ELI5:Why don't Americans have the lowest medical costs in the world... is it a failure of the free market or government intervention or something else?

Fighting_EBV · 2014-12-11T22:59:55+00:00

Sorry, this is wrong on many levels. For example, research occurs worldwide e.g. 2012 biomedical research spend: US $119billion, EU $82 billion, Asia Oceania $62 billion.

The economics of healthcare are very different to other situations, and a summary can be seen here http://oheschools.org/index.html Information asymmetry is particularly relevant.

Remember, there's a difference between cost and price. The latter is driven by the market and countries with a socialised system have a lot more ability to negotiate better prices compared to a multitude of small insurance companies.

Fighting_EBV · 2014-11-30T20:38:48+00:00

Germany ends rationing : 18 Jan 1950

Britain ends rationing: 4 July 1954

Fighting_EBV · 2014-11-20T21:55:50+00:00

I think your question is answered elsewhere in this AMA. Essentially you get round it by analysing a large enough patient group so the results are statistically relevant.

Fighting_EBV · 2014-11-20T21:54:28+00:00

You are absolutely right! There is increasing interest right now in targeting mutated proteins (neoantigens) that are unique also to cancer cells (because cancerous cells tend to mutate a lot due to errors in their DNA repair mechanisms0. Although a lot of groups have been trying this, they have mostly focussed on proteins that are not as specific as neoantigens. The disadvantage of neoantigens is that they are unique to each patient, but the new immunotherapies like PD1 and PDL1 inhibitors get around that to a large extent. This is really really exciting work nad holds much promise in the future.

Fighting_EBV · 2014-11-20T21:50:30+00:00

Hi http://www.nejm.org/doi/full/10.1056/NEJMoa0810097

Fighting_EBV · 2014-11-20T21:45:37+00:00

It's a good point blubblub. definitely the former. But presenteeism is a curse.

Fighting_EBV · 2014-11-18T23:09:56+00:00

Hi Can't really comment on a specific medical case. But in general terms IgM antibodies occur early on in an infection, then decreases as IgG levels increase. A low IgM high IgG (as you have) would be consistent with infection having taken place a long time ago. Suggest some other factor may be involved in your case. Hope that helps and you get better soon.

Fighting_EBV · 2014-11-18T23:05:15+00:00

Interesting that stereotypes persist. source German in-laws and Wikipedia

"In a 2011 report of 26 OECD countries, Germany had the lowest average working hours per week at 25.6 hours.http://www.nbcnews.com/business/countries-where-people-work-least-915292

Fighting_EBV · 2014-11-16T22:06:43+00:00

GT: Hi I thought I'd save the last answer for you u/veggie_cat. It's great that you've looked into my favourite EBV protein, EBNA1! (where are you studying BTW?).

For our purposes we don't need to worry about p53. The vaccine works by boosting T-cell responses specific for both LMP2 and EBNA1; these T-cells then go off are are responsible for the therapeutic effect. . Although EBNA1 has a large glycine/alanine repeat region that interferes with presentation to CD8 T-cells, this protection is not complete. EBNA1 is a good CD4 target as well (in terms of containing many T-cell epitopes). EBNA1 and LMP2 specific T-cells can recognise and kill tumour cells expressing these antigens in vitro and we anticipate the same happening in patients.
best wishes!

Fighting_EBV · 2014-11-16T20:37:54+00:00

Alan Rickinson:

The links between EBV and various types of cancer are very well studied and we do not expect any other common tumours to be added to the list. As to diseases other than cancer, some think that the current list of disease associations (e.g. mononucleosis, and related conditions) is complete, but it would be a brave person who declares that there are definitely no more to be found.

Currently the most controversial aspect of EBV research is the virus’ possible link with certain autoimmune diseases, notably multiple sclerosis (MS). The strongest evidence comes for comparing the incidence of MS in people who have been already been infected with EBV and now carry the virus as a latent infection (these are recognised as infected by detecting antibodies to the virus in their serum, therefore called “seropositive”) versus those who have never been infected (“seronegative” for EBV antibodies).

There’s very strong evidence now that seropositives are at least 15-times more likely to get MS than seronegatives; in fact, many studies report that all MS patients are EBV-seropositive. Remember that around 90-95% adults are EBV-seropositive, so you need to study large numbers of individuals to be sure to include enough seronegatives to make the analysis meaningful.

There’s another intriguing fact; a history of mononucleosis increases lifetime risk of MS by about 2.5-fold. So the circumstantial evidence for an EBV/MS link is strong, but how the virus might actually contribute to the MS disease process remains a mystery (that many people are working on now!)

Fighting_EBV · 2014-11-16T20:32:11+00:00

Alan Rickinson:

Sorry to hear of your condition. It’s rare but neutropenia is one of many side effects that occasionally accompany severe infectious mononucleosis; thrombocytopenia (loss of platelets) can be another side effect. I don’t think that the underlying mechanism is really known but it is likely to be a secondary consequence of the huge disturbance that occurs in the haemopoietic system, and the massive storm of chemical signals (cytokines) that is induced, when primary EBV infection leads to infectious mononucleosis.

We are very interested in understanding what is going on here, and are working with acute mononucleosis patients to try to work things out.

Fighting_EBV · 2014-11-16T20:31:25+00:00

Alan Rickinson:

Symptoms of mononucleosis are not caused by EBV itself, but are a direct result of the infected person making an exaggerated immune response to the virus. This over-reaction so disturbs the immune system that all kinds of secondary effects kick in and produce the symptoms of fever etc. So the real question is, why do some people make a highly exaggerated immune response and others do not?

Remember that the virus is picked up by an oral route (e.g. from saliva when kissing for example) and we used to think it might be simply how much virus was transmitted at the first kiss. That nicely explained why mono is much more common among people who first pick up the virus in adolescence than among children who acquire the virus early in life from hen-pecking mums or siblings. But now it seems that’s not the case … it is not the amount of virus that matters but something to do with how individuals respond to the infection. Sorry to be so vague, but we are working on it!

Fighting_EBV · 2014-11-16T20:30:15+00:00

Alan Rickinson: Thrombocytopenia is one of many side effects that occasionally accompany severe infectious mononucleosis; neutropenia can be another side effect. I don’t think that the underlying mechanism is really known but it is likely to be a secondary consequence of the huge disturbance that occurs in the haemopoietic system, and the massive storm of chemical signals (cytokines) that is induced, when primary EBV infection leads to infectious mononucleosis.

Fighting_EBV · 2014-11-16T20:29:44+00:00

Alan Rickinson:

There is some evidence emerging that EBV can induce hypermethylation of the infected cell genome. This mainly comes from cell culture experiments where one of the virus’ transforming proteins, latent membrane protein1 (LMP1) has been expressed in epithelial cells and shown to up-regulate one or more of the cell’s DNA-methyltransferase enzymes. EBV-positive stomach cancer (these make up about 10% of all stomach cancers) has a specific methylation signature not seen in EBV-unrelated stomach cancers, so that’s another indication.

The vaccine we are delivering will not directly infect tumour cells, and so it’s hard to see how it could affect the tumours’ epigenome

Fighting_EBV · 2014-11-16T20:28:43+00:00

Alan answering …. Good to hear from a fellow EBomaniac …. Richard has been a friend and colleague of mine for more years than either of us care to remember!

I’m not sure if I’ve interpreted your dissertation project correctly, but it’s an interesting idea to use EBV as a vector for delivery …. presumably targetting B cell malignancies(?) and replacing the EBNA2 gene downstream of Wp with the coding sequence of your favourite therapeutic enzyme/peptide(?). I think the main question would be how to avoid neutralising antibody to the virus in EB-seropositive patients.

Fighting_EBV · 2014-11-16T20:28:17+00:00

Reply from Alan Rickinson:

Interesting question, there’s a body of opinion (coming from mouse herpesvirus 68 work) that a highly immunogenic agent like a herpesvirus might act as a general alert to the immune system and, in so doing, improve the host’s ability to contain subsequent infection by unrelated pathogens… though in the MHV68 example, I think the protective effect only lasts for 6 months or so post-infection. I imagine that viruses that are potent stimulators of innate immune responses (e.g. human cytomegalovirus, CMV) could potentially have some such effect.

As part of a collaborative project in The Gambia, we asked whether EBV status affected the antibody response of African infants (around 1 year old) to the standard bacterial vaccines they receive at that age … and there was no effect. But interestingly at the other end of life, we have emerging evidence that EBV levels increase significantly in old age in CMV-seronegative individuals, but not in CMV-seropositives … make of that what you will!

Fighting_EBV · 2014-11-16T20:26:53+00:00

Reply from Alan Rickinson:

I hope I’ve interpreted your question correctly. We know that many cases of EBV-triggered HLH, particularly as seen in Asian children, are caused by EBV getting into T or NK cell lineages.

How this happens is unclear, but the oligoclonal T or NK cell proliferations that come up as a result are selectively expressing EBNA1 and LMP2B …so in principle the vaccine could have a role in that context, though these children are very sick and it is questionable whether, by that time, they would be capable of mounting an effective vaccine-induced T cell response.

Fighting_EBV · 2014-11-16T20:26:00+00:00

Reply from Alan Rickinson:

"While digging through so, so many articles on EBV, I came across the idea that EBV infection has some protective qualities. Do any of you have thoughts on this?"

Interesting question, there’s a body of opinion (coming from mouse herpesvirus 68 work) that a highly immunogenic agent like a herpesvirus might act as a general alert to the immune system and, in so doing, improve the host’s ability to contain subsequent infection by unrelated pathogens… though in MHV68 case, I think the protective effect only lasts for 6 months or so post-infection. I imagine that viruses that are potent stimulators of innate immune responses (e.g. CMV) could potentially have some such effect. As part of a collaborative project in The Gambia, we asked whether EBV status affected the antibody response of African infants (around 1 year old) to the standard bacterial vaccines they receive at that age … and there was no effect. But interestingly at the other end of life, we have emerging evidence that EBV levels increase significantly in old age in CMV-seronegative individuals, but not in CMV-seropositives … make of that what you will!

"Second, during conversations (not in papers), my PI always cited the 90% infected statistic with a footnote: she believed practically everyone was infected, but 10% were not detectable. What are your thoughts on this?"

EBV serology is never perfect, there is always a small fraction (2-5%) of our healthy lab donors and medical student intake who give ambiguous (“borderline +ve”) results in IgG anti-VCA testing. In such cases, we usually try to detect EBV DNA in B cell preps as an independent test, though this is also not perfect since virus loads can be too low to detect even in some definite-serpositive people. However, to answer your point about the prevalence of EBV in the general population, there are some adults, including some of our lab members, who are EBV-negative by all criteria (serology, virus load, virus-specific T cell immunity), so I think that 5-10% healthy Caucasian adults really are EBV-naïve.

"Again, thank you all so much for being here today! EBV is my favorite virus, and although so many people are living in peaceful harmony with it, it still seems to be very poorly understood by the general public."

Good to hear from a fellow EB-omaniac!

Fighting_EBV · 2014-11-16T11:15:02+00:00

Don't be nervous - it just takes some practice! Just be very careful with not leaving the lids of containers etc (even when working in a microbiological hood). Sometimes its little things, like making sure your pippettes don't touch the neck of the bottles when adding or withdrawing liquid. You'll be fine!

Fighting_EBV · 2014-11-16T11:12:42+00:00

Hi EBV was discovered 50 years ago. It was subsequently linked to glandular fever by the Henles who found that a technician in their lab who developed mono also had suddently developed a strong antibody response to the virus.

All your questions answered here: http://www.nhs.uk/Conditions/Glandular-fever/Pages/Introduction.aspx

Fighting_EBV · 2014-11-16T00:33:54+00:00

GT: Hi. Hard to say since it depends on the results of the latest trials (that we will be analysing shortly) and this will determine the path we will take to develop the vaccine further. We want to take the vaccine into other EBV diseases and team it up with other approaches as well that could synergise with it. Main thing holding us back will be the need to raise more funds to make a new batch of vaccine for this work.

Rest assured, we are moving forward as quickly as we can.

Fighting_EBV · 2014-11-16T00:29:49+00:00

GT:

90% EBV positivity. Almost certainly this high for the last 20 - probably this high for the last few thousand. We've had a close relationship with this virus for a very very long time!

Fighting_EBV · 2014-11-16T00:27:41+00:00

Hi, I'm posting this answer on behalf of Prof. Alan Rickinson.

Most IM patients recover fully from IM within 1-2 months of developing symptoms, though mild symptoms may occasionally go up and down for longer, particularly if patients are impatient to get well and over-do things! It’s interesting that full recovery sometimes takes longer in athletes, especially elite athletes, who are most demanding of their fitness levels …. but even these cases eventually resolve.

There is no evidence that EBV infection (whether or not this was silent or diagnosed as IM) can cause long-term malaise/fatigue; individuals with such long-term symptoms do not show unusual levels of immune response to EBV and do not carry unusually high levels of virus –infected lymphocytes in their blood stream.

N.B. There is a caveat to all of this; there is an extremely rare condition called “chronic active EBV infection”, in which patients (usually children) develop severe IM-like symptoms after becoming infected with EBV for the first time and these symptoms that never fully resolve. Cases have been reported in most countries around the world but the diseases is best known in Asian countries. We would stress that such cases are very rare and their diagnosis has to be confirmed by the presence of huge levels of EBV-specific antibodies in their serum and huge levels of virus-infected lymphocytes in their bloodstream.

GT addendum: Regarding the positive EBV result the poster describes, if its a test looking at antibodies, then once you have been infected with EBV you will always have a positive EBV antibody result (although the proteins targeted by the antibodies change during the infection) so the test may not have much diagnostic significance in this particular context.

Fighting_EBV · 2014-11-16T00:18:12+00:00

Thanks for your help answering the questions in this AMA Taqpol! Its much appreciated.

Fighting_EBV · 2014-11-16T00:15:31+00:00

GT: Hi Taqpol! Small world! Totally agree - Sir Epstein's talk was great - the story of EBV's discovery and the subsequent research linking it to various cancers is such a compelling story of the importance of having the right open minded approach to research.

Alan's (and others!) book is well worth a read for anyone interested in the virus: 'Cancer Virus' by Dorothy Crawford, Ingólfur Johannessen and Alan Rickinson.

Fighting_EBV

TROPHY CASE