The very first red flag that something was very, very wrong with the 'XMRV=CFS' paper went up before the actual paper was published.
On the woo-rag Huffington Post, the anti-vaxer David Kirby posted a very, very odd comment from the lead researcher on the paper, Judy Mikovits:
And then Dr. Mikovits dropped a bombshell that is sure to spark controversy."On that note, if I might speculate a little bit," she said, "This might even explain why vaccines would lead to autism in some children, because these viruses live and divide and grow in lymphocytes -- the immune response cells, the B and the T cells. So when you give a vaccine, you send your B and T cells in your immune system into overdrive. That's its job. Well, if you are harboring one virus, and you replicate it a whole bunch, you've now broken the balance between the immune response and the virus. So you have had the underlying virus, and then amplified it with that vaccine, and then set off the disease, such that your immune system could no longer control other infections, and created an immune deficiency."
So there you have it - a possible explanation of regressive autism in a significant number of cases associated with immune system deregulation triggered by vaccination.
There is nothing at all wrong with 'speculating'. In fact, just having fun speculating is a necessary component of Science itself. But there is a difference between speculating about the causes/effects of your experimental data and fear mongering. Telling the general public 'XMRV IN VACCINES CAUSES AUTISM!!!' is not a thought experiment-- Its seeding fear in the public based on zero experimental evidence. Basically, the kind of shockingly unethical behavior we now know to expect from Mikovits et ass.
But the story did not stop there. The XMRV-->CFS proponents quickly aligned themselves with the King and Queen of anti-vaxers, Andrew Wakefield and Jenny McCarthy. They partnered with snake-oil companies selling potions 'for treating autism'. They spread whispers in patient communities about aaaaaall this research they had connecting XMRV to autism.
Minor problem.
This 'research' has never surfaced within the scientific community.
"XMRV-->autism" is, for all intents and purposes, an internet meme started by Judy Mikovits October 12, 2009, nothing more. But it has evolved from a 'not funny' meme into a 'could hurt/kill a child' meme, thanks in part to Daddy Mengele Age of Autism contributor, Kent Heckenlively:
XMRV (HGRV) is Not Dead - The Rituximab Story
The researchers I have spoken with about XMRV and autism have told me their suspicion...
As explained to me by advocates in the chronic fatigue syndrome/ME community...
... I'm not suggesting any solutions in this article. I'm just raising the possibility that this research with rituximab may have finally shown us the target.
"Im not saying parents should put their autistic children on Rituximab. Im just propagating a science-free internet meme and telling desperate parents that Rituximab will cure their autistic kid."
Let me make something perfectly clear: There is currently zero evidence XMRV (HGRV is not a real phrase) could be a real human pathogen, much less that it is a human pathogen, much less that it is causing CFS, much less that it is causing autism, much less that it is causing any human disease.
To use a highly controversial 'connection' between XMRV and CFS and internet rumors of XMRV-Autism/CFS-Autism 'connections' to casually suggest that any child anywhere should be put on a life-threatening drug to 'cure' autism?
... There are no words.
There are just no words for how horrifying this is.
Thank goodness there are Autism advocates who see right through this sick 'game'.
Don't use GMO's to Treat Autism!! (at least not this one)
Are some of you having trouble following this train of logic? Good, 'cuz there isn't any train of logic. A study showing that rituximab helps CFS patients who don't have evidence of XMRV infection has nothing to do with autism, not even if you believe (in the absence of any data) that XMRV causes autism.
The Rituximab Story: not evidence for XMRV and NOT a potential autism therapy
Here's the "logic" behind Mr. Heckinlively's article: XMRV has been linked to autism (he ignores the more recent data against this idea). XMRV has been linked to chronic fatigue syndrome (once again, he ignores the data which goes against they hypothesis). Therefore, autism and chronic fatigue syndrome must share some sort of link. In this case, a small study has been published which claims that Rituximab helped a number of patients with chronic fatigue syndrome.One of the many glaring problems in this train of logic is the fact that the researchers in this particular study looked for XMRV in their subjects. And didn't find it. So, the link between this group of CFS patients and autism, tenuous as it was from the start, is basically absent.
I swear to god, if one child, anywhere, is hurt or killed because of this internet meme...
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hope for children and adults WITH ME arthritis possibly autism . WE NEED OPEN RESERCH FOR ALL DISEASES not picking and choseing what illness deserves to have reserch into treatment. thinking that arthritis sufferers or autism such as children with arthritis or autism could die so should not have reserch into treatments such as rituximab isnt going to help anyone
Is this the cure for arthritis?
by JENNY HOPE, Daily Mail
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Add to My Stories
Scientists have developed a drug that can bring remarkable improvements to the lives of hundreds of thousands of arthritis sufferers.
A single course of treatment will provide relief from crippling pain and joint damage for rheumatoid arthritis patients for up to a year.
Some sufferers who have tested the drug, rituximab, have been able to return to near-normal life after 20 years of restricted activity. British doctors behind the groundbreaking treatment claim it could eventually lead to a cure for the severely disabling disease which affects almost 400,000 people in the UK.
Most conventional medication for rheumatoid arthritis offers only limited pain relief and does not stop the degenerative process that can destroy joints and bones. But researchers led by Professor Jo Edwards at University College London have found dramatic improvements in patients using rituximab.
The drug - which is also used for cancer sufferers - acts by suppressing antibody production within the immune system and breaking a key part of the cycle that triggers and fuels arthritic inflammation.
More than half of patients in the trial showed 'major improvements' and a further one-fifth had a 'brilliant response' to the drug. Professor Edwards said on average the benefits last up to a year - when further treatment could be given --and in some cases the disease has returned in a weakened form.
Sufferers who have led restricted lives for 20 years can now return to near-normal levels of activity, he said.
The most encouraging results were obtained when rituximab, also known as Mabthera, was given with another anti-arthritis drug called methotrexate. A separate study shows rituximab may also help an auto-immune disease called lupus.
Professor Edwards released the interim results of the trial today at an American College of Rheumatology meeting in the U.S. He said further tests were needed before the manufacturers would have sufficient data to apply for a licence for use in rheumatoid arthritis, and this could take three years.
He said a course of treatment costs about £4,000. 'But this is cheap compared with some other new drugs for rheumatoid arthritis,' he added.
Fergus Logan, chief executive for the Arthritis Research Campaign said: 'These results look extremely positive, and are very, very encouraging for patients with severe rheumatoid arthritis, although we're talking about remission here rather than a cure.
'As a future treatment for severe rheumatoid arthritis, rituximab looks promising. 'The results of larger trials over a longer period of time will undoubtedly answer some of our concerns.'
Read more: http://www.dailymail.co.uk/news/article-144675/Is-cure-arthritis.html#i…
But you're not answering the important question, do I use Rituximab in addition to the AZT cocktail or instead?
Mikovits research on XMRV and "neuroimmune" disorders (including autism which isn't a neuroimmune disorder) surfaced as a poster presentation at one of the earliest XMRV conferences. From memory they tested 17 people who were the supposed sufferers and family relatives and found no pattern. The conclusion was "No significance can be drawn from these results".
One was Heckenlively's wife (positive for XMRV with useless test). Another was his autistic daughter (negative with the same useless test). I don't know whether his wife took ARVs for an infection she didn't have.
He wrote about the supposed connection at that time and now (no wiser) he is writing about it again.
In fairness, I don't think she meant "'XMRV IN VACCINES CAUSES AUTISM!!!" I think that she meant "'XMRV YOU + VACCINES CAUSES AUTISM!!!" I think she was implying that you get autism if you are already infected with XMRV and then vaccinated. Equally stupid, of course =P
First, I want to say thank you for blogging. My knowledge of retroviruses is now marginally greater than zero.
I have a question (probably a stupid question) that seems to fit here about as well as anywhere: If retroviruses target specific cells (like B and T cells), how do they ever become endogenous? Are there cases where these viruses mess with sex cells by accident and get passed on, or are only retroviruses that specifically target sex cells the only ones to get fixed in the population?
It would be so much easier to raise money to save little autistic kids infected with XMRV compared to old people with CFS....that's why Judy Mikovits tried to connect the dots, in my opinion.
I can't visit the AOA site or read anything Heckinlively writes..makes me gag.
What Mikovits really wanted to say was 'green our vaccines from 5-AZA and IL-2 + PHA'
Mikovits was certainly the âbroadcasterâ of the XMRV>>CFS>>>Vaccine>>>>Immune Imbalance >>>>>Autism meme, but genesis of the meme involved other players. Exactly when Mikovits began to embrace Wakefieldism is not on record, but the WPI as conceived by Annette Whittemore was created with a novel presentation of âneuroimmune diseaseâ that was straight out of the Woo archive. That Mikovitâs âspeculationâ just happened to fit precisely with the compass set by Annette Whitemore âherâ Institution, might be thought a little too convenient to be free of âconfirmation biasâ (confirmation that Mikovits was âon boardâ and that Whittemore was right about Autism, CFS, SWS, MS etc, all being linked). The ideation of a vaccine connection was already established in both the mythology of GWS and Autism, albeit in totally different contexts â GWS is exclusively an adult chronic heath challenge, Autism is an infant developmental challenge with only limited association with chronic ill health. However there is also a vaccine connection with CFS in that while 60-70% of CFS patients report onset of their chronic ill health to have followed a viral type infection and a smaller percentage report no significant event at onset, some CFS patients do report onset of chronicity to have followed adult vaccination. The WPI has never explicitly identified itself with the antivax crew, however Whittemoreâs âneuroimmune diseaseâ seems bespoke built to accommodate a âvaccines are dangerousâ perspective. Itâs difficult not to see Mikovits as having used her âscientific authorityâ in the cause of enabling the anti science, or perhaps more accurately âpartialist scienceâ, upon which the WPI was founded, providing succour not only to the âpartialist scienceâ tendency among CFS patient groups, but also to the anti vax activists. Mikovits and WPI have certainly been approved of by antivaxers such as Heckenlively and in turn Heckenlively has be quoted on CFS forums where the strongly pro XMRV crowd frequently display strong antivax sentiments. It seems probable that a number of antivax activists are actually using âCFS patientâ pseudonymous identities to promote their views on CFS forums and it may well be that some of the crazier CFS âadvocatesâ are merely antivax sock puppets carrying on their âwarâ against the evil vaccinators, by other means.
@In Vitro Infidelium
So are you saying that attenuated vaccines are a good idea in patients with a compromised immune system? You can't just dismiss all concerns about vaccines with the Wakefield wand.
Neuroimmune disease is the way many CFS researchers and experts refer to CFS given the neurological/immunological data in the scientific literature. It has nothing to do with vaccines. You are reading too much into it. You can hardly complain that others don't have their facts straight when you make little effort yourself.
ERV is correct. Leftbrainrightbrain's take on Heckenlively's glaringly scientifically deficient post was spot on.
@9 - by "many" would you mean Mikovits + Goldberg (one of WPI's early advisors)? (http://www.nids.net/?page_id=296)
When I heard Dr. Mikovits talk on the subject of XMRV and autism in person at a 2009 UOP lecture in Stockton, CA, I recall her parsing her words differently. If I recall correctly, she stated that it might be possible that a combination of an autistic child, XMRV infection, and an immune response from certain vaccines could complicate/exacerbate the autism. More like what PoodleStomper said. She explicitly made it clear that she was not saying that either XMRV or vaccines caused autism.
I personally never got the connection for ME/CFS to autism until recent years. The commonality is that they are both extreme hot-button scientific topics with forceful views on both sides. Nature Magazine has a special on autism this month: http://www.nature.com/news/specials/aut ... l#features which explores some of the issues.
Scientists can not even agree on what autism is, if it is increasing in the population, or what might cause it. Its all a big mystery, and if you look at the considerable funding, it seems to be lopsided in favor of certain areas of inquiry over others for no apparent reason. Well, ME/CFS is sort of like that too.
Now, with the Rituximab study, certain tantalizing possible linkages are starting to tease out. For instance, the most deadly side effect attributable to Rituximab is progressive multifocal leukoencephalitis (PML).
Evidently, in a small but deadly number of Rituximab treated patients, JVC virus becomes activated and eats the brain white matter of those individuals: http://www.medicalnewstoday.com/releases/150657.php
The same or similar JVC virus is found in in the brains of autopsied autism victims:
http://www.ncbi.nlm.nih.gov/pubmed/2034 ... t=Abstract
And now we are told that ME/CFS patients, at least a subset, get better on Rituximab. Is there a true linkage, or is this merely incidental research that is not actually related? I will leave it to the scientists to sort it out.
As far as putting autistic children on Rituximab, I do not see that getting past any ethics panels ever. Treatment is by expensive infusions, and you would need a lot of money and a cancer doc. As well as parents that were willing to expose their child to possible deadly side effects.
Even ME/CFS patients that were clamoring for ARVs are not lining up for Rituxumab; ME/CFS forum polls show that. I know that I would personally not chance it because the possibility of PML is a complete deal killer for me.
So are you saying that attenuated vaccines are a good idea in patients with a compromised immune system?
I wasnât aware I wrote anything that suggested vaccine prescription for anyone, whatever their health status; I merely described the history and elements of the generation of the XMRV>>CFS>>>Vaccine>>>>Immune Imbalance >>>>>Autism meme. If you are implying that CFS is characterised by a compromised immune system, then where is the consistent evidence for that ? If your point is a general one then the question can only be answered on a case by case basis where benefits and risks are apropriatey assessed, however the burden of evidence is that in all but those who are seriously immuno-compromised, vaccination is the safest option. Vaccination will always carry a risk, and while in principle the individual is asked to accept risk on behalf of society for the benefit of âherd immunityâ, in practice it is those who are immuno-defficient who are most at risk of serious illness from wild viruses. The mildly immuno-compromised are in general better off with the protection of vaccination, while those who are severely immuno-compromised benefit greatly from everyone else getting vaccinated. The great irony of Wakefieldism is that it actually exposed those who really canât risk personal vaccination because of their immuno-suppressed status, to far more wild virus, because many of those who would benefit directly did not receive the protection, and by so doing increased the size of the infectious reservoir.
Neuroimmune disease is the way many CFS researchers and experts refer to CFS given the neurological/immunological data in the scientific literature.
Who ? Where ? When ?
Given that no one has any effective clinical description of CFS, beyond symptomology, I donât see how anyone could be described as a CFS âexpertâ, true some physicians receive patient approval, but letâs see some sustained scientific publication before âexpertiseâ is conferred. And given the nugatory levels of research into CFS, how can there be âmanyâ researchers ?
Neuroimmune disease may be a meaningful term when used in clearly defined contexts such as those applied in articles published by the Journal of Neuroimmunology http://www.jni-journal.com/home. JoN has published just five articles dealing with CFS since 1995 and those yield but a single scopus listed cite. Nowhere in the published literature is there a scientifically valid description of neuroimmunological disease as used inclusively by the WPI, if other researchers are now using the term in realtionship to CSF, they should either be referencing their own justifying research, or some other validating source. That the is fragmentary evidence of neurological character, and seperately further fragmentary evidence for immunological character of CFS, is no justification for conflation into the term âneuroimmune diseaseâ which has seperate and specific meaning. CFS patients do not need more partialist science fiction written about the ill health which afflicts them, and at this stage âneuroimmune diseaseâ in CFS is more fiction than truth.
http://7thspace.com/headlines/398147/false_negative_results_from_using_…
@In Vitro Infidelium
"But the WPI as conceived by Annette Whittemore was created with a novel presentation of âneuroimmune diseaseâ that was straight out of the Woo archive."
Almost full acknowledge (for talking about a XMRV/Autism connection Mikovits should get a public slap, Klarsfeld-style) â except for that sentence above.
This is were I have to disagree. (Or maybe you should elaborate you critiqe of what your actual problem with "neuroimmune" or the WPI is)
First there is cognitive disfunction in CFS (and FMS). Just check Anthony Komaroff / Harvard. *) (Or would you say he is from the "Woo" area?). I would call it "neuro", but hey, maybe there is a subtle lingo distinction where the "neuro" label isn't justified and something else would be more fitting. But it definitely isn't psychologic/psychiatric/psychosomatic â "scientific fields" *I* say tend to go way into the "woo" area, but you might disagree.
Secondly, there is immune involvement, just check Nancy Klimas' work. I admit, the data here isn't as good as in the neuro-department, but hey, that's what it's like if all the researchers think it is a "Woo"-disease. :-)
And while I think Mikovits makes terrible pseudoscience, I give the WPI still (skeptical) benefit of the doubt. Let's see if they can get out of the quagmire they got themselves in.
-------
*) Plus there are tons of anecdotal patient reports. Search for Brain-Fog or Fibro-Fog. Read "Osler's Web".
And personally, it is really, really interesting if.
One.
Just.
Can't.
Think.
There are situations were I
Can't.
For.
My.
Life.
Put.
A.
Thought.
Together.
Yeah, together with feeling ill, investigating this this under the "neuroimmune" label instead of a psych-label is really totally woo.
"Letâs see some sustained scientific publication before âexpertiseâ is conferred."
Nancy Klimas. She works/researches both on HIV/AIDS and CFS. She is the best when it comes to the immune-system involvment in CFS (from my POV). Ask her how amazingly tough it is to get funding to do research for CFS. Look for NK-cell cytotoxcity (or lack of thereof) So, yeah, I would like to have "sustained scientific publication", but some data is here. It is sparse, but it is a start.
"Given that no one has any effective clinical description of CFS, beyond symptomology, I donât see how anyone could be described as a CFS âexpertâ, true some physicians receive patient approval, but letâs see some sustained scientific publication before âexpertiseâ is conferred"
Oh, if only someone would provide us with solid proof for the causation for this disease! And give it to us as a nice wrapped gift on a silver plate! And dear Buddha, please bring me a pony and a plastic rocket too! Oh how I wish.
Just read: Ian Lipkin is doing a deep-sequencing study, and he has choosen Nancy Klimas to do the patient selection for him. While others are bemoaning that there are little facts available, some people are doing research and are able to find experts in this disease (BTW: Nancy isn't the only one). Newton researched alchemy, that's the way it is when science knows little about a topic. Stay skeptical, but stop painting it all as "woo" if you aren't able to take a bias-free look into it.
http://trialx.com/curetalk/2011/11/dr-ian-lipkin-and-dr-mady-hornig-use…
âWe show quite clearly a wide range of infectious agents can trigger similar pathways in immune system that result in similar outcomes so it may well be that there are many pathogens who have capacity to cause chronic fatigue syndrome by either inducing autoimmunity or some sort of impact on the immune function which results in activation,â said Lipkin, who plans to examine other hypotheses as well depending on the results of initial tests.
â¦
Both Dr. Lipkin, who is a board certified neurologist, and Dr. Hornig, who is a board certified psychiatrist, stress that while they believe ME/CFS is a neuropsychiatric disorder because of the problems with concentration, memory and autonomic nervous system involvement, they do not consider it psychosomatic.
http://trialx.com/curetalk/2011/11/dr-ian-lipkin-and-dr-mady-hornig-use…
While I disagree with the psychiatric-part, is it a far step from a neuropsychiatric disorder â (potentially) caused by an infectious agent â that activates the immune system, to say it is neuroimmune?
@11
a decent scientist wouldn't have speculated about a possible connection between XMRV and autism in a public talk, without significant evidence to warrant such a link, and there isn't any evidence. It doesn't matter how she parsed her words...she connected the dots in a way that was irresponsible and self-serving.
@ Tony Mach âStay skeptical, but stop painting it all as "woo" if you aren't able to take a bias-free look into it.â
I havenât âpainted anythingâ â woo coloured or otherwise, I was very deliberate in what I wrote: â"But the WPI as conceived by Annette Whittemore was created with a novel presentation of âneuroimmune diseaseâ that was straight out of the Woo archive." Iâm not sure that the meaning could be any clearer in standard English â 1. the presentation was novel and 2. the presentation was straight out of the Woo archive. I made no implication about any research. The semantics of wooism frequently appropriates science for unscientific presentation, that is âpartialist scienceâ, which is precisely what Annette Whittemore, whether by design or ignorance, has done with with her invocation of âneuroimmune diseaseâ as a connective element to diverse conditions which have no scientifically established connections. That Mikovits chose to work under such a banner could be considered to provide a serious question over her commitment to scientific integrity, as does her willingness to specualte in terms that accord with the WPIâs dubious banner.
is it a far step from a neuropsychiatric disorder â (potentially) caused by an infectious agent â that activates the immune system, to say it is neuroimmune ?
YES ! Neurological symtoms plus immune symptoms do not = neuroimmune. One could conceivably but confusingly use neuro/immune as a shorthand for âneurological and immunologicalâ but âneuroimmuneâ implies something very specific, while neuropsychiatric is different again (which is why medics have developed the different terms duh !). In very rough terms âneuroimmune is concerned with processes, which may or may not be disease or symptomology specific. Neuropsychiatric implies disease affecting the nervous system, (very particularly the brain) which produces symptomology which falls within the purview of psychiatry and the specialisms of neuropsychiatry and neurochemistry. If (as most of us affected by M.E/CFS claim) that the illness is strongly characterised by cognitive dysfunction, the ascription to neuropsychiatric is inescapable, however it says nothing about causality or detailed aetiology and for the sake precision Iâd suggest using a construct on the lines of âM.E/CFS is a condition having neuropsychiatric characteristicsâ. Whether neuroimmune processes are involved in all or one or more subsets, or no cases of M.E/CFS, only further research will show.
This is interesting up to the last comment.
If this is just an internet meme, the product of quacks, then why are you worried about children being harmed? No body is going to be given dangerous chemo therapy on the back of this, its going to be years before CFS patients maybe, just maybe, see any benefits from this work.
I think that last remark about children being hurt almost smacks of tabloid headlines, loaded as it is with emotion - leave that to the idiots who post youtube videos of children screaming after being poked with a needle, as some kind of evidence as how evil doctors are.
I guess it would be fair to come back to that with the very real dangers of vacinne scares resulting in lack of uptake, and hence increased incidence of infections, but that is not the same as putting children on a chemotherapy regime - I mean who is going to do this - backstreet doctors on nothing but a meme?
If Autism isn't Neurological then what is it?
Children get ME too, not just wrinkly oldies suffering for their fiftieth year of disease.
Abbie, you're so smart. How about you solve the mystery of ME, and Autism whilst you're at it?
Abbie, I read one of your links on this article, where you wrote: "I mean, really. This is utter and complete nonsense from a scientific standpoint. Bacteria can't "make" metals. They can only consume and excrete them, unchanged. "
http://scienceblogs.com/insolence/2009/05/the_price_of_anti-vaccine_fan…
Here are a couple of articles that suggest that fungi and bacteria in the intestinal system are able to convert mercury into the nanoparticle form (methyl mercury).
"Transformations of inorganic mercury by Candida albicans and
Saccharomyces cerevisiae"; Applied and Environmental Microbiology, Jan
1991; 57:1:245-247; S Yannai; I Berdicevsky, L Duek; Dept. of Food
Engineering and biotechnology, and Unit of Microbiology, Faculty of
Medicine, Technion-Israel Institute of Technology. PMID:2036011
The methylization of mercuric chloride by human intestinal bacteria";
Experentia, 31:9; 1975; Sept 15, 1064-5; IR Rowland; P Grasso; MJ
Davies; British Industrial Biological Research Association,
Woodmansterne Road, Cashalton, Surrey, SM5 4DS, England. PMID: 1100426
Whether this is related to autism, I don't know. But it does suggest that the bugs actually do something (and something that's potentially problematic) to the metals rather than just excreting them "unchanged."
>Given that no one has any effective clinical description of CFS, beyond symptomology, I donât see how anyone could be described as a CFS âexpertâ, true some physicians receive patient approval, but letâs see some sustained scientific publication before âexpertiseâ is conferred. And given the nugatory levels of research into CFS, how can there be âmanyâ researchers ?
nu·ga·to·ry adj \Ënü-gÉ-Ëtȯr-Ä, Ënyü-\
1: of little or no consequence : trifling, inconsequential
2: having no force : inoperative
Here is a medical literature review on CFS. There are 600+ papers showing a wide variety of abnormalities.
While it certainly is true that funding research into the illness a level corresponding to its seriousness and prevalence undoubtedly would result in even more articles, what is there already is certainly not "nugatory."
https://docs.google.com/viewer?a=v&pid=explorer&chrome=true&srcid=0B7A3…
David,
Who is going to do this? Actually there are plenty of examples of parents putting their autistic kids on dangerous medications based upon faulty or unproven hypotheses. The use of industrial chelators to "treat" autism comes to mind.
In other news, WPI is suing Mikovits, as "several laboratory notebooks, a personal computer and flash drives" have gone missing from the WPI around the time of Mikovits got fired. Mikovits is vehemently denying having anything to do with it.
http://www.washoecourts.com/index.cfm?page=casedesc&case_id=CV11-03232#
Also check this thread for a message from Whittemore and a letter from Mikovits's lawyer to Whittemore:
http://forums.phoenixrising.me/showthread.php?14668-Letter-from-Annette…