.  After all, this happened not so long ago with West Nile virus.  The permanent emergence of a pathogen into a new population requires a long-term method of transmission from one potential host to another.  This can be easy, such as the spread from one infected person to another by aerosol as with SARS, or it can be a little more complicated if something like an insect vector is needed.  In the case of WNV, this happened because the virus can be spread by several different species of mosquito.  One of these, Culex pipiens, is extremely common in the Northestern US where WNV was first introduced.  Once some viral particles were ingested by Culex mosquitoes, and those mosquitoes fed on and infected some birds, it was all downhill from there. 

Culex pipiens, one of the mosquitoes that transmits WNV

But that was the past.  What is the wave of the Arbovirus future?  There is a lot of talk about Dengue, since there have been cases in Florida and its favorite mosquito vector, Aedes aegypti, is prevalent in the Southeast.  That said, I'd put my money on his lesser-known (for the moment!) cousin, Chikungunya .  The mortality rate of Chik is comparable to WN and Dengue (notably not DHF), and the clinical presentation including high levels of fever and pain is similar.  Chronic joint damage can and does occur, and so Chik presents a possibility of creating a lot of chronic pain patients.  Chik virus is spread by one of two mosquitoes, either Aedes aegypti or Aedes albopictus (the Asian tiger mosquito).  This is the reason many of us are watching Chik more closely than Dengue.  While A. aegypti lives in the Southeast, the Asian tiger mosquito is found across the US, making Chik's possible distribution similar to WNV. The Asian tiger mosquito is far more aggressive, making it more likely to transmit.  As of now, the strain of Chik that has emerged in the Caribbean seems to prefer A. aegypti.  However, there would be a strong evolutionary advantage for that strain if it adapted to A. albopictus transmission.  Or, of course, another strain that prefers it could be imported!  

Chikunguya: take it to the bank

Image by AJC1

11:00 Dose of EIDology: MERS, the Newfangled SARS

MERS and SARS, the Mean-Spirited Cousins of a Common Cold Virus

Perhaps you've heard of a disease called MERS ('Middle Eastern Respiratory Syndrome') in the last year or so.   This is especially prescient since it just took two more lives this morning.   MERS is severe viral pneumonia, and has a case fatality rate of about 30%.  The virus that causes it, MERS-CoV, first appeared in humans in 2012 in Saudi Arabia.  Since then cases have been reported in numerous countries (including the US), though most patients have had recent travel to the Mid East or a household contact who has.  This is because MERS does not appear to spread easily from person-to-person, and those who have it have almost exclusively become infected by contact with camels or dromedaries.

SARS ('Severe Acute Respiratory Syndrome') though...SARS was scary.  SARS was a disease worthy of the recent Ebola hysteria.  SARS had a 10% case-fatality rate, and was extremely contagious by droplet aerosol.  SARS emerged in humans in 2002 in Guangdong China following contact between humans and civet cats.  Within weeks, it has spread to other continents and a major satellite outbreak occurred in Toronto.  SARS took months to come under control under the auspices of some of the best healthcare and epidemiological care in the world.  

Ballet Students in China During the SARS Outbreak

Are these new viruses?  Not really, no.  They are both part of a family called Coronaviruses, which have long been recognized as minor pathogens of humans.  They are one of the major causative agents of the common cold.  Why are MERS-CoV and SARS Co-V so much more deadly?  It has to do with an idea called host adaptation (check back at 5:00!).  A question to consider as a preview: Does a good pathogen kill its host?

10:00 Dose of EIDology: What is an 'Emerging Infectious Disease?'

...And Where do They 'Emerge' From?  

An emerging infectious disease ('EID') is a disease with a microbial cause that is new to a given population.  A disease can be considered "emerging" if it has never before been seen in humans (such as MERS), or it can be considered emerging if it is new to a geographic area (such as West Nile encephalitis in the US over the last decade).  Finally, a disease can be considered "re-emerging" if it was well controlled for many years, but has resurged (such as tuberculosis in Western countries).

Altered geographic distributions are often related to social factors affecting global interconnectedness.  Re-emerging diseases are often related to lapsed control measures (such as vaccination rates) or loss of effectiveness of control measures (such as those giving rise to multi-drug resistant tuberculosis).  Completely new emerging diseases, from AIDS to EBOLA to MERS, do frequently have a commonality: they are introduced into humans from animals.  What are the principles behind that, and how does it work?  That's a 5:00 thing!

Keep Calm and Help.

Remember when we as a profession said to keep calm about Ebola?  This is your friendly reminder to listen next time, because you'll remember this time.  We as a profession made statements regarding relative risk and recovery potential, and all came to pass.  There are no active Ebola infections in the US.  There is no widespread disease afflicting the masses here.  Everything the profession predicted was correct.  All is well...here.

We should be frenzied about Ebola, but not because we think there will be a massive outbreak in the US.  We as a populous should be frenzied because there is currently a panic-worthy situation particularly in Sierra Leone, whose cases are accelerating at the fastest pace yet.  We as a profession are desperately trying to communicate that.  Thousands of people are in immediate danger from Ebola.  None of those people reside in a Western country. Millions of people have the personal or political resources to solve this problem for those thousands...and the overwhelming majority live in Western countries.  That would be you, reader.  You are not in a position of danger, but you are in a position to help.  As discussed yesterday, the keys to good clinical outcomes for Ebola are low tech but labor intensive.  Every one of us in Western countries are in a position to help.  Give a small donation, for a little in abundance is a lot (note especially Google's 1 Today campaign, where they match each $1 with an additional  $2).  Contact your members of Congress, and support those who have their priorities straight on this matter.  Volunteer to go abroad yourself.  Submit an idea for how to approach this problem (socially, technically, medically, via engineering, whatever) to USAID.  Discuss this outbreak rationally and practically.  Trust my profession-we do not benefit in any way from misleading or endangering you.    

Some Resources to Explore:

USAID Grand Challenge Idea Submission

Google OneDay Initiative (donations go to MSF, PIH, and IRC):


Facebook's Newsfeed Donation Drive (donations go to  IMC, Save the Children, or RedCross/Red Crescent)


MSF ("Doctors Without Borders"), to Donate or Work


Partners in Health, to Donate or Work

To paraphrase the tee shirts: Keep Calm and Help.

The Last US Ebola Patient has Recovered, and We Have Learned Something Critical

Dr. Craig Spencer was declared free of Ebola today, and now becomes the 8th patient to recover from this virus of the 9 that were treated here in the US.  For those keeping score, that would be 1 death in 9 patients, or a mortality rate of 11%.  It is worth noting that the Thomas Duncan, the patient who succumbed to Ebola, was not treated until late in the disease process.  Here is what we can draw from this:

1.) Early diagnosis and intervention leads to excellent clinical outcomes

2.) Supportive therapy is quite effective at resolving this infection

3.) Employing rapid, early, aggressive care essentially inverts the mortality rate of Ebola Virus Disease


What does this new knowledge mean for the ongoing outbreak in Liberia, Guinea, and Sierra Leone?  It indicates that low tech solutions are quite effective; however, they are quite labor intensive and require very early intervention.  Perhaps the strategy should move toward recruitment and training of healthcare workers, and possibly more importantly, outreach.  Reports indicate that patients and their families are still hesitant to seek treatment because it (understandably) has the reputation of being ineffective.  It is critical that we change that!

Research in The National Interest, Indeed

Research in The National Interest, Indeed

Last week, Rep Lamar Smith (R-Texas) posted a piece on the Congress Blog entitled "Research in the National Interest".  This sounds like a very reasonable read, calling for support of innovation and science.  Straight talk, if you will.  Unfortunately, it is a re-run of a movie we in the business have seen before.

Every so often, a politician or a pundit will frenzy the masses by generating a list of Federally-funded research projects that they deem unworthy of support, judging by the title.  The make it sound as those these were earmarked funds gifted to professors seeking to feed their own intellectual superiority complex.  the truth, as it tends to be, is quite different.  Smith went after some National Science Foundation (NSF) projects, and neglected to discuss how NSF funding decisions are made.  Proposals are reviewed anonymously by three experts in the given field, and those reviews are then discussed among a panel of twelve experts.  NSF funding is very, very difficult to obtain.  The success rate for having a project funding is extremely low.  In other words, the proposals for the projects that Smith finds a "waste of taxpayer money" likely presented extremely persuasive arguments to those best in position to judge that they were important.  Social science isn't my area, but I'm comfortable trusting that.  In addition, one aspect of Federal science grants is that they are unambiguous job creators.  Having prepared several Federal agency budgets, most of the costs go to salary support for technical staff and student workers.  Finally, Smith argues that money should be spent on "interdisciplinary research to understand how the brain works could lead to cures in dementia, Parkinson’s disease as well has how to treat traumatic injury and combat wounds".  Representative Smith, I believe you are confusing the mission of NSF with that of NIH.  NSF does not fund clinical research.  I understand your confusion; it's not as though you Chair on the House Committee on Science, Space, and Technolo...oh wait.  This is awkward.

Smith includes a cutting remark about public dollars "being used to provide free foreign vacations to college professors".  I won't bother engaging on the absurdity of that point, having spent my own "free foreign vacations" (apparently like a total sucker) working.  I'll provide my own rhetorical question to the Congressman himself: Given your below-the-median attendance for roll-call votes and relocation of your family, why should the taxpayers of Texas be providing you with a free vacation destination in Washington D.C.?  

5:00 Dose of Fluology: Your FluCast Calls for...

Your Flucast Calls For...

Evolutionary forecasting is a very cool idea.  The long and short of it is that we can look at the rates of genetic change in a certain population, look at the changes in rate by certain evolutionary drivers, look at the impact that one genetic change might have on the development of another, and come up with predictions about what could happen to that population in the future.

This concept is being applied to Influenza with great gusto.  The population changes quickly, and we have a very solid understanding of which factors drive evolutionary change in this virus.  There is also exciting potential for forecasting here: imagine if one could predict the "drifting" of seasonal flu strains, and make the seasonal vaccine accordingly!  Imagine if one could predict the changes that make a strain TamiFlu resistant, and make an alternative compound to treat them.  This is very cool stuff.

It is also a strong comment about the importance of basic research, and the understanding of biological principles.  We make new medicines by understanding how things work.  

4:00 Dose of Fluology: Shifting, Drifting, VaxnTamiFlu Escaping...

Shifting, Drifting, VaxAndTamiFlu Escaping...

A good deal of this series has talked about novel/pandemic flu strains, and how they arise.  The process of new strain development detailed at 3:00 is called antigenic shift, and it occurs very suddenly and more or less "completely".  One changing event generates a new strain.  We also talked (albeit indirectly) about how these strains will not be covered by flu vaccines, since they are designed using existing flu strains.  This begs a question:

If there is a certain amount of flu vaccine failure each year, and there is not a new pandemic strain every year, how can that happen? 

This happens because of the sneaky and subtle cousin of antigenic shift, antigenic drift.  Influenza has a design "flaw" of sorts, in that it is not particularly good at making exact copies of itself.  Think of a hand-copied note vs. a scanned image.  The scanned image is nearly always going to be perfect no matter how many times the file is copied, whereas the handwritten note?  Not so much.  I put "flaw" in quotes because it isn't really a flaw at all.  Influenza benefits tremendously from this variation.  It allows the virus to escape the immune system of previously infected people so that they can be re-infected.  By the same logic, if it has changed (or, "drifted") enough from the original version, it can infect vaccinated people.  This is what leads to vaccine failures: the person has raised an immune response, but the circulating viruses have escaped it by antigenic drift.  This happens variably by year.  Some years it does not happen much, and the flu vaccine works very well.  Other years it happens to a substantial extent-we call those "bad match" years.  In the same way that immune responses (naturally derived or vaccine-associated) are escaped, TamiFlu and Relenza can also be escaped.  The "N spike" drifts just as much as the other components, and if it drifts enough, the medications stop binding to it.  When that happens, they no longer work.

Antigenic shift may be more dramatic, but antigenic drift is just as important to influenza pathogenesis.  In fact, I'd argue it's more important. 

3:00 Dose of Fluology: Who is This Tamiflu?

Who is This Tamiflu?

Tamiflu is an antiviral medication that was designed for use on flu infections.  It doesn't work universally against all viral infections, and thus can only be used very specifically.  Remember the N spikes discussed at 2:00?  Tamiflu binds onto them and prevents them from doing their job.  What is their job?  See below!

Look at Part E of that figure, or the act of newly formed flu viruses exiting an infected cell.  In order to "free" themselves, they need a way of cutting their lines so that they can float away and infect the next cell.  The "N spikes" (neuraminidase, if you prefer) is how they accomplish this.  If Tamiflu is present, it prevents the cutting, and the new virus cannot infect the next cell.  It doesn't "kill" the viruses, but if prevents them from spreading further.  In this way, if stops flu disease in its tracks, and allows the immune system to play catch-up and remove the existing viruses.

The bad news here is that Tamiflu resistance can develop, and it is.  This is a futuristic problem we should keep an eye on!

Disclaimer: I only used Tamiflu because it has greater name recognition.  Relenza works very much the same way.

2:00 Dose of Fluology: Where Do New Flu Strains Come From? Thin Air?

 Where Do New Flu Strains Come From?  Thin Air?

Pigs, usually, by way of birds.  This makes sense; I promise.  To catch the whole thing, we need to think first about Influenza virus itself.

Influenza virus encodes genes on several different pieces of RNA,as illustrated here:

   

Influenza "segmented genome": Looks a bit like fusili pasta

One of those segments carries the gene for the green spikes on the surface, and  a different segment carries the gene for the purple "hammers".  Let's call the graan spikes "H" and the purple hammers "N".  Can anyone guess where this is going?  If you are infected with a flu strain with certain versions of H and N (let's call them versions "2" and "3" ), you would have a flu strain called H3N2.  If you were simultaneous infected with another strain, each with version "1", you would have H1N1.  If both viruses infected the same one of your cells, and something in the virus "assembly line" went wrong, it is possible to generate chimeric viruses with mixed-up segments.  We could call those H1N2, or H3N1.  New strains?  Sure.  But these guys aren't quite so dangerous, because all are of "human" origin.

Back to pigs and pandemic, though.  A human flu virus will typically infect only certain hosts, and the same can be said for avian (bird) flu.  Pigs, though...pigs are trouble.  Pigs have their own flu viruses, but can also be infected with human flu strains and bird flu strains.  If a sad, unfortunate pig is coinfected with both a human and a swine flu virus, a chimeric variant can emerge that is not strictly of human origin.  If said chimeric virus infected another pig which was also infected with an avian strain, a three-part chimera can form.  That guy is big trouble.  That virus has no adaptation to humans, and humans have no intrinsic immunity to anything like it.  This one is far more likely to generate a pandemic.

So there you have it.  They don't fall from the sky, but they do come from the farm.  Take home message: keep your livestock away from each other!

12:00 Dose of Fluology: Of Urban Legends and Flu Shots

Of Urban Legends and Flu Shots

Seasonal flu shots contain a mixture of 3 strains ("versions"...think of them as dog breeds) of Influenza.  Two are Influenza A variants, and one is an Influenza B.  The variants change from year to year, and are selected based on the best guess of which strains will predominate in any given flu season.  This is often not the same year-to-year, hence the need for an annual shot.  The viruses used to generate the standard vaccine are grown in chicken eggs, purified, killed with formalin, purified again, washed extensively, measured, and then packed into vials for injected vaccines (NOTE: the synthesis and principles here do not apply to FluMist). Let's consider some common features of flu shots:

1.) They are killed.  Ergo, they are not alive.

2.) They are strain-specific.  Ergo, they do not protect against all strains ("versions") of flu.

3.) They are killed with formaldehyde before purification.  Ergo, they do not contain formaldehyde.

4.) They contain flu antigens.  Ergo, they do not prevent you from contacting things that are not the flu.

This is important to point out, since common things said about flu vaccines are:

1a.) "Flu shots give me the flu!"

2a.) "Flu shots don't really protect against flu"

3a.) "Flu shots have formaldehyde in them!!!!!  They're poison!"

4a.) See 2a.  See also, 10:00 dose about what clinical states are not flu (Patients 1 and 2), versus those that are (Patient 3).

So you see, this is not entirely straightforward.  However, what is straightforward is that you have greatly reduced odds of contracting Influenza if you have a gotten a flu shot.  

11:00 Dose of Fluology: What Exactly is Pandemic Flu?

What Exactly is Pandemic Flu?

Is it here?  Do I have it?  If I could have it, and I'm not dead, why should I be scared of it?  Wait, should I be scared of it?  Ahh!  Loud noises!

The answers, respectively, are: Not at the moment, probably not, there's a good reason/keep reading, vigilant but not panicked, and shhhhhh.

First thing's first, let's define "pandemic".  MedNet defines it as an epidemic (a sudden outbreak) that becomes very widespread and affects a whole region, a continent, or the world due to a susceptible population.  Good enough for me, though I would KO "region" from that list.  So a flu pandemic would be an epidemic that spans across the globe.  Because flu tends to be seasonal, and North America flu season is different from Australian flu season, to get a full-on flu pandemic concurrently happening all over the world requires some extenuating circumstances.  Those circumstances usually involve how virulent (ie, severe or deadly) a given flu strain is, and the background immunity of the world's population.  In this case, a pandemic-causing flu strain is usually quite virulent, and the world's population has little to no immunity.  

How does that happen, exactly?  Pandemic flu strains are nearly always newly emerging.  In other words, they didn't exist prior to the current pandemic.  Where do they come from, one might ask?  They arise from a process called antigenic shift, which I'll talk about this afternoon.  Sufficed to say, since they are new, and the human population has not yet "seen" them (immunologically speaking), they tend to rip through what is a completely susceptible population.  This is why they tend to have higher death tolls, and create a little more panic than "garden variety" flu.  Remember Patient #3 from the 10:00 dose: everyone is that sick, no one is immune, and it's a little scary.

Fortunately, flu surveillance is quite good, flu shots are reasonably straightforward to generate, oseltamivir is a good drug, and pandemic strain emergence is getting more and more straightforward to forecast. 

10:00 Dose of Fluology: What Influenza Is, and Is Not.

What Influenza Is, and Is Not.

Red-nosed, Miserable Person (sniffle, sniffle, cough, cough): "I have the flu."

Pale, Shaky, Greenish person (*redacted for grossness*): "I have the stomach flu."

Feverish, Pale, Person Speaking from Their Bed (deep, often productive cough): "I have the flu."

We've probably heard all of these presentations, but only one of these people is probably correct.  Influenza is a viral respiratory infection, and causes damage to the upper and lower respiratory tract.  That would be nose, throat, trachea, bronchi, and lungs, for anyone keeping score.  Upper tract infections (head colds) usually involve the nose, throat, and occasionally trachea, but are typically are not due to influenza virus.  Similarly, influenza is not a gastrointestinal illness.  It can cause GI symptoms, mind you, but if your problem consists exclusively of vomiting and diarrhea, you do not have the flu.  A flu shot would not have helped prevent the illness of patient #1 or Patient #2, but more on that at 12:00.

Person #3 is the likely flu patient.  Person #3 is at high risk for complications, and has a non-negligible chance of death from their illness.  This is why the flu is spoken about with such seriousness by healthcare workers.  

Person #1 and Person #2 do not have influenza.  Both of them have an excellent chance of recovering.  

Often people do not seem overly concerned about the flu.  This is because, in many cases, we as a population consider all 3 people to be "flu patients".  If we all recognized that the very, very sick person is the only flu patient, and is pretty representative of all flu patients, perhaps we would be more worried about it.  Influenza is not a trivial illness.  However, what we think of as "the flu" is far too inclusive.  Whenever you hear "flu", think of Person #3, not 1 or 2.

 Stage set for further discussion~

The TCBM Moment

My First TCBM Moment in Quite Some Time

My Associate Dean uses a phrase to describe the experience of a medical student realizing their humanity in relation to the humanity of a patient in a difficult situation: The TCBM Moment.  TCBM, of course, means "that could be me."  It is a sudden and powerful burst of empathy that can often be terrifyingly painful.  I myself haven't had one in quite some time.  There is a tendency to become numb to sickness and suffering when you think about if from the weeds virtually every day of your life, for self-preservation if nothing else.

I then watched this short piece about an Ebola-stricken village in Sierra Leone from the BBC, as recommended by Dr. Heather Lander via Twitter (@PathogenPhD).  Bam!  There it was: a TCBM Moment.  Oh don't get me wrong: I'm not frightened that I will suddenly develop Ebola.  This was much more visceral (no pun intended).  Without diminishing the video's impact, I'll just say that there is a moment when a mother has a child who has a headache.  Is he infected?  Who knows?  Should he be sent where the sick people are to protect the others?  What if he just has a headache, and then becomes infected when he initially wasn't?  One thing is virtually guaranteed: if he goes, he will die.  Would she, as his mother, stay with him while he develops Ebola and dies, or should she stay with the other children?  If she goes with the first, she herself would likely become infected and die in the end, leaving the others alone.  If she does not, she is sending her little boy off to die alone.

I sat at my desk and cried, because it was such a gut-wrenching moment.  How does one make such a decision?  

I have two sons.  I do not know, and I hope I never find out.  Would I go with the sick one and abandon the healthy?  Would I send the sick one away to protect the healthy one's chance at having some semblance of a family intact?  I don't know.  To the woman in the video, I would say this:

I am sorry.  My tears do not help you, but I'm sorry.  By a favorable turn of chance, I was born in a Western country and my boys are safe.  Our experience is new, but it seems that we rarely die of Ebola here.  Our medical interventions involve low tech, labor-intensive treatments.  In other words, there is no reason that so many have to die, if we would support your treatment adequately.  We can do better.  In another life, you could be me and I could be you.  I owe it to you to do better.         

It's Almost That Time of Year Again

It's Almost That Time of Year Again

...and no, I don't mean flu season.  I actually mean Lassa fever season.  This disease isn't on the tip of everyone's tongue, largely because it is fairly restricted to West Africa, and kills a mere 30% of patients.  It's the Diet Coke of viral hemorrhagic fevers, if you like.  That said, when large numbers of people are infected annually, that 30% is a very, very big number.  The good news is that Lassa fever responds reasonably well to the drug Ribivirin, and some wonderful aid agencies have strong programs to provide it to patients.

Here's the rub that is illiciting a collective "uh oh":  we seem to have this other viral hemorrhagic fever making noise this year.  Perhaps you've heard about it?  This presents a two-pronged problem.  First, there are not enough available health care workers to care for the routinely infirm, never mind all of the Ebola patients.  This does not bode well for the expected influx of Lassa patients.  Second, both diseases are viral hemorrhagic fevers, and they are easily confused in the absence of confirmatory diagnostics.  There is a high probability that Lassa patients will be taken for Ebola patients, and then not treated with Ribivirin and exposed to Ebola.  Similarly, Ebola patients may be exposed to Lassa.  There is a high chance for dual infections and inappropriate treatment.

In as much as we are worried about flu season confusion in the West, I expect there to be some Lassa season anxiety in West Africa.

What Does Ebola Have to Do With Flu?

What Does Ebola Have to Do With Flu?

In principle, nothing.  In our current reality, quite a bit.  There seems to be a bit of confusion about why we keep mentioning these two things together.  They're different diseases with different risk factors, transmission patterns, treatments, and clinical outcomes, after all.  What's with that, one might ask.

It's almost flu season.  During flu season, it is predictable that thousands of Americans will become infected, infect others, and seek treatment.  It is also predictable that many will develop complications requiring hospitalization.  It is also predictable that many will die.  But I digress.  

People developing flu will have fever, malaise, nausea, headache, and myalgia at the onset of illness.  People developing Ebola will have fever, malaise, nausea, headache, and myalgia at the onset of illness.  In other words, the early stages of both diseases are very similar.  If you think you are getting the flu, you are unlikely to beeline for the local ER.  If you think you are getting Ebola, you are.  The problem is that the average "you", those who have been in direct contact with symptomatic Ebola patients notwithstanding, almost certainly has the flu.  If not, there are roughly 7 billion things more likely to be wrong with you than early-onset Ebola.

If you rush to the ER, you are exposing every other patient in the waiting room to influenza.  Some of them are not of sufficient health to resolve it.  You are taking an ER bed.  You are taking healthcare workers' time from other patients.  You are also exposing yourself to potential secondary infections.  Everyone is far better off with you taking some ibuprofen and going to bed, or at the most visiting your PCP and getting some Tamiflu.  Of course, you could get a flu shot and reduce the situation from occurring at all.

In our current state of confusion, with an alarmingly askew perception of ones' chances of contracting Ebola, ERs are likely to have a very, very, very long and arduous flu season.  That is why they're discussed together.  We are trying very hard to preempt the predictable outcome of sick flu patients taking themselves for sick Ebola patients.  That is something they should not have to experience being frightened of.

Just a Reminder of What is on the Horizon

Influenza A H7N9 (Newfangled Bird Flu)

The WHO confirmed two additional cases of high path avian influenza H7N9 in China the other day, one of which was fatal.  While the situation is under control, it is definitely worth watching!  As of now, H7N9 principally requires contact with infected birds, though limited human-to-human transmission has been reported.  The sky is not falling, but keep an eye on this.

Reason Prevails in Maine

Reason Prevails in Maine

A district court judge in Maine has lifted the state-imposed quarantine order on the clinically normal, uninfected, Kaci Hickox.  Justice LaVerdiere indicated that the court was aware the the actions and cult of fear were based on "bad science and bad information", and ruled in favor of Hickox, provided that she continue self-monitoring practices as recommended by MSF and the CDC.  Governor LePage responded with displeasure, indicating that his responsibility was to keep the public safe in the State of Maine.  I, for one, am grateful that at least one public servant recognized that my safety as a Maine resident has precious little to do with Kaci Hickox.

Finally, I am grateful for the well-deserved commendation Justice LaVerdiere gave to Nurse Hickox:
"We would not be here today unless Respondent generously, kindly and with compassion lent her skills to aid, comfort and care for individuals stricken with a terrible disease. We need to remember as we go through this matter that we owe her and all professionals who give of themselves in this way a debt of gratitude.”

Let's not forget how and why we the public came to know her name.  

Bonus Dose of Ebolology: The Perception of Controversy

The Perception of Controversy

If I hear one continuous theme throughout this outbreak from non-colleague friends, it is that they do not know what to believe.  Ebola is terrifying.  The CDC says not to worry.  The news talks about it constantly.  The President reminds us that only 2 people have contracted this disease on US soil...ever.  There are forced quarantines implemented by state governors.  Anthony Fauci says they're ridiculous.  When presented with conflicting information, it is human nature to play things safe.  Why risk the disease with the 90% mortality rate that kills you after your bleed from your eyeballs?  

The trouble is that there is virtually no scientific controversy here.  Those of us who underwent nearly a decade of training on the topic are feeling quite reasonably confident about directions, control measures, and risk assessment.  The volume of news coverage is not proportional to the risk posed.  Let me say that again for the folks in the cheap seats: constant discussion on CNN does not necessarily equate to constant and unrelenting risk of your own death by Ebola.  It just doesn't.

With regard to the actions of Chris Christie and Andrew Cuomo (and coming soon to the debate from Maine, our own Paul LePage)...they are not scientists.  They are pandering to the masses.  This does not mean that they have some special insight or knowledge.  It means that they are playing on public fears.  A frightened public rallies around its leader.  That is their expertise, and they utilize it very well.  Sidebar: do note that I am equally chiding a D and an R, here.  They are doing what they know how to do: rally the public and play on mood.  They are not scientists, and their actions should in no way be interpreted as evidence of anything other than their career choices.

This issue could not have been encapsulated better than in this interview with the Dr. Robert Dixon, UMaine-Fort Kent VP for Academic Affairs, who was answering why UMFK student Ted Wilbur, Kaci Hickox's boyfriend, would not be allowed on campus until November.  Pay close attention to what he says at 0:42.  "Even though the science is one aspect of this, we have to pay attention to the way people feel."  No, sir, you don't.  You have an opportunity to stand up and say, "I trust the experts, and am encouraging us as a community to calm down."  You blew it, Dr. Dixon.  You, of all people in all professions, chose to disregard academics and evidence, and bow to hysteria.  Well done.

No wonder everyone is confused.

Trust the people who do this for a profession.  Remember the motives of those in other professions.  There is no controversy here.  There is a mixed message, but not mixed evidence.  The evidence overwhelmingly indicates that we are all going to be okay.

 

5:00 Dose of Ebolology: Closing the Borders is not the Answer

Closing the Borders is not the Answer

This is a question that will not go away.  It seems like such a simple solution, doesn't it?  Don't let anyone in, and we'll be safe.  This is not so simple, as it were.  

1.) If someone passes through enough countries, it will be very difficult to track their origins.  Stoppage of fever monitoring and contact tracing because "our borders are closed" would be irresponsible and ineffective.

2.) Mali reported its first case this week, and it is not clear if Cote d'Ivorie has active cases or not.  There would constantly be countries added and taken off the "block" list.

3.) What does one do with a U.S. citizen who wishes to come home?  There are major civil liberty issues at play here.

4.) MSF, USAID, and related aid groups desperately need help.  We should not make it harder for volunteers to come and go.

The key to preventing more cases in the US and Europe is stopping this epidemic in West Africa.  Let our workers come and go as they need.

Bonus post coming tonight, post Trick or Treating!

4:00 Dose of Ebolology: Ny, NJ, and Kaci Hickox

New York, New Jersey, and Kaci Hickox

Imagine you have just spent a month away from home.  You've been in 100+ degree temperatures, in cumbersome gear, doing work that can only be described as truly emotionally draining.  I'd imagine looking forward to seeing my loved ones, breathing fresh air, and sleeping in my own bed.  After hours of transit, you're finally back in the US!


...and you're immediately taken into custody.  You do not know why.  You are forced to miss you connecting flight, because you've been detained by authorities.  You have not broken any laws, and do not have a lawyer.  You were on your way home, and did not imagine you'd need one.  You did not imagine that the states of NY and NJ had gone insane during your flight.

You are taken to a tent.  It is not heated.  No one is allowed to come in and see you without being "cleared" by the authorities detaining you.  You are not sick, but they are telling you that you are a threat to the public.  You've seen sick people, ironically, and know exactly who poses a threat to public health.  You are being held, and no one is telling you when you can leave.  No one is telling you who has the authority to hold you.  You have, effectively, lost your right to Habeas Corpus when you have done nothing wrong.

That is what happened to Kaci Hickox.  She is not sick, and poses no risk as of now.    

That is why she is so angry.  You know what?  She has every right to be.  We should be angry on her behalf.

(NOTE: I am currently writing this in the great state of Maine, where Kaci is out and about on her bike right now.  Ride on, Friend~)

3:00 Dose of Ebolology: Why is there no Vaccine for this??

Why is there no Vaccine for this??

There will be.  Treatment with antibodies (via ZMapp or blood trunsfusion) works very, very well.  That is a promising sign that vaccination will be successful.  Human trials begin in West Africa in January, as led by Institute for Human Virology and others.

Stay tuned: this is a major tool to be added to the toolbox imminently.

2:00 Dose of Ebolology: The Drame Brothers

The Drame Brothers 
Amadou and Pape Drame are 11- and 13-year-old brothers who live in New York City.  They recently moved to the US from Senegal.  Notably, Senegal is a West African nation, and it did have a very small number of (properly contained) Ebola cases.  None have been reported since August.  Needless to say, there is no reason to expect a Senagalese individual would be an Ebola carrier.  A few weeks back, the Drame brothers started to be teased at school, and other kids wouldn't pass them the ball during gym or let them play on common equipment.  Last week, Amadou sneezed while at school.  Some kid shouted "he has Ebola!!"  He was then punched in the face.  Pape came to help his brother.  Both were beaten up.  A month ago, both boys loved their school, and were happy to be in America.  These kids did nothing wrong.  Similar stories of persecution and bullying of West Africans are started to creep out, and I am beyond disappointed by it.  We are all responsible for perpetuating this climate if we are not working to change it.  Listen to experts.  Do not listen to newscasters.  Do not listen to politicians.  Listen to experts.  When we don't, we create and enable a climate where these boys are targeted and beaten.  They deserve better.  

1:00 Dose of Ebolology: Ebola's Mortality Rate in Context

Ebola's Mortality Rate in Context

Further Update: Dr. Craig Spencer has fully recovered, is from of Ebola, and has been released from the hospital.  This officially brings the case:fatality ratio in the US to 1:9

UPDATE: Dr. Craig's Spencer's condition has been upgraded to "stable" from "serious but stable".  Hopefully he continues to recover, and will become person #8 to walk out of the hospital.

EBOLA KILLS UP TO 90% OF THOSE INFECTED!!!!!!!!!!!!  

So scream the headlines.  For a long time, this was absolutely true.  Depending on the strain and healthcare options available at the site of an outbreak, it is often still true.  The official mortality rate of the current epidemic in West Africa is wavering between 50% and 55%.  In other words, this outbreak is a little less "fatal" than others, but still-living or dying has the same odds as a coin flip.  The mortality rate in West Africa is disturbingly high, and we as a society can and should do better.  Why am I and my colleagues NOT PANICKING ABOUT AN OUTBREAK IN THE US????

Clinical outcomes from Ebola cases are very context dependent.  Effective treatments such as fever control, fluid replacement, dialysis if need be, and passive transfer of antibodies do exist, and Western countries have the infrastructure to administer these interventions quite effectively.  9 people have been diagnosed/treated in the United States.  1 (Thomas Eric Duncan) has died, and it is important to note that Duncan did not receive treatment until he was already critically ill.  1 (Craig Spencer) is hospitalized and his condition is serious but stable.  The other 7 have walked out of the hospital completely recovered.  

In other words, in a Western healthcare setting, the mortality rate is more or less inverted.  This is still quite serious-I do not mean to minimize it-but let's keep it in perspective and context.

12:00 Dose of Ebolology: How dangerous are Dr. Spencer and Nurse Hickox's Actions?

12:00 Dose of Ebolology: How dangerous are Dr. Spencer and Nurse Hickox's Actions?

Drumroll for an anticlimax......

They are not dangerous.  Neither of these extensively trained professionals have done anything wrong that will endanger the public.  Please think it through for a minute: both of these individuals gave large blocks of their time to put themselves at risk (actual risk) in order to curb the spread of disease.  Why in the world would either one then turn around and callously enable the spread of disease?  That narrative does not make sense.

Craig Spencer was monitoring himself.  When he developed a low-grade fever (and was not likely to be shedding virus), he immediately and properly sought treatment under strict isolation.

Kaci Hickox is not sick.  As of this point, there is no evidence that she is infected.  If she is, and later develops clinical signs, she will be isolated.

These people are servants of humanity, and deserve our respect.  They do not deserve to be demonized.  Finally, and more practically, they are not dangerous.

   

11:00 Dose of Ebolology: Africa is a Very Big Place

11:00 Dose of Ebolology: Africa is a Very Big Place

Reports abound this week of children, teachers, principals, and office workers being sent home (notably without sickness) because they had recently visited an African country.  The epidemic is centered in Africa-this is true-  but it is a very, very, very big place.  The principal banned from school in Louisiana because he had visited Zambia?  That would be roughly equivalent to quarantining people in Seattle because we have a case in New York.  That is ridiculous.

Sending home school children because they have recently been in countries with NO active cases?  Also ridiculous...and potentially very damaging.  These children are missing schoolwork and lessons.  They are missing playing with their friends.  They are potentially being stigmatized (more on this potential danger-literally- at 2:00).  Their parents are forced to secure childcare...and pay for it...or miss work themselves.  All this because not enough of us can effectively read a map?  This is not okay.  This is hysteria, and we as a society are simply enabling bad behavior.

Ebolology Part 2: More Calming Balm

...because Part 1 was not enough to create a counter-epidemic of rationality!

For our 10:00 dose of Ebolology, I think I'll simply hit you with another dose of calming balm.  Reread and refresh, and then we'll discuss new aspects of this growing mess at 11:00.  

Please share; spread reason, not fear!!!

 Original Text (as linked above):

10:00 Dose of Ebolology: Dr. May's Calming Balm.

We've all heard it: "stay calm", said by dudes in suits who may appear not to have a handle on things. Meanwhile, the internets rage with panic. If you know and trust me, please hear this one: do stay calm, and keep things in perspective. With respective to the infirm and the deceased, we are not talking about a large number of people here in the US and in Europe. Said people are truly not particularly contagious, unless you are sprayed by their innards (hence secondary infections from index cases tending to be nurses and physicians). Said people are also usually not up walking around once symptomatic, which is when they are contagious, because, you see, they are quite sick. If you've had contact with a patient, please be vigilant. If you have not, please be calm. I promise these will get more interesting and practical, but I figured this one needed to come first.

A Letter from MSF Regarding Dr. Spencer and Nurse Hickox

Like many MSF supporters, I received a letter this evening addressing the action taken by Dr. Craig Spencer prior to his clinical illness becoming apparent.  If you are concerned about Dr. Spencer, or are interested in Nurse Hickox's situation, please click here to view the letter.

There is no need for concern.  Please pay these professionals the respect they deserve~

Happy Birthday, Jonas Salk

Today Dr. Jonas Salk, inventor of the world's first polio vaccine, would have been 100.  His vaccine (the "IPV") is still in use.

Today, millions of children are alive and well because of this man (and/or his rival and colleague, Dr. Albert Sabin).

I am grateful for today's Google Doodle, which honors Dr. Salk.  It serves as a reminder that there was a time when scientists and physicians that broke new ground and did risky work for the good of humanity were heroes.  I think it's time we brought that back~

5:00 Dose of Vaccinology: The Herd Immunity Argument

5:00 Dose of Vaccinology: The Herd Immunity Argument

Often, people justify not vaccinating their children because of "herd immunity".  The reasoning goes that this notion should keep their child safe without being vaccinated, so why risk ("risk", really) it?  Before my verdict on this is given, allow me to quickly define herd immunity.  This is the concept that disease transmission requires a certain level of susceptible population density, and if the susceptible population is tiny because most people are immune, that disease transmission will not occur.  In other words, if 198 adults and 2 children are standing in a crowd and 1 of the children has the chicken pox, very little will probably happen because the majority of the adults are immune.  Make sense?  Okay, moving on.

Point 1: Not everyone in a given population can be vaccinated for various completely valid reasons (congenital immune deficiency, cancer treatments, ingredient allergy, whatever).  Similarly, not everyone who is vaccinated responds equally well and achieves protective immunity.  These individuals are protected by herd immunity.

Point 2: So the argument goes, vaccines are "potentially dangerous" so you will allow your child to benefit form herd immunity.

Point 3: this not only reduces the robustness of herd immunity for those who must rely on it (see point 1), but implicitly implies that you will gladly reap the benefit of someone else's risk (again, "risk") without a valid need to do so, which...

Point 4: Makes you kind of an ass.

Unprofessional?  Yes.  So very true, however.

  

4:00 Dose of Vaccinology: What are These Toxins I hear About?

4:00 Dose of Vaccinology: What are These Toxins I hear About?

Like all good urban legends, this one has a grain of truth in it.  There are "toxins" in some vaccines, and they are exactly what you want immunity against.  First, a disclaimer.  I am not talking about mercury.  The words "vaccine" "toxin" and "mercury" have all mated into some kind of amorphous blob of scary with two pecks of unrelated truthiness in it.  A small number of vaccines (NOT ALL) contain a small amount of mercury as a preservative.  On a parts-per-million basis, getting one of these shots roughly approximates eating a tuna sandwich.  Another point to consider is that there is a preservative in them for a very good reason.  If you're wondering what it is, ask one of those poor folks who had fungal spores jacked into their spine a couple of years ago.  Moving on...

The actual "toxins" in some vaccines were alluded to in the 11:00 dose that referenced diphtheria.  Some bacterial species actually cause their disease symptoms by producing toxins.  I also mentioned this when discussing cholera in Haiti a few days back.  Since the toxin generates the disease, the toxin is the most important thing to raise protective immunity against.  Purified bacterial toxins that lead to tetanus, pertussis, diphtheria (and, now in clinical trials, C. diff!!) are deactivated enough to not cause their associated diseases while still generating protective immunity.  Voila!

So, the toxins aren't toxic in this case.  The sicknesses are avoided.  All is just fine.