Is Zopiclone Bad for Seniors?

Zopiclone + Seniors = Bad Mix

by Rudy Sanchez, B.Sc.Pharm, RPH

 

The most popular prescription drug for insomnia may not be the best choice for seniors. 

If you or someone you know is a senior and is one of the millions of patients taking these oval blue pills to help you sleep, you should read on. (Note: we are not talking about the “other” popular blue pill).

Zoomers are active, vital and healthy...not groggy, tired and sedentary.

What is our definition of a senior? Someone who actually watched the Beatles on the Ed Sullivan TV show, not on YouTube. Or maybe it is someone who has no idea what YouTube is.

 

zopiclone, a sleeping pill

Read on to find out…

               -why zopiclone is a poor choice for seniors

               -why you should not drive the morning after taking zopiclone

               -why you may not be as smart as you were if you take zopiclone

               -why zopiclone may land you in the hospital with a broken hip

               -why it is so hard to get off the drug

               -what are some alternatives if you are on zopiclone and want off

What is zopiclone?

Pharmacists and biochemists love molecular structures.. everyone say MEH

Zopiclone belongs to a class of drugs called cyclopyrrilones which also include eszopiclone (Lunesta), zolpiderm (Ambien) and zaleplon (Sonata). They are also called Z Drugs, because they all start with Z and it’s a convenient, neat marketing tool for drugs that helps you get the ZZZ’s. So clever, these pharmaceutical people. 

increase in GABA activity produces relaxation

The inventors of the drugs were been able to classify them as non-benzodiazepine, removing them from the tainted reputation of Xanax.  The developers of the drug found  a different  mechanism of action. Whereas benzodiazepine drugs mimic GABA (gamma-amino butyric acid) at the receptors, the cyclopyrrilones increase the transmission of GABA. The net effect is the same: they both increase the effect of GABA. Side effects and drug cessation symptoms are similar between zopiclone and benzodiazepine.  It is not necessarily a better drug, but the marketing of a non-benzo is definitely better.

remember the Xanax controversy?

Why is GABA so important? It is the most plentiful neurotransmitter in the brain and reduces excitability of neurons. It manages this by increasing the passage of chloride ions into the neuron cells, leading to decreased neuronal activity, increased relaxation and decreased anxiety.

GABA ia a major inhibitory neurotransmitter in the brain

Think of GABA as the anti-caffeine. You know how caffeine makes you awake, energetic and jittery? Caffeine does this by neutralizing GABA in the brain. So consider GABA as caffeine in reverse.

think of GABA as the anti-caffeine (and caffeine as anti-GABA)

 

Shortly after the introduction of the zopiclone,  a study by Gaillot (1987) measured zopiclone plasma levels in seniors. When compared to non-seniors,  plasma levels were higher by  168% and the plasma  half-life of the drug increased from 5.1 hours to 8.1 hours. In seniors, not only does the drug stay around longer, it also reaches more than double the blood level. Gaillot (1987) explains that this double whammy is a result of the extensive hepatic (liver) metabolism of the drug. Reduced liver metabolism in seniors causes the difference. The real effect of this is morning sedation and grogginess through the day after. 

zopiclone impairs driving for up to 11 hours after taking it

 

Caffeine is the GABA counterpart, so going for coffee is a perfectly natural instict

A study by Leufkens in 2009 compared the effects of zopiclone, temazepam and a placebo on the driving ability of the elderly and found that zopiclone impairs the driving ability for 11 hours after it is taken. This poses a hazard for the typical senior who sleeps at 11 o’clock and drives at 9:00 the next morning to go to  Tim Horton’s .. because he needs that cup of doubledouble. He/she  is more likely to have driving impairment this much later. 

 

glutamate is excitatory, GABA is inhibitory

Zopiclones evil twin makes it more addicting. Part of zopiclones action is through its active metabolite, desmethylzopiclone, which is even more powerful than the parent compound. Although the hypnotic (sleep inducing) activity of the drug is from the unchanged parent drug, the active metabolite desmethylzopiclone inhibits NMDA (N-methyl-D-asparate) in the brain as well as blocking nicotinic acetylcholine receptors. NMDA is an excitatory neurotransmitter  and has been studied in the breeding of “Doogie Mice”. These mice learn very quickly ( the reference is to Doogie Howser, MD) since their NMDA receptors are stimulated. NMDA is responsible for learning and remembering new information. Suppression of NMDA activity by the zopiclone metabolite leads to degradation of these learning skills. Is it possible that zopiclone makes you dumber?  Blocking of the nicotinic acetylcholine receptors causes anti-chollinergic side effects such as dry mouth, loss of balance and bladder infections. Most seniors already suffer from these conditions.

doogie mice are smarter from NMDA receptor stimulation

 

One of the main side effects of zopiclone is a disturbance  of motor coordination. This is a result of three effects:  the blocking of the nicotinic acetylcholine receptors by desmethylzopiclone causes dizziness. Secondly, the prolonged grogginess is from the extended half-life.  Thirdly, the inhibition of GABA transmission affects body balance through a mechanism called the sway effect.  A study by Mets (2010) measured the impairment of body balance and concluded that the elderly patients on zopiclone are more likely to fall, leading to possible fractures. Combined with increased incidence  of osteoporosis in the elderly (especially in female seniors),  the sway effect makes zopiclone more dangerous.

In North America, every 18 seconds, a senior is admitted in the hospital due to a fall

How long do all these negative effects last? More bad news. A study by Puustinen (2014)  measured cognitive and psychomotor impairment in elderly patients who have been taking zopiclone and found that the problem persists for six months after the drug is stopped. 

female seniors are more likely to have osteoporosis

What to do? 

Do not stop your zopiclone suddenly. Talk to your physician. There is complete list of drugs that are not recommended for the elderly. It was first published by Dr. Mark Beers in 1991 and in this list, there are recommended alternative prescription drugs. Called The Beers List, it recommends low dose trazodone and low dose doxepin as alternatives.  Please do not ask your doctor for his beer list, that is another thing entirely.

The Beers List, not the beer list

Marigold Compounding Pharmacy can work with your doctor to successfully navigate the withdrawal from the drug so that the cessation symptoms are reduced.  Sometimes described as the wash in-wash out method, it involves compounding dilutions of the zopiclone (as little as 5% increments) over a period of ten to twenty weeks. This is available with a prescription order from you doctor and can be compounded by Marigold Compounding Pharmacy.

learn progressive muscle relaxation

Non-drug therapy is also recommended by Dr. Beers. Some considerations are sleep hygiene techniques, meditation, Traditional Chinese Medicine, homeopathic medicine,  teas,  progressive muscle relaxation, magnesium and medicinal herbs. In combination, these strategies have been found successful in restoring sleep.

magnesium helps sleep and is a common deficiency

References:

Gaillot J, Le Roux Y, Houghton GW, Dreyfus JF. Critical factors for

pharmacokinetics of zopiclone in the elderly and in patients with liver and renal

insufficiency. Sleep. 1987;10 Suppl 1:7-21. PubMed PMID: 3438645.

Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic

dysfunction. Eur J Clin Pharmacol. 2008 Dec;64(12):1147-61. doi:

10.1007/s00228-008-0553-z. Epub 2008 Sep 2. Review. PubMed PMID: 18762933.

Leufkens TR, Vermeeren A. Highway driving in the elderly the morning after

bedtime use of hypnotics: a comparison between temazepam 20 mg, zopiclone 7.5 mg,

and placebo. J Clin Psychopharmacol. 2009 Oct;29(5):432-8. doi:

10.1097/JCP.0b013e3181b57b43. PubMed PMID: 19745642.

Puustinen J, Lähteenmäki R, Polo-Kantola P, Salo P, Vahlberg T, Lyles A,

Neuvonen PJ, Partinen M, Räihä I, Kivelä SL. Effect of withdrawal from long-term 

use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older 

adults. Eur J Clin Pharmacol. 2014 Mar;70(3):319-29. doi: 10.1007/s00228-013-1613-6. Epub 2013 Dec 12. PubMed PMID: 24337417.

Mets MA, Volkerts ER, Olivier B, Verster JC. Effect of hypnotic drugs on body 

balance and standing steadiness. Sleep Med Rev. 2010 Aug;14(4):259-67. doi:

10.1016/j.smrv.2009.10.008. Epub 2010 Feb 18. PubMed PMID: 20171127

 

Diarzilla: Surviving The Norovirus

Diarzilla: Surviving the Norovirus

  by Rudy Sanchez, B.Sc.Pharm.,  RPH

Godzilla...meet a scarier monster: Diarzilla!

In the movie Godzilla, the scary monster rises from the sea and everyone runs. With the attack of Norovirus (NV), aka Diarzilla, people run…to the bathroom.

 

 I get to talk about poop. Yeah!!

 

 Projectile vomiting and explosive diarrhea unabated for three days is no laughing matter. It will literally bring you to your knees.  There are about 21 million norovirus cases per year in North America and it is often confused with food poisonings.  Understanding the virus gives us tools on how to deal with the disease.

 

Norovirus is small and deadly

How do you know its Diarzilla? The mark of the virus is its virulence and speed. One day you are on top of the world and the next day you are in deep..umm.. doodoo (scientific term). This will last pretty much continuously for 20 to 60 hours and then it will stop. The gestation period is two to three days so in that time, somebody in the household will catch it.  There are ways to avoid this. 

 

 The symptoms are similar to bacterial food poisoning, but there are few differences. If it is a bacteria (for example, salmonella), you will be the only one sick and it will abate after 48 hours.  

 

In both cases, loss of body electrolytes lead to other symptoms of fatigue, muscle pain, headaches, stomach cramps and dizziness. This is of special importance for infants and children who can get dehydrated just like that! You did not see me snap my fingers, but I did.

 

Cruise ships dump raw sewage into the ocean

  Another thing to keep in mind is that NV is a nosocomial virus. This super fancy word means that is incubates in closed settings such as nursing homes, hospitals, cruise ships, schools, and restaurants. All it takes is for one person to start the contamination pattern, such as a worker not washing hands after going to the bathroom. In cruise ship epidemics, the virus has been traced to shellfish or oysters which pick up the virus from sewage waters running into the ocean. Maybe it’s a cycle of cruise ships dumping sewage into the ocean. How many cruise ships get norovirus epidemics? About 14 a year.

 

 

Since oysters filter the water, they are natural carriers of the virus.  

 

78% of surfaces in a hospital room were infected

  What happens? The virus spreads by fecal-oral route…fecal matter carrying the virus makes it way into your gut either through food (contaminated by a food handler) or more simply, by your hands touching your mouth. In a study by Verani (2014) on contamination of surfaces in a hospital setting, 78% of surfaces were found contaminated. This included counter tops, door handles, bed rails, telephones, floors, windowsills… all of these outside the bathroom. A person flushing the toilet creates an aerosol of droplets which contaminate surfaces. Once these droplets spread on hard surfaces (floor, sink and counter top), they are carried outside to the room.

 

 A study by Verhoef (2010) traced two genotypes of the virus and determined that 21% of all outbreaks are from food borne sources (for example, shellfish) with the rest being from fecal transport. This implies that the virus itself mutates when inside the human host.  The study shifts the focus on hygiene measures as the main consideration in controlling spread of the infection. 

 

 The virus is one of the smallest particles known: 38 nanometers.  To get an idea of how small this is, a stack of 1,215 noroviruses is the thickness of tissue paper. A red blood cell is 7,000 nanometers across, relatively huge. The small size of the virus presents a problem. The dust mask you bought at the hardware store will not filter the virus.  Even an N100 mask, the highest density available,  filters down to 300 nanometers. This virus is very very problematic because of its size. 

 

Cursory disinfectant with household cleaners will not kill the virus

 Toilet seats are often made from injection molded polystyrene which are porous.  (I hope you don’t have a wooden toilet seat, even worse) The 38 nm virus imbeds into the plastic material of the toilet seat and is small enough to stay in the plastic even with cleaning.  A cursory wiping with disinfectant is far from an effective method. Who in his right mind would remove the toilet seat (not that easy) and soak in hydrogen peroxide for 10 minutes (expensive) and then re-install it (inconvenient). 

 

 But there is an alternative: of course there is. Would we stand stymied by 38 nanometers? Of course not! We are the smarter species! Smarter maybe, but I’m not sure if we are as cool ..viruses are pretty amazing.        

No toilet seat... no problem

  Crazy solution to the problem: The toilet bowl itself is made from vitreous china...quite dense and guess what? Non porous. The solution is this: remove the toilet seat. Then the next step is to get used to cold unforgiving china touching your derriere. I said we are smart, I did not say we are gracious.

 

Points of viral entry: mouth, nose, eyes

  The virus enters your body through the nose, mouth, eyes. It can not enter the skin, unless the skin is broken. It will adhere to the skin and if you touch your eyes, nose and mouth, it gets you that way.  The virus begins to multiply in the small intestine, taking 12 to 48 hours to do so. The invasion triggers an immune response, first with T cells and then B cells.  The Beta cells will kill the virus but the key strategy is to have good immunity, The immune response also triggers the “dump-and-flee” response which protects the body by vomit and diarrhea.

 

So when you are throwing up with projectile vomit and sitting on the cold seat-less toilet with rocket poop, you have to repeat this mantra:

 

I am fighting this norovirus

Getting it out is desirous

In three days I will feel much better

Damn you …infected oyster!

The virus sheds for about thirty days

In a study on the shedding dynamics of the norovirus, Kirby (2014), researchers measured  stool viral titers over a 35 day period and found that the virus was shed in stools up to three weeks after the resolution of symptoms.  This indicates that preventative measures to reduce transmission have to be maintained for this long after the remission of symptoms of the last member of the household.

 Now we get to the reason you have read this post: How to prepare for Diarzilla.

 

Diarzilla Preparedness Kit

 Kit Number 1: Nobody is Sick, But the Neighbours Are

 At this point, nobody is sick, but you have heard of some people in the neighborhood getting the norovirus. Maybe a nursing home or hospital ward has been quarantined. You get prepared by strengthening your immunity. Start by taking 20 billion CFU’s of probiotics a day starting now. If no infections happen, then it still helps your immunity.  Makes sure that you are eating a 2:1 ratio of vegetables to everything else. Take immunity builders such as echinacea, elderberry, goldenseal and astragalus everyday (pick one or a combination).  

 

 Take Vitamin C, 500mg , three times a day. 

 

say no to that invitation to the clam bake

  Refuse the invitation to the neighbor's oyster-bake-luau-get-together for a month.

How many people used that toilet?

  Try not to visit prisons, day cares, train stations, airports, submarines, nursing homes, hospitals and avoid public washrooms if at all possible. 

 

 Review and practice proper hand washing technique by watching this YouTube video. Remember that the food handlers of the household have to wash their hands all the time, before handling food and after going to the washroom.

 http://www.youtube.com/watch?v=8jxt7Op4hKo

 Let’s tackle cleaning the bathroom. First remove any clutter, bottles, rubber duckys, and those decorative soaps-that-you-will-never-use from Aunt Matilda.  There should be no clutter to catch or trap viral colonies. After your bathroom is bare, clean it thoroughly as normal, but this is just the “pre-clean”. Then comes the real cleaning: disinfect by spraying all surfaces (toilet, counters, walls , floors, window sills) with 3% hydrogen peroxide, allowing it to dry off completely. Then spray it again with a 50% solution of vinegar and water, again allowing it to dry off completely. 

 

think of all this clutter as virus traps

  Always take a shower after you clean your bathroom, putting your bacteria-splattered clothes and towels in a plastic bag to wash separately, and to finish off, disinfect the shower. Singing La Donna Y Mobile at the top of your lungs  finishes off the job with aplomb.

 

 Get in the habit of using your dishwasher for all utensils and plates within 24 hours. Include your toothbrushes, plus any glasses that you use in the bathroom, in your dishwasher load.

 

Kit Number 2:  When Diarzilla Claims the First Victim

 Not counting the Kenny G Relaxation Vol. 1 and II  tapes, here is a complete list of supplies that you may need:

 Wide aluminum foil, one box

Nitrile gloves from Costco

Two boxes of disposable unscented baby wipes in plastic bins

Shower caps

Ski mask or diving mask

N91 or N100 face masks from Midland Tools

Heavy Duty Ziploc bags, 1 box

5 gallon bucket with lid, with handle (available at paint stores)

2 spray bottles, marked V-Mix and HP-Mix

Disposable coveralls (sold at paint shops or at Midland Tools)

Vinegar , diluted 50:50 with water to make V-Mix

Hydrogen Peroxide 3% to make HP-Mix

Distilled Witch Hazel, alcohol free ( for  hemorrhoids)

 

Activated Charcoal Capsules

Probiotics 20 Billion

Bananas

Rice

Apple Sauce

Quinoa

Broth ingredients (soup bones, celery, ginger, inions, garlic)

Hydralyte powder

  Homeopathic for diarrhoea: Aloe 200CH, Arsenicum 30CG

  Homeopathic for vomiting:  Ipeca 200CH, Nux Vomica 200CH

 

HP-Mix is 3% Hydrogen Peroxide

V Mix is 50:50 vinegar and water

Replace lost electrolytes by dissolving one packet of Hydralyte in a glass of water. One glass per 50 pounds of body weight per day. This is very important in children since their body fluid volume is smaller.  This prevents fatigue, dizziness and loss of energy. The general rule, one throw up: one glass. One poopdemeanor: two glasses.

 

 Activated Charcoal will help reduce diarrhea and scrub the gut, two capsules three times a day for three days. This is really helpful at the first stages  and helps vomiting, diarrhoea, nausea and cramps.

 

 Homeopathic Aloe and Arsenicum are for diarrhea.  Take two pellets of Aloe every 2 hours on day 1, change to Arsenicum on day 2 following the same dose, revert to Aloe on day 3, Arsenicum again on day 4. For children, the dose is one pellet each time instead of 2 pellets.

 

 Homeopathic Ipeca and Nux Vomica are for vomiting.  Take two pellets of Ipeca every 2 hours on day 1, change to Nux Vomica on day 2 following the same dose, and revert to Ipeca on day 3, Nux Vomica again on day 4. For children, the dose is one pellet each time instead of 2 pellets.

 

BRAQ Diet: bananas, rice, applesauce, quinoa (substituted for toast)

  The recommended food follows the acronym BRAQ.  This is a variation of the BRAT diet (T for toast). This is a bland diet consisting of bananas, rice, applesauce and quinoa. This maintains a minimum level of energy while allowing easy digestion. In cooking your rice and quinoa, use bone broth. Bone broth is prepared by boiling for two hours, one pound of bones (chicken, bison, beef or deer) in one gallon of water to which two tablespoonfuls of vinegar is added. Add celery, ginger, onion and garlic as well. 

 

 How to vomit: the best technique is to vomit directly into a Ziploc bag, holding it close to your mouth. Immediately, close the Ziploc bag and throw it into your 5 gallon bucket and close the lid. Once a day, this bucket is to be directly emptied into a garbage bag (outside the house) and thrown away. The bucket is disinfected by spraying with the HP-Mix , and then V-Mix (first hydrogen peroxide and then vinegar).

 

unscented baby wipes in vinegar or hydrogen peroxide soak

  How to disinfect the skin after throwing up? Take the box of unscented baby wipes and dump 500mls of hydrogen peroxide in one, label it HP Wipes. The other one gets 500 mls of 50% vinegar solution and this gets labelled V Wipes. These hand wipes are your sanitation wipes. They are used to wipe hands, mouths, bums, legs. For hard surfaces, the spray method instead.  The wipes are used in sequence: HP Wipes, wait for 5 minutes and then V Wipes after. 

 

For wiping after diarrhea, wipe with toilet paper nromally , then disinfect the skin. The HP wipes will not sting (for wiping bums), but the V Wipes will, so this can be skipped for that area.  In the case of hemorrhoids developing, then you can substitute witch hazel for the V wipes to reduce pain and swelling. It still needs to be preceded by the HP wipes. After the first few bouts of diarrhea, the  burning can be relieved this way.

Back to the seat-less toilet:

This is your friend

 Remember that flushing causes dispersion of droplets. What are we going to do  about the toilet flush if we have removed the seat?  Solution: remove the cover portion of the toilet seat and wrap it with aluminum foil. If you use the wide foil, it should cover it without any seams. Before you flush the toilet, cover the toilet with your aluminum clad seat. Then you can flush away. The foil can be removed and replaced on a regular basis.  Foil is cheap.. do not skimp. Remember to fold dirty side in, clean side out. These are things than your grandmother taught you, just reviewing.

 

 Here is a very important piece of the puzzle: the sick person is quarantined to eat in his/her room. The bathroom that he/she uses is not used by any other person. All plates are soaked in V-Mix in a bucket before transport. This batch is disinfected in the dishwasher as a single load. As noted, this has to be maintained for 30 days, since the virus is still shedding after the symptoms are gone. 

  Continuity of the sanitation cycle (dirty to dirty, clean to clean) has to be maintained for 30 days. Breaking this continuity allows transmission out of the loop or into the loop. Breaking this 30 day rule is one of the simplest causes of norovirus spreading. 

 

Just repeat: I am more smarter than this virus. I mean, am smarter than this virus.

 Who gets to clean the bathroom?

Meet T101 , The Terminator, not afraid of muck, yuck and the color brown

  Obviously, not the patient. We will call this person T-101 (this is the name of the robot in Terminator.. unfazed by poop)

 

 T-101 puts on the garb: coveralls (from experience, disposable coveralls withstand washing up to 7 times, bit hang to dry only), shower cap, nitrile gloves, diving mask. He has a full roll of paper towels, his two spray bottles of HP (hydrogen peroxide 3%) and V (vinegar 50%). He goes in the bathroom and disinfects it as above, disinfecting the seat-less toilet, garbage can, tub, shower, counters, floors, walls and doorknobs. Spray everything with HP-V (one after the other. All the garbage goes into the 5 gallon bucket which is taken outside directly to the trash. T-101 jumps into the shower and puts all his/her clothes, including the towel and shower curtain, into a garbage bag. The laundry is immediately done as a separate load.

 

Diarzilla Kit No. 3: The Whole Family is Sick

 Things get serious if the infection was not controlled by the quarantine measures. The dishwasher is used everyday and each person’s cutlery and plate is marked with a tagging system so these are not shared.  The bathroom used by the people who are sick is separated from the bathroom of the people are not sick. 

 

 Remember the 30 day quarantine for the last person sick, as the members of the household are carriers for all this time, even though they are asymptomatic.

you get attached to the bathroom/prison after a while

  Also, it is debated if there is immunity granted the first person who was sick. Will this person likely contract it again. As viruses are able to mutate,  in the study by Verhoef (2010), immunity is more likely within the same set of infections. In this case, the first person sick will not get it back. However, it does not prevent anyone from getting the norovirus again in the future, being that it will be a different genotype.

 

Very Important Lesson from T101: Suck It Up

 The lesson learned: any squeamishness on your part, or on person known as T101’s part, in dealing with vomit and faeces, will be construed by the enemy as weakness and it will win this battle. So be strong, cowboy up and deal with it. ( Jump around to the theme from Rocky … raise your hands!! Yeah!!! We won!! We beat a 38nanometer virus!!!)

 

take this s**t and stuff it...wait a minute...NOOOOO!!!

To give some class to this topic,

 Some Pretty S**tty References Thrown Up in Random Order:

 Verani M, Bigazzi R, Carducci A. Viral contamination of aerosol and surfaces through toilet use in health care and other settings. Am J Infect Control. 2014 May 9. pii: S0196-6553(14)00249-1. doi: 10.1016/j.ajic.2014.03.026. [Epub ahead of print] PubMed PMID: 24818773.

Barclay L, Park GW, Vega E, Hall A, Parashar U, Vinjé J, Lopman B. Infection control for norovirus. Clin Microbiol Infect. 2014 May 11. doi: 10.1111/1469-0691.12674. [Epub ahead of print] PubMed PMID: 24813073.

Bert F, Scaioli G, Gualano MR, Passi S, Specchia ML, Cadeddu C, Viglianchino C, Siliquini R. Norovirus Outbreaks on Commercial Cruise Ships: A Systematic Review and New Targets for the Public Health Agenda. Food Environ Virol. 2014 May 17. [Epub ahead of print] PubMed PMID: 24838574.

Verhoef L, Vennema H, van Pelt W, Lees D, Boshuizen H, Henshilwood K, Koopmans M; Food-Borne Viruses in Europe Network. Use of norovirus genotype profiles to differentiate origins of foodborne outbreaks. Emerg Infect Dis. 2010 Apr;16(4):617-24. doi: 10.3201/eid1604.090723. PubMed PMID: 20350375; PubMed Central PMCID: PMC3321941.

Kirby AE, Shi J, Montes J, Lichtenstein M, Moe CL. Disease course and viral shedding in experimental Norwalk virus and Snow Mountain virus infection. J Med Virol. 2014 Feb 14. doi: 10.1002/jmv.23905. [Epub ahead of print] PubMed PMID:24531909.