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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 Anonymized User (not verified) on

This parasite origin scenario in Plasmodium vivax malarial recurrence is or is becoming, after a decade of malariological denial, a "Miles Markus told you so" situation!

When he looks in the mirror, he sees a golden halo shining brightly above his head.

No horns are visible.

Submitted by Miles Markus on

As regards comments here, no comment or elaboration from me.

Submitted by Anonymized User (not verified) on

If you think of the historical non-recognition of "the hypnozoite guy" (to use a known description), and add to that the more recent publication-ignoring antics, is it surprising that an "enough is enough" frame of mind could kick in?

No, it isn’t at all surprising.

What is remarkable, though, is that it did not happen sooner.

And don’t lose sight of the fact that he isn’t the naughty boy here.

Submitted by Anonymized User (not verified) on

We are introducing a citation ethics course for students, having discovered that they apparently do not hear about this sort of thing during the course of their training at our institution.

 

Submitted by Anonymized User (not verified) on

Maybe always incorporate ethics matters into the publishing / paper-writing sessions that are occasionally run at malaria conferences by journal editors for early career attendees.

Submitted by Miles Markus on

There is a bad background to particular non-citation deviousness that took place. It tipped a scale, actually, leading to the above blog. But as things stand, the less said about that matter, and others, the better. The skeletons need to be put to rest.

Submitted by Anonymized User (not verified) on

So perhaps it can be concluded that it seems unlikely that future omission of key original references in this whole context would easily go undetected now. Any studious avoidance of referencing appropriately, or creative referencing, would no doubt be horribly conspicuous, i.e. if pertinent citations are not there.

Submitted by Anonymized User (not verified) on

So perhaps it can be concluded that it seems unlikely that future omission of key original references in this whole context would easily go undetected now. Any studious avoidance of referencing appropriately, or creative referencing, would no doubt be horribly conspicuous, i.e. if pertinent citations are not there.

Submitted by Anonymized User (not verified) on

In defence of people who did not cotton on to the dual Plasmodium vivax malarial recurrence idea:

Many or most malariologists are epidemiologists, clinicians, cell biologists, mathematicians, biochemists, molecular biologists, etc., not experienced parasitologists.

Submitted by Anonymized User (not verified) on

A useless piece of information is that Miles Markus attended the same high school as Elon Musk!

Submitted by Anonymized User (not verified) on

Coincidentally, for that matter, Elon Musk and Miles Markus happened to attend the same elite primary school as well, I have just discovered; but in different eras. Not that this is related to malaria per se.

Submitted by Anonymized User (not verified) on

The question remains as to whether any misguided journal manuscript reviewers have been fiddling around with (including censoring) referencing connected with recurrent malaria? This point has been raised before. Just asking.

Perhaps it has not happened, although there has been a suggestion (unsupported by any evidence) that it has; which is the reason for speculating.

If it has (for the sake of argument), such interference could to an extent explain some of the referencing phenomena displayed by published papers, as alluded to or detailed in the above blog and subsequent postings.

Whether or not manuscript referee input is a partial explanation for the puzzling past referencing patterns concerned might well remain a mystery forever.

Submitted by Miles Markus on

A comment in passing:

Lest the impression be gained that I knew Elon Musk (who could have died from P. falciparum malaria around 2000/1 after his infection wasn’t initially diagnosed correctly in the USA), it is not the case. I never met him.

I did very briefly cross paths with his mother, before she became his mother. This happened mainly when she was a Dietetics student and I was temporarily teaching Zoology (before going to study in the UK), which was one of her first-year subjects at university.

Submitted by Anonymized User (not verified) on

Some of the above comments have been checked by perusing literature. Here is a quotation from a randomly selected 2020 publication (many similar examples could be given):

... dormant liver stages, hypnozoites, which can activate ... leading to repeated onset of blood stage infection ....

Three references follow the sentence, being citations for papers published in 2011, 2014, and 2017, respectively. Those articles talked about hypnozoites but none of them, nor their authors, had anything to do with the naming or discovery of the hypnozoite, or the original interpretation of the Plasmodium vivax biology that is stated in the sentence. Perhaps there was an ulterior motive for having those citations, which in this instance are not self-citations.

Omission of any mention of a primary author(s) in a referenced sentence like the one quoted above is unethical, although novice researchers might not be fully aware of the fact that such omission is not on the level. Furthermore, except to the uninitiated or half-asleep reader, this type of incorrect referencing looks both amateurish and silly.

From examination of the recurrent malarial literature sampled, it would seem that authors and journal manuscript reviewers need to keep an eye on referencing in the hypnozoite context (and other contexts too, of course). This would be to ensure that original literature is cited – either only, i.e. alone, as has correctly been done in many publications, however; or together with citations such as those mentioned above, provided that the subsequent papers actually contribute something to the story. Unless they do that, they will be superfluous references.

Reputation-wise, it is not in the interests of authors to indulge in specious referencing. The hypnozoite might come home to roost.

Submitted by Anonymized User (not verified) on

Being familiar with the overall subject, I wish to say that the example in the previous comment is a relatively mild illustration of poor scholarship.

A better (in the sense of worse) example is this one, also from a 2020 publication:

To quote, ... hypnozoites, or dormant liver stages, which lead to recurrent infections.

A single reference (not a self-citation) was given in support hereof. The reference is a post-2000 article (published in a different year from the three papers mentioned in the previous comment) that, originality-related in terms of both its content and who its authors are, had absolutely nothing to do with anything covered in the statement quoted above. This is a perfect example of how not to cite.

Part of the explanation (when non-self-citations are involved) must be that authors are just copying what other authors have done; a case of the blind following the blind. Another possibility is that authors have in mind, when referencing hypnozoite matters, who they plan to suggest to journal editors as potential manuscript reviewers.

Submitted by Anonymized User (not verified) on

Equally inappropriate self-citations (or of close co-workers) in the same context, now noticed by some of us, are another story (preferably untold). In these instances, reference to an author(s) who had something to do with hypnozoites originally is conspicuous by its absence.

Submitted by Anonymized User (not verified) on

Wow! There is much recurrent malarial analysis in a large number of papers published in recent years that is heavily hypnozoite-orientated.

How much of this stuff is valid (asked previously; sort of) if many presumed relapses are actually recrudescences that originated from e.g. bone marrow or splenic merozoites? I.e. a subject that has been covered in the blog and by various comments here.

Submitted by Anonymized User (not verified) on

For the mini-seminar which is part of their ethics course, some of our students are choosing to do an analysis of hypnozoite-related and recurrent malaria-associated citations in the published literature.

Submitted by Anonymized User (not verified) on

Here is a bit of history, observed by the people who were there.

At a conference workshop discussion five years ago, Miles Markus began to suggest a research approach concerning the double origin idea of Plasmodium vivax malarial recurrence (which is the subject of this blog). Some of the workshop participants had (and still have) facilities and opportunities that were (and still are) suitable for related investigations.

One of the workshop Chairmen (not a classical parasitologist) obviously didn’t have the faintest idea what Prof. Markus was talking about (but then did anybody?), and cut him short, apparently thinking that it was nonsense. So the latter person did not say any more at the time to anyone.

This incident might have set understanding of aspects of recurrent P. vivax malaria back a little, time-wise.

Bart G.J. Knols's picture
Submitted by Bart G.J. Knols on

The discussion on this topic is closed for now. Anyone interested in further discussions on this can contact Prof. Markus directly.

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