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Modern Explanation for Plasmodium vivax Malarial Recurrences

April 20, 2020 - 00:04 -- Miles Markus

Malariologists have recently reiterated, in more than one paper, the notion that the non-bloodstream origin of Plasmodium vivax malarial recurrence is both hypnozoites (a term coined by me long ago [1]) and merozoites, not hypnozoites only. It has happened without any acknowledgement relating to the existing literature on the subject. Although the glaring omissions might have been inadvertent, let us nevertheless not become confused as to the background here. What needs to be pointed out is that this is not an original (new) idea. Far from it, in fact.

The opinion was first put forward almost a decade ago. The situation has in a way been vaguely reminiscent of what is said to have occurred in terms of how some people reacted when it was stated that the Earth is round, not flat. The plasmodial scenario was sketched (flogged) in a number of conference presentations between 2010 and 2020 (see [2] for details) and was the subject of a dozen or so papers that incrementally provided supporting rationale (some of the points made have now been repeated by other authors). This body of literature is far too large (and therefore familiar to many people) for any cavalier disregarding or unethical obfuscation thereof to be inconspicuous, i.e. go unnoticed. Such analysis had never been undertaken before in the context concerned. The concept [3–6] was both infamous and unique for about 7 years in that up until 2018, only the originator (see Table 1 in [4]) believed it to be correct. In other words, there were no other adherents. This zero statistic is based on what appeared and did not appear in the literature on malaria. It does not include two privately expressed (oral) comments of agreement, made to me recently by individuals who before that had not yet accepted the malarial recurrence idea which is the subject of this blog.

Some researchers are now, commendably, adding expanded (thus, confirmatory) analysis and excellent data. An example is the finding that there is a greater P. vivax parasite biomass in bone marrow than hitherto appreciated. Such evidence supports the already (i.e. previously) established, but not yet generally accepted, 9-year-old viewpoint regarding the likely parasite niche origins in recurring P. vivax malaria [3–6]. The important experimental and histopathological evidence alluded to above is new but the bimodal recurrence concept per se, which was developed as from 2011 on the basis of multiple criteria and novel extrapolation, is not new. To philosophize in respect of the concept, the wheel was irrefutably invented nearly a decade ago. Therefore, it cannot be re-invented, considering that it irreversibly already exists. Its existence is actually very widely known amongst malariologists (although perhaps not universally so), if only because of the (now in the process of reversing) infamy elicited since 2011 by the conventional hypnozoite dogma-destroying, new recurrence source suggestion. The original hypnozoite recurrence concept [7] is to be regarded as correct, however [8,9], as far as it goes – i.e. correct up to a point.

In conclusion, it is finally albeit slowly becoming recognized that non-circulating parasite sources of recurrent P. vivax malaria are probably both hypnozoites and extravascular/sequestered merozoites, not hypnozoites only. See [3–6] for the 2017–2019 articles concerning this long-standing, dual-origin recurrence concept. Most of the earlier papers on the concept (dating back to 2011) are listed in [4] but they can also be traced easily elsewhere [2].

SOURCES OF RELEVANT INFORMATION

1. “Malaria: origin of the term ‘hypnozoite’” https://doi.org/10.1007/s10739-010-9239-3

2. https://www.researchgate.net/profile/Miles_Markus

3. “Malaria eradication and the hidden parasite reservoir” http://dx.doi.org/10.1016/j.pt.2017.03.002

4. “Biological concepts in recurrent Plasmodium vivax malaria” https://doi.org/10.1017/S003118201800032X

5. “New evidence for hypnozoite-independent Plasmodium vivax malarial recurrences” https://doi.org/10.1016/j.pt.2018.08.010

6. “Killing of Plasmodium vivax by primaquine and tafenoquine” (despite the title, this concerns the latest recurrence concept) https://doi.org/10.1016/j.pt.2019.08.009

7. “The hypnozoite concept, with particular reference to malaria” https://doi.org/10.1007/s00436-010-2072-y

8. “A dual fluorescent Plasmodium cynomolgi reporter line reveals in vitro malaria hypnozoite reactivation” https://doi.org/10.1038/s42003-019-0737-3

9. “Transition from plasmodial hypnozoite to schizont demonstrated” https://doi.org/10.1016/j.pt.2020.01.011

Comments

Submitted by Miles Markus on

The November 2019 drug article (listed in the blog), in which a connection was made with the 9-year-old recurrence concept, was highlighted by Andrew Lover in a tweet earlier this year. Click, in his tweet, on the "cell.com" link to the article. Inter alia, note the 5th bullet point under "Open Questions" in Box 1 in the article. Perhaps not obvious, but the answers might (or might not) have implications in respect of the conclusions reached in a large number of papers that have been published on aspects of malaria. Long story. Anyway, if the link below is "clickable", it should bring up the tweet.

https://twitter.com/AndrewALover/status/1232719396516368385?ref_src=twsrc%5Etfw%7Ctwcamp%5Etweetembed%7Ctwterm%5E1232719396516368385&ref_url=https%3A%2F%2Fplu.mx%2Fplum%2Fa%2F%3Fdoi%3D10.1016%2Fj.pt.2019.08.009%26theme%3Dplum-sciencedirect-theme%26hideUsage%3Dtrue

 

Submitted by Miles Markus on

With reference to the blog (see above), I appreciate the comments received in the meantime from some leading malariologists who thought I had gone mad when, years ago, I came up with the alternative P. vivax malarial recurrence hypothesis. The number of people who now “believe” it has increased.

Submitted by Miles Markus on

Further to the "Comment" concerning the paper to which there was a link in Andrew Lover’s tweet (the clickable website appears in the blog as well): The answers to the "Open Questions" in Box 1, bullet point 5, in the article could indirectly affect (in part) interpretational matters arising from, inter alia, studies involving mathematical modelling and molecular characterization of parasites. Notably, the answers might (or might not) have implications in respect of conclusions related to the origin of P. vivax recurrences as based on recurrence patterns following drug treatment.

Submitted by Miles Markus on

To belabour the point made in the blog above, check out this previous blog; and particularly the Comments that follow it:

https://malariaworld.org/blog/why-does-vivax-malaria-recur

Reading between the lines in the Comments relating to the earlier blog will reveal that the non-citation scenario which has now manifested had been a premonition (strong gut feeling that the citation deficiency would occur)! It was anticipated partly because of previous experience. That former experience is described in an illuminating paragraph in the following publication:

https://doi.org/10.1016/j.pt.2020.01.011

There is evidence that both "then" and "now", not all of the authors concerned were aware (at least not initially, anyway) that there were seemingly blatant literature-associated omissions from their own papers.

The weird phenomenon of clearly inappropriate and counterproductive failure to give credit where credit is due (turning what might otherwise have been good publications into defective ones) has euphemistically been explained away in the past as follows: "The malaria field is competitive". Although that is an accurate statement, I would express things differently, especially when phrasing has carelessly been "lifted" from the non-cited paper(s), thereby giving the game away! But be this as it may.

The interesting citation irregularity circus surrounding P. vivax malarial recurrences that is reflected above obviously includes a classical example of insult having been added to injury.

Submitted by Miles Markus on

Concerning this malarial recurrence subject: What will be revealing for posterity (including historians) as regards the integrity of authors is what papers they cite (and how, exactly) or do not cite in future publications of theirs. Time will tell.

Submitted by Miles Markus on

This (see the Blog and Comments) is not merely a trivial matter of omission of inconsequential literature references. It is indistinguishable from plagiarism of important and hitherto unique new Plasmodium vivax recurrence-associated ideas ("unique" meaning NEVER previously raised or discussed by any other authors in the context concerned).

Even though further (i.e. confirmatory) information and analysis surrounding some of those original ideas has now been added by (in) the offending paper(s), active plagiarism is still involved if the non-citation of ideas was intentional. Readers familiar with (or who become familiar with) the content of the publications listed at the end of the Blog, and the earlier ones mentioned in the Blog, can very easily form their own opinions as to whether or not they think that something dodgy happened. That is, if they encounter and have perused such a "suspect" journal article(s) – as I have done.

In the event that ethical authors should choose to cite, in relation to the biology of P. vivax malarial recurrence, a literature-deficient publication(s) in any manuscript of theirs, they should henceforth also include a primary 2011–2019 malaria recurrence-related reference(s). Otherwise, original pertinent literature will by default again be conspicuous by its absence, especially following the revelations made above in the Blog and Comments.

Any repetition of the bizarre and irresponsible reference omission act that has taken place will inevitably lead to unprecedented aggravation of the debacle, by "putting a match to a powder keg". That would not do anybody any good. What would be best is to wisely avoid precipitating further drama in the first place, by ensuring that ethical citation practice is the order of the day.

Submitted by Anonymized User (not verified) on

Any questionable future citation events concerning this subject (including inaccurate self-citations) will clearly and justifiably go down in history, to the detriment of the citing authors.

Submitted by Anonymized User (not verified) on

It is obvious that correct future citing would nip this problem in the bud and, therefore, make it quietly go away.

Submitted by Miles Markus on

The immediate outcome of citation inaccuracy is the following (although this is self-evident):

As indicated somewhere above, it is no secret that other authors in the overall malaria field have likewise experienced unacceptable goings-on in relation to the citation of publications that they have authored. Thus, the curious P. vivax recurrence-related, reference omission phenomenon, both old (going back 4 decades) and more recent, is not unique.

In cases where non-citation or seemingly devious (dishonest) citation in connection with something "new" (i.e. not yet accepted malariological knowledge) has been inadvertent, this is perfectly understandable if very little had previously been published on the particular malarial topic concerned.

When there is an existing body of literature, however, the reader cannot necessarily discern, depending partly on the size of the body of literature: (A) Whether inaccurate citation or non-citation was intentional. Or (B) Whether it is purely profound ignorance (of the specific malarial subject area) that is on display.

Submitted by Anonymized User (not verified) on

In regard to the saga (see above), this publication teaches us what an ethically correct paper looks like citation-wise:

Obaldía N 3rd & Nuñez M. 2020. On the survival of 48 hr Plasmodium vivax Aotus monkey-derived ex vivo cultures: the role of leucocytes filtration and chemically defined lipid concentrate media supplementation. Malaria Journal 19: 278.

https://doi.org/10.1186/s12936-020-03348-9

Submitted by Anonymized User (not verified) on

One notes that the ethical handling of literature in the paper highlighted in the previous Comment here (see above) does not apply only to the matter of the origin of recurrences.

It is at the same time a shining example of an antidote to the following situation:

"Some parasitologists have been puzzled by the fact that the coining of the term 'hypnozoite' ... is rarely appropriately credited in publications. The explanation is that the omission appears to be largely habitual, since the first half of the 1980s, when papers either did not mention or downplayed (inadvertently or otherwise) the matter of the name's origin. Thirty years of dormancy, so to speak, elapsed before attention was first drawn in the literature (in 2010) to the original anomaly – which dates from 1980, the time of the discovery of the Plasmodium hypnozoite".

This paragraph is quoted from: https://doi.org/10.1016/j.pt.2020.01.011

Submitted by Anonymized User (not verified) on

It is a good thing to now be aware that citations are often inappropriate ones (or are missing) where the word "hypnozoite" is first mentioned in papers – especially when largely irrelevant publications are referred to pseudo-authoritatively instead of those that actually discuss hypnozoite-related matters from the most informed perspective. However, many authors lately have, no doubt, simply been following, uncritically, what other authors in the new millennium have done; the hypnozoite having been named before malariologists younger than 42 years of age were born. So when authors (particularly young ones) have cited literature poorly or inaccurately in the hypnozoite context, they will probably have done this unintentionally in most instances.

Submitted by Anonymized User (not verified) on

Re the previous comment here, it often happens in science. A paper that has little or nothing to do with the price of eggs gets cited (frequently self-citation that reflects an exercise in self-delusion), and then other people re-cite it. Poor citation of this kind does not necessarily go unnoticed, however; in which case the intended purpose has effectively backfired. For one thing, respect amongst peers is not elicited.

Submitted by Anonymized User (not verified) on

Arising from comments here – this trait, in the eyes of some of us who have discussed it, makes Nicanor Obaldia a respected researcher.

Submitted by Anonymized User (not verified) on

In the malaria field, citation of papers e.g. by friends of the authors (or self-citations), to the exclusion of literature that is more pertinent, has occurred not only in relation to hypnozoites.

Various researchers know from personal experience that the habit is more widespread than this – as has been stated in at least one of the postings here. However, the point bears repeating.

Submitted by Anonymized User (not verified) on

Relevant to this thread is, clearly, the following statement (link below) in the MalariaWorld Newsletter by the eminent, late Professor Wallace Peters. He wrote: "... it is often forgotten that he [Miles Markus] was the first to apply this term [hypnozoite] in relation to Plasmodium vivax."

https://malariaworld.org/comment/278#comment-278

Submitted by Miles Markus on

With reference to the previous posting, something comes to mind re Prof. Wallace Peters, who was an old school, true gentleman, and highly respected by everyone.

When I uttered the word "hypnozoite" in public for the first time upon introducing it for Plasmodium at the Spring Meeting of the British Society for Parasitology (University of Kent, Canterbury, UK, 5–7 April 1978), a titter was audible in the room, no doubt because the unfamiliar name sounded strange (if not absurd) to the audience initially. One could almost sense some people thinking: "WHAT is this guy doing?" Then suddenly the word wasn’t so funny anymore, apparently, because there was dead silence (which prevailed for the rest of the talk).

Afterwards, Prof. Peters came to speak to me. He had nice things to say; and indicated that he strongly supported the coining of the term "hypnozoite".