Differential Metabolites and Metabolic Pathways Involved in Aerobic Exercise Improvement of Chronic Fatigue Symptoms in Adolescents..., 2022, Zhao

Full title: Differential Metabolites and Metabolic Pathways Involved in Aerobic Exercise Improvement of Chronic Fatigue Symptoms in Adolescents Based on Gas Chromatography–Mass Spectrometry

Abstract

Studies have found that the prevalence of chronic fatigue syndrome (CFS) in adolescents has continued to increase over the years, affecting learning and physical health. High school is a critical stage for adolescents to grow and mature. There are inadequate detection and rehabilitation methods for CFS due to an insufficient understanding of the physiological mechanisms of CFS. The purpose of this study was to evaluate the effect and metabolic mechanisms of an aerobic running intervention program for high school students with CFS.

Forty-six male high school students with CFS were randomly assigned to the exercise intervention group (EI) and control group (CFS). Twenty-four age- and sex-matched healthy male students were recruited as healthy controls (HCs). The EI group received the aerobic intervention for 12 weeks, three times a week, in 45-min sessions; the CFS group maintained their daily routines as normal. The outcome measures included fatigue symptoms and oxidation levels. Keratin was extracted from the nails of all participants, and the oxidation level was assessed by measuring the content of 3-Nitrotyrosine (3-NT) in the keratin by ultraviolet spectrophotometry. All participants’ morning urine was collected to analyze urinary differential metabolites by the GC-MS technique before and after the intervention, and MetaboAnalyst 5.0 was used for pathway analysis.

Compared with before the intervention, the fatigue score and 3-NT level in the EI group were significantly decreased after the intervention. The CFS group was screened for 20 differential metabolites involving the disruption of six metabolic pathways, including arginine biosynthesis, glycerolipid metabolism, pentose phosphate pathway, purine metabolism, β-alanine metabolism, and arginine and proline metabolism. After the intervention, 21 differential metabolites were screened, involved in alterations in three metabolic pathways: beta-alanine metabolism, pentose phosphate metabolism, and arginine and proline metabolism.

Aerobic exercise was found to lessen fatigue symptoms and oxidative levels in students with CFS, which may be related to the regulation of putrescine (arginine and proline metabolism), 6-Phospho-D-Gluconate (starch and sucrose metabolism pathway), and Pentose (phosphate metabolism pathway).

Open access, https://www.mdpi.com/1660-4601/19/4/2377/htm

 

Diagnosis is stated to be Fukada but the intervention used makes this less than credible:

"The total duration of exercise was no less than 45 min, with each session consisting of a 5-min warm-up, 20–30 min of aerobic running, and a 10-min relaxation period. Heart rate was monitored by wearing an activity band."

The choice of entirely male cohorts is novel, plus there's also the somewhat Orwellian:

"2.1. Participants
The participants were from a high school in Shaanxi Province, China, a full-time closed management school where students with CFS are concentrated."

Almost all the intervention references are to the usual GET suspects up to an including Larun. The defining statement in the discussion:

"CFS is a more severe form of persistent fatigue, with symptoms such as fatigue, pain in certain parts of the body, memory and cognitive decline, and poor resistance to illness"

is supported by reference to Yancey and Thomas 2012, ignoring this 2013 criticism of that paper: Article on CFS Does Not Reflect Current Best Treatment Practices

There is no reporting of harms, drop out or comorbidity. The participants are reduced to chemical outputs.

"5. Conclusions
CFS has become one of the major problems affecting human health in the 21st century. In this study, we found that 12 weeks of aerobic running could alleviate the symptoms of chronic fatigue and decline the oxidative level of the body in male high students. The metabolomic results indicated that the improvement of chronic fatigue symptoms might be related to the regulation of putrescine (arginine and proline metabolism) and 6-Phospho-D-Gluconate (starch and sucrose metabolic pathway and pentose phosphate metabolic pathway). It is important to schedule daily exercise for high school students."

 

Was looking at the results of table 2. The fatigue score was 4.1 points lower in the intervention but the standard deviation beforehand was only 0.14? So that makes for a mean difference of 29 standard deviations! That's incredibly large.

I also entered 10.72 and 10.14 in the GRIM test and it didn't work out.

The fatigue scale used has 14 questions where you can score 0 to 1. So the total score is somewhere between 0 and 14. The 0 makes things difficult but I think we can ignore these for the baseline scores because all patients had chronic fatigue syndrome which isn't compatible with a total score of 0 on a fatigue scale with 14 questions.

There were 23 patients in both the intervention and control group at baseline. The minimum change on for the total score on the scale is 1 point so the lowest possible change for the group mean would be 1/23. With that increment you can reach 10.13 or 10.73 but not 10.14 or 10.72. As the calculations below indicate, it doesn't seem like rounding issues could explain this.

247 x (1/23) = 10.739

233 x (1/23) = 10.130​

I might be a bit too suspicious but there also seem to bea lot of returning patterns in the sd reported (see the colors highlighted below)

 

I often and easily hit the maximum heart rate recommended by the authors just walking or even standing up. I go outside and walk on most days, as able on that day. Then again I'm not an adolescent anymore.

Right now my heart rate is 87 while sitting. It probably went up because I've eaten something. Standing up made it increase to 105. So I've hit my maximum heart rat just standing up. The other day I recorded increases of a little more than 30 just from standing up after lying down which is consistent with POTS, although these days the increase is more typically around 20.

 

Sadly this quote "‘If you are reading a study that is un-blinded, with subjective outcome measures, then you may as well stop reading it and move on.’"* pretty much says it all i.e. don't read on. I say sadly because I'm a failed chemistry technician - so the references to Gas Chromatography–Mass Spectrometry (pretty high end kit) indicated resources that should have been supported by sound experimental design.

They used subjective outcome criteria (questionnaires) these may indeed be "widely used" but they shouldn't given that electronic activity monitoring is both more accurate and deliverable (FitBit type devices).

Also, if you're going to say that certain things have changed, then best to have a comparable control group i.e. people who have comparable (low) initial activity levels (difficult to achieve) and are then subject to the same intervention.

"Pity" sums it up - some objective outcome data and this would have been worth publishing.

Thanks to CRG for the humours reference to

Unfortunately CRGs explanation of the circumstances why led to the current views of ME/CFS, in the UK**, indicate a similar dystopian culture.



Quotes from the paper re measuring the outcome of the intervention:
"The effect of the intervention has been measured primarily by rating scales of symptom levels, including fatigue as measured by the Fatigue Scale and the Fatigue Severity Scale [30]."
[30] Jason, L.A.; Torres-Harding, S.; Friedberg, F.; Corradi, K.; Njoku, M.G.; Donalek, J.; Reynolds, N.; Brown, M.; Weitner, B.B.; Rademaker, A.; et al. Non-pharmacologic Interventions for CFS: A Randomized Trial. J. Clin. Psychol. Med. Settings 2007, 14, 275–296.

"2.3. Fatigue Level Measurement
In this study, the fatigue level of students was used as the evaluation index of the effect of the exercise intervention. The fatigue scale 14 (FS-14) developed by [56] of the British Institute of Psychological Medicine is widely used to measure the severity of fatigue. The 14-item scale assesses two dimensions of chronic fatigue: physical fatigue (Items 1–8) and mental fatigue (Items 9–14). The participant selects “yes” or “no” for each item, with “yes” being scored as 1 and “no” as 0. The total fatigue score is calculated by summing all items. The Chinese version of the Fs-14 has good reliability and validity [57]. The evaluation was carried out before and after the exercise intervention."



*https://www.s4me.info/threads/nice-...s-now-been-published.6197/page-42#post-406768
**https://www.s4me.info/threads/new-n...-2022-flottorp-et-al.24548/page-7#post-407591

 

Anyone able to have a look at this? I don't think these figures can be right.

Perhaps @sTeamTraen could have a look? @JohnTheJack

 

Re: "2.1. Participants
The participants were from a high school in Shaanxi Province, China, a full-time closed management school where students with CFS are concentrated."

Having consulted a knowledgeable person this is probably not as weird as it sounds in translation and what is meant is a 'rural boarding school' which are common in rural China, notably Shaanxi Province. However even against that background there must be serious concerns about using this student population in a medical study - https://fsi.stanford.edu/docs/boarding_schools

>
"REAP administered the survey to 400 principals in 10 randomly selected counties in Shaanxi Province to collect baseline data. The survey covered five aspects of boarding: facilities, management, provision of diet and nutrition, student behavior, and communication between schools and parents.

The survey generated a number of new findings useful for increasing general understanding of the state of boarding school investment and quality of facilities and management in China's boarding schools. Mergers have occurred in about 38 percent of schools. In response to issues surrounding long school commutes, the government has invested heavily in boarding schools. In Shaanxi, 45 percent of schools in poor areas have boarding schools facilities. More than 15 percent of primary school children live in boarding schools.

However, the quality of boarding school facilities and the nature of boarding school management are so low that they may be harmful to students. Safety, hygiene, supervision, diet and nutrition are all serious problems in China's rural primary boarding schools."
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