According to an article in DER SPIEGEL, 4 patients of an alternative medicine centre died, while several other websites reported that the figure amounted to ‘just’ three. The centre in question is the Klaus Ross clinic in the German town of Bruggen-Bracht on the border with the Netherlands.
In addition to these fatalities, several further patients are being treated in hospital and German prosecutors in the town of Moenchengladbach have urged other patients showing any symptoms to “urgently seek medical advice.” Dutch police, who are supporting the inquiry, appealed for information from other patients, as newspapers reported the clinic had been using an experimental transfusion.
Concern was first raised when a 43-year-old Dutch woman with breast cancer complained of headaches and became confused after being treated at the clinic on July 25. She later lost the ability to speak, and died on July 30. The “cause of her death remains unclear,” the German prosecutors said in a statement earlier this week. Many Dutch people are known to have visited the clinic and while “it is not yet known exactly what happened, there is a health risk to patients who have undergone treatment at this clinic”, according to a statement by Dutch police.
Klaus Ross was cited saying that “one of our patients unexpectedly has passed away… We regret this seriously and are in shock as we heard the news. Our thoughts and deep condolences are with her family, friends and loved ones… we regret the suspicion set in the media that alternative medicine, and our clinic especially, could be held responsible…. Alternative medicine is always an extra tool to battle diseases.” Allegedly, Ross always advised patients to be monitored by their own doctors.
The centre in question specialised in ‘biological’ cancer therapies and beauty treatments; it has now been closed and Ross has reportedly been charged with manslaughter. The interventions on offer include a wide range of unproven therapies, including detox, oxygen therapy, various supplements, immunotherapy and hyperthermia. According to some reports, the therapy implicated in the fatalities was 3- bromopyruvate (3BP). 3BP is an experimental cancer treatment which is currently attracting much, mostly pre-clinical research. One review article summarized the evidence such:
Although the “Warburg effect”, i.e., elevated glucose metabolism to lactic acid (glycolysis) even in the presence of oxygen, has been recognized as the most common biochemical phenotype of cancer for over 80 years, its biochemical and genetic basis remained unknown for over 50 years. Work focused on elucidating the underlying mechanism(s) of the “Warburg effect” commenced in the author’s laboratory in 1969. By 1985 among the novel findings made two related most directly to the basis of the “Warburg effect”, the first that the mitochondrial content of tumors exhibiting this phenotype is markedly decreased relative to the tissue of origin, and the second that such mitochondria have markedly elevated amounts of the enzyme hexokinase-2 (HK2) bound to their outer membrane. HK2 is the first of a number of enzymes in cancer cells involved in metabolizing the sugar glucose to lactic acid. At its mitochondrial location HK2 binds at/near the protein VDAC (voltage dependent anion channel), escapes inhibition by its product glucose-6-phosphate, and gains access to mitochondrial produced ATP. As shown by others, it also helps immortalize cancer cells, i.e., prevents cell death. Based on these studies, the author’s laboratory commenced experiments to elucidate the gene basis for the overexpression of HK2 in cancer. These studies led to both the discovery of a unique HK2 promoter region markedly activated by both hypoxic conditions and moderately activated by several metabolites (e.g., glucose), Also discovered was the promoter’s regulation by epigenetic events (i.e., methylation, demethylation). Finally, the author’s laboratory turned to the most important objective. Could they selectively and completely destroy cancerous tumors in animals? This led to the discovery in an experiment conceived, designed, and conducted by Young Ko that the small molecule 3-bromopyruvate (3BP), the subject of this mini-review series, is an incredibly powerful and swift acting anticancer agent. Significantly, in subsequent experiments with rodents (19 animals with advanced cancer) Ko led a project in which 3BP was shown in a short treatment period to eradicate all (100%). Ko’s and co-author’s findings once published attracted global attention leading world-wide to many other studies and publications related to 3BP and its potent anti-cancer effect. This Issue of the Journal of Bioenergetics and Biomembranes (JOBB 44-1) captures only a sampling of research conducted to date on 3BP as an anticancer agent, and includes also a Case Report on the first human patient known to the author to be treated with specially formulated 3BP. Suffice it to say in this bottom line, “3BP, a small molecule, results in a remarkable therapeutic effect when it comes to treating cancers exhibiting a “Warburg effect”. This includes most cancer types.
While 3BP seems to show some promise, clinical trials have not yet been published and another review correctly cautioned that clinical trials using 3BP are needed to further support its anticancer efficacy against multiple cancer types…
The person in charge of the centre, Klaus Ross, has no medical qualifications but claims to have studied naturopathy and was a ‘Heilpraktiker’. As such, he is probably not licenced to administer 3BP to cancer patients.
A standard series of out-patient cancer treatments at Mr Ross’ clinic was reported to cost around 10 000 Euros.
33 Responses to Fatalities in a German alternative medicine clinic caused by 3BP?
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This situation is shocking. Klaus Ross is offering several treatments that are, as far as I can determine, largely pulled out of thin air.
The quality of the Dutch text on his web site is quite bad. While this is hardly proof of anything, it at least hints at his reluctance to invest in quality communication, i.e. he has no respect for his patients.
I can’t help but giggle when I see he mentions ‘natural’ and ‘non-toxic’ treatments. I think I far prefer a toxic treatment that keeps me alive to a non-toxic treatment that kills me.
Perhaps the German and Dutch governments will find in this case a reason for becoming less tolerant of quackery.
it seems that this Heilpraktiker had patients mainly from Holland and Belgium. his clinic was close to these borders but in Germany. this is because the German law allows much quackery that is forbidden in the other countries. much like the clinics ‘across the border’ of the US in Mexico.
He clearly knows more about legislation than about medicine.
Germany is one of the most advanced countries on the planet, in spite of (or perhaps thanks to) of the terrible events still in living memory. Yet, they still have a system that allows life-threatening nonsense. It is so contradictory, and so sad.
Looking at some things he uses, according to his site, I doubt these are neither non-toxic, nor natural, like for instance MMS, DCA and 3BP.
It seems that ‘toxic’ and ‘natural’ are irregular adjectives. “Your treatment is toxic, mine is natural”.
On the front page, it clearly says:
I always wonder how naturoquacks can make such claims. In my opinion, sticking needles into people and use them to empty bags of any number of liquids into their vascular systems is not particularly natural.
That whole first page is so disgusting, I have no words to describe it.
Here is some of the scientific background on 3-Bromopyruvate.
The knowledge base for 3-BP in cancer has been growing during the last 15 years of research.
http://www.3bpko.com/
The pdf (second row on the left) “A translational study “case report” on the small molecule …” from a hospital in Frankfurt/Main Germany was an initial patient report of 3-BP with a strong treatment effect. The teenage patient from the Netherlands had a large response to 3-BP. As noted in the article the patient achieved a near cancer free status on his last lab: “This lack of tumor cells in the ascites …”.
The American inventors of 3-BP had to go to Germany to treat with 3-BP due to Germany’s unique medical laws. Few if any other modern nations would allow treating a patient based only on an animal study. Due to these restrictions on patient rights, America and the UK have introduced Right to Try Laws.
After the initial success with 3-BP, several other nations now permit 3-BP treatment including the United States, Canada, Mexico, Columbia, among others. None of these clinics have reported any problem with 3-BP treatment.
This report from a melanoma patient energized the entire 3-BP community. After this report, several clinics in the United States and Canada were opened. As can be seen in Figure 3B, this patient achieved a near metabolic cure of his cancer. His lactic acid levels decreased from 4500 to 12 during his treatment. He experienced no side effects.
http://www.ncbi.nlm.nih.gov/pubmed/24636230
I think you are misleading us: as far as I know, no country has licensed 3BP for routine cancer care.
Yes, this is quite correct. 3-BP is no where allowed as a routine, officially endorsed treatment.
Yet, at the same time there are now several clinics that have offered the treatment. Some have now been using it for a year or two. Dayspring Cancer Clinic in Arizona has posted some very positive responses to 3-BP.
I myself do not completely understand how it was deemed legal to allow treatment with a “pharmaceutical” drug that has never completed an official phase 1 trial. Alternative clinics
typically offer “natural” treatments not “drug” treatments. 3-BP along with other anti-glycotics
(e.g. DCA and methylglyoxal) are part of a new wave of alternative medicine that have bypassed
traditional regulatory approval.
I have watched the 3-BP story develop over the last few years and have posted to the cancercompass forum. The problems with the Bracht clinic have been known to us for almost a year.
That’s one of the reasons alternologists are to be avoided: they do not care about what is legal, only about snatching as much money as possible from their marks.
I am not entirely clear about the legal status of 3-BP. The American clinics that offer 3-BP appear to be operating within the legal norms of their state (perhaps under Right to Try legislation). Dayspring now has 5 anecdotal reports on their website of very impressive responses to 3-BP treatment. There are quite a few other anecdotes of success that are being reported to the web. Canada has a program that allows desperately ill patients with no further approved treatments to seek out and be treated with non-approved therapies.
The money argument is not entirely persuasive with 3-BP. 3-BP is a widely used and inexpensive industrial chemical. Enforcing a patent for 3-BP in such a context would be nearly impossible. Dayspring charges $25,000 for a month of 3-BP treatment; if it were a patent protected product it would easily cost many hundreds of thousands of dollars.
One of the world’s most respected cancer hospitals, MD Anderson, has created an even more powerful version of 3-BP called 3-BrOP. They have also decided not to move it into the clinic. This is possibly due to the fact that 3-BrOP is also a simple chemical that might have an unenforceable patent.
In the recent incident it should be noted that it is highly unlikely that 3-BP was the direct cause of the fatalities of the patients. This is because 3-BP is typically highly unstable. It would be surprising if the 3-BP treatment which was received by the patients lasted much more than even a few hours. The patients did not have symptoms for up to days later. They would not be expected to have any 3-BP in their system at that point. Tumor Lysis Syndrome, though, is a possibility.
I have been reading and posting about 3-BP for many years now. From what I now understand, I would without question seek a low dose of 3-BP, if I had end stage cancer. A low dose of 3-BP might cost $1000 and might take a day at a clinic. This would be money and time very well spent. The low dose 3-BP would indicate whether I would be a responder. (I would also suggest such treatment to close family members and friends) If I were shown to be a potential responder I would then continue with fairly moderate dose 3-BP treatment. The Bracht clinic apparently was treating with aggressive 3-BP doses.
If confirmed, how credible does that make their claims of 100% organic and natural treatments?
Furthermore, how is a Heilpraktiker qualified to administer such treatments?
I understand “100% organic and natural treatments” to be words intended not to have any particular meaning. They are part of the entire alternative medicine vocabulary that I do not fully comprehend. I do not have much faith in most of alternative medicine.
To me, 3-BP is not really an alternative medicine at all. There are published patient reports of those treated with 3-BP, many of the scientists behind it are highly regarded, several Nobel prizes have been awarded to those in metabolic research (Warburg etc.),… I think of 3-BP more as experimental medicine. There are problems with commercializing such a simple molecule, so it is stuck as an unofficial medicine.
I find it encouraging that 3-BP appears to have upped the quality of alternative treatments offered to seriously ill cancer patients. Dayspring Cancer Clinic is regarded as one of the top rated alternative clinics in America. Before 3-BP they offered a range of alternative medicines that I do not have a great deal of confidence in. However, now that 3-BP has emerged, they are highlighting it as one of their more promising treatments. We need to realize that people will likely go to these alternative clinics no matter what, if people are discouraged from taking 3-BP they will simply be pushed to other alternative alternative medicines that have no scientific credibility whatsoever.
We can quibble about the research behind 3-BP, though quite a bit of other alternative medicine is simply bizarre and should rightly be described as fraud. Harsh critiques of 3-BP will simply lower the standards of alternative medicine.
It is hard to argue that 3-BP lacks at least face credibility. Nearly any chemical that is similar to lactate has anti-cancer properties. DCA, methylglyoxal, 3-BrOP … there are many of them. Some have published clinical trials that have shown benefit.
The clinic’s web page for 3-BP appears to be reasonably congruent with the facts. 3-BP enters cancer cells through the MCT-1 transporter protein in an acidic context which results in a non-toxic treatment. The two published patient reports showed little in the way of toxic side effects even though these patients had extreme tumor burdens. It is highly selective to cancer cells.
I think it is misleading, though, to claim that only 3-5% of cancers would show no glucose uptake and thus would not benefit from 3-BP treatment. It is known that a fair proportion of patients treated with only 3-BP will not respond. The main factor for non-response appears to be having low MCT-1 expression. It is possible that those trained in 3-BP could help convert such non-responders into responders, though this is only speculation.
As it is, there are clearly a subset of patients that do have significant responses to 3-BP treatment. One of the great benefits with 3-BP is that such patients can be quickly identified. Selecting for such patients in a clinical trial would almost certainly result in a positive result for 3-BP.
http://www.biologische-kankerbehandelen.nl/de/behandelingen-kanker/3-bromopyruvate/
@Compass
Your little essay on the technicalities of 3BP is misplaced.
Your apologist attitude demonstrated in these words:
is hopefully only due to profound ignorance of the subject.
In the original post, Prof. Ernst wrote: “3BP is an experimental cancer treatment which is currently attracting much, mostly pre-clinical research.”
No one is arguing that 3BP is ineffective or useless (as ‘shaken water’ for example) or does not have a potential for medical utility. 3BP is unproven – yet.
While it is unproven, use of it outside professionally conducted trials is not only to be classified as “alternative medicine”, it should be considered criminally negligent. If it proves to be efficacious and useful, use of it will be ‘medicine’ and should not be managed by incompetent amateurs.
What this discussion is about is not the potential applicability of 3BP. It is about the activities of people who think they can grab a bottle of something and start healing seriously ill people with it just because reports say it is being investigated for possible efficacy and someone fooled them to think they are “alternative” doctors who can take over where genuine medicine ends.
Naturopaths by any name are demonstrably naive, incompetent amateurs who have falsely been led to believe they can play doctor.
This needs to be stopped or at least put under strict safety limitations and surveillance as they constitute a real and evident danger to public health by enticing people to go to their “clinics” in desperation for treatments that are, if not useless, then unproven and mismanaged as demonstrated.
This is what this post and this discussion is about.
Some of the alternative clinics that offered 3-BP have now withdrawn this treatment in order to await for further investigation into the Bracht incident. These clinics have now returned to Laetrile and other more dubious cancer treatments. No one might be arguing that 3-BP is ineffective or useless, though I for one suggest that Laetrile is ineffective and useless. This was exactly my point. The conversation has now shifted from discussing a treatment (3-BP) that no one argues is ineffective or useless to a range of treatments that are ineffective and useless.
In a democracy, what is understood as criminal is related to what the people decide is criminal. Several nations in the world have made significant steps to change their legal norms surrounding patient choice. For example, America now has a nearly nation wide program that allows seriously ill patients to access early stage clinical medicines. These Right to Try laws were advanced under the principle that terminally ill patients have a fundamental human right to seek treatments that could help them when established medicines are not likely to be of benefit to them. Right To Try laws received strong bipartisan support.
I do not disagree that there are problems with the alternative clinic model. It appears that in most nations that medically licensed doctors are not typically allowed to treat with non-approved medicines. [This, however, is not universally true.] Once patients progress through the approved treatments, they are often banished from the medical system. At this point one of their only options is to seek treatment from alternative medicine. It would seem best if medically trained doctors were allowed to use their best judgment to help these patients, even if this were to mean going beyond approved medicines. This appears to be the law in Germany. Other nations should also consider adopting this model.
The 5 clients were given vitamin injections or drip feeds while they were in the Bracht ‘clinic’ by the Heilpraktiker (not a doctor in any way imaginable), because they showed unexpected reactions to the 3BP drip feeds they were there for. Klaus Roß was alarmed by the vomiting noises, the violence with which that did occurred and the frequency with which they did occurred. To hear or see vomiting by clients was normal there. But this was different.
Yes, this did occur while they were in that ‘clinic’, on the treatment seats, under his ‘supervision’. He worked alone most of the time.
What he didn’t do was call a real doctor (Notartzt), or ambulance to transport them to hospital.
The first victim of this quack died within 12 hours of the 3BP drip feed. The other 2 within the next days. 2 Other victims of this deadly quack are still in hospital, fighting for their lives.
Perhaps it was the 3BP, perhaps 3BP reacting with other quackery he used MMS, 2DG, DCA, but it sure as hell was during treatment of which the quack said he used 3BP from the USA for, rather then the 3BP he used earlier that was sourced from Germany.
The clients after the vitamin injections/drip feeds were sent home were over the next hours and days their condition did get bad and they went to hospitals.
All this is in statement by an eyewitness, the wife of the first victim, the Belgian woman, in newspapers.
The clinic isn’t ‘already using 3BP for years’, the clinic isn’t even 2 years in his ownership.
Please Compass person, don’t hide or bend facts because you want to promote an unproven or tested substance. It’s as unethical as was the use of quackery like that by laypersons Klaus Roß (a medical equipment salesman) in his ‘hope for sale’ shop was doing.
I was not clear in that comment.
Another clinic (not Bracht) offers 3-BP intratumoral injections.
This clinic’s website states: “Over the years … intratumoral 3-Bromopyruavte injections.”
I have no intention or motivation to hide, bend or distort facts.
I have a long standing interest in 3-Bromopyruvate and I am very interested in knowing more about its anti-glycolytic potential.
There is no shortcut to such knowledge. The path to it is well charted and not without risk. Preclinical testing first then clinical trials of increasing numerical power. Trying to second guess this process increases the risk to patients substantially.
I am also very unsure how we have landed in a situation in which a “pharmaceutical” drug was able to bypass traditional regulatory control. There seems to be a range of possible factors involved.
For example, there are these impressive patient reports, 2 of which have been published into the scientific literature. “This lack of tumor cells in the ascites suggested that the tumors in the liver were well encapsulated … The rate of tumor necrosis due to 3BP treatment seems to exceed all known cytostatic drugs.” Admittedly these statements from the published liver patient were only intended to be understood within the context of TACE which is substantially different from how 3-BP was later used.
Also there has been ongoing reporting of the 3-BP story in the media and elsewhere. The public interest in 3-BP then encouraged clinics to provide the treatment. Not to mention the FDA granting permission to start a phase 1 trial several years ago.
This permission was granted after significant preclinical research. This preclinical research has now been ongoing for over 15 years. 3-BP is probably one of the most extensively studied chemicals that has never started a clinical trial.
Clearly it would be the best way forward to have clinical trials for 3-BP. Yet, the hundreds of millions of dollars that would be required for this to occur have not as yet materialized. The scientists who have researched 3-BP for all these years would very much like to see clinical trials start. This is exactly what they requested in their latest review article on 3-BP.
Furthermore, 3-BP is a non-optimized chemical. A pharmaceutical company would never move it to market. These companies spend years trying to find the best possible compound out of a wide range of analogs. 3-BrOP has already shown that 3-BP could be made better and safer. The optimal version of 3-BP has yet to be found. Without involving pharmaceutical companies with substantial financial resources, 3-BP will remain a compound with enormous unrealized potential.
Yes, for what I read, he used IV dose, of 250mg… while the safe dose is oral 2mg per kg. A Huge difference. Perhaps cause tumor lysis, so massive, it triggered Sepsis. If it is anything like the DCA, (half-life of 24Hr.) it would be gone from the plasma in 48 hours, BUT reactive issues are a different story. In any case, a physician ought to oversee the application, not an unlicensed naturopath , and IV should NOT be legal without a licensed physician order, and a licensed nurse anyhow. Low oral doses are effective, and safe. This is what mainstream quacktitioners fear the most. Once combined with Short-wave Hyperthermia, or Microwave Hyperthermia, it produces a powerful breakdown of tumors.
Giving 250 mg IV 3-BP doses is very dangerous. I thought this lesson had already been learned.
Do you have a url for the 250 mg dose and TLS suggestion?
The original liver patient also received a 250 mg loading dose in a German hospital. Two weeks later when a dose of 125 mg was given the patient went into what was thought to have been a fatal coma. The patient survived and further doses were reduced. Was the Bracht clinic not aware of this?
A 250 mg dose would have been 5.0 mg/kg for a 50 kg women. For a fixed 250 mg dose this could have been especially dangerous for the petite women.
David Gorski has now discussed these cases on ScienceBasedMedicine.
https://www.sciencebasedmedicine.org/3-bromopyruvate-the-latest-cancer-cure-they-dont-want-you-to-know-about/
The ‘evidence’ for 3BP having anti-cancer effects appears amazingly thin.
Yes, in this blog’s comment section he emphatically refutes any assertion that 3-BP is “quack medicine”.
I also find it interesting that 3-BP has been used in the clinic for several years now as an intra-tumoral treatment for cancer. Directly injecting high molar 3-BP would likely have impressive anti-cancer effects. This would be entirely obvious by simply looking at the tumor. I do not suppose that they would have continued using 3-BP as an intra-tumoral treatment if the results were not impressive as there are other such treatments available.
He was a quack. He didn’t know what he was doing. He wasn’t a doctor. The clinic consisted of 3 rooms with 4 treatment seats each and some office space and 1 person. There wasn’t a MRI or PET or other scanner. He (apperently) used widely available cancer indication test sets of which results can be very wrongly interpreted by a layman as everybody knows all to well. Because his medical education was zero, it is very doubtful that he had control over what he was doing as treatment. He mixed different ‘cures’ like MMS, 2DA, DCA etc. and seems to have been testing his results himself.
Perhaps he was in it to ‘help’ people, perhaps he was in it for the money. There are reports that people sold cars or their house to finance alternative treatment at his and other ‘clinics’.
His former partner and the man who did set up the clinic in it’s first form (Andre Hartel) said in an interview: He (Klaus Roß) had little experience in treating cancer patients. Andre Hartel left the clinic and Klaus Roß took over 1.5 year ago. Hartel was the financier that needed Roß for his Heilpraktiker license.
So why did he go on? Succes?
One column by a well know Dutch writer said it like this: The dead don’t make accusations.
He was selling hope to the people in their last phase for whom there was no legal, alternative, treatment possible in the Netherlands, but used the difference in law between the 2 countries to ‘help’ them. His website was in Dutch. It was aimed at people over the border for a reason.
By Steven Novella: NeuroLogica Blog » Deaths in Alternative Cancer Clinic Investigated
I am sure it will be a great relief to all those (including myself) on this thread to learn that a formulation of 3-Bromopyruvate is now scheduled to enter a phase 1 clinical trial next year.
http://www.businesswire.com/news/home/20170426005840/en/PreScience-Closes-Institutional-Financing
Your death could smell after orange juice. (MMS doesn’t mean make me sweet !!)
One should be able to distinguish between
sodium chlorite
and
sodium chloride
http://www.gesundheit.ch/mms/
After severe problems caused by the former Government of South Africa related to the treatment of HIV/ AIDS (remember the Matthias Rath case) now there is a new business model for Africa and the whole universe.
(annotation:) Don’t mix it up with the latest religious sects in Africa offering deliverance from all all sins by drinking Domestos / Demestos as an undiluted remedy:
https://www.watson.ch/Blogs/Sektenblog/193507462-Und-sie-trinken-Reinigungsmittel—–als-sei-es-ein-Zaubertrank-Gottes
http://www.daserste.de/information/politik-weltgeschehen/weltspiegel/videos/suedafrika-wenn-der-pastor-mit-domestos-heilt-100.html
Isn’t this a similar nonsense announced by people who to me look like being psychotic?
https://www.nexus-magazin.de/artikel/lesen/mms-ein-wundermittel-fuer-afrika-und-auch-den-rest-der-welt-teil-1/2
http://www.krisenvorsorge.com/mms/
http://mms-seminar.com/mms-tropfen-zutaten-bezugsquellen-was-beachten/#
https://www.prema-seva-naturheilpraxis.de/infothek-preise/naturheilkundliche-fachartikel/therapie-mit-chlordioxid-cds-cdl-mms-dmso/
http://www.praxis-schell.de/therapien/mms/
http://faq4h.bplaced.net/cds-mms.php
and doesn’t it look like as if even a medical preliminary study and exam AND having finished a study in natural sciences cannot stop people to promote such nonsense?
https://faszinationmensch.com/2016/07/08/mms-ein-paar-erfahrungen-mit-cdsplus/
I am offering the links above for more research about this dangerous CAM subject.
The current state of the investigation in Germany appears to indicate that the Bracht incident was a result of substantial overdosing of the patients. The investigators’ finding of fact has disclosed that the patients were overdosed by up to over ten times the established dose of 3-BP. This substantially changes the context of the conversation.
he was just sentenced: 2 years suspended prison sentence
https://www.sueddeutsche.de/panorama/heilpraktiker-krebstherapie-1.4525117
South Korean company has announced intention to invest 40 billion KRW and begin clinical trial with 3-BP over the near term.
A co-winner of the Nobel Prize in Medicine for 2019 was a co-author on the below paper which is
a cyclo-dextrin formulation of 3-Bromopyruvate that is thought to be preparing to enter a phase
1 clinical trial.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300523/