BC007 - what are your thoughts?

[Osaca]

That's not what I meant. Of course, depending on the damage, the expression of the disease can be different and of course there are then different groups, but to go back to your example, with MS, we know that the body's immune system attacks the central nervous system (brain and spinal cord). This leads to inflammation and damage to the protective covering around nerve fibers, and symptoms vary in severity depending on where this inflammation occurs. But the way the disease works, is always the same. What I mean by that is, if the cause is in some these autoantibodies, i dont find it likely that in another person, it is suddenly intestinal bacteria for example (if the trigger was the same virus). Lets exclude Long Covid, we know that it can be an umbrella term for different diseases such as organ damage, MECFS type, etc.
Again that's just my theory, but if these aabs play a major role, it think it will be the cause in the majority of MECFS. (exluding those with spinal cord problems)

That is still something we'll continue to see very differently, which is of course totally fine. Grouping people based on invisible symptom presentation, which is of course the best that can be currently done, has never ever led to a disease with a unifying cause, nor a singular treatment approach (as would be in the case of BC007). For MS we simply can't say "the way the disease works, is always the same", because we don't know how the disease works. It might not always be the same mechanism even in a scneraio where we have reliable biomarkers. I very strongly doubt ME/CFS will always be the same mechanism and cause and in the absence of biomarkers I find it extremely unlikely.

We already know of multiple disease that have a very similar, if not almost identical, symptomatic presentation as ME/CFS, would they not have a biomarker, these diseases would all be considered to be the same disease. I don't see how ME/CFS is any different. If anything I think that if there was a unifying disease mechanism for ME/CFS then we'd probably be a lot further in research. We both acknowledge that Long-Covid is a highly variable umbrella term for different diseases, however this just makes it even far more likely that a certain symptomatic presentation would be another umbrella term, or do you disagree on this and if so I'd be interested in why?

 

[hapl808]

For MS we simply can't say "the way the disease works, is always the same", because we don't know how the disease works.

Yes, this is also my understanding. If it always worked the same, then presumably the same DMTs would be effective. Yet it's very individual. In addition, we don't really have 'reliable' biomarkers, as a lot of MS is based on the theory of what's happening, since I don't believe we can measure myelin damage, but instead are looking at what we think an MRI is showing.

I could be wrong, but I believe we 'think' we know what is happening with MS, but we don't know why and we can't really prove what's going on in any individual case. In other words, a neurologist looking at an MRI can't tell you what symptoms the patient is experiencing, or an accurate prognosis.

 

[Dude]

It's not like I have definite proof of my theory. But everything I have read and especially everything that has been published lately points to these GPCR receptors (at least for me). Like for example the 2022 Muscle Study from Scheibenbogen, with the theory of the dysfunctional B2AdR receptors or the Study from 2009, with increased MRNA expressions associated with sensory functions and adrenergic responses after exercise. And last but not least, everyone that received BC, was either healed or had most symptoms vanished. So at this point, there is no evidence, that it will not work for all.

There are even scientists like prusty that believe, that there is only one theory and one explanation, even though, he has another theory.

With MS, we don't know what triggers it, but we do know that the immune system mistakenly attacks the myelin sheath, leading to inflammation. Which is in my defintion of, „they way it works“ but i know what you mean, there could be diffrent ways how this happens and progress.

Feel free to comment, I respect every other opinion on the subject.

 

[Osaca]

It's not like I have definite proof of my theory. But everything I have read and especially everything that has been published lately points to these GPCR receptors (at least for me). Like for example the 2022 Muscle Study from Scheibenbogen, with the theory of the dysfunctional B2AdR receptors or the Study from 2009, with increased MRNA expressions associated with sensory functions and adrenergic responses after exercise.

This is something I've very commonly seen in patients. We often interpret studies and results that have never ever been replicated, or in this case even contradict other results, and have very small sample sizes as very black and white, whilst in reality everything is far more grey or often even just turns out to be pure noise. A lot can be achieved by rolling dice sufficiently often, ask the monkey on a typewriter that became Shakespeare.

The 2022 muscle study by Scheibenbogen is a great example. I also first thought that the 2022 muscle study from Scheibenbogen is relatively clear and yields a strong positive results, but when you dive further into it or ask an expert in this topic some questions on this study, see for example the thorough discussion here https://www.s4me.info/threads/muscl...-scheibenbogen-wirth-et-al.30853/#post-451041 you realise that, that isn't the case at all. Rob Wüsts recent response on Twitter to the study was basically that he cannot understand or explain any of the study results and he is an expert in that exact field studying exactly those things. I've certainly also seen and thoroughly read all the bits and pieces of research pointing towards GCPR-aabs, which makes me hopeful that we'll get answers next year, whatever those answers might be, but research is far more complex than an oversimplification based on these observations and medicine isn't an exact science in the first place. That is why what is the expertise and "pet theory" of some great researchers, in this case essentially Scheibenbogen, Hohberger, Wallukat, Bergquist and the Japanese team, is a completely irrelevant field of research to others like Iwasaki. Your school of research, country of education and residence and personal experience has a massive impact on what you believe too be a valuable field of research, this applies both to researchers and patients. In Germany GPCR-AABs are the reincarnation of Jesus Christ when it comes to solving ME/CFS and Long-Covid, whilst in the US essentially no one even gives a fuck about them.

Currently the studies on GPCR-AABs (for example https://pubmed.ncbi.nlm.nih.gov/34589868/, https://www.frontiersin.org/articles/10.3389/fimmu.2022.981532/full#f2, https://www.sciencedirect.com/science/article/pii/S0889159115300209?via=ihub, https://www.sciencedirect.com/science/article/pii/S2589909021000204?via=ihub) are not corroborating each other either, they often even completely invalidate or at least contradict each other. That doesn't at all mean that something isn't going on here, it just means that we don't know whether something might be going on. We simply have no idea whether in 20 years Scheibenbogen's muscle study will have thousands of citations or whether it'll be forgotten forever and covered by dust.

That being said GPCR-aabs are certainly one of the most hopeful avenues of research, backed by lots of different findings. Firstly because we have multiple therapeutics currently exiting to target the believed mechanisms, but mainly because we'll have all the answers once BC007, Efgartigimod and the 5 IA trials release their data by the end of next year. In either way we'll get answer.

And last but not least, everyone that received BC, was either healed or had most symptoms vanished. So at this point, there is no evidence, that it will not work for all.

There hasn't been any information on how many patients have really been given BC007, so I don't think we can say this with any certainty. What happened to the Mehlsen rumours? We have some magical news reports, one great case study, the prevention of the publication of the ME/CFS case study, a big Phase 2 study currently running, as well as Berlin Cures hinderance to cooperate in a study which was fully financed by the German government. Overall the communication has been atrocious, which is to be expected in the pharmacological field. People tend to forget that Rituximab had far more scientific evidence, anecdotal reports and case studies of people being completely cured, before it eventually completely flunked. That's just how scientific progress works. So far IA has rather been hit and miss, but we'll learn more after next year, the trials are more than justified and should have started years ago.

With MS, we don't know what triggers it, but we do know that the immune system mistakenly attacks the myelin sheath, leading to inflammation. Which is in my defintion of, „they way it works“ but i know what you mean, there could be diffrent ways how this happens and progress.

We have parts and pieces of how MS might work, based purely on some limited markers, which is infinitely more than what we have for ME/CFS, but we have no idea of what is actually going on, what we might be seeing could just a pixel of the image (with MS they are of course far closer from going to pixel to partial image then they are in ME/CFS) and I'm not even talking about "how this happens and progress". We have diagnostic tools for certain markers in the body, but that doesn't have to tell you anything about how things work. This is the case for the majority of autoimmune diseases.

That is not to say that there can't be medical progress and treatments without proper understanding. All of medicine and pharmaceutics is progress without true understanding, definite proofs don't exist and nobody should care how something properly works if you can just treat a person and with something that gives this person his/her life back.

Feel free to comment, I respect every other opinion on the subject.

I certainly agree with you on that. I definitely don't want to attack your opinion and very much appreciate this discussion. I hope my words don't come off to harsh, which is very common on the internet and I apologise if that is the case. Everything I say is also just my personal opinion and can be talken with as much salt as wanted.

In general, I'd like to see less activism targeting drug approval agencies for a specific drug currently undergoing a trial. Everyday there are hundreds of posts on Twitter along the lines of "when will the EMA approve BC007, what is the German Government doing to help Berlin Cures". I feel that this is largely misdirected activism that could be used far more efficiently elsewhere. People seem to worry about BC007 having positive results in their Phase 2 trial and not coming to the market, when the more realistic scenerio is that we're left without options because the trial flunked and we didn't advocate sufficiently for fundamental research and general funding of trials and trial platforms and research to begin with or didn't even advocate for a general change in the approval process for drugs targeting LC and ME/CFS.

 

[Dude]

This is something I've very commonly seen in patients. We often interpret studies and results that have never ever been replicated, or in this case even contradict other results, and have very small sample sizes as very black and white, whilst in reality everything is far more grey or often even just turns out to be pure noise. A lot can be achieved by rolling dice sufficiently often, ask the monkey on a typewriter that became Shakespeare.

I have also made this observation quite a few times. There is even a term for it: "confirmation bias" The tendency to select and interpret information in such a way that it confirms one's own expectations. I would even say, that I am also biased on this topic because of the preliminary results. But as I said, I don't want to force my opinion on anyone and honestly, I also lack the necessary expertise to really give a serious assessment, but from everything I've heard and read, I wouldn't be surprised (to put it in neutral terms) if BC007 will help the majority. Then again, we have all these Absorption stories, targeting the AAB's. The studies you posted, they may contradict each other, but at least they show abnormalities at the receptors. Then the cure from the guy Ingo in that Facebook group. Could be coincidence. So the mystery is certainly not solved, but a lot of things point to this AAB/GPCR area. But as you say, I hope we will have more clarity mid next year.

In Germany GPCR-AABs are the reincarnation of Jesus Christ when it comes to solving ME/CFS and Long-Covid, whilst in the US essentially no one even gives a fuck about them.

That is well said, you can also see this on this forum, where the interest seems to be very limited compared to other topics.

There hasn't been any information on how many patients have really been given BC007, so I don't think we can say this with any certainty. What happened to the Mehlsen rumours?

That's right, but those from phase 1 (5 people?) all seem to have had improvements or even became healthy again. We do not know if there were also failures, at least nothing was published. I didn't heard of the Mehlsen story, I just looked it up. Very dubious indeed.

In general, I'd like to see less activism targeting drug approval agencies for a specific drug currently undergoing a trial. Everyday there are hundreds of posts on Twitter along the lines of "when will the EMA approve BC007, what is the German Government doing to help Berlin Cures"

I also think that some of the hype that has arisen from it is exaggerated, as long as we do not know whether it works at all, but then again i think, if it helps even one politician to draw attention to the fact that there is a disease here, where people are desperately waiting for a therapy, then maybe it has done something good. In addition, it can not hurt to create a certain awarness for the case that it is the advertised universal cure.

 

[Dude]

Sorry, had to delete this in case someone from the board will have the chance to take lart in the trail.

 

[hapl808]

We have parts and pieces of how MS might work, based purely on some limited markers, which is infinitely more than what we have for ME/CFS, but we have no idea of what is actually going on, what we might be seeing could just a pixel of the image (with MS they are of course far closer from going to pixel to partial image then they are in ME/CFS) and I'm not even talking about "how this happens and progress". We have diagnostic tools for certain markers in the body, but that doesn't have to tell you anything about how things work. This is the case for the majority of autoimmune diseases.

This is my understanding of MS. Until I had more muscular problems and started researching, I thought our measurements of MS were much more objective. Instead, my understanding is it's a general framework built on various theorized proxies for hypothesized underlying conditions. Even the "what's going on" is pretty limited which is why prognoses for MS patients are notoriously difficult.

 

[datadragon]

Butyrate is not only involved with autoantibodies from the above post but also Butyrate suppresses demyelination and enhances remyelination and butyrate is also lower at the same time as a downstream effect of the gut dysbiosis. The oral administration of butyrate significantly ameliorated demyelination, even though the accumulation of microglia into demyelinated lesions was not affected. Furthermore, we showed that butyrate treatment significantly suppressed lysolecithin-induced demyelination and enhanced remyelination in an organotypic slice culture in the presence or absence of microglia, suggesting that butyrate may affect oligodendrocytes directly. Butyrate treatment facilitated the differentiation of immature oligodendrocytes. Oral treatment with acetate showed mild improvement, but the difference did not reach statistical significance. Oral treatment with propionate did not ameliorate demyelination so its butyrate so far from what I can see.https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1552-y

This research had mentioned that the 4EPS (4-ethylphenyl sulfate) metabolite, produced by bacteria that reside in the mouse gut, can travel to the brain and alter the function of brain oligodendrocytes cells which were altered. These cells are important in part because they produce a protein called myelin, which acts as a protective coating around neurons and nerve fibers called axons, like insulation around an electrical wire. The team found that in the presence of 4EPS, oligodendrocytes are less mature and consequently produce less myelin and also anxiety. https://www.nature.com/articles/s41586-022-04396-8

Synaptic plasticity is the fundamental cellular mechanism of learning and memory, but recent research reveals that myelin-forming glia, oligodendrocytes (OL), are also involved https://www.nature.com/articles/s42003-022-04116-y Copper interestingly is involved with alzheimers as mentioned elsewhere.

The myelin sheath is made of phospholipids whose synthesis depends on cytochrome c oxidase activity. Cytochrome c oxidase, the terminal oxidase in the electron transport chain, is copper dependent. They used a copper reducer to induce demyelination and this goes back to ceruloplasmin production needed to make copper and iron usable (bio available). Ceruloplasmin, a copper-containing acute phase plasma protein, has been shown to be regulated by 13-cis retinoic acid, a metabolite of Vitamin A https://www.ncbi.nlm.nih.gov/pubmed/3655940
which requires zinc in Vitamin A metabolism and therefore can be lowered over prolonged inflammation or infection due to lower uptake and availability of zinc. I've been trying to explain that research here
https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2442240

Sometimes drugs will work great as they would have an effect on all downstream areas but sometimes they cant replace all the functions of the missing nutrient. A recent work previously highlighted the ability of butyrate to enhance the expression of AhR-dependent genes through its histone deacetylase inhibitor (HDACi) properties. We confirmed the butyrate-activating role at the transcriptional level on AhR-dependent genes in Caco-2 and HT-29 cell lines. Interestingly, other HDACi that could enhance AhR-dependent gene expression were unable to mimic the butyrate dependent-activation of the AhR reporter system https://www.nature.com/articles/s41598-018-37019-2

 

[Dude]

Swiss trail site now open.

https://kofam.ch/en/snctp-portal/searching-for-a-clinical-trial/197561/study/63948

 

[Hoosierfans]

Swiss trail site now open.

https://kofam.ch/en/snctp-portal/searching-for-a-clinical-trial/197561/study/63948

@Dude, can you explain in kindergarten level terms, what separates BC007 from something like high dose IVIG?

I have the GPCR antibodies out the wazoo (scientific term) including the Beta-2. On the basis of all the wazoo in my blood, I found a doc here willing to do high dose IVIG with me…tried for 9 months without results.

I am wondering for patients like me, who have failed IVIG, if that’s determinative that other antibody targeting drugs won’t work — whether it’s Rituximab, one of the -pheresis methods, BC007.

 

[Dude]

@Dude, can you explain in kindergarten level terms, what separates BC007 from something like high dose IVIG?

I have the GPCR antibodies out the wazoo (scientific term) including the Beta-2. On the basis of all the wazoo in my blood, I found a doc here willing to do high dose IVIG with me…tried for 9 months without results.

I am wondering for patients like me, who have failed IVIG, if that’s determinative that other antibody targeting drugs won’t work — whether it’s Rituximab, one of the -pheresis methods, BC007.

I'm not an expert, but isn't ivig given for reduced levels of igg? If you have elevated levels of gpcr antibodies, then according to the current status you are a candidate for bc. However, it is still not clear how it actually works. The most likely mechanism is the removal of the antibodies, but this still does not explain why they are not simply produced again.

 

[Hoosierfans]

I'm not an expert, but isn't ivig given for reduced levels of igg?

No, it’s not. It’s given in LOW doses for CVID / reduced levels of IGG but given in HIGH doses (often referred to as “autoimmune dosing”) for lots of autoimmune disorders. The theory is that by flooding the system with healthy IGG / antibodies, which includes antibodies to auto antibodies, it “pushes out” the errant antibodies and signals to the body to only make appropriate / healthy antibodies. It’s very broad spectrum — it doesn’t target any specific antibody or group of antibodies….kind of like broad spectrum antibiotics.

https://onlinelibrary.wiley.com/doi/full/10.1111/voxs.12037

 

[SWAlexander]

reCOVer: BC-007 study starts

October 10, 2023
excerpt translate english:

The reCOVer clinical phase II study by the Eye Clinic (Director: Prof. Dr. Friedrich E. Kruse) at the University Hospital Erlangen is investigating the molecular pathway of certain autoantibodies in post-COVID syndrome. In this context, the phase II study with the drug BC 007 is now starting in Erlangen. The first post-COVID patients can be treated with BC 007 in autumn 2023.

reCOVer is funded by the Federal Ministry of Education and Research and is a joint project between the University Hospital of Erlangen, the Max Planck Institute for the Physics of Light in Erlangen and the Humboldt University of Berlin. In addition to molecular analyzes relating to functional autoantibodies against G protein-coupled receptors (GPCR), the clinical phase II study with BC 007 in the post-COVID clinical picture is now starting in Erlangen. BC 007 is a potential drug candidate against post-COVID syndrome and other autoimmune diseases with functional autoantibodies against GPCR. In 2021, laboratory experiments and four healing attempts at the Erlanger Eye Clinic provided initial indications that BC 007 can neutralize these autoantibodies and could potentially help improve symptoms.

continue reading: https://www-fau-de.translate.goog/2..._sl=de&_x_tr_tl=en&_x_tr_hl=en&_x_tr_pto=wapp

 

[Dude]

One of the participants in Erlangen, where it is probably less about the therapeutic success of BC and more investigation on how it works, reports, The functional AAB will be measured in the study. He also said that he was previously negative with Elisa and now with functional positive.

https://twitter.com/i/web/status/1727657222170202126

 

[SWAlexander]

One of the participants in Erlangen, where it is probably less about the therapeutic success of BC and more investigation on how it works, reports, The functional AAB will be measured in the study. He also said that he was previously negative with Elisa and now with functional positive.

All I know there are about 30 participants and some receive a placebo. The pharma industry is suddenly very interested in BC007. Google transl: https://www-boerse-de.translate.goo..._sl=de&_x_tr_tl=en&_x_tr_hl=en&_x_tr_pto=wapp

I personally have not much confidence in ELISA testing, or let me say it depends on who is reading the results.
I had 2 different outcomes from the same blood draw (not Erlangen or Berlin).

I suspect the trial is about functional autoantibodies (AAB) directed against G-protein-coupled receptors,
A friend sent me this link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716247/
indicating that may is what Prof. Scheibenbogen aiming for. There is a new acronym "fAAK" for associated diseases.
Prof. Scheibenbogen was very upset in an interview, saying that ME is a treatable illness and it got intentionally the label of psycho-illness. Two professors in Germany are now fighting the "Psycho label".

 

[Osaca]

The RECOVER trial published their protocol a long time ago: https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-001781-35/DE.

I'm somewhat dissapointed that they are completely neglecting ELISA, especially as it could be valuable to compare the assays as part of this investigative trial. ELISA is extremely reliable, tested and proven over and over again in autoimmune diseases. For every currently known autoimmune disease caused by functional autoantibodies ELISA is completely sufficient and extremely reliable, thus far there's never been a need for other assays.

Unfortunately, the test offered by Berlin Cures is neither validated nor does it measure the "binding to cells". It simply measures how rat cells react to IgG (with a few added blockers in the hope of excluding other autoantibodies) and they don't test for affinity for binding to cells, so calling the test "functional" might be quite a stretch already, because you don't actually known what the test measures since applying human IgG to mice in itself is already problematic and it doesn't measure affinity/avidity to bind to receptors.

 

[SWAlexander]

thus far there's never been a need for other assays.

I´m not so convinced, that "ELISA is completely sufficient".
example:
Besides ELISA (Enzyme-Linked Immunosorbent Assay), there are several other types of blood tests available, each serving different diagnostic purposes.
Here are some of them:

1. Complete Blood Count (CBC): This is a commonly used blood test that measures different components of blood, including red blood cells, white blood cells, hemoglobin, hematocrit, and platelets. It's used to diagnose conditions like anemia, infection, and many other disorders.
2. Blood Chemistry Panel (or Biochemical Profile): This test measures various chemicals in the blood and is used to assess the functioning of organs such as the kidneys and liver. It can include tests for blood glucose, electrolytes, enzymes, hormones, lipids (cholesterol and triglycerides), and other metabolic substances.
3. Coagulation Tests: These tests, including Prothrombin Time (PT) and Partial Thromboplastin Time (PTT), evaluate how well the blood clots and can help diagnose bleeding disorders or monitor the effectiveness of anticoagulant therapy.
4. Blood Enzyme Tests: These measure levels of specific enzymes in the blood. For example, Troponin is often used to diagnose a heart attack, and liver enzymes can indicate liver damage.
5. Blood Gases Test: It measures the amount of oxygen and carbon dioxide in the blood and the pH level, which can help determine how well the lungs are functioning.
6. Serology Tests: Like ELISA, these tests are used to detect antibodies or antigens in the blood, often used to diagnose infections or immune responses.
7. Lipid Profile: This test measures the levels of different types of fats in the blood, including cholesterol and triglycerides, important for assessing cardiovascular risk.
8. Hormone Tests: These tests measure hormone levels in the blood and are used to diagnose and monitor conditions related to thyroid, adrenal, pituitary, and reproductive health.
9. Molecular Tests (PCR): These tests detect genetic material from specific organisms or genes. They are used for various purposes, including the diagnosis of infectious diseases and genetic disorders.
10. Blood Typing: Used to determine an individual's blood group (A, B, AB, or O) and Rh factor (positive or negative), essential for blood transfusions.

Each of these tests provides different information and is chosen based on the suspected condition or disease.

 

[Osaca]

I´m not so convinced, that "ELISA is completely sufficient".
example:
Besides ELISA (Enzyme-Linked Immunosorbent Assay), there are several other types of blood tests available, each serving different diagnostic purposes.

The statement is "For every currently known autoimmune disease caused by functional autoantibodies ELISA is completely sufficient." This is not a questionable statement, it is simply a straightforward fact. Studies and clinical practice has verified that if you have an currently known autoimmune disease caused by a functional autoantibody you simply use an ELISA assay to show that this is the case by measuring the levels of said antibody. Consequentially there isn't a need for a different assay. This means that for all the autoimmune diseases that we currently know to be mediated by a functional autoantibody, ELISA is completely sufficient, usually at an individual level and definitely at a population level. There is no doubt about this. The scientific consensus is clear and the levels in ELISA aren't questionable, but have shown to be reliable, which adds to the question whether these play any role in LC/ME/CFS since we aren't getting clear test results in any studies.

None of the tests you mentioned on your Chat-GPT list actually have anthying to do with how one detects (auto-)antibodies, which is the subject at matter when discussing testing for aab's (for example in the ELISA vs. bioassay debate). A list in this case would be:

• ELISA
• Western Blot
• Immunofluorescence (IF)
• Immunoprecipitation
• Multiplex Immunoassays
• Radioimmunoassay (RIA)
• Line Immunoblot Assay (LIA)
• Enzyme Immunoassays (EIA)
• Cell-Based Assays (Bioassay)

 

[SWAlexander]

It seems that you didn't read my statement.

It seems you have not read the link: Google transl: https://www-boerse-de.translate.goo..._sl=de&_x_tr_tl=en&_x_tr_hl=en&_x_tr_pto=wapp
Berlin is looking for "numerous other diseases associated with fAAKs"

 

[Osaca]

It seems you have not read the link: Google transl: https://www-boerse-de.translate.goo..._sl=de&_x_tr_tl=en&_x_tr_hl=en&_x_tr_pto=wapp
Berlin is looking for "numerous other diseases associated with fAAKs"

I have, but that is the difference between knowing something and hypothesising about something that could be possible. Above I've always written about "autoimmune diseases known to be caused by a fAAK". We don't know if there are other diseases caused by fAAKs, that we don't know about yet (for example possibly Glaucoma, LC or ME/CFS), because quite simply it's impossible to know the unknown.

However I can only reiterate what I've said in the previous posts, for those autoimmune diseases we already know about that are caused by a fAAK, for example Graves disease, ELISA has always been sufficient.