Silent progression on disease modifying treatment. Ibudilast insufficiently effective neuroproptection. What more do neuros need to know, before they implement combination treatments

S

Silent progression in disease activity-free relapsing multiple sclerosis. Cree BAC, Hollenbach JA, Bove R, Kirkish G, Sacco S, Caverzasi E, Bischof A, Gundel T, Zhu AH, Papinutto N, Stern WA, Bevan C, Romeo A, Goodin DS, Gelfand JM, Graves J, Green AJ, Wilson MR, Zamvil SS, Zhao C, Gomez R, Ragan NR, Rush GQ, Barba P, Santaniello A, Baranzini SE, Oksenberg JR, Henry RG, Hauser SL. Ann Neurol. 2019;85(5):653-666.

OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, “no evidence of disease activity” at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS:Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.RESULTS:Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

Relapses Are Associated with Short‐Term but Not Confirmed or Long‐Term Disability Worsening

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White Matter Lesions Contribute to MS Relapses.

CRAB drugs were 2.4‐fold more likely to be associated with relapses compared to high‐potency therapies (natalizumab, mitoxantrone, rituximab, cyclophosphamide).

Radiographic disease activity as defined by new brain lesions on T2‐weighted imaging correlated strongly with clinical relapses. However, the development of new T2 lesions did not correlate with EDSS worsening measured, but I guess EDSS is dominated by spinal cord events so brain MRI is not going to be totally informative

Long‐Term Brain Volume Loss and Disability Progression

Rates of relative brain volume loss for participants with either relapses or increasing disability are significantly greater than the rate found in clinically quiescent participants. Significant differences were found for comparisons between the “stable disability without relapse” and “increased disability without relapse,” “increased disability with relapse,” and “stable disability with relapse” groups.

Although relapses may contribute to relative brain volume loss in subjects without increasing disability (p = 0.027), there was no apparent additional impact of relapses in the group of subjects with worsening disability (p = 0.486). Similarly, there was no apparent additional impact of increased disability in the group of subjects with relapses (p = 0.999).

Results indicated that age‐adjusted baseline brain atrophy was associated with both an increased risk of long‐term disability 

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So people continue to deterirorate as there brain shrinks. But remeber…life makes you loose 0.15% a year

The analyses showed that treatment with CRAB therapy reduced brain atrophy compared to no treatment and that escalation to natalizumab is potentially associated with further stabilization of brain volume loss despite natalizumab‐treated participants having lower baseline brain volumes, which they interpret as a marker of disease severity. Therefore treatment is beneficial and being on a high efficay is what you want.

So this is not news you want to hear, in that people continue to deteriorate despite being treated to inhibit relapses. They call this silent progression. I call it ineffective disease control because we are not learning from biology. MS is inflammatory from beginnning to end and MS is neurodegenerative from beginning to end and the factors that drive these pathologies need different treatments. Monotherapies to target one or the other will not work effectively…it is not rocket science. If you are not new to the blog we have been saying this for years. But the great and the good need to say this before people wake up. Monotherapies should be a thing of the past, but they are not. We continue to put people on ineffective therapy.

Whilst hunting for neuroprotective agents we continue to do the same, as we are doing monotherapy trials, but if you do not deal with the inflammation properly then you are not targeting the problem biology.

 

Ibudilast was it a FLuke?

AAN 2019. Effect of Ibudilast on Neurofilament-light Chain in Progressive MS: Analysis from a Phase II Trial Fox R et al. 

Objective: To report the effect of ibudilast on serum and CSF neurofilament-light (NfL) from the phase II trial of ibudilast in progressive MS.

Background: Serum NfL is a candidate biomarker of treatment response in multiple sclerosis (MS) clinical trials. Ibudilast 100 mg/d was found to slow the progression of brain atrophy in SPRINT-MS, a 255-patient randomized, placebo-controlled 96-week phase II trial of progressive MS. We evaluated the effect of ibudilast on serum and CSF NfL in SPRINT-MS.

Design/Methods: Serum samples were collected at screening, 8, 48, and 96 weeks. In an optional sub-study, 75 patients consented to CSF sampling, which was collected at screening, 48, and 96 weeks. NfL was assayed using the SIMOA immunoassay.

Results: Mean baseline serum NfL was 33.5+22.4 and 40.3+54.1 pg/ml in ibudilast and placebo groups, respectively. Mean baseline CSF NfL was 1616.7+1474.4 and 1301.2+822.2 pg/ml in ibudilast and placebo groups, respectively. Over the course of the study, there was no between-group difference in NfL in either serum (P=0.35) or CSF (P=0.62). In some subjects, changes in NfL were observed concomitantly with new/enlarging T2 lesions, which suggests confounding by active inflammation.

Conclusions: Ibudilast treatment was not associated with a decline in either serum or CSF NfL. Inflammatory activity may have confounded the intended use of NfL to measure neurodegeneration.

We have been hoping that neurofilament would be a biomarker surrogate for nerve damage in MS. Here they looked at the effect of neuroafilament after Ibudilast treatment and found no effect. Does this mean that idudilast is not affecting progression? It rather suggests that the inflammation is not under-control suffieicnetly. Although the people in the trial were allowed to use CRAB drugs until, in my opinion, we start highly-efffective treatments straight away we will continue to lose brain.

Using ibudilast without effective control of inflammation is the same as controling inflammation without effective neuroprotection

What’s lost is lost and so by not controling disease (PPMS above, RRMS below) properly you loose nerves. Above it was placebo versus ocrelizumab and the all are switched to orelizumab.

Below people were treated with beta interferon and ocreliumab. By being on beta interferon the people lost 2 years worth of brain (0.15% a year is normal brain loss) before they switched.  I just don’t get this approach:-(

 

About the author

MouseDoctor

69 comments

  • OK. To sum up. If inflammation is not controlled you progress to 2nd ms. Regardless of taking Ibudalist. Ocrelizumab suppresses new t2 lessions by 99%. So why do patients still progress to 2nd ms when damage has stopped? Why is it people on HSCT and alem stop progressing to 2nd ms? In addition notice CDI without neuroprotection?

    • Why is it people on HSCT and alem stop progressing to 2nd ms?

      Stronger treatment does it.

      Ocrevus..Tysabri..Rituximab don’t give these results and will give you
      a case of secondary progressive ms in 10..20..30 years. Guaranteed.

      Total immune cell depletion stops smouldering ms and loss of brain.
      Problem is 2 died out of 24 back in 2002.
      Also saw a woman on facebook got Leukemia in Mexico and no longer
      received patient survey/questionaires from the clinic.

      “Dr. Freedman, who is also the Director of MS Research at The Ottawa Hospital. “Our study is unique in that we used a stronger cocktail of drugs to eliminate the immune system, we followed the participants for a very long time(4-13 years} and the majority of our participants have had significant, long-lasting responses.”

      70 percent of participants experienced a complete stop in disease progression.

      The average rate of brain shrinkage, typically a measure that correlates with MS progression, returned to levels associated with normal aging.

      https://mssociety.ca/resources/news/article/ms-breakthrough-replacing-diseased-immune-system-halts-progression-and-allows-repair

        • “If you wait too long there can be progression even with HSCT”

          Absolutely needs to be done in first 10 years after that it’s
          salvage hstc which sometimes works…

          But how are people to know if neurologists never talk
          about hstc…and in fact usually actively discourage it.

          There should be a info. hstc paper given to people
          when first diagnosed…but nuerologists don’t seem
          to care to..
          They love to say it’s dangerous and might
          not work…which is true..but doing nothing guarantees
          progressive disease.

      • Thanks ANOX. It was more a rhetorical question. Wanted MD to admit he was wrong about b therapy being a cure. Like MD2… MN, Dr K, etc and stop using the line patients in alem trial were in earlier phase of disease. I thank my lucky stars I was almost about to get ocre but was forced to take alem instead. As soon as high brain atrophy results came out for ocre when it reduced inflammation by 98% I knew something was amiss. I have been saying so for the last 2 years. Only Prof G saw the same ocre was not a cure.

  • Great post MD, thanks.

    Why does Barts offer to do a trial of ocrezulimab, cladribine or alemtuzumab combine with and without ibudilast, alpha lipoic acid or a Na channel blocker in both RRMS and progressive MS patients?

    • I have suggested to DrK amd MS Society that DrK adds an extra arm to #chariotMS, but it has cost implications. I can,t make it happen, but it would be an opportunity missed not to do it.

      The community need to lobby otherwise you will get more monotherapy studies. STAT2 is just one example. Now that siponimod and cladribine have been approved for SPMS (in US) and ocrelizumab for PPMS you could do it. Ocrelizumab and ibudilast in PPMS?.

      Likewise ProfG and myself have been saying for sometime that this approach should be done in any future charity trial..Nobody has listened so far:-(

        • To slow the damage. You can wait for a cure and do nothing or you can act with what is available…..we are still waiting for a cure and alot of damage can accumulate. Your choice.

          • I agree.

            …but do nothing is the treatment
            worldwide for ppms and spms.
            By themselves neither would seem
            to do much…possibly together.

          • But this is only with “active” MS? What do you do if no relapses for the last 6 years and MRI looks the same, but still progressing.

          • “and do nothing or you can act with what is available…..we are still waiting for a cure and alot of damage can accumulate. Your choice.”

            What choice..?

            You have any idea what it would cost..?

            No govt. will pay for even one of those.

          • What drug costs are these..?

            MouseDoctor
            May 12, 2019 at 11:36 pm

            Cost….About £8.40 x 12 + 7 x £65 a year/max

          • Minocycline…when reading animal studies see if the compound was neutralized if it was put into the peritoneum. In some studies it is used orally but in many it is put into the peritoneal cavity. There are reports that it is very anti-inflammatory in EAE. We did not find this but we neutralized it before use, because it is very acidic if you don’t (It is like injecting sulphuric acid) and probably dissolves the peritoneum in many animal experiments stressing them and this is immunosuppressive if you do not neutralize the pH, as it is about PHh1-2. Therefore the animal experiments used to justify the human trial were largely bogus. It was trialled in optic neurtitis where it had some effect, but the wrong trial, probably because people cannot see that immunosuppression and true neurotection are not the same. But as immunosuppression is neuroprotective you try the agent as a neuroptrotective in a study where you need an immunosuppressive. Minocycline is an anti-biotic that is reported to be a microglial inhibitor. In our hands it was not a great immunosuppressive but it can be neuroprotective but not as neurorptoective as other agents.

        • @MightyMouse

          I have taken Minocin+Plaquenil for 8 months (one of my self experiments).
          I mostly did it because of its immunomodulating effects (RA patients that started on M needed less cortisone in the long term of the disease), plus of course the neuroprotective and antiflammatory effects.
          The thing with minocycline is that its still an antibiotic that will rip your guts after some months on it. After a point I just couldn’t tolerate it anymore, plus I got a bad acne on it (its an anti-acne drug so probably got resistant bacteria strains because it was not combined with topicals).
          Glad you found the piece that is combined with Plaquenil, a very safe antimalarian drug for lupus that has not been used in MS.

  • Nice post

    Have read the whole paper eyestarday and “slept” over it

    The one thing i like to say is that you can´t take any conclusions about treatment efficacy

    Why?

    1º RRms patients baseline group had 9 years into disease the “shredder” (disease)

    If i can remember alemtuzumab trial patients where 2 years into disease so more brain repair capacity

    2ª 32,1 % of RRms patients had no treatment or no active treatment at baseline
    (The remaining where on 1 line treament )

    3ª What ´s even more striking is that after 10 years RRms patient group that are current not activily treated

    grew from 89 patients to 107 patients

    So … there is a considerable propotion of patients that are either ,not treated or ,not active treated even during the study duration period

    Makes it hard to get any conclusions about treatment efficacy

    Obrigado

    • So what combinations should we be exploring in clinical practice? What would neurologists be comfortable prescribing considering the lack of clinical trial ‘evidence’? What treatment should patients be asking for on top of their chosen DMT?

    • Not helpful. You’re either part of the solution or you’re part of the problem. Here is my suggestion, Start pushing your neurologist to try combination therapies including those with neuroprotective properties (suggestions welcome). Inform them that ‘evidence’ isn’t limited to double-blind placebo controlled studies. Play an active role in your treatment regime. Be prepared to take treatment risks. Clearly you already believe current treatments are ineffective. So, why not push the envelope? What have you got to lose? Shit or get off the pot.

      Moderators, this is my view and one that I feel should be made public. I understand the frustration concerning treatment efficacy, especially for progressive MS. However, people need to start voicing their opinions. Ineffective treatment is shit treatment. Push big pharma to do better. Push physicians to look outside the box. Time is brain and the clock is ticking.

        • Nice one indeed. For someone with PPMS no neurologist can / wants to treat. And who said I didn’t discuss with my neurologists?

          Nasty nasty nasty. Maybe critique yourselves first, before lashing out at others you know nothing about.

          • Give the guy a break!
            He is a scientist not a neurologist to start with, and even if he was a neuro, he would not be in a position to prescribe via the open forum of a blog!
            Get real – he is disseminating info pro-bono. That’s it. No need for ad-hominem attacks.

      • Oh, I’m definitely part of the problem!! Untreatable PPMS with spinal lesions. Find some other more appropriate way to vent?

        • I have a family member in the same boat and I understand your frustrations. But simply saying that all treatment options are ineffective (i.e. offer no benefit) doesn’t help the discourse on promoting better treatment options. We need to start pushing for combination therapies across all disease phenotypes so we can answer the “= who know’s” component of your response.

          Please accept my apologies for my prior terse response. I too am frustrated but we need to channel that frustration into advocacy and demanding more from big pharma. and treating physicians. For example, I’m gonna demand a combination therapy for my family member that includes a neuroprotective agent. Will it work? Maybe, maybe not, but at least we’ll have more to draw from when we look at the next treatment plan, and the next, and so on.

          I will be more careful with my comments moving forward. I accept my response wasn’t proportionate to your comment.

        • For some reason, my apology wasn’t posted. So i’ll try again. My response was terse and disproportionate to your comment. I apologise. I have a family member with progressive MS and understand your frustrations. However, I think we need to push combination therapies with physicians and those funding and writing the study protocols. We need to try answer the ‘= who knows’ in your response.

          I will be more careful with my comments moving forward.

          • I would expect PPMS patients that have no treatment options to have a good record of self experiments on potential treamtment, like I see in Chronic Fatigue Syndrome patients or Friedrichs ataxia ones. But I have found none. The only self experiment to find in MS is LDN and vitamins 🙁 You can blame science and doctors but if you stand passive too, well you have a piece of the blame.

          • Ok Anonymous, what treatment combinations would you like explored? There are bodies that fund clinical research. I have successfully applied for grant money on behalf of a number of companies and organisations. What research is important to you as patient with progressive MS? Where should the research focus? I ask because i’m genuinely interested. The only way to get physicians to listen is to provide the evidence.

            I certainly have no intention of being passive. I intend on shaking as many branches as possible.

          • These things need to be discussed between patients (in patient forums), because medical professionals are usually conservative and discouraging and do not want to get involved (and blamed) from any side effects.
            I believe that if there wasn’t the forums for chronic fatigue patients all these years, it would still be considered a “womans depression symptom” and not a real disease (of course you will see a lot of stupid things in these forums too, but still things evolve faster than mainstream research). You can go to the recent post on this site “ProfFranlinstein…” to see a case of self experiment though. Good research ahead is absolutely necessary.

          • Concerning chronic fatigue, I comply agree with your comments. The extent and debilitating nature of this illness was downplayed (or misunderstood) by physicians for far too long. I’ll check out ProfFranlinstein as you suggest.

            I don’t think all physicians are reluctant to engage in conversations about treatments. My experience is that it’s been a mixed bag. But their is certainly those that are unwilling to explore left of centre treatment options because of the perceived (or real) medico-legal risk. With that said, I’d very much like to get a study up and running designed by pwMS testing a hypothesis that is important to them, be it treatment, prevention, aetiology etc. I work in clinical research so I do understand what this entails. Fanciful perhaps but i’m willing to give it a crack with some support from people who have the time, energy and ideas. The money could be a problem but hey, this crap got funded: https://www.nbcnews.com/feature/nbc-out/finger-length-could-provide-clue-one-s-sexual-orientation-study-n922291

  • Anonymous
    May 15, 2019 at 8:18 am –

    Do you yourself have PPMS? Do you live in a very remote area? Alone? No? Maybe reign in your unpleasant judgemental attitude a bit? It does not help anyone.

    • Umm, it was a genuine question. No judgement intended. I’m truly interested in what the research community should focus on to meet YOUR needs. Better outreach services? Better drugs to treat symptom control? Given everyone is anonymous, I don’t actually know who I’m responding to.

  • “I would expect PPMS patients that have no treatment options to have a good record of self experiments”

    And end up an anecdote. Great.

    • So what’s the solution? How do people with progressive MS not end up an anecdote? This is my greatest fear for my loved one and something I’m trying to prevent on s daily basis.

      • Well designed trials.

        Everyone’s MS is different, every body is different, different genes, different environmental exposures, different lifestyles… Just because a person does well on some treatment means nothing.

        • I’m not entirely sure that I agree with this statement. If a certain patient responds to a certain treatment then it very much means something for that particular patient. I understand the importance of evidence based practice don’t get me wrong, but there is a very real benefit in reframing the debate concerning what is and is not considered clinical evidence. Given that the disease course in MS is so variable, can we generalise the outcomes of highly controlled clinical trials where disease phenotypes seem to be artificially derived? Why should a neurologist dismiss a case study brought before them by a patient as not being evidence if the current evidence based treatments have failed them?

          I do agree that we need better designed trials. I see many study protocols on a day to day basis (not specific to MS) and many are very poorly designed where the outcome measures do necessarily allow the sponsor to test the hypothesis (if a hypothesis is even stated). Sometimes the measures aren’t even validated in the population / condition being studied. Don’t even get me started on patient information sheets and how they communicate treatment risk.

          • I agree up to a point, but how do you know a particular patient wouldn’t have done well anyway, regardless of drug X? With my PPMS, I’m doing well with a lot of effort in lifestyle, diet, exercise. But I can’t recommend that wholesale to others with MS as the only approach, because others may have more inflammatory disease or whatever which may respond better to drug intervention.

          • ‘How do you know whether a particular patient wouldn’t have done well anyway, regardless of drug X’ – Well, you could take a baseline over a period of time, then implement treatment with drug X. If things improve then it suggest the drug is of benefit to that particular patient. This is evidence.

            I’m not advocating for the existing evidence base to be ignored. What I am saying is the evidence framework shifts once the existing ‘gold-standard’ evidence and associated treatments are exhausted. At this point, should physicians be ignoring case studies as evidence? I understand that doctors have a duty of care for their patients and must uphold their Hippocratic oath. However, unless there is a clear harm from implementing a treatment, why should it not be explored and if it is, why only in a clinical trial setting? I suspect physicians don’t want to do it because of the medico-legal perils with using a drug off-license.

            There is evidence supporting the wide ranging benefits of exercise in pwMS. There is also some evidence that suggests eating a healthy, well balanced diet low in saturated fat may slow down disease progression. Now, they are not blinded studies but does this mean they do not constitute evidence? Moreover, exercise and a healthy diet does not place people at harm. So, I would have no problems advocating for both as secondary preventative measure and neither would any neurologist.

          • It’s not really evidence of anything. Just that drug X had no harmful effect on person A, or maybe it did benefit person A. And it says nothing about what it will do for others. This is like Facebook group drug trialling. It can carry no scientific weight.

  • Why are you all hiding your names? Apart from the fact it makes it hard to follow the conversations it just seems ridiculous.

    ‘You can blame science and doctors but if you stand passive too, well you have a piece of the blame.’ A name to that little gem would be good. I am not criticizing the comment, as a pwms it has made me think about my stance on the subject but why do you not have the courage to reveal yourself?

    I have spoken much crap on here at times and I have a tendency to chop and change my views, ms is affecting my cognition and my mental health and I have come to expect that I may say things that I might later regret. I could hide my name to save showing myself up but I won’t because this is the reality of the disease for me. Is it that you all work in the field and are not allowed to express personal views?

    • Hi Julie! Nice to put a name to a comment. I for the life of me didn’t know which anonymous person I offended and which I didn’t. So, I just apologised to everyone. I use a pseudonym because I do work for pharmaceutical companies who may not like my opinion on certain things (for example, their crappy study designs).

      I admire your stance though.

      • That is a frustrating position for you, that gives me a new topic to read up on – study designs.

        Your admiration is misplaced, I am just bloody minded and menopausal! 🙂

    • The controvertial anonynous here.
      I am sorry if I hurt someone’s feelings, it was not my intention, after all I am a patient too. A single patient does not have a blame and I am not trying to make the victim be the effender, I was just trying to emphazise on the importance of patient communities like I see in other diseases (the ones I come across during my MS research). I personally have self experimented with 4 different drugs through my research (not vitamins/supplements), because I believe that any positive effect I might find can make a big difference not only to me but to all MS patients. But that’s just me. I want to point that self experimenting can be dangerous, for your disease or general health. I apologize again.

      • MouseDoctor has done an excellent job in highlighting questionable trial designs. The ibidulast study above is a great example. His other posts on the ethics of placebo controlled studies in MS patients are also very pertinent (as are his comments on the Bart’s team not participating in highly effective treatment vs CRAB studies due to a lack of clinical equipoise). Ben Goldacre and David Healy (both British) give excellent examples in their critiques of the pharmaceutical industry. Their views at times can be extreme (which I don’t necessarily agree with), but their voice and what they have to say should definitely be heard.

          • Approved specifically for neuroprotection in pwMS? If so then no, none to my knowledge but I’m not a neurologist.

          • There are lots of drugs for neuroprotection…but they have not been approved for MS and probably won’t be because pharma are not doing the studies. Academics do not do studies in a way currently required by the regulators. Importantly they have not been shown to work in phase III trials. If you are in the UK, you could be eligable to participate in the MS STAT2 trial. They need over one thousand people to go either on placebo or the high-dose statin.

            If it works…we say great…but then what? What is the plan for what’s next? Pharma would not have got away with this trial becasue there is one-dose and a high dose that we know some people will not tolerate well. If it works there will be no evidence that the much lower, standard dosing doesn’t work too. Maybe they should have controlled it with a CNS -impermeable statin. If just as good it may be about influences on co-morbidities.

            It is not going to get licenced unless Sir Jeremy has something up their sleeve, as it costs money to licence a drug, and to maintain it and with this comes responsibilities. Will it get used off-label by doctors, some will many probably won’t. Many doctors dont do much reading and won’t even know about it.

          • Some of these drugs with potential, will not be favoured by the MS community because of their side-effects, indeed the lamotrigine trial failed not because the concept was a bad idea, it failed because of poor trial design and importantly because people in the trial were not taking the drug because it was poorly tolerated. It may have been better tolerated in people with less advanced disease. Will we ever know

          • The problem is the list is not up to date and has wishful thinking

            E.G. Amiloride and riluzole both failed in MS-SMART

            E.G. Microglial inhibitor we have beta interferon and copaxone…I fell off my chair laughinng/crying when I saw this…do we believe that any of these agents get into the brain?. I know that copaxone can do everything, but it bearly inhibits relapse and am aware of the tosh about neuroprotection and yes I am taking an extreme view here.

          • Do you have s more recent summary article covering neuroprotective agents that you could share? Some investigator lead phase 4 studies have resulted in changes to license indications. So, it does happen.

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