Difference between revisions of "Wiki:Sandbox"
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== The problem with clinical trials ==
== The problem with clinical trials ==
Many independent lines of evidence, including epidemiologic studies, clinical observations and investigations using animal models, have pointed to the idea that humans need exposure to helminths in order to enjoy optimal immune function, and the many hundreds of reports by self-treaters featured elsewhere in this wiki attest to the therapeutic benefits of reworming. However,
Many independent lines of evidence, including epidemiologic studies, clinical observations and investigations using animal models, have pointed to the idea that humans need exposure to helminths in order to enjoy optimal immune function, and the many hundreds of reports by self-treaters featured elsewhere in this wiki attest to the therapeutic benefits of reworming. However, not been confirmed by the majority of clinical trials.
=== Trials of pig whipworm ova (TSO) ===
=== Trials of pig whipworm ova (TSO) ===
Revision as of 23:11, 13 October 2021
Given that hookworms shed a layer of skin before entering a host, it is very unlikely that hookworms would transmit infectious organisms to a host, and a literature search yielded no record of pathogen transmission between hookworm and host.  However, the possibility of pathogen transmission between hookworm hosts as a result of inoculation by one individual with larvae grown from the faeces of another has not been ruled out unequivocally. This is why the commercial providers of NA periodically test their reservoir donors for a range of communicable diseases such as HIV and hepatitis, always use an antimicrobial wash to clean the larvae they supply, and then ship them in a weak antibiotic solution. These precautionary measures are as far as the hookworm providers can go to obviate the risk of pathogen transmission, given that helminths are living organisms, and would be killed by any attempt to completely sterilise them.
Hookworm larvae do not need to be cleaned if they have been grown at home for use by the same individual who provided the stool sample for their incubation. However, if that individual wishes to share the larvae they have grown, these can be cleaned using one of the following methods.
Collect the brown water from the bottom of the container used for incubation and leave this in a champagne glass for 24 hours. Then add one or two drops of bleach to one litre of water and use some of the resulting bleach solution to almost fill a second champagne glass. The next day, use a pipette to carefully draw up the worms that have settled to the bottom of the champagne glass containing the brown water. Avoid squeezing the pipette once it is in the water because this would create bubbles that would disturb any sediment and distribute the larvae. Instead, slightly squeeze the bulb of the pipette before it enters the water, and hold this position carefully until the pipette reaches the bottom of the glass, where it can be gently released to collect the larvae. Then add the larvae collected to the bleach solution in the second champagne glass. Leave the larvae in the bleach solution for a further 24 hours. The following day, use a pipette to draw up the larvae from the bottom of the bleach solution and transfer them to a microscope slide for counting in preparation for inoculation, or add them to an eppendorf tube containing fresh water (distilled, filtered or bottled water, or dechlorinated tap water) for supply to someone else. 
Add one drop of commercially available 5% Lugol’s iodine to 5 ml of water (distilled, filtered or bottled water, or dechlorinated tap water) to create a 0.02% iodine solution. Then add 1 ml of this solution to 1 ml of water containing the larvae to be cleaned. After the larvae have spent 20 minutes in this solution, the iodine should be neutralised by adding a pinch of ascorbic acid (vitamin C) powder to the solution. Neutralisation of the iodine is confirmed when sufficient ascorbic acid has been sprinkled into the water to make this completely clear.
Larvae that have been cleaned by any method will have a shorter shelf life than those that have not been cleaned.
The problem with clinical trials
Many independent lines of evidence, including epidemiologic studies, clinical observations and investigations using animal models, have pointed to the idea that humans need exposure to helminths in order to enjoy optimal immune function, and the many hundreds of reports by self-treaters featured elsewhere in this wiki attest to the therapeutic benefits of reworming. However, these benefits have not been confirmed by the majority of clinical trials, due to the use of inappropriate scientific methodology.
Trials of pig whipworm ova (TSO)
The first helminth to be systematically investigated by researchers was TSO, the ova of the pig whipworm, Trichuris suis, and results from early trials of TSO carried out in the first few years of the 21st century were very encouraging.     But a raft of twelve trials carried out by a different research team between 2008 and 2017, to investigate the effect of TSO in five different diseases, produced such universally lacklustre results that all but three of them were discontinued prematurely.            
The researchers involved in this unprecedented project made two critical errors in their study design, the first of which was to use a trial length of only 12 weeks. While this is the standard trial period used in pharmaceutical research, it is not appropriate for studies of live helminths, which only begin to produce consistent effects after 12 weeks, and, in some cases may produce no indication of benefit whatsoever during the first two years. 
Arguably the most critical mistake was to insist on the use of a novel TSO formulation with a pH of 5.0, even though the investigators were advised against this by the product’s manufacturer, who knew from his own product development work that TSO is most effective when formulated with a pH of 2.4, which was the formulation used in the earlier, more successful trials.
Other significant errors in the design of these trials included the use of a single dose size for all participants, when it is known that the helminth dosage requirements of individuals can vary by as much as a factor of 10, and poor subject selection, which is revealed by the high rate of improvement in the placebo group in some cases.
With so few clinical trials of helminthic therapy having been carried out previously, the sheer number of these “failed” studies overwhelmed the existing helminthic therapy research base to deliver a body blow to the therapy’s reputation.
Other researchers began referencing these trials in support of assertions that TSO is ineffective. For example, four of these trials were included in a meta-analysis of six studies which concluded that TSO therapy showed no statistical benefit for IBD patients.  Apart from the issues with the product's pH, only one of the trials reviewed in this analysis had lasted for longer than 12 weeks, and the remit of that particular study was only to assess the safety and tolerability (not efficacy) of a single dose of TSO.
This glut of poorly designed trials, and consequently flawed meta-analyses, by researchers who clearly had not fully understood the therapy they were investigating, also appears to have dissuaded other researchers from investigating helminthic therapy. This may explain why, after increasing steadily for around 50 years, the annual number of published papers in which “helminthic therapy” is mentioned plateaued from 2014 onwards. (Data from PubMed.)
Trials of the human hookworm (NA)
TSO is not the only living helminth to have failed to reveal its true colours when tested using methods developed to assess the performance of pharmaceutical products. In 2007, Correale and Farez had revealed that patients with multiple sclerosis who were hosting helminths experienced a reduced number of disease exacerbations compared with patients who were helminth-free.  However, when researchers at Nottingham University published the results for a randomized double-blinded placebo-controlled trial in which patients with RRMS were colonised by hookworms  they reported that the statistical endpoint determined for the trial had not been reached, so concluded this helminth appeared to be ineffective against RRMS. Yet closer examination of the data revealed that more than half the patients given hookworms had not developed any new lesions.  And socio-medical research has shown that NA is extremely effective at treating MS, with a success rate of approximately 50% for the progressive form of the disease and more than 90% for relapsing-remitting MS. 
Self-treaters provide the most reliable data
Unless the scientists conducting trials to assess the effects of hosting living helminths cease treating these organisms as pharmaceutical products and take into account the unique and dynamic nature of each individual helminth/host relationship when designing formal studies, clinical trials will continue to fail to demonstrate the benefits offered by reworming.
Until this reality is understood, accepted and acted upon by researchers, the best evidence for the benefits of helminth replacement will continue to come from the collated experience of self-treaters, as has been suggested by Venkatakrishnan, et al.